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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ALTACE safely and effectively. See full prescribing information for
ALTACE.
ALTACE (ramipril) Capsule s, Oral
Initial U.S. Approval: 1991
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning
When pregnancy is detected, discontinue ALTACE as soon
as possible (5.6).
Drugs that act directly on the renin-angiotensin system can
cause injury and death to the developing fetus (5.6).
----------------------------RECENT M AJOR CHANGES-------------------------
Boxed Warning: Fetal Toxicity
xx/2012
Warnings and Precautions: Fetal Toxicity (5.6)
xx/2012
----------------------------INDICATIONS AND USAGE--------------------------
ALTACE® is indicated for the treatment of hypertension. It may be used alone
or in combination with thiazide diuretics. (1.1).
In patients 55 years or older at high risk of developing a major cardiovasc ular
event, ALTACE is indicated to reduce the risk of m yocardial infarction,
stroke, or death from cardiovascular causes (1.2).
ALTACE is indicated in stable patients who have demonstra ted clinical signs
of congestive heart failure post-myocardial infarction (1.3).
----------------------DOSAGE AND ADMINISTRATION----------------------
Hypertension: Initial dose is 2.5 mg to 20 mg once daily. Adjust dosage
according to blood pressure response after 2–4 weeks of treatment. The usual
maintenance dose following titr ation is 2.5 mg to 20 mg daily as a single d ose
or equally divided doses (2.1).
Reduction in the risk of myocardial infarction, stroke, or death from
cardiovascular causes: 2.5 mg once daily for 1 week, 5 mg once daily for 3
weeks, and increased as tolerated to a maintenance dose of 10 mg once daily
(2.2).
Heart failure post-myocardial infarction: Starting dose of 2.5 mg twice daily.
If patient becomes hypotensive at this dose, decrease dosage to 1.25 mg twice
daily. Increase dose as tolerated toward a target dose of 5 mg twice daily, with
dosage increases about 3 weeks apart (2.3).
Dosage adjustment: See respective sections pertaining to dosage adjustment in
special situations (2.5).
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Capsule: 1.25 mg, 2.5 mg, 5 mg, 10 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------
Angioedema related to previous treatment with an ACE inhibitor, or a history
of hereditary or idiopathic angioedema. (4).
-----------------------WARNINGS AND PRECAUTIONS-----------------------
ACE inhibitor use has been associated with the following:
Angioedema, with increased risk in patients with a prior history (5.1)
Hypotension and hyperkalemia (5.5, 5.8)
Renal impairment: monitor renal function during therapy (5.3)
Increased risk of renal impairment when co mbined with another blocker of the
rein-angiotensin-aldosterone system (5.7)
Rare cholestatic jaundice and hepatic failure (5.2)
Rare neutropenia and agranulocytosis (5.4)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions in patients with hypertension included
headache, dizziness, fatigue, and cough (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at
1-800-438-1985 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
Diuretics: Possibility of excessive hypotension (7.1).
Lithium: Use with caution (7.3).
Gold: Nitritoid reactions have been reported (7.4).
NSAIDS use may lead to increased risk of renal impairment and loss of
antihypertensive effect (7.5).
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Pregnancy: Discontinue drug if pregnancy is detected (5.6, 8.1).
Nursing mothers: ALTACE use is not recommended in nursing mothers (8.3).
See 17 for PATIENT COUNSELING INFORMATION
Revised: 04/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: FETAL TOXICITY
1 INDICATIONS AND USAGE
1.1 Hypertension
1.2 Reduction in the Risk of Myocardial Infarc tion, Stroke, and Death
from Cardiovascular Causes
1.3 Heart Failure Post-Myocardial Infar ction
2 D OSAGE AND ADMINISTRATION
2.1 Hypertension
2.2 Reduction in Risk of Myocardial Infarction , Stroke, and Death from
Cardiovascular Causes
2.3 Heart Failure Post-Myocardia l Infarction
2.4 General Dosing Information
2.5 Dosage Adjustment
3 DOSAGE FORMS AND STRENGTH S
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
5.2 Hepatic Failure and Impaired Live r Function
5.3 Renal Impairment
5.4 Neutropenia an d Agranulocytosis
5.5 Hypotension
5.6 Fetal Toxicity
5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
5.8 Hyperkalemia
5.9 Cough
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
6.3 Clinical Laboratory Test Findings
7 DRUG INTER ACTIONS
7.1 Diuretics
7.2 Other Antihypertensive Agents
7.3 Lithium
7.4 Gold
7.5 Non-Steroidal Anti-Inflammatory A gents including Selective
Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
7.6 Other
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMA COLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Hypertension
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from
Cardiovascular Causes
14.3 Heart Failure Post-Myocardial Infarction
16 HOW SUPPLIED/STORAGE A ND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Angioedema
17.2 Neutropenia
17.3 Symptomatic Hypotension
Reference ID: 3114769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________________________________________________________________________
_
17.4 Pregnancy
17.5 Hyperkalemia
*Sections or subsections omitted from the full prescribing information are not listed
FULL PRESCRIBING INFORMAT ION
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue ALTACE as soon as possible (5.6).
Drugs that act directly on the renin-angiotensin system can cause injury and
death to the developing fetus (5.6).
1 INDICATIONS AND USAGE
1.1 Hypertension
ALTACE® is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.
1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
ALTACE is indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a
history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one othe r
cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or
documented microalbuminuria), to redu ce the risk of myocardial infarction, stroke, or death from cardiovascular causes.
ALTACE can be used in addition to other needed trea tment (such as antihypertensive, antiplatelet, or lipid-lowering
therapy) [see Clinical Studies (14.2)].
1.3 Heart Failure Post-Myocardial Infarction
ALTACE is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first
few days after sustaining acute myocardial infarction. Administration of A LTACE to such patients has been shown to
decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and
progression to severe/resistant heart failure [see Clinical Studies (14.3)].
2 DOSAGE AND ADMINISTRATION
2.1 Hypertension
The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood
pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in two
equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the
dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure i s not
controlled with ALTACE alone, a diuretic can be added.
2.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
Initiate dosing at 2.5 mg once dai ly for 1 week, 5 mg once daily for the next 3 weeks, and then increase as tolerated, to a
maintenance dose of 10 mg once daily. If the patient is hy pertensive or recently post-myocardial infarction, ALTACE can
also be given as a divided dose.
2.3 Heart Failure Post-Myocardial Infarction
For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the
recommended starting dose of ALTACE is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at t his
dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a
target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.
After the initial dose of ALTACE, observe the patient under medical supervision for at least two hours and until blo od
pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as th is may
Reference ID: 3114769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ALTACE does not
preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see
Warnings and Precautions (5.5), Drug Interactions (7.1)].
2.4 General Dosing Information
Generally, swallow ALTACE capsules whole. The ALTACE capsule can also be opened and the contents sprinkled on a
small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juic e. To be sure that ramipril is
not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and
stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of ALTACE with potassium supplements, potassium salt substitutes, or potassium-sparing
diuretics can lead to increases of serum potassium [see Warnings and Precautions (5.8)].
2.5 Dosage Adjustment
Renal Impairment
Establish baseline renal function in patients initiating ALTACE. Usual regimens of therapy with ALTACE may be
followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25 %
of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see Use in Specific P opulations
(8.6)].
Hypertension
For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily.
Dosage may be titrated up ward until blood pressure is controlled or to a maximum total daily dose of 5 mg.
Heart Failure Post-Myocardial Infarction
For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ALTACE once daily. The
dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical
response and tolerability.
Volume Depletion or Renal Artery Stenosis
Blood pressure decreases associated with any dos e of ALTACE depend, in part, on the presence or absence of volume
depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstance s are
suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response.
3 DOSAGE FORMS AND ST RENGTHS
ALTACE (ramipril) is supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril.
4 CONTRAINDICATIONS
ALTACE is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient
who has experienced angioedema during therapy with any other ACE inhibit or).
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid and Possibly Related Reactions
Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the
metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including
ALTACE) may be subject to a variety of adverse reactions, some of them serious.
Angioedema
Head and Neck Angioedema
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while
receiving an ACE inhibitor.
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE
inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
Reference ID: 3114769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
tongue, or glottis occurs, discontinue treatment with ALTACE and institute appropriate therapy immediately. Where there
is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g.,
subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly [see Adverse Reactions (6)].
In considering the use of ALTACE, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema
in Black patients than in non-Black patients.
In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) w as
reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different
statistically.
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal
pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 e sterase
levels were normal. The angioedema was diagnosed by procedures includ ing abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential
diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing trea tment with hymenoptera venom while receiving ACE inhibitors sustained life-
threatening anaphylactoid reactions. In the same patients, t hese reactions were avoided when ACE inhibitors were
temporarily withheld, but they reappeared upon inadverten t rechallenge.
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly
with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein
apheresis with dextran sulfate absorption.
5.2 Hepatic Failure and Impaired Liver Function
Rarely, ACE inhibitors, inc luding ALTACE, have been associated with a syndrome that starts with cholestatic jaundice
and progresses to fulminan t hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood.
Discontinue ALTACE if patient develops jaundice or marked elevations of hepatic enzymes.
As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver
function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried
out in hypertensive patients with impaired liver function.
5.3 Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in
susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activit y
of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ALTACE, may be associate d with
oliguria or progressive azotemia and rarely with acute renal failure or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increas es in blood urea nitrogen and serum
creatinine may occur. Experience with anoth er ACE inhibitor suggests that these increases would be reversible upon
discontinuation of ALTACE and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of
therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in
blood urea nitrogen and serum creatinine, usually minor and transient, especially when ALTACE has been given
concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage
reduction of ALTACE and/or discontinuation of the diuretic may be required.
5.4 Neutropenia and Agranulocytosis
In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and
hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow
depression may occur. He matological reactions to ACE inhibitors are more likely to occur in patients with collagen-
vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white
blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal
function.
5.5 Hypotension
Reference ID: 3114769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General Considerations
ALTACE can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been
increased. Like other ACE inhibitors, ALTACE, has been only rarely associated with hypotension in uncomplicated
hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-
depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volu me-
and salt-depletion before initiating therapy with ALTACE.
If excessive hypotension oc curs, place the patient in a supine position and, if necessary, treat with intravenous infusion of
physiological saline. ALTACE treatment usually can be continued following restoration of blood pressure and volume.
Heart Failure Post-Myocardial Infarction
In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic
hypotension occasionally can occur following the initial dose of ALTACE. If the initial dose of 2.5 mg ALTACE cannot
be tolerated, use an initial dose of 1.25 mg ALTACE to avoid excessive hypotension. Consider reducing the dose of
concomitant diuretic to decrease the incidence of hypotension.
Congestive Heart Failure
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause
excessive hypotension , which may be associated with oliguria or azotemia and rarely, with acute renal failure and death.
In such patients, initiate ALTACE therapy under close medical supervision and follow patients closely for the first 2
weeks of treatment and w henever the dose of ALTACE or diuretic is increased.
Surgery and Anesthesia
In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotens in
II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of
this mechanism can be corrected by volume expansion.
5.6 Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal
renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with
fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,
hypotension, renal failure, and death. When pregnancy is detected, discontinue ALTACE as soon as possible [see U se in
Specific Populations (8.1)].
5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System
Telmisartan
The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ
damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 5 6
months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite
endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experience d
an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis)
compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not
recommended.
5.8 Hyperkalemia
In clinical trials with ALTACE, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of
hypertensive patients recei ving ALTACE. In most cases, these were isolated values, which resolved despite continued
therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the
development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing
diuretics, potassium supplements, and/or potassium-containing salt substitutes, whi ch should be used cautiously, if at all,
with ALTACE [see Drug Interactions (7.1)].
5.9 Cough
Reference ID: 3114769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has be en
reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin
converting enz yme inhibitor induced-cough in the differential diagnosis of cough.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the r ates
observed in practice.
Hypertension
ALTACE has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in
U.S. controlled trials, and 1107 were studied in foreign con trolled trials. Almost 700 of these patients were treated for at
least one year. The overall incidence of reported adverse events was similar in ALTACE and placebo patients. The mo st
frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ALTACE in
placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one
was more common in ALTACE patients than in patients given placebo. Generally the side effects were mild and transie nt,
and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side
effect was required in approximately 3% of U.S. patients treated with ALTACE. The most common reaso ns for
discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%).
Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled
trials in more than 1% of patients treated with ALTACE, only asthenia (fatigue) was more common on ALTACE than
placebo (2% [n=13/651] vs. 1% [n=2/286], respectively).
In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome i n the ALTACE
group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE
inh ibitors was recognized, some of these eve nts may rep resent ramipril-induced cough. In a later 1-year study, increased
cough was seen in almost 12% of ALTACE patients, with about 4% of patients requiring discontinuation of treatment.
Reduction in the Risk of Myocardial Inf arct ion, Stroke, and Death from Cardiovascular Causes
HOPE Study
Safety data in the Heart Outco mes Prevention E valuation (HO PE) study were collected as reasons for discontinuation or
temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril
Efficacy (AIRE) trial. The ra te of angioedema was the same as in previous clinical trials [see Warnings and Precautions
(5.1)].
Table 1. Reasons for Discontinuation or Temporary Interruption of Treatment—HOPE Study
Placebo
(N=4652)
ALTACE
(N=4645)
Discontinuation at any time
32%
34%
Permanent discontinuation
28%
29%
Reasons for stopping
Cough
2%
7%
Hypotension or dizziness
1.5%
1.9%
Angioedema
0.1%
0.3%
Heart Failure Post-Myocardial Infarction
AIRE Study
Adverse reactions (except laboratory abnormalities) considered possibly/probab ly rel ated to study drug that occurred in
more than 1% of p atients and more frequently on ALTACE are shown below. The incidences are from the AIRE study.
The follow-up tim e was between 6 and 46 months for this study.
Reference ID: 3114769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Percentage of Patients with Adverse Even ts Possibly/ Probably Related to Study Drug—Placebo-
Controlled (AIRE) Mortality Study
Adverse Event
Placebo
(N=982)
ALTACE
(N=1004)
Hypotension
5%
11%
Cough increased
4%
8%
Dizziness
3%
4%
Angina pectoris
2%
3%
Nausea
1%
2%
Postural hypotension
1%
2%
Syncope
1%
2%
Vomiting
0.5%
2%
Vertigo
0.7%
2%
Abnormal kidney function
0.5%
1%
Diarrhea
0.4%
1%
Other Adverse Reactions
Other adverse reactions reported in controlled clinical trials (in less than 1% of ALTACE patients), or rarer events seen i n
post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):
Body as a whole: Anaphylactoid reactions [see Warnings and Precautions (5.1)].
Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) [see Warnings and Precaution s
(5.5)], syncope, and palpitations.
Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia.
Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in
0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving ALTACE plus a diuretic.
Renal: Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor,
usually transient, increases in blood urea nitrogen and serum creatinine when taking ALTACE, particularly when
ALTACE was given concomitantly with a diuretic [see Warnings and Precautions (5.3)].
Angioneurotic e dema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ALTACE [see
Warnings and Precautions (5.1) ].
Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes
suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased
salivation, and taste disturbance.
Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever),
photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and
Stevens-Johnson syndrome.
Neurologic and Psychiatric: Anxiety, amnes ia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia,
neuropathy, paresthesia, somnolence, tinnitus , tremor, vertigo, and vision disturbances.
Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA ,
an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity,
rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has
been reported.
Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.
6.2 Post-Marketing Experience
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported du ring
ALTACE therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal
relationship is unknown.
6.3 Clinical Laboratory Test Findings
Reference ID: 3114769
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving ALTACE
alone, and in 1.5% of patients receiving ALTACE and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5%
of patients receiving ALTACE alone and in 3% of patients receiving ALTACE with a diuretic. None of these increases
required discontinuation of treatment. Increas es in these laboratory values are more likely to occur in patients with renal
insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to
be especially likely in patients with renal artery stenosis [see Warnings and Precautions (5.3)]. As ramipril decreases
aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing
diuretics with caution, and monitor the patient’s serum potassium frequently [see Warnings and Precautions (5.8)].
Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%,
respectively) were rare, occurring in 0.4% of patients receiving ALTACE alone and in 1.5% of patients receiving
ALTACE plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocri t.
Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely asso ciated
with ALTACE administration. Elevations of liver enzymes, serum bilirubin, uric acid, and bloo d glucose have been
reported, as have cases of hyponatremia a nd scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials,
less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or
abnormal liver-function tests.
7 DRUG INTERACTIONS
7.1 Diuretics
Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an
excessive reduction of blood pressure after initiation of therapy with ALTACE. The possibility of hypotensive effects
with ALTACE can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prio r to
initiation of treatment with ALTACE. If this is not possible, red uce the starting dose [see Dosage and Administration (2)].
ALTACE can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone,
amiloride, triam terene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if
concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
7.2 Other Antihypertensive Agents
Limited exp erience in controlled and uncontrolled trials combining ALTACE with a calcium channel blocker, a loop
diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE
inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lowe r
blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
The combin ation of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart
rate).
In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased
incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups
receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended [see Dual
Blockade of the Renin-Angiotensin-Aldosterone System (5.7)].
7.3 Lithium
Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients rec eiving ACE inhibitors
during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also
used, the risk of lithium toxicity may be increased.
7.4 Gold
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in
patients on therapy with injectable gold (sodium aurothiomalate) and concomitan t ACE inhibitor therapy including
ALTACE.
7.5 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors)
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In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function,
co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may resul t
in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor
renal function periodically in patients receiving ramipril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
7.6 Other
Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, ci metidine,
indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation
effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum
phenprocoumon levels or interfere with the patients’ state of anticoagulation.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces feta l
renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with
fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria,
hypotension, renal fa ilure, and death. When pregnancy is detected, discontinue ALTACE as soon as possible. These
adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after ex posure to antihypertensive use in the first trimester have not
distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management
of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for
a particular patient, apprise the mother of the potential risk to the fetus. Perform serial u ltrasound examinations to assess
the intra-amniotic environment. If oligohydramnios is observed, discontinue ALTACE unless it is considered life-saving
for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be
aware, however, that oligohydramnios may not ap pear until after the fetus has sustained irreversible injury. Closely
observe infants with histories of in utero exposure to ALTACE for hypotension, oliguria, and hyperkalemia [see Use in
Specific Populations (8.4)].
8.3 Nursing Mothers
Ingestion of a single 10 mg oral dose of ALTACE resulted in undetectable amounts of ramipril and its metabolites in
breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single
dose, do not use ALTACE in nursing mothers.
8.4 Pediatric Use
Neonates with a history of in utero exposure to ALTACE:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange
transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal
function. Ramipril, which crosses the placenta, can be removed from the neonatal circulation by these means, but limited
experience has not shown that such removal is central to the treatment of these infants.
Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in
very young rats given a single dose of ALTACE.
8.5 Geriatric Use
Of the total number of p atients who received ALTACE in U.S. clinical studies of ALTACE, 11.0% were ≥65 years of age
while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients
Reference ID: 3114769
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and younger patients, and other reported clinical experience has not identified differences in responses between the eld erly
and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels an d area under
the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.
8.6 Renal Impairment
A single-dose pharmacokinetic study was conducted i n hypertensive patients with varying degrees of renal impairment
who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of
creatinine clearance: normal (>80 mL/min), mild impairment (40-80 mL/min), moderate impairment (15-40 mL/min), and
severe impairment (<15 mL/min). On average, the AUC0-24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold
higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the
group with normal renal function. Over all, the results suggest that the starting dose of ramipril should be adjusted
downward in patients with moderate-to-severe renal impairment.
10 OVERDOSAGE
Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral do ses as
high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The m ost
likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such
determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) th at might
accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be
effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but
angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypot ensive effect of ramipril
is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by inf usion of
normal saline solution.
11 DESCRIPTION
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crys talline substance soluble in polar
organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.
The CAS Registry Number is 87333-19-5. Ramipril’s chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3
phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester.
The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell
contains yello w iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 m g capsule shell
contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.
The structural formula for ramipril is:
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structural formula
Its empirical formula is C
32N O and its molecular weight is 416.5.
5
23H
2
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by
hepatic cleavage of the ester group.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl
dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II
also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II,
which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. In hypertensive patients with normal renal function treated with ALTACE alone for up
to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from
baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline
greater than 0.75 mEq/L. In the sam e study, approximately 2% of patients treated with ALTACE and hydrochlorothiazide
for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and
approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see Warnings an d
Precautions (5.8)]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity.
The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE
activity, there by reducing angiotensin II formation in tissue and plasma.
Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of ALTACE remains to be elucidated.
While the mechanism through which ALTACE lowers blood pressure is believed to be primarily suppression of the renin
angiotensin-aldosterone system, ALTACE has an antihypertensive effect even in patients with low-renin hypertension.
Although ALTACE was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin
hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, tha n
non-Black patients.
12.2 Pharmacodynamics
Single doses of ramipril of 2.5 mg–20 mg produce app roximately 60%–80% inhibition of ACE activity 4 hours after
dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more ca use
plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remainin g
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24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE
binding sites by ramiprilat and relatively slow release from those sites.
12.3 Pharmacokinetics
Absorption
Following oral administration of ALTACE, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The
extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal
tract, although the rate of absorption is reduced.
In a trial in which subjects received ALTACE capsules or the contents of identical capsules dissolved in water, dissolved
in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the us e or non-use of the
concomitan t liquid or food.
Distribution
Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak
plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is
about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of
0.01 µg/mL–10 µg/mL.
Metabolism
Ramipril is almost completely metabolized to ramiprilat, which ha s about 6 times the ACE inhibitory activity of ramipril,
and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which
are inactive.
Plasma concentrations of ramipril and ramiprilat incr ease with increased dose, but are not strictly dose-proportional. The
24-hour AUC for ramiprilat, however, is dose-proportional over the 2 .5 mg-20 mg dose range. The absolute
bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared
with the same dose of ramipril given intravenously.
After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state
concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses
(2.5 mg), but the difference is clinically insignificant.
Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination ph ase,
terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral
compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent
binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent
elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal
elimination phase has a prolo nged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the
ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ALTACE
5 mg-10 mg, the half-life of ra miprilat concentrations within the therapeutic range was 13–17 hours.
In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and
trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these
patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of
diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak
concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic
function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.
Excretion
After oral administr ation of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and
about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or
unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the
administered dose is recovered in urine as unchanged ramipril.
The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function.
Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m2 had higher peak and trough
ramiprilat levels and slightly longer times to peak concentrations.
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13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of
up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are
about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No
mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in
a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and
degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as
500 mg/kg/day did not produce adverse effects on fertility.
No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body
surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the
recommended human dose.
14 CLINICAL STUDIES
14.1 Hypertension
ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for
hypertension. It was approximately as effective as other ACE inhibitors and as atenolol.
Administration of ALTACE to patients with mild to moderate hypertension results in a reduction of both supine and
standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypot ension is
infrequent, although it can occur in patients who are salt- and/or volume-depleted [see Warnings and Precautions (5.5)].
Use of ALTACE in combination with thiazide diuretics gives a blood pressure low ering effect greater than that seen with
either agent alone.
In single-dose studies, doses of 5 mg–20 m g of ALTAC E lowered bl ood pressure within 1–2 ho urs, with peak reductions
achieved 3–6 hours after dosing . The antihy pertensive effect of a sin gle dose persisted for 24 hours. In longer term (4–12
weeks) controlled studies, once-d aily dos es of 2.5 mg–10 mg were similar in their effect, lowering supine or standing
systolic and diastolic blo od pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of
peak vs. trough effect, the trough effect represented about 50-60% of the peak response. In a titr ation study comparing
divided (bid) vs. qd treatment, the divided regimen was superi or, indicating that for some patien ts, the antihypertensive
effect with once-daily dosing is not adequately maintained.
In most trials, the antih ypertensive effect of ALTACE increased during the first several weeks of repeated measurements.
The antihyperte nsive effect of ALTACE has been shown to continue during long-term therapy for at least 2 years. Abrupt
withdrawal of ALTACE has not resulted in a rapid increase in blood pressure. ALTACE has been compared with other
ACE inhibitors, beta-blockers, and thiazide diuretics. A LTACE was approximately as effective as other ACE inhibitors
and as atenolol. In both C aucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than
ramipril.
ALTACE was less effective in blacks than in Caucasian s. The effect iveness of ALTACE was not influenced by age, sex,
or weight.
In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied
by a 15% increase in ren al blood flow. In healthy volunteers, glomerular filtration rate was unchanged.
14.2 Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
The HOPE study was a large, multicenter, randomized, double-blind, placebo-controlled, 2 x 2 factorial design study
conducted in 9541 patients (4645 on ALTACE) who were 55 years or older and considered at high risk of developing a
major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes
that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low
HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment
with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low
ejection fraction (<0.40). This study was designed to examine the long-term (mean of 5 years) effects of ALTACE (10 mg
orally once daily) on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes.
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The HOPE study results showed that ALTACE (10 mg/day) significantly reduced the rate of myocardial infarction,
stroke, or death from cardiovascular causes (826/4652 vs. 651/4645, relative risk 0.78), as well as the rates of the 3
components of the combined endpoint. The relative risk of the composite outcomes in the ALTACE group as compared to
the placebo group was 0.78% (95% confidence interval, 0.70–0.86). The effect was evident after about 1 ye ar of
treatment.
Table 3. Summary of Combined Components and Endpoints—HOPE Study
Outcome
Placebo
(N=4652)
n (%)
ALTACE
(N=4645)
n (%)
Relative Risk
(95% CI)
P-Value
Combined Endpoint
Myocardial
infarction, stroke, or
death from
cardiovascular cause
826 (17.8%)
651 (14.0%)
0.78 (0.70–0.86)
P=0.0001
Component
Endpoint
Death from
cardiovascular causes
377 (8.1%)
282 (6.1%)
0.74 (0.64–0.87)
P=0.0002
Myocardial infarction
570 (12.3%)
459 (9.9%)
0.80 (0.70–0.90)
P=0.0003
Stroke
226 (4.9%)
156 (3.4%)
0.68 (0.56–0.84)
P=0.0002
Overall Mortality
Death from any cause
569 (12.2%)
482 (10.4%)
0.84 (0.75–0.95)
P=0.005
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Figure 1. Kaplan-Meier Estimates of the Composite Outcome of Myocardial Infarction, Stroke, or Death from
Cardiovascular Causes in the Ramipril Group and the Placebo Group graph
ALTACE was effective in different demographic subgroups (i.e., gender, age), subgroups defined by underlyi ng disease
(e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient
data to determine whether or not ALTACE was equally effective in ethnic subgroups.
This study w as designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor.
Effects of ALTACE on the combined endpoint and its components were similar in diabetics (N=3577) to t hose in the
overall study population.
Table 4. Summary of Combined Endpoints and Components in Diabetics—HOPE Study
Outcome
Placebo
(N=1769)
n (%)
ALTACE
(N=1808)
n (%)
Relative Risk
Reduction
(95% CI)
P-Value
Combined Endpoint
Myocardial
infarction, stroke, or
death from
cardiovascular cause
351 (19.8%)
277 (15.3%)
0.25 (0.12–0.36)
P=0.0004
Component
Endpoint
Death from
cardiovascular causes
172 (9.7%)
112 (6.2%)
0.37 (0.21–0.51)
P=0.0001
Myocardial infarction
229 (12.9%)
185 (10.2%)
0.22 (0.06–0.36)
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P=0.01
Stroke
108 (6.1%)
76 (4.2%)
0.33 (0.10–0.50)
P=0.007
Figure 2. The Beneficial Effect of Treatment with ALTACE on the Composite Outcome of Myocardial Infarction,
Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups graph
Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional t o the
number of patients in each group. The dashed line indicates overall relative risk.
The benefits of ALTACE were observed among patients who were taking aspirin or other anti-platelet agents, beta-
blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.
14.3 Heart Failure Post-Myocardial Infarction
ALTACE was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 20 06-patient, double-
blind, randomized, parallel-group study comparing ALTACE to placebo in stable patients, 2–9 days after an acute
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myocardial infarctio n, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction.
Patients in severe (NYHA class IV) heart failure, patients wi th unstable angina, patients with heart failure of congenital or
valvular etiology, and patients with contraindications to ACE inhi bitors were all excluded. The majority of patients had
received thromboly tic therapy at the time of the index infarction, and the average time between infarction and initiation of
treatment was 5 day s.
Patients randomized to ALT ACE treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused
undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a
target regimen (achieved in 77% of patients randomized to ALTACE) of 5 mg twice daily. Patients were then followed
for an average of 15 months, with the range of follow-up between 6 and 46 months.
The use of ALTACE was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of
the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of
congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively.
The benefits of ALTACE therapy were seen in both genders, and they were not affected by the exact timing of the
initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in
patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80%
of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers
(about 15%), and digoxin (about 12%).
16 HOW SUPPLIED/STORAGE AND HANDLING
ALTACE is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules. Descriptions of ALTACE capsules are
summarized below.
Capsule Strength
Capsule Color
Package
Configuration
NDC#
1.25 mg
yellow
Bottle of 100
61570-110-01
2.5 mg
orange
Bottle of 100
61570-111-01
5 mg
red
Bottle of 100
61570-112-01
10 mg
Process Blue
Bottle of 100
61570-120-01
Dispense in well-closed container with safety closure.
Store at controlled room temperature (59º–86ºF).
17 PATIENT COUNSELING INFORMATION
17.1 Angioedema
Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the
first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes,
lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing
physician.
17.2 Neutropenia
Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of
neutropenia.
17.3 Symptomatic Hypotension
Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported.
Advise patients to discontinue ALTACE if syncope (fainting) occurs, and to follow up with their health care providers.
Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ALTACE can
lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
17.4 Pregnancy
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23BFemale patients of childbearing age should be told about the consequences of exposure to Altace during pregnancy.
Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to
their physicians as soon as possible.
17.5 Hyperkalemia
Advise patients not to use salt substitutes containing potassium without consulting their physician.
Distributed by:
Monarch Pharmaceuticals, Inc.
Bristol, TN 37620
(A wholly owned subsidiary of King Pharmaceuticals, Inc.)
Manufactured by:
King Pharmaceuticals, Inc.
Bristol, TN 37620
LAB-0581-1.0
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|
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2025-02-12T13:46:16.420561
|
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Attachment 1
Page 1
Class Suicidality Labeling Language for Antidepressants
[This section should be located at the beginning of the package insert with bolded font and
enclosed in a black box]
[Insert established name]
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of [Insert established name] or any other
antidepressant in a child or adolescent must balance this risk with the clinical need. Patients
who are started on therapy should be observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Anafranil is not approved for use in
pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings
and Precautions: Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs
(SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive
compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over
4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or
behavior (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%,
twice the placebo risk of 2%. No suicides occurred in these trials.
[This section should be located under WARNINGS. Please note that the title of this
section should be bolded, and it should be the first paragraph in this section.]
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. There has been a long-standing concern that antidepressants
may have a role in inducing worsening of depression and the emergence of suicidality in certain
patients. A causal role for antidepressants in inducing suicidality has been established in pediatric
patients.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in
children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving
over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 2
thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The
average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
There was considerable variation in risk among drugs, but a tendency toward an increase for almost
all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there
were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive
disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is
unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond
several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes, either increases or
decreases. Such observation would generally include at least weekly face-to-face contact with
patients or their family members or caregivers during the first 4 weeks of treatment, then every
other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12
weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and suicidality,
especially during the initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being treated with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between
the emergence of such symptoms and either the worsening of depression and/or the emergence of
suicidal impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted
about the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality, and
to report such symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for [Insert established name] should be
written for the smallest quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose. Families and caregivers of adults being treated for depression should be similarly
advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled trials) that treating
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 3
such an episode with an antidepressant alone may increase the likelihood of precipitation of a
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described
above represent such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a
family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established
name] is not approved for use in treating bipolar depression.
[This section should be located under PRECAUTIONS, Information for Patients.]
Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with [Insert established name] and should
counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in
Children and Adolescents is available for [Insert established name]. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide
and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur
while taking [Insert established name].
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other
unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during
antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients
should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes
may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior
and indicate a need for very close monitoring and possibly changes in the medication.
[This section should be located under PRECAUTIONS, Pediatric Use.]
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not
been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk).
Anyone considering the use of Anafranil in a child or adolescent must balance the potential risks with
the clinical need.
[Continue with remainder of the section.]
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 1
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal
thoughts and actions can also be caused by depression, a serious medical condition that is commonly
treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called
suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with depression or
other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to
4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar
pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became
suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or
his moods or actions, especially if the changes occur suddenly. Other important people in your child's
life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other
important people). The changes to look out for are listed in Section 3, on what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see other side)
You should call your child's healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child's healthcare provider right away if your child exhibits any of the following signs for
the first time, or if they seem worse, or worry you, your child, or your child's teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without first talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can
lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal
thinking or actions. It is important to discuss all the risks of treating depression and also the risks of
not treating it. You and your child should discuss all treatment choices with your healthcare provider,
not just the use of antidepressants.
Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric
depression.
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) .
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 3
Your healthcare provider may suggest other antidepressants based on the past experience of your child
or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants.
Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is
prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare
provider or pharmacist where to find more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:16.626791
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019906s032lbl.pdf', 'application_number': 19906, 'submission_type': 'SUPPL ', 'submission_number': 32}
|
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Page 1 of 23
Anafranil®
Clomipramine Hydrochloride Capsules USP
(25 mg, 50 mg, and 75 mg)
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of major
depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
clomipramine hydrochloride or any other antidepressant in a child, adolescent, or young
adult must balance this risk with the clinical need. Short-term studies did not show an
increase in the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction in risk with antidepressants compared to placebo in
adults aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages who are
started on antidepressant therapy should be monitored appropriately and observed closely
for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers
should be advised of the need for close observation and communication with the prescriber.
Clomipramine hydrochloride is not approved for use in pediatric patients except for
patients with obsessive compulsive disorder (OCD) (see WARNINGS: Clinical Worsening
and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use).
DESCRIPTION
Anafranil®, (clomipramine hydrochloride capsules USP), is an antiobsessional drug that belongs
to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants.
Anafranil is available as capsules of 25, 50, and 75 mg for oral administration.
Clomipramine hydrochloride USP is 3-Chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-
dibenz[b,f]azepine monohydrochloride, and its structural formula is:
C19H23ClN2 ● HCl MW = 351.31
Clomipramine hydrochloride USP is a white to off-white crystalline powder. It is freely soluble
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2 of 23
in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane.
Inactive Ingredients. D&C Red No. 33 (25-mg capsules only), D&C Yellow No. 10, FD&C Blue
No. 1 (50-mg capsules only), FD&C Yellow No. 6, gelatin, magnesium stearate, methylparaben,
propylparaben, starch (corn), and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors through its
effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown,
but CMI’s capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important.
Pharmacokinetics
Absorption/Bioavailability – CMI from Anafranil capsules is as bioavailable as CMI from a
solution. The bioavailability of CMI from capsules is not significantly affected by food.
In a dose proportionality study involving multiple CMI doses, steady-state plasma concentrations
(Css) and area-under-plasma-concentration-time curves (AUC) of CMI and CMI’s major active
metabolite, desmethylclomipramine (DMI), were not proportional to dose over the ranges
evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day, although Css and AUC
are approximately linearly related to dose between 100 to 150 mg/day. The relationship between
dose and CMI/DMI concentrations at higher daily doses has not been systematically assessed,
but if there is significant dose dependency at doses above 150 mg/day, there is the potential for
dramatically higher Css and AUC even for patients dosed within the recommended range. This
may pose a potential risk to some patients (see WARNINGS and PRECAUTIONS, Drug
Interactions).
After a single 50-mg oral dose, maximum plasma concentrations of CMI occur within 2 to 6
hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL). After multiple
daily doses of 150 mg of Anafranil, steady-state maximum plasma concentrations range from 94
ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI and from 134 ng/mL to 532 ng/mL (mean, 274
ng/mL) for DMI. Additional information from a rising dose study of doses up to 250 mg
suggests that DMI may exhibit nonlinear pharmacokinetics over the usual dosing range. At a
dose of Anafranil 200 mg, subjects who had a single blood sample taken approximately 9 to 22
hours, (median 16 hours), after the dose had plasma concentrations of up to 605 ng/mL for CMI,
781 ng/mL for DMI, and 1386 ng/mL for both.
Distribution – CMI distributes into cerebrospinal fluid (CSF) and brain and into breast milk.
DMI also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein binding of CMI
is approximately 97%, principally to albumin, and is independent of CMI concentration. The
interaction between CMI and other highly protein-bound drugs has not been fully evaluated, but
may be important (see PRECAUTIONS, Drug Interactions).
Metabolism – CMI is extensively biotransformed to DMI and other metabolites and their
glucuronide conjugates. DMI is pharmacologically active, but its effects on OCD behaviors are
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3 of 23
unknown. These metabolites are excreted in urine and feces, following biliary elimination. After
a 25-mg radiolabeled dose of CMI in two subjects, 60% and 51%, respectively, of the dose were
recovered in the urine and 32% and 24%, respectively, in feces. In the same study, the combined
urinary recoveries of CMI and DMI were only about 0.8% to 1.3% of the dose administered.
CMI does not induce drug-metabolizing enzymes, as measured by antipyrine half-life.
Elimination – Evidence that the Css and AUC for CMI and DMI may increase
disproportionately with increasing oral doses suggests that the metabolism of CMI and DMI may
be capacity limited. This fact must be considered in assessing the estimates of the
pharmacokinetic parameters presented below, as these were obtained in individuals exposed to
doses of 150 mg. If the pharmacokinetics of CMI and DMI are nonlinear at doses above 150 mg,
their elimination half-lives may be considerably lengthened at doses near the upper end of the
recommended dosing range (i.e., 200 mg/day to 250 mg/day). Consequently, CMI and DMI may
accumulate, and this accumulation may increase the incidence of any dose- or plasma-
concentration-dependent adverse reactions, in particular seizures (see WARNINGS).
After a 150-mg dose, the half-life of CMI ranges from 19 hours to 37 hours (mean, 32 hr) and
that of DMI ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state levels after multiple
dosing are typically reached within 7 to 14 days for CMI. Plasma concentrations of the
metabolite exceed the parent drug on multiple dosing. After multiple dosing with 150 mg/day,
the accumulation factor for CMI is approximately 2.5 and for DMI is 4.6. Importantly, it may
take two weeks or longer to achieve this extent of accumulation at constant dosing because of the
relatively
long
elimination
half-lives
of
CMI
and
DMI
(see
DOSAGE
AND
ADMINISTRATION). The effects of hepatic and renal impairment on the disposition of
Anafranil have not been determined.
Interactions – Co-administration of haloperidol with CMI increases plasma concentrations of
CMI. Co-administration of CMI with phenobarbital increases plasma concentrations of
phenobarbital (see PRECAUTIONS, Drug Interactions). Younger subjects (18 to 40 years of
age) tolerated CMI better and had significantly lower steady-state plasma concentrations,
compared with subjects over 65 years of age. Children under 15 years of age had significantly
lower plasma concentration/dose ratios, compared with adults. Plasma concentrations of CMI
were significantly lower in smokers than in nonsmokers.
INDICATIONS AND USAGE
Anafranil is indicated for the treatment of obsessions and compulsions in patients with
Obsessive-Compulsive Disorder (OCD). The obsessions or compulsions must cause marked
distress, be time-consuming, or significantly interfere with social or occupational functioning, in
order to meet the DSM-III-R (circa 1989) diagnosis of OCD.
Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego-dystonic.
Compulsions are repetitive, purposeful, and intentional behaviors performed in response to an
obsession or in a stereotyped fashion, and are recognized by the person as excessive or
unreasonable.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4 of 23
The effectiveness of Anafranil for the treatment of OCD was demonstrated in multicenter,
placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-
week study in children and adolescents 10 to 17 years of age. Patients in all studies had
moderate-to-severe OCD (DSM-III), with mean baseline ratings on the Yale-Brown Obsessive
Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean baseline rating of 10 on the
NIMH Clinical Global Obsessive Compulsive Scale (NIMH-OC). Patients taking CMI
experienced a mean reduction of approximately 10 on the YBOCS, representing an average
improvement on this scale of 35% to 42% among adults and 37% among children and
adolescents. CMI-treated patients experienced a 3.5 unit decrement on the NIMH-OC. Patients
on placebo showed no important clinical response on either scale. The maximum dose was 250
mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all children and adolescents.
The effectiveness of Anafranil for long-term use (i.e., for more than 10 weeks) has not been
systematically evaluated in placebo-controlled trials. The physician who elects to use Anafranil
for extended periods should periodically reevaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Anafranil® (clomipramine hydrochloride capsules USP) is contraindicated in patients with a
history of hypersensitivity to Anafranil or other tricyclic antidepressants.
Anafranil should not be given in combination, or within 14 days before or after treatment, with a
monoamine oxidase (MAO) inhibitor. Hyperpyretic crisis, seizures, coma, and death have been
reported in patients receiving such combinations.
Anafranil is contraindicated during the acute recovery period after a myocardial infarction.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior
(suicidality) or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders themselves are the
strongest predictors of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and
young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric
disorders. Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5 of 23
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-
term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
increase in the younger patients for almost all drugs studied. There were differences in absolute
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6 of 23
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about
the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for clomipramine
hydrochloride should be written for the smallest quantity of capsules consistent with good patient
management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that clomipramine hydrochloride is not approved for use in
treating bipolar depression.
Seizures
During premarket evaluation, seizure was identified as the most significant risk of Anafranil use.
The observed cumulative incidence of seizures among patients exposed to Anafranil at doses up
to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at 365 days. The cumulative
rates correct the crude rate of 0.7% (25 of 3519 patients) for the variable duration of exposure in
clinical trials.
Although dose appears to be a predictor of seizure, there is a confounding of dose and duration
of exposure, making it difficult to assess independently the effect of either factor alone. The
ability to predict the occurrence of seizures in subjects exposed to doses of CMI greater than 250
mg is limited, given that the plasma concentration of CMI may be dose-dependent and may vary
among subjects given the same dose. Nevertheless, prescribers are advised to limit the daily dose
to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children and adolescents (see
DOSAGE AND ADMINISTRATION).
Caution should be used in administering Anafranil to patients with a history of seizures or other
predisposing factors, e.g., brain damage of varying etiology, alcoholism, and concomitant use
with other drugs that lower the seizure threshold.
Rare reports of fatalities in association with seizures have been reported by foreign post-
marketing surveillance, but not in U.S. clinical trials. In some of these cases, Anafranil had been
administered with other epileptogenic agents; in others, the patients involved had possibly
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 7 of 23
predisposing medical conditions. Thus a causal association between Anafranil treatment and
these fatalities has not been established.
Physicians should discuss with patients the risk of taking Anafranil while engaging in activities
in which sudden loss of consciousness could result in serious injury to the patient or others, e.g.,
the operation of complex machinery, driving, swimming, climbing.
PRECAUTIONS
General
Suicide – Since depression is a commonly associated feature of OCD, the risk of suicide must be
considered. Prescriptions for Anafranil should be written for the smallest quantity of capsules
consistent with good patient management, in order to reduce the risk of overdose.
Cardiovascular Effects – Modest orthostatic decreases in blood pressure and modest
tachycardia were each seen in approximately 20% of patients taking Anafranil in clinical trials;
but patients were frequently asymptomatic. Among approximately 1400 patients treated with
CMI in the premarketing experience who had ECGs, 1.5% developed abnormalities during
treatment, compared with 3.1% of patients receiving active control drugs and 0.7% of patients
receiving placebo. The most common ECG changes were PVCs, ST-T wave changes, and
intraventricular conduction abnormalities. These changes were rarely associated with significant
clinical symptoms. Nevertheless, caution is necessary in treating patients with known
cardiovascular disease, and gradual dose titration is recommended.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena – Patients treated with
Anafranil have been reported to show a variety of neuropsychiatric signs and symptoms
including delusions, hallucinations, psychotic episodes, confusion, and paranoia. Because of the
uncontrolled nature of many of the studies, it is impossible to provide a precise estimate of the
extent of risk imposed by treatment with Anafranil. As with tricyclic antidepressants to which it
is closely related, Anafranil may precipitate an acute psychotic episode in patients with
unrecognized schizophrenia.
Mania/Hypomania – During premarketing testing of Anafranil in patients with affective
disorder, hypomania or mania was precipitated in several patients. Activation of mania or
hypomania has also been reported in a small proportion of patients with affective disorder treated
with marketed tricyclic antidepressants, which are closely related to Anafranil.
Hepatic Changes – During premarketing testing, Anafranil was occasionally associated with
elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%, respectively) of
potential clinical importance (i.e., values greater than 3 times the upper limit of normal). In the
vast majority of instances, these enzyme increases were not associated with other clinical
findings suggestive of hepatic injury; moreover, none were jaundiced. Rare reports of more
severe liver injury, some fatal, have been recorded in foreign postmarketing experience. Caution
is indicated in treating patients with known liver disease, and periodic monitoring of hepatic
enzyme levels is recommended in such patients.
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Hematologic Changes – Although no instances of severe hematologic toxicity were seen in the
premarketing experience with Anafranil, there have been postmarketing reports of leukopenia,
agranulocytosis, thrombocytopenia, anemia, and pancytopenia in association with Anafranil®
(clomipramine hydrochloride capsules USP) use. As is the case with tricyclic antidepressants to
which Anafranil is closely related, leukocyte and differential blood counts should be obtained in
patients who develop fever and sore throat during treatment with Anafranil.
Central Nervous System – More than 30 cases of hyperthermia have been recorded by
nondomestic postmarketing surveillance systems. Most cases occurred when Anafranil was used
in combination with other drugs. When Anafranil and a neuroleptic were used concomitantly, the
cases were sometimes considered to be examples of a neuroleptic malignant syndrome.
Sexual Dysfunction – The rate of sexual dysfunction in male patients with OCD who were
treated with Anafranil in the premarketing experience was markedly increased compared with
placebo controls (i.e., 42% experienced ejaculatory failure and 20% experienced impotence,
compared with 2.0% and 2.6%, respectively, in the placebo group). Approximately 85% of males
with sexual dysfunction chose to continue treatment.
Weight Changes – In controlled studies of OCD, weight gain was reported in 18% of patients
receiving Anafranil, compared with 1% of patients receiving placebo. In these studies, 28% of
patients receiving Anafranil had a weight gain of at least 7% of their initial body weight,
compared with 4% of patients receiving placebo. Several patients had weight gains in excess of
25% of their initial body weight. Conversely, 5% of patients receiving Anafranil and 1%
receiving placebo had weight losses of at least 7% of their initial body weight.
Electroconvulsive Therapy – As with closely related tricyclic antidepressants, concurrent
administration of Anafranil with electroconvulsive therapy may increase the risks; such
treatment should be limited to those patients for whom it is essential, since there is limited
clinical experience.
Surgery – Prior to elective surgery with general anesthetics, therapy with Anafranil should be
discontinued for as long as is clinically feasible, and the anesthetist should be advised.
Use in Concomitant Illness – As with closely related tricyclic antidepressants, Anafranil should
be used with caution in the following:
(1) Hyperthyroid patients or patients receiving thyroid medication, because of the possibility of
cardiac toxicity;
(2) Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or urinary
retention, because of the anticholinergic properties of the drug;
(3) Patients with tumors of the adrenal medulla (e.g., pheochromocytoma, neuroblastoma) in
whom the drug may provoke hypertensive crises;
(4) Patients with significantly impaired renal function.
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Withdrawal Symptoms – A variety of withdrawal symptoms have been reported in association
with abrupt discontinuation of Anafranil, including dizziness, nausea, vomiting, headache,
malaise, sleep disturbance, hyperthermia, and irritability. In addition, such patients may
experience a worsening of psychiatric status. While the withdrawal effects of Anafranil have not
been systematically evaluated in controlled trials, they are well known with closely related
tricyclic antidepressants, and it is recommended that the dosage be tapered gradually and the
patient monitored carefully during discontinuation (see DRUG ABUSE AND DEPENDENCE).
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with clomipramine
hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about
“Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts
or Actions” is available for clomipramine hydrochloride. The prescriber or health professional
should instruct patients, their families, and their caregivers to read the Medication Guide and
should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may
have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking clomipramine hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
early during antidepressant treatment and when the dose is adjusted up or down. Families and
caregivers of patients should be advised to look for the emergence of such symptoms on a day-
to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s
prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an increased
risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
changes in the medication.
Physicians are advised to discuss the following issues with patients for whom they prescribe
Anafranil:
(1) The risk of seizure (see WARNINGS);
(2) The relatively high incidence of sexual dysfunction among males (see Sexual Dysfunction);
(3) Since Anafranil may impair the mental and/or physical abilities required for the performance
of complex tasks, and since Anafranil is associated with a risk of seizures, patients should be
cautioned about the performance of complex and hazardous tasks (see WARNINGS);
(4) Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants
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concurrently, since Anafranil may exaggerate their response to these drugs;
(5) Patients should notify their physician if they become pregnant or intend to become pregnant
during therapy;
(6) Patients should notify their physician if they are breast-feeding.
Drug Interactions
The risks of using Anafranil in combination with other drugs have not been systematically
evaluated. Given the primary CNS effects of Anafranil, caution is advised in using it
concomitantly with other CNS-active drugs (see Information for Patients). Anafranil should
not be used with MAO inhibitors (see CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when Anafranil is administered
with anticholinergic or sympathomimetic drugs.
Several tricyclic antidepressants have been reported to block the pharmacologic effects of
guanethidine, clonidine, or similar agents, and such an effect may be anticipated with CMI
because of its structural similarity to other tricyclic antidepressants.
The plasma concentration of CMI has been reported to be increased by the concomitant
administration of haloperidol; plasma levels of several closely related tricyclic antidepressants
have been reported to be increased by the concomitant administration of methylphenidate or
hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by the concomitant
administration of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect may
be anticipated with CMI as well. Administration of CMI has been reported to increase the plasma
levels of phenobarbital, if given concomitantly (see CLINICAL PHARMACOLOGY,
Interactions).
Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing isozyme
cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian
population (about 7% to 10% of Caucasians are so-called “poor metabolizers”); reliable
estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and
other populations are not yet available. Poor metabolizers have higher than expected plasma
concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the
fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or
quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the
activity of this isozyme and make normal metabolizers resemble poor metabolizers. An
individual who is stable on a given dose of TCA may become abruptly toxic when given one of
these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6
include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are
substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C
antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors
(SSRIs), e.g., fluoxetine, sertraline, paroxetine, and fluvoxamine, inhibit P450 2D6, they may
vary in the extent of inhibition. Fluvoxamine has also been shown to inhibit P450 1A2, an
isoform also involved in TCA metabolism. The extent to which SSRI-TCA interactions may
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pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the
SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of
the SSRIs and also in switching from one class to the other. Of particular importance, sufficient
time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine,
given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of agents in the tricyclic antidepressant class (which includes Anafranil) with
drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for
either the tricyclic antidepressant agent or the other drug. Furthermore, whenever one of these
drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant agent may be
required. It is desirable to monitor TCA plasma levels whenever an agent of the tricyclic
antidepressant class including Anafranil is going to be co-administered with another drug known
to be an inhibitor of P450 2D6 (and/or P450 1A2).
Because Anafranil is highly bound to serum protein, the administration of Anafranil to patients
taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may cause an
increase in plasma concentrations of these drugs, potentially resulting in adverse effects.
Conversely, adverse effects may result from displacement of protein-bound Anafranil by other
highly bound drugs (see CLINICAL PHARMACOLOGY, Distribution).
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found in two 2-year bioassays in rats at doses up to 100
mg/kg, which is 24 and 4 times the maximum recommended human daily dose (MRHD) on a
mg/kg and mg/m2 basis, respectively, or in a 2-year bioassay in mice at doses up to 80 mg/kg,
which is 20 and 1.5 times the MRHD on a mg/kg and mg/m2 basis, respectively.
In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg, which is
6 times, and approximately equal to, the MRHD on a mg/kg and mg/m2 basis, respectively.
Pregnancy Category C
No teratogenic effects were observed in studies performed in rats and mice at doses up to 100
mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg
basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m2 basis. Slight nonspecific
embryo/fetotoxic effects were seen in the offspring of treated rats given 50 and 100 mg/kg and of
treated mice given 100 mg/kg.
There are no adequate or well-controlled studies in pregnant women. Withdrawal symptoms,
including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had
taken Anafranil until delivery. Anafranil should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Nursing Mothers
Anafranil® (clomipramine hydrochloride capsules USP) has been found in human milk. Because
of the potential for adverse reactions, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the drug to the mother.
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Pediatric Use
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have
not been established (see BOX WARNING and WARNINGS, Clinical Worsening and
Suicide Risk). Anyone considering the use of Anafranil in a child or adolescent must balance the
potential risks with the clinical need.
In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients
received Anafranil for up to 8 weeks. In addition, 150 adolescent patients have received
Anafranil in open-label protocols for periods of several months to several years. Of the 196
adolescents
studied,
50
were
13
years
of
age
or
less
and
146
were
14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE
REACTIONS) is similar to that observed in adults.
The risks, if any, that may be associated with Anafranil’s extended use in children and
adolescents with OCD have not been systematically assessed. The evidence supporting the
conclusion that Anafranil is safe for use in children and adolescents is derived from relatively
short term clinical studies and from extrapolation of experience gained with adult patients. In
particular, there are no studies that directly evaluate the effects of long term Anafranil use on the
growth, development, and maturation of children and adolescents. Although there is no evidence
to suggest that Anafranil adversely affects growth, development or maturation, the absence of
such findings is not adequate to rule out a potential for such effects in chronic use.
The safety and effectiveness in pediatric patients below the age of 10 have not been established.
Therefore, specific recommendations cannot be made for the use of Anafranil in pediatric
patients under the age of 10.
Geriatric Use
Clinical studies of Anafranil did not include sufficient numbers of subjects age 65 and over to
determine whether they respond differently from younger subjects; 152 patients at least 60 years
of age participating in various U.S. clinical trials received Anafranil for periods of several
months to several years. No unusual age-related adverse events were identified in this
population. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Commonly Observed
The most commonly observed adverse events associated with the use of Anafranil and not seen
at an equivalent incidence among placebo-treated patients were gastrointestinal complaints,
including dry mouth, constipation, nausea, dyspepsia, and anorexia; nervous system complaints,
including somnolence, tremor, dizziness, nervousness, and myoclonus; genitourinary complaints,
including changed libido, ejaculatory failure, impotence, and micturition disorder; and other
miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain, and
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visual changes.
Leading to Discontinuation of Treatment
Approximately 20% of 3616 patients who received Anafranil in U.S. premarketing clinical trials
discontinued treatment because of an adverse event. Approximately one-half of the patients who
discontinued (9% of the total) had multiple complaints, none of which could be classified as
primary. Where a primary reason for discontinuation could be identified, most patients
discontinued because of nervous system complaints (5.4%), primarily somnolence. The second-
most-frequent reason for discontinuation was digestive system complaints (1.3%), primarily
vomiting and nausea.
There was no apparent relationship between the adverse events and elevated plasma drug
concentrations.
Incidence in Controlled Clinical Trials
The following table enumerates adverse events that occurred at an incidence of 1% or greater
among patients with OCD who received Anafranil in adult or pediatric placebo-controlled
clinical trials. The frequencies were obtained from pooled data of clinical trials involving either
adults receiving Anafranil (N=322) or placebo (N=319) or children treated with Anafranil
(N=46) or placebo (N=44). The prescriber should be aware that these figures cannot be used to
predict the incidence of side effects in the course of usual medical practice, in which patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, provide the
physician with a basis for estimating the relative contribution of drug and nondrug factors to the
incidence of side effects in the populations studied.
Incidence of Treatment-Emergent Adverse Experience
in Placebo-Controlled Clinical Trials
(Percentage of Patients Reporting Event)
Adults
Children and Adolescents
Body System/
Adverse Event*
Anafranil
(N=322)
Placebo
(N=319)
Anafranil
(N=46)
Placebo
(N=44)
Nervous System
Somnolence
54
16
46
11
Tremor
54
2
33
2
Dizziness
54
14
41
14
Headache
52
41
28
34
Insomnia
25
15
11
7
Libido change
21
3
-
-
Nervousness
18
2
4
2
Myoclonus
13
-
2
-
Increased appetite
11
2
-
2
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Paresthesia
9
3
2
2
Memory impairment
9
1
7
2
Anxiety
9
4
2
-
Twitching
7
1
4
5
Impaired concentration
5
2
-
-
Depression
5
1
-
-
Hypertonia
4
1
2
-
Sleep disorder
4
-
9
5
Psychosomatic disorder
3
-
-
-
Yawning
3
-
-
-
Confusion
3
-
2
-
Speech disorder
3
-
-
-
Abnormal dreaming
3
-
-
2
Agitation
3
-
-
-
Migraine
3
-
-
-
Depersonalization
2
-
2
-
Irritability
2
2
2
-
Emotional lability
2
-
-
2
Panic reaction
1
-
2
-
Aggressive reaction
-
-
2
-
Paresis
-
-
2
-
Skin and Appendages
Increased sweating
29
3
9
-
Rash
8
1
4
2
Pruritus
6
-
2
2
Dermatitis
2
-
-
2
Acne
2
2
-
5
Dry skin
2
-
-
5
Urticaria
1
-
-
-
Abnormal skin odor
-
-
2
-
Digestive System
Dry mouth
84
17
63
16
Constipation
47
11
22
9
Nausea
33
14
9
11
Dyspepsia
22
10
13
2
Diarrhea
13
9
7
5
Anorexia
12
-
22
2
Abdominal pain
11
9
13
16
Vomiting
7
2
7
-
Flatulence
6
3
-
2
Tooth disorder
5
-
-
-
Gastrointestinal disorder
2
-
-
2
Dysphagia
2
-
-
-
Esophagitis
1
-
-
-
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Eructation
-
-
2
2
Ulcerative stomatitis
-
-
2
-
Body as a Whole
Fatigue
39
18
35
9
Weight increase
18
1
2
-
Flushing
8
-
7
-
Hot flushes
5
-
2
-
Chest pain
4
4
7
-
Fever
4
-
2
7
Allergy
3
3
7
5
Pain
3
2
4
2
Local edema
2
4
-
-
Chills
2
1
-
-
Weight decrease
-
-
7
-
Otitis media
-
-
4
5
Asthenia
-
-
2
-
Halitosis
-
-
2
-
Cardiovascular System
Postural hypotension
6
-
4
-
Palpitation
4
2
4
-
Tachycardia
4
-
2
-
Syncope
-
-
2
-
Respiratory System
Pharyngitis
14
9
-
5
Rhinitis
12
10
7
9
Sinusitis
6
4
2
5
Coughing
6
6
4
5
Bronchospasm
2
-
7
2
Epistaxis
2
-
-
2
Dyspnea
-
-
2
-
Laryngitis
-
1
2
-
Urogenital System
Male and Female Patients Combined
Micturition disorder
14
2
4
2
Urinary tract infection
6
1
-
-
Micturition frequency
5
3
-
-
Urinary retention
2
-
7
-
Dysuria
2
2
-
-
Cystitis
2
-
-
-
Female Patients Only
(N=182)
(N=167)
(N=10)
(N=21)
Dysmenorrhea
12
14
10
10
Lactation (nonpuerperal)
4
-
-
-
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Menstrual disorder
4
2
-
-
Vaginitis
2
-
-
-
Leukorrhea
2
-
-
-
Breast enlargement
2
-
-
-
Breast pain
1
-
-
-
Amenorrhea
1
-
-
-
Male Patients Only
(N=140)
(N=152)
(N=36)
(N=23)
Ejaculation failure
42
2
6
-
Impotence
20
3
-
-
Special Senses
Abnormal vision
18
4
7
2
Taste perversion
8
-
4
-
Tinnitus
6
-
4
-
Abnormal lacrimation
3
2
-
-
Mydriasis
2
-
-
-
Conjunctivitis
1
-
-
-
Anisocoria
-
-
2
-
Blepharospasm
-
-
2
-
Ocular allergy
-
-
2
-
Vestibular disorder
-
-
2
2
Musculoskeletal
Myalgia
13
9
-
-
Back pain
6
6
-
-
Arthralgia
3
5
-
-
Muscle weakness
1
-
2
-
Hemic and Lymphatic
Purpura
3
-
-
-
Anemia
-
-
2
2
Metabolic and Nutritional
Thirst
2
2
-
2
*Events reported by at least 1% of Anafranil patients are included.
Other Events Observed During the Premarketing Evaluation of Anafranil
During clinical testing in the U.S., multiple doses of Anafranil® (clomipramine hydrochloride
capsules USP) were administered to approximately 3600 subjects. Untoward events associated
with this exposure were recorded by clinical investigators using terminology of their own
choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of
individuals experiencing adverse events without first grouping similar types of untoward events
into a smaller number of standardized event categories.
In the tabulations that follow, a modified World Health Organization dictionary of terminology
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Page 17 of 23
has been used to classify reported adverse events. The frequencies presented, therefore, represent
the proportion of the 3525 individuals exposed to Anafranil who experienced an event of the
type cited on at least one occasion while receiving Anafranil. All events are included except
those already listed in the previous table, those reported in terms so general as to be
uninformative, and those in which an association with the drug was remote. It is important to
emphasize that although the events reported occurred during treatment with Anafranil, they were
not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on one or
more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in less than 1/1000 patients.
Body as a Whole – Infrequent - general edema, increased susceptibility to infection, malaise.
Rare - dependent edema, withdrawal syndrome.
Cardiovascular System – Infrequent - abnormal ECG, arrhythmia, bradycardia, cardiac arrest,
extrasystoles, pallor. Rare - aneurysm, atrial flutter, bundle branch block, cardiac failure,
cerebral hemorrhage, heart block, myocardial infarction, myocardial ischemia, peripheral
ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.
Digestive System – Infrequent - abnormal hepatic function, blood in stool, colitis, duodenitis,
gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis, hemorrhoids, hepatitis,
increased saliva, irritable bowel syndrome, peptic ulcer, rectal hemorrhage, tongue ulceration,
tooth caries. Rare - cheilitis, chronic enteritis, discolored feces, gastric dilatation, gingival
bleeding, hiccup, intestinal obstruction, oral/pharyngeal edema, paralytic ileus, salivary gland
enlargement.
Endocrine System – Infrequent - hypothyroidism. Rare - goiter, gynecomastia,
hyperthyroidism.
Hemic and Lymphatic System – Infrequent - lymphadenopathy. Rare - leukemoid reaction,
lymphoma-like disorder, marrow depression.
Metabolic and Nutritional Disorder – Infrequent - dehydration, diabetes mellitus, gout,
hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia. Rare - fat intolerance,
glycosuria.
Musculoskeletal System – Infrequent - arthrosis. Rare - dystonia, exostosis, lupus
erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.
Nervous System – Frequent - abnormal thinking, vertigo. Infrequent - abnormal coordination,
abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions, delirium, delusion, dyskinesia,
dysphonia, encephalopathy, euphoria, extrapyramidal disorder, hallucinations, hostility,
hyperkinesia, hypnagogic hallucinations, hypokinesia, leg cramps, manic reaction, neuralgia,
paranoia, phobic disorder, psychosis, sensory disturbance, somnambulism, stimulation, suicidal
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 18 of 23
ideation, suicide attempt, teeth-grinding. Rare - anticholinergic syndrome, aphasia, apraxia,
catalepsy, cholinergic syndrome, choreoathetosis, generalized spasm, hemiparesis, hyperesthesia,
hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism,
neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic reaction,
stupor, suicide.
Respiratory System – Infrequent - bronchitis, hyperventilation, increased sputum, pneumonia.
Rare - cyanosis, hemoptysis, hypoventilation, laryngismus.
Skin and Appendages – Infrequent - alopecia, cellulitis, cyst, eczema, erythematous rash,
genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular rash, skin
discoloration. Rare - chloasma, folliculitis, hypertrichosis, piloerection, seborrhea, skin
hypertrophy, skin ulceration.
Special Senses – Infrequent - abnormal accommodation, deafness, diplopia, earache, eye pain,
foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste loss. Rare -
blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos, glaucoma, keratitis, labyrinth
disorder, night blindness, retinal disorder, strabismus, visual field defect.
Urogenital System – Infrequent - endometriosis, epididymitis, hematuria, nocturia, oliguria,
ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal pain, urethral
disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage. Rare - albuminuria,
anorgasmy, breast engorgement, breast fibroadenosis, cervical dysplasia, endometrial
hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal cyst, uterine inflammation,
vulvar disorder.
DRUG ABUSE AND DEPENDENCE
Anafranil has not been systematically studied in animals or humans for its potential for abuse,
tolerance, or physical dependence. While a variety of withdrawal symptoms have been described
in association with Anafranil discontinuation (see PRECAUTIONS, Withdrawal Symptoms),
there is no evidence for drug-seeking behavior, except for a single report of potential Anafranil
abuse by a patient with a history of dependence on codeine, benzodiazepines, and multiple
psychoactive drugs. The patient received Anafranil for depression and panic attacks and
appeared to become dependent after hospital discharge.
Despite the lack of evidence suggesting an abuse liability for Anafranil in foreign marketing, it is
not possible to predict the extent to which Anafranil might be misused or abused once marketed
in the U.S. Consequently, physicians should carefully evaluate patients for a history of drug
abuse and follow such patients closely.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including
alcohol) is common in deliberate tricyclic overdose. As the management is complex and
changing, it is recommended that the physician contact a poison control center for current
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 19 of 23
information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic
overdose. Therefore, hospital monitoring is required as soon as possible.
Human Experience
In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil
either alone or in combination with other drugs. One death involved a patient suspected of
ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose
of 5750 mg. The 10 nonfatal cases involved doses of up to 5000 mg, accompanied by plasma
levels of up to 1010 ng/mL. All 10 patients completely recovered. Among reports from other
countries of Anafranil overdose, the lowest dose associated with a fatality was 750 mg. Based
upon postmarketing reports in the United Kingdom, CMI’s lethality in overdose is considered to
be similar to that reported for closely related tricyclic compounds marketed as antidepressants.
Manifestations
Signs and symptoms vary in severity depending upon factors such as the amount of drug
absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical
manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and
CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or
width, are clinically significant indicators of tricyclic toxicity. Other CNS manifestations may
include drowsiness, stupor, ataxia, restlessness, agitation, delirium, severe perspiration,
hyperactive reflexes, muscle rigidity, and athetoid and choreiform movements. Cardiac
abnormalities may include tachycardia, signs of congestive heart failure, and in very rare cases,
cardiac arrest. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and
oliguria or anuria may also be present.
Management
Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway,
establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of
observation with cardiac monitoring and observation for signs of CNS or respiratory depression,
hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary.
If signs of toxicity occur at any time during this period, extended monitoring is required. There
are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients
had clinical evidence of significant poisoning prior to death and most received inadequate
gastrointestinal decontamination. Monitoring of plasma drug levels should not guide
management of the patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic overdose should receive
gastrointestinal decontamination. This should include large volume gastric lavage followed by
activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage.
Emesis is contraindicated.
Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best
indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to
maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 20 of 23
hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate
should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO2 < 20
mmHg
is
undesirable.
Dysrhythmias
unresponsive
to
sodium
bicarbonate
therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C
antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability
in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange
transfusions, and forced diuresis generally have been reported as ineffective in tricyclic
poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the potential for
abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are
ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not
recommended except to treat life-threatening symptoms that have been unresponsive to other
therapies, and then only in consultation with a poison control center.
Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt suicide by
other means during the recovery phase. Psychiatric referral may be appropriate.
Pediatric Management – The principles of management of child and adult overdosages are
similar. It is strongly recommended that the physician contact the local poison control center for
specific pediatric treatment.
DOSAGE AND ADMINISTRATION
The treatment regimens described below are based on those used in controlled clinical trials of
Anafranil in 520 adults, and 91 children and adolescents with OCD. During initial titration,
Anafranil should be given in divided doses with meals to reduce gastrointestinal side effects. The
goal of this initial titration phase is to minimize side effects by permitting tolerance to side
effects to develop or allowing the patient time to adapt if tolerance does not develop.
Because both CMI and its active metabolite, DMI, have long elimination half-lives, the
prescriber should take into consideration the fact that steady-state plasma levels may not be
achieved until 2 to 3 weeks after dosage change (see CLINICAL PHARMACOLOGY).
Therefore,
after
initial
titration,
it
may
be
appropriate
to
wait
2 to 3 weeks between further dosage adjustments.
Initial Treatment/Dose Adjustment (Adults)
Treatment with Anafranil should be initiated at a dosage of 25 mg daily and gradually increased,
as tolerated, to approximately 100 mg during the first 2 weeks. During initial titration, Anafranil
should be given in divided doses with meals to reduce gastrointestinal side effects. Thereafter,
the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg
daily. After titration, the total daily dose may be given once daily at bedtime to minimize
daytime sedation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 21 of 23
Initial Treatment/Dose Adjustment (Children and Adolescents)
As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in
divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as
tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller. Thereafter, the
dosage may be increased gradually over the next several weeks up to a daily maximum of 3
mg/kg or 200 mg, whichever is smaller (see PRECAUTIONS, Pediatric Use). As with adults,
after titration, the total daily dose may be given once daily at bedtime to minimize daytime
sedation.
Maintenance/Continuation Treatment (Adults, Children, and Adolescents)
While there are no systematic studies that answer the question of how long to continue Anafranil,
OCD is a chronic condition and it is reasonable to consider continuation for a responding patient.
Although the efficacy of Anafranil after 10 weeks has not been documented in controlled trials,
patients have been continued in therapy under double-blind conditions for up to 1 year without
loss of benefit. However, dosage adjustments should be made to maintain the patient on the
lowest effective dosage, and patients should be periodically reassessed to determine the need for
treatment. During maintenance, the total daily dose may be given once daily at bedtime.
HOW SUPPLIED
Anafranil® (clomipramine hydrochloride capsules USP)
Capsules 25 mg – ivory body imprinted in black with “M” and melon-yellow cap imprinted in
black with “ANAFRANIL 25 mg”
Bottles of 30.......................................NDC 0406-9906-03
Capsules 50 mg – ivory body imprinted in black with “M” and aqua blue cap imprinted in black
with “ANAFRANIL 50 mg”
Bottles of 30.......................................NDC 0406-9907-03
Capsules 75 mg – ivory body imprinted in black with “M” and yellow cap imprinted in black
with “ANAFRANIL 75 mg”
Bottles of 30.......................................NDC 0406-9908-03
Storage – Store at 20º to 25ºC (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in well-closed containers with a child-resistant closure. Protect from moisture.
ANIMAL TOXICOLOGY
Phospholipidosis and testicular changes, commonly associated with tricyclic compounds, have
been observed with Anafranil. In chronic rat studies, changes related to Anafranil consisted of
systemic phospholipidosis, alterations in the testes (atrophy, mineralization) and secondary
changes in other tissues. In addition cardiac thrombosis and dermatitis/keratitis were observed in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 22 of 23
rats treated for 2 years at doses which were 24 and 10 times the maximum recommended human
daily dose (MRHD), respectively, on a mg/kg basis, and 4 and 1.5 times the MRHD,
respectively, on a mg/m2 basis.
Anafranil and M are registered trademarks of Mallinckrodt Inc.
Manufactured by
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
for Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.
Medication Guide
Antidepressant Medicines, Depression and other Serious Mental Illnesses,
and Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s antidepressant
medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started or
when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 23 of 23
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the
following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
•
new or worse irritability
•
acting aggressive, being angry, or violent
•
acting on dangerous impulses
•
an extreme increase in activity and
talking (mania)
•
other unusual changes in behavior or
mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare provider.
Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating it.
Patients and their families or other caregivers should discuss all treatment choices with the
healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines
that you or your family member takes. Keep a list of all medicines to show the healthcare
provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child’s healthcare provider for more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.
Rev 050707
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:16.782736
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019906s34lbl.pdf', 'application_number': 19906, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,836
|
Anafranil™
(clomipramine hydrochloride) Capsules USP
(25 mg, 50 mg, and 75 mg)
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of clomipramine hydrochloride or any other
antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Clomipramine hydrochloride
is not approved for use in pediatric patients except for patients with obsessive
compulsive disorder (OCD) (see WARNINGS, Clinical Worsening and Suicide
Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric
Use).
DESCRIPTION
Anafranil™ (clomipramine hydrochloride) Capsules USP is an antiobsessional drug that
belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic
antidepressants. Anafranil is available as capsules of 25, 50, and 75 mg for oral
administration.
Clomipramine hydrochloride USP is 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro
5H-dibenz[b,f]azepine monohydrochloride, and its structural formula is:
Page 1 of 27
10_2012.2
Reference ID: 3209061
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
C19H23ClN2 ● HCl
MW = 351.31
Clomipramine hydrochloride USP is a white to off-white crystalline powder. It is freely
soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether
and in hexane.
Inactive Ingredients. D&C Red No. 33 (25 mg capsules only), D&C Yellow No. 10,
FD&C Blue No. 1 (50 mg capsules only), FD&C Yellow No. 6, gelatin, magnesium
stearate, methylparaben, propylparaben, starch (corn), and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors
through its effects on serotonergic neuronal transmission. The actual neurochemical
mechanism is unknown, but CMI’s capacity to inhibit the reuptake of serotonin (5-HT) is
thought to be important.
Pharmacokinetics
Absorption/Bioavailability – CMI from Anafranil capsules is as bioavailable as CMI
from a solution. The bioavailability of CMI from capsules is not significantly affected by
food.
In a dose proportionality study involving multiple CMI doses, steady-state plasma
concentrations (Css) and area-under-plasma-concentration-time curves (AUC) of CMI and
CMI’s major active metabolite, desmethylclomipramine (DMI), were not proportional to dose
over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day,
although Css and AUC are approximately linearly related to dose between 100 to
150 mg/day. The relationship between dose and CMI/DMI concentrations at higher daily
doses has not been systematically assessed, but if there is significant dose dependency at
doses above 150 mg/day, there is the potential for dramatically higher Css and AUC even
for patients dosed within the recommended range. This may pose a potential risk to some
patients (see WARNINGS and PRECAUTIONS, Drug Interactions).
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After a single 50 mg oral dose, maximum plasma concentrations of CMI occur within
2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL).
After multiple daily doses of 150 mg of Anafranil, steady-state maximum plasma
concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI and from
134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for DMI. Additional information from a
rising dose study of doses up to 250 mg suggests that DMI may exhibit nonlinear
pharmacokinetics over the usual dosing range. At a dose of Anafranil 200 mg, subjects
who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours),
after the dose had plasma concentrations of up to 605 ng/mL for CMI, 781 ng/mL for
DMI, and 1386 ng/mL for both.
Distribution – CMI distributes into cerebrospinal fluid (CSF) and brain and into breast
milk. DMI also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein
binding of CMI is approximately 97%, principally to albumin, and is independent of CMI
concentration. The interaction between CMI and other highly protein-bound drugs has
not been fully evaluated, but may be important (see PRECAUTIONS, Drug
Interactions).
Metabolism – CMI is extensively biotransformed to DMI and other metabolites and their
glucuronide conjugates. DMI is pharmacologically active, but its effects on OCD
behaviors are unknown. These metabolites are excreted in urine and feces, following
biliary elimination. After a 25 mg radiolabeled dose of CMI in two subjects, 60% and
51%, respectively, of the dose were recovered in the urine and 32% and 24%,
respectively, in feces. In the same study, the combined urinary recoveries of CMI and
DMI were only about 0.8% to 1.3% of the dose administered. CMI does not induce drug-
metabolizing enzymes, as measured by antipyrine half-life.
Elimination – Evidence that the Css and AUC for CMI and DMI may increase
disproportionately with increasing oral doses suggests that the metabolism of CMI and
DMI may be capacity limited. This fact must be considered in assessing the estimates of
the pharmacokinetic parameters presented below, as these were obtained in individuals
exposed to doses of 150 mg. If the pharmacokinetics of CMI and DMI are nonlinear at
doses above 150 mg, their elimination half-lives may be considerably lengthened at
doses near the upper end of the recommended dosing range (i.e., 200 mg/day to
250 mg/day). Consequently, CMI and DMI may accumulate, and this accumulation may
increase the incidence of any dose- or plasma-concentration-dependent adverse
reactions, in particular seizures (see WARNINGS).
After a 150 mg dose, the half-life of CMI ranges from 19 hours to 37 hours (mean,
32 hr) and that of DMI ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state
levels after multiple dosing are typically reached within 7 to 14 days for CMI. Plasma
concentrations of the metabolite exceed the parent drug on multiple dosing. After
multiple dosing with 150 mg/day, the accumulation factor for CMI is approximately
2.5 and for DMI is 4.6. Importantly, it may take two weeks or longer to achieve this
extent of accumulation at constant dosing because of the relatively long elimination half-
lives of CMI and DMI (see DOSAGE AND ADMINISTRATION). The effects of hepatic
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and renal impairment on the disposition of Anafranil have not been determined.
Interactions – Co-administration of haloperidol with CMI increases plasma
concentrations of CMI. Co-administration of CMI with phenobarbital increases plasma
concentrations of phenobarbital (see PRECAUTIONS, Drug Interactions). Younger
subjects (18 to 40 years of age) tolerated CMI better and had significantly lower steady-
state plasma concentrations, compared with subjects over 65 years of age. Children
under 15 years of age had significantly lower plasma concentration/dose ratios,
compared with adults. Plasma concentrations of CMI were significantly lower in
smokers than in nonsmokers.
INDICATIONS AND USAGE
Anafranil™ (clomipramine hydrochloride) Capsules USP is indicated for the treatment of
obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD).
The obsessions or compulsions must cause marked distress, be time-consuming, or
significantly interfere with social or occupational functioning, in order to meet the DSM
III-R (circa 1989) diagnosis of OCD.
Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego
dystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in
response to an obsession or in a stereotyped fashion, and are recognized by the person as
excessive or unreasonable.
The effectiveness of Anafranil for the treatment of OCD was demonstrated in
multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in
adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients
in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the
Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean
baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH
OC). Patients taking CMI experienced a mean reduction of approximately 10 on the
YBOCS, representing an average improvement on this scale of 35% to 42% among
adults and 37% among children and adolescents. CMI-treated patients experienced a
3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical
response on either scale. The maximum dose was 250 mg/day for most adults and
3 mg/kg/day (up to 200 mg) for all children and adolescents.
The effectiveness of Anafranil for long-term use (i.e., for more than 10 weeks) has not
been systematically evaluated in placebo-controlled trials. The physician who elects to
use Anafranil for extended periods should periodically reevaluate the long-term
usefulness
of
the
drug
for
the
individual
patient
(see
DOSAGE
AND
ADMINISTRATION).
CONTRAINDICATIONS
Anafranil is contraindicated in patients with a history of hypersensitivity to Anafranil or
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other tricyclic antidepressants.
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with Anafranil or within
14 days of stopping treatment with Anafranil is contraindicated because of an increased
risk of serotonin syndrome. The use of Anafranil within 14 days of stopping an MAOI
intended to treat psychiatric disorders is also contraindicated (see WARNINGS and
DOSAGE AND ADMINISTRATION).
Starting Anafranil in a patient who is being treated with linezolid or intravenous
methylene blue is also contraindicated because of an increased risk of serotonin
syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Myocardial Infarction
Anafranil is contraindicated during the acute recovery period after a myocardial
infarction.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation and
behavior (suicidality) or unusual changes in behavior, whether or not they are taking
antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of
11 antidepressant drugs in over 77,000 patients. There was considerable variation in
risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of
suicidality across the different indications, with the highest incidence in MDD. The risk
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differences (drug vs placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of
cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
18-24
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64
≥65
1 fewer case
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants can delay
the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications, both
psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who
are experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric,
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should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report such
symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for clomipramine
hydrochloride should be written for the smallest quantity of capsules consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the
initial presentation of bipolar disorder. It is generally believed (though not established in
controlled trials) that treating such an episode with an antidepressant alone may
increase the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an antidepressant,
patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that clomipramine hydrochloride is not approved for use in treating bipolar
depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported
with SNRIs and SSRIs, including Anafranil, alone but particularly with concomitant use
of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair
metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor,
rigidity,
myoclonus,
hyperreflexia,
incoordination),
seizures,
and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be
monitored for the emergence of serotonin syndrome.
The concomitant use of Anafranil with MAOIs intended to treat psychiatric disorders is
contraindicated. Anafranil should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene
blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the
administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient
taking Anafranil. Anafranil should be discontinued before initiating treatment with the
MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
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If concomitant use of Anafranil with other serotonergic drugs, including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort
is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Anafranil and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic
treatment should be initiated.
Seizures
During premarket evaluation, seizure was identified as the most significant risk of
Anafranil use.
The observed cumulative incidence of seizures among patients exposed to Anafranil at
doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at
365 days. The cumulative rates correct the crude rate of 0.7% (25 of 3519 patients) for
the variable duration of exposure in clinical trials.
Although dose appears to be a predictor of seizure, there is a confounding of dose and
duration of exposure, making it difficult to assess independently the effect of either
factor alone. The ability to predict the occurrence of seizures in subjects exposed to
doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI
may be dose-dependent and may vary among subjects given the same dose.
Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in
adults and 3 mg/kg (or 200 mg) in children and adolescents (see DOSAGE AND
ADMINISTRATION).
Caution should be used in administering Anafranil to patients with a history of seizures
or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and
concomitant use with other drugs that lower the seizure threshold.
Rare reports of fatalities in association with seizures have been reported by foreign
postmarketing surveillance, but not in U.S. clinical trials. In some of these cases,
Anafranil had been administered with other epileptogenic agents; in others, the patients
involved had possibly predisposing medical conditions. Thus a causal association
between Anafranil treatment and these fatalities has not been established.
Physicians should discuss with patients the risk of taking Anafranil while engaging in
activities in which sudden loss of consciousness could result in serious injury to the
patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.
PRECAUTIONS
General
Suicide – Since depression is a commonly associated feature of OCD, the risk of
suicide must be considered. Prescriptions for Anafranil should be written for the
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smallest quantity of capsules consistent with good patient management, in order to
reduce the risk of overdose.
Cardiovascular Effects – Modest orthostatic decreases in blood pressure and modest
tachycardia were each seen in approximately 20% of patients taking Anafranil in clinical
trials; but patients were frequently asymptomatic. Among approximately 1400 patients
treated with CMI in the premarketing experience who had ECGs, 1.5% developed
abnormalities during treatment, compared with 3.1% of patients receiving active control
drugs and 0.7% of patients receiving placebo. The most common ECG changes were
PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These
changes were rarely associated with significant clinical symptoms. Nevertheless,
caution is necessary in treating patients with known cardiovascular disease, and
gradual dose titration is recommended.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena – Patients treated
with Anafranil have been reported to show a variety of neuropsychiatric signs and
symptoms including delusions, hallucinations, psychotic episodes, confusion, and
paranoia. Because of the uncontrolled nature of many of the studies, it is impossible to
provide a precise estimate of the extent of risk imposed by treatment with Anafranil. As
with tricyclic antidepressants to which it is closely related, Anafranil may precipitate an
acute psychotic episode in patients with unrecognized schizophrenia.
Mania/Hypomania – During premarketing testing of Anafranil in patients with affective
disorder, hypomania or mania was precipitated in several patients. Activation of mania
or hypomania has also been reported in a small proportion of patients with affective
disorder treated with marketed tricyclic antidepressants, which are closely related to
Anafranil.
Hepatic Changes – During premarketing testing, Anafranil was occasionally associated
with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%,
respectively) of potential clinical importance (i.e., values greater than 3 times the upper
limit of normal). In the vast majority of instances, these enzyme increases were not
associated with other clinical findings suggestive of hepatic injury; moreover, none were
jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in
foreign postmarketing experience. Caution is indicated in treating patients with known
liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such
patients.
Hematologic Changes – Although no instances of severe hematologic toxicity were
seen in the premarketing experience with Anafranil, there have been postmarketing
reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in
association with Anafranil use. As is the case with tricyclic antidepressants to which
Anafranil is closely related, leukocyte and differential blood counts should be obtained in
patients who develop fever and sore throat during treatment with Anafranil.
Central Nervous System – More than 30 cases of hyperthermia have been recorded
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by nondomestic postmarketing surveillance systems. Most cases occurred when
Anafranil was used in combination with other drugs. When Anafranil and a neuroleptic
were used concomitantly, the cases were sometimes considered to be examples of a
neuroleptic malignant syndrome.
Sexual Dysfunction – The rate of sexual dysfunction in male patients with OCD who
were treated with Anafranil in the premarketing experience was markedly increased
compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20%
experienced impotence, compared with 2.0% and 2.6%, respectively, in the placebo
group). Approximately 85% of males with sexual dysfunction chose to continue
treatment.
Weight Changes – In controlled studies of OCD, weight gain was reported in 18% of
patients receiving Anafranil, compared with 1% of patients receiving placebo. In these
studies, 28% of patients receiving Anafranil had a weight gain of at least 7% of their
initial body weight, compared with 4% of patients receiving placebo. Several patients
had weight gains in excess of 25% of their initial body weight. Conversely, 5% of
patients receiving Anafranil and 1% receiving placebo had weight losses of at least 7%
of their initial body weight.
Electroconvulsive Therapy – As with closely related tricyclic antidepressants,
concurrent administration of Anafranil with electroconvulsive therapy may increase the
risks; such treatment should be limited to those patients for whom it is essential, since
there is limited clinical experience.
Surgery – Prior to elective surgery with general anesthetics, therapy with Anafranil
should be discontinued for as long as is clinically feasible, and the anesthetist should be
advised.
Use in Concomitant Illness – As with closely related tricyclic antidepressants,
Anafranil should be used with caution in the following:
(1) Hyperthyroid patients or patients receiving thyroid medication, because of the
possibility of cardiac toxicity;
(2) Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or
urinary retention, because of the anticholinergic properties of the drug;
(3) Patients with tumors of the adrenal medulla (e.g., pheochromocytoma,
neuroblastoma) in whom the drug may provoke hypertensive crises;
(4) Patients with significantly impaired renal function.
Withdrawal Symptoms – A variety of withdrawal symptoms have been reported in
association with abrupt discontinuation of Anafranil, including dizziness, nausea,
vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In
addition, such patients may experience a worsening of psychiatric status. While the
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withdrawal effects of Anafranil have not been systematically evaluated in controlled
trials, they are well known with closely related tricyclic antidepressants, and it is
recommended that the dosage be tapered gradually and the patient monitored
carefully during discontinuation (see DRUG ABUSE AND DEPENDENCE).
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with clomipramine
hydrochloride and should counsel them in its appropriate use. A patient Medication
Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness,
and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. The
prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking clomipramine hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s prescriber
or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
Physicians are advised to discuss the following issues with patients for whom they
prescribe Anafranil:
(1) The risk of seizure (see WARNINGS);
(2) The relatively high incidence of sexual dysfunction among males (see Sexual
Dysfunction);
(3) Since Anafranil may impair the mental and/or physical abilities required for the
performance of complex tasks, and since Anafranil is associated with a risk of
seizures, patients should be cautioned about the performance of complex and
hazardous tasks (see WARNINGS);
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(4) Patients should be cautioned about using alcohol, barbiturates, or other CNS
depressants concurrently, since Anafranil may exaggerate their response to these
drugs;
(5) Patients should notify their physician if they become pregnant or intend to become
pregnant during therapy;
(6) Patients should notify their physician if they are breast-feeding.
Drug Interactions
The risks of using Anafranil in combination with other drugs have not been
systematically evaluated. Given the primary CNS effects of Anafranil, caution is advised
in using it concomitantly with other CNS-active drugs (see Information for Patients).
Anafranil should not be used with MAO inhibitors (see CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when Anafranil is
administered with anticholinergic or sympathomimetic drugs.
Several tricyclic antidepressants have been reported to block the pharmacologic effects
of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with
CMI because of its structural similarity to other tricyclic antidepressants.
The plasma concentration of CMI has been reported to be increased by the concomitant
administration of haloperidol; plasma levels of several closely related tricyclic
antidepressants have been reported to be increased by the concomitant administration
of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and
decreased by the concomitant administration of hepatic enzyme inducers (e.g.,
barbiturates, phenytoin), and such an effect may be anticipated with CMI as well.
Administration of CMI has been reported to increase the plasma levels of phenobarbital,
if given concomitantly (see CLINICAL PHARMACOLOGY, Interactions).
Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the
Caucasian population (about 7% to 10% of Caucasians are so-called “poor
metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or quite
large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the
activity of this isozyme and make normal metabolizers resemble poor metabolizers. An
individual who is stable on a given dose of TCA may become abruptly toxic when given
one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome
P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine)
and many that are substrates for P450 2D6 (many other antidepressants,
phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all
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the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline,
paroxetine, and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition.
Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA
metabolism. The extent to which SSRI-TCA interactions may pose clinical problems will
depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.
Nevertheless, caution is indicated in the co-administration of TCAs with any of the
SSRIs and also in switching from one class to the other. Of particular importance,
sufficient time must elapse before initiating TCA treatment in a patient being withdrawn
from fluoxetine, given the long half-life of the parent and active metabolite (at least
5 weeks may be necessary). Concomitant use of agents in the tricyclic antidepressant
class (which includes Anafranil) with drugs that can inhibit cytochrome P450 2D6 may
require lower doses than usually prescribed for either the tricyclic antidepressant agent
or the other drug. Furthermore, whenever one of these drugs is withdrawn from co
therapy, an increased dose of tricyclic antidepressant agent may be required. It is
desirable to monitor TCA plasma levels whenever an agent of the tricyclic
antidepressant class including Anafranil is going to be co-administered with another
drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).
Because Anafranil is highly bound to serum protein, the administration of Anafranil to
patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may
cause an increase in plasma concentrations of these drugs, potentially resulting in
adverse effects. Conversely, adverse effects may result from displacement of protein-
bound Anafranil by other highly bound drugs (see CLINICAL PHARMACOLOGY,
Distribution).
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found in two 2-year bioassays in rats at doses up to
100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose
(MRHD) on a mg/kg and mg/m2 basis, respectively, or in a 2-year bioassay in mice at
doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m2
basis, respectively.
In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg,
which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m2 basis,
respectively.
Pregnancy Category C
No teratogenic effects were observed in studies performed in rats and mice at doses up
to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD)
on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m2 basis.
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Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats
given 50 and 100 mg/kg and of treated mice given 100 mg/kg.
There are no adequate or well-controlled studies in pregnant women. Withdrawal
symptoms, including jitteriness, tremor, and seizures, have been reported in neonates
whose mothers had taken Anafranil until delivery. Anafranil should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Anafranil has been found in human milk. Because of the potential for adverse reactions,
a decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in the pediatric population other than pediatric patients with
OCD have not been established (see BOX WARNING and WARNINGS, Clinical
Worsening and Suicide Risk). Anyone considering the use of Anafranil in a child or
adolescent must balance the potential risks with the clinical need.
In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46
outpatients received Anafranil for up to 8 weeks. In addition, 150 adolescent patients
have received Anafranil in open-label protocols for periods of several months to several
years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were
14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE
REACTIONS) is similar to that observed in adults.
The risks, if any, that may be associated with Anafranil’s extended use in children and
adolescents with OCD have not been systematically assessed. The evidence
supporting the conclusion that Anafranil is safe for use in children and adolescents is
derived from relatively short term clinical studies and from extrapolation of experience
gained with adult patients. In particular, there are no studies that directly evaluate the
effects of long term Anafranil use on the growth, development, and maturation of
children and adolescents. Although there is no evidence to suggest that Anafranil
adversely affects growth, development or maturation, the absence of such findings is
not adequate to rule out a potential for such effects in chronic use.
The safety and effectiveness in pediatric patients below the age of 10 have not been
established. Therefore, specific recommendations cannot be made for the use of
Anafranil in pediatric patients under the age of 10.
Geriatric Use
Clinical studies of Anafranil did not include sufficient numbers of subjects age 65 and
over to determine whether they respond differently from younger subjects;
152 patients at least 60 years of age participating in various U.S. clinical trials
received Anafranil for periods of several months to several years. No unusual age-
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related adverse events were identified in this population. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function and of concomitant disease or other drug
therapy.
ADVERSE REACTIONS
Commonly Observed
The most commonly observed adverse events associated with the use of Anafranil and
not seen at an equivalent incidence among placebo-treated patients were
gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and
anorexia; nervous system complaints, including somnolence, tremor, dizziness,
nervousness, and myoclonus; genitourinary complaints, including changed libido,
ejaculatory failure, impotence, and micturition disorder; and other miscellaneous
complaints, including fatigue, sweating, increased appetite, weight gain, and visual
changes.
Leading to Discontinuation of Treatment
Approximately 20% of 3616 patients who received Anafranil in U.S. premarketing
clinical trials discontinued treatment because of an adverse event. Approximately one-
half of the patients who discontinued (9% of the total) had multiple complaints, none of
which could be classified as primary. Where a primary reason for discontinuation could
be identified, most patients discontinued because of nervous system complaints (5.4%),
primarily somnolence. The second-most-frequent reason for discontinuation was
digestive system complaints (1.3%), primarily vomiting and nausea.
There was no apparent relationship between the adverse events and elevated plasma
drug concentrations.
Incidence in Controlled Clinical Trials
The following table enumerates adverse events that occurred at an incidence of 1% or
greater among patients with OCD who received Anafranil in adult or pediatric placebo-
controlled clinical trials. The frequencies were obtained from pooled data of clinical trials
involving either adults receiving Anafranil (N=322) or placebo (N=319) or children
treated with Anafranil (N=46) or placebo (N=44). The prescriber should be aware that
these figures cannot be used to predict the incidence of side effects in the course of
usual medical practice, in which patient characteristics and other factors differ from
those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, provide the physician
with a basis for estimating the relative contribution of drug and nondrug factors to the
incidence of side effects in the populations studied.
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Incidence of Treatment-Emergent Adverse Experience
in Placebo-Controlled Clinical Trials
(Percentage of Patients Reporting Event)
Adults
Children and
Adolescents
Body System/
Adverse Event*
Anafranil
(N=322)
Placebo
(N=319)
Anafranil
(N=46)
Placebo
(N=44)
Nervous System
Somnolence
54
16
46
11
Tremor
54
2
33
2
Dizziness
54
14
41
14
Headache
52
41
28
34
Insomnia
25
15
11
7
Libido change
21
3
-
-
Nervousness
18
2
4
2
Myoclonus
13
-
2
-
Increased appetite
11
2
-
2
Paresthesia
9
3
2
2
Memory impairment
9
1
7
2
Anxiety
9
4
2
-
Twitching
7
1
4
5
Impaired concentration
5
2
-
-
Depression
5
1
-
-
Hypertonia
4
1
2
-
Sleep disorder
4
-
9
5
Psychosomatic disorder
3
-
-
-
Yawning
3
-
-
-
Confusion
3
-
2
-
Speech disorder
3
-
-
-
Abnormal dreaming
3
-
-
2
Agitation
3
-
-
-
Migraine
3
-
-
-
Depersonalization
2
-
2
-
Irritability
2
2
2
-
Emotional lability
2
-
-
2
Panic reaction
1
-
2
-
Aggressive reaction
-
-
2
-
Paresis
-
-
2
-
Skin and Appendages
Increased sweating
29
3
9
-
Rash
8
1
4
2
Pruritus
6
-
2
2
Dermatitis
2
-
-
2
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Acne
2
2
-
5
Dry skin
2
-
-
5
Urticaria
1
-
-
-
Abnormal skin odor
-
-
2
-
Digestive System
Dry mouth
84
17
63
16
Constipation
47
11
22
9
Nausea
33
14
9
11
Dyspepsia
22
10
13
2
Diarrhea
13
9
7
5
Anorexia
12
-
22
2
Abdominal pain
11
9
13
16
Vomiting
7
2
7
-
Flatulence
6
3
-
2
Tooth disorder
5
-
-
-
Gastrointestinal disorder
2
-
-
2
Dysphagia
2
-
-
-
Esophagitis
1
-
-
-
Eructation
-
-
2
2
Ulcerative stomatitis
-
-
2
-
Body as a Whole
Fatigue
39
18
35
9
Weight increase
18
1
2
-
Flushing
8
-
7
-
Hot flushes
5
-
2
-
Chest pain
4
4
7
-
Fever
4
-
2
7
Allergy
3
3
7
5
Pain
3
2
4
2
Local edema
2
4
-
-
Chills
2
1
-
-
Weight decrease
-
-
7
-
Otitis media
-
-
4
5
Asthenia
-
-
2
-
Halitosis
-
-
2
-
Cardiovascular System
Postural hypotension
6
-
4
-
Palpitation
4
2
4
-
Tachycardia
4
-
2
-
Syncope
-
-
2
-
Respiratory System
Pharyngitis
14
9
-
5
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Rhinitis
12
10
7
9
Sinusitis
6
4
2
5
Coughing
6
6
4
5
Bronchospasm
2
-
7
2
Epistaxis
2
-
-
2
Dyspnea
-
-
2
-
Laryngitis
-
1
2
-
Urogenital System
Male and Female Patients Combined
Micturition disorder
14
2
4
2
Urinary tract infection
6
1
-
-
Micturition frequency
5
3
-
-
Urinary retention
2
-
7
-
Dysuria
2
2
-
-
Cystitis
2
-
-
-
Female Patients Only
Dysmenorrhea
(N=182)
12
(N=167)
14
(N=10)
10
(N=21)
10
Lactation (nonpuerperal)
4
-
-
-
Menstrual disorder
4
2
-
-
Vaginitis
2
-
-
-
Leukorrhea
2
-
-
-
Breast enlargement
2
-
-
-
Breast pain
1
-
-
-
Amenorrhea
1
-
-
-
Male Patients Only
Ejaculation failure
(N=140)
42
(N=152)
2
(N=36)
6
(N=23)
-
Impotence
20
3
-
-
Special Senses
Abnormal vision
18
4
7
2
Taste perversion
8
-
4
-
Tinnitus
6
-
4
-
Abnormal lacrimation
3
2
-
-
Mydriasis
2
-
-
-
Conjunctivitis
1
-
-
-
Anisocoria
-
-
2
-
Blepharospasm
-
-
2
-
Ocular allergy
-
-
2
-
Vestibular disorder
-
-
2
2
Musculoskeletal
Myalgia
13
9
-
-
Back pain
6
6
-
-
Arthralgia
3
5
-
-
Muscle weakness
1
-
2
-
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Hemic and Lymphatic
Purpura
3
-
-
-
Anemia
-
-
2
2
Metabolic and
Nutritional
Thirst
2
2
-
2
*Events reported by at least 1% of Anafranil patients are included.
Other Events Observed During the Premarketing Evaluation of Anafranil
During clinical testing in the U.S., multiple doses of Anafranil were administered to
approximately 3600 subjects. Untoward events associated with this exposure were
recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion of
individuals experiencing adverse events without first grouping similar types of untoward
events into a smaller number of standardized event categories.
In the tabulations that follow, a modified World Health Organization dictionary of
terminology has been used to classify reported adverse events. The frequencies
presented, therefore, represent the proportion of the 3525 individuals exposed to
Anafranil who experienced an event of the type cited on at least one occasion while
receiving Anafranil. All events are included except those already listed in the previous
table, those reported in terms so general as to be uninformative, and those in which an
association with the drug was remote. It is important to emphasize that although the
events reported occurred during treatment with Anafranil, they were not necessarily
caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are those
occurring on one or more occasions in at least 1/100 patients; infrequent adverse
events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring
in less than 1/1000 patients.
Body as a Whole – Infrequent - general edema, increased susceptibility to infection,
malaise. Rare - dependent edema, withdrawal syndrome.
Cardiovascular System – Infrequent - abnormal ECG, arrhythmia, bradycardia,
cardiac arrest, extrasystoles, pallor. Rare - aneurysm, atrial flutter, bundle branch block,
cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial
ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.
Digestive System – Infrequent - abnormal hepatic function, blood in stool, colitis,
duodenitis, gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis,
hemorrhoids, hepatitis, increased saliva, irritable bowel syndrome, peptic ulcer, rectal
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hemorrhage, tongue ulceration, tooth caries. Rare - cheilitis, chronic enteritis, discolored
feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal
edema, paralytic ileus, salivary gland enlargement.
Endocrine System – Infrequent - hypothyroidism. Rare - goiter, gynecomastia,
hyperthyroidism.
Hemic and Lymphatic System – Infrequent - lymphadenopathy. Rare - leukemoid
reaction, lymphoma-like disorder, marrow depression.
Metabolic and Nutritional Disorder – Infrequent - dehydration, diabetes mellitus, gout,
hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia. Rare -
fat
intolerance, glycosuria.
Musculoskeletal System – Infrequent - arthrosis. Rare - dystonia, exostosis, lupus
erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.
Nervous System – Frequent - abnormal thinking, vertigo. Infrequent - abnormal
coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions,
delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria, extrapyramidal
disorder, hallucinations, hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia,
leg cramps, manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory
disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt, teeth-
grinding. Rare - anticholinergic syndrome, aphasia, apraxia, catalepsy, cholinergic
syndrome,
choreoathetosis,
generalized
spasm,
hemiparesis,
hyperesthesia,
hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism,
neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic
reaction, stupor, suicide.
Respiratory System – Infrequent - bronchitis, hyperventilation, increased sputum,
pneumonia. Rare - cyanosis, hemoptysis, hypoventilation, laryngismus.
Skin and Appendages – Infrequent - alopecia, cellulitis, cyst, eczema, erythematous
rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular
rash, skin discoloration. Rare - chloasma, folliculitis, hypertrichosis, piloerection,
seborrhea, skin hypertrophy, skin ulceration.
Special Senses – Infrequent - abnormal accommodation, deafness, diplopia, earache,
eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste
loss. Rare -
blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos,
glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus,
visual field defect.
Urogenital System – Infrequent - endometriosis, epididymitis, hematuria, nocturia,
oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal
pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage.
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Rare - albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical
dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal
cyst, uterine inflammation, vulvar disorder.
DRUG ABUSE AND DEPENDENCE
Anafranil has not been systematically studied in animals or humans for its potential for
abuse, tolerance, or physical dependence. While a variety of withdrawal symptoms
have been described in association with Anafranil discontinuation (see PRECAUTIONS,
Withdrawal Symptoms), there is no evidence for drug-seeking behavior, except for a
single report of potential Anafranil abuse by a patient with a history of dependence on
codeine, benzodiazepines, and multiple psychoactive drugs. The patient received
Anafranil for depression and panic attacks and appeared to become dependent after
hospital discharge.
Despite the lack of evidence suggesting an abuse liability for Anafranil in foreign
marketing, it is not possible to predict the extent to which Anafranil might be misused or
abused once marketed in the U.S. Consequently, physicians should carefully evaluate
patients for a history of drug abuse and follow such patients closely.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion
(including alcohol) is common in deliberate tricyclic overdose. As the management is
complex and changing, it is recommended that the physician contact a poison control
center for current information on treatment. Signs and symptoms of toxicity develop
rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as
possible.
Human Experience
In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with
Anafranil either alone or in combination with other drugs. One death involved a patient
suspected of ingesting a dose of 7000 mg. The second death involved a patient
suspected of ingesting a dose of 5750 mg. The 10 nonfatal cases involved doses of up
to 5000 mg, accompanied by plasma levels of up to 1010 ng/mL. All 10 patients
completely recovered. Among reports from other countries of Anafranil overdose, the
lowest dose associated with a fatality was 750 mg. Based upon postmarketing reports in
the United Kingdom, CMI’s lethality in overdose is considered to be similar to that
reported for closely related tricyclic compounds marketed as antidepressants.
Manifestations
Signs and symptoms vary in severity depending upon factors such as the amount of
drug absorbed, the age of the patient, and the time elapsed since drug ingestion.
Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension,
convulsions, and CNS depression including coma. Changes in the electrocardiogram,
particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.
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Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness,
agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, and
athetoid and choreiform movements. Cardiac abnormalities may include tachycardia,
signs of congestive heart failure, and in very rare cases, cardiac arrest. Respiratory
depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and oliguria or anuria
may also be present.
Management
Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway,
establish an intravenous line, and initiate gastric decontamination. A minimum of
6 hours of observation with cardiac monitoring and observation for signs of CNS or
respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks,
and seizures is necessary.
If signs of toxicity occur at any time during this period, extended monitoring is required.
There are case reports of patients succumbing to fatal dysrhythmias late after overdose;
these patients had clinical evidence of significant poisoning prior to death and most
received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels
should not guide management of the patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic overdose
should receive gastrointestinal decontamination. This should include large volume
gastric lavage followed by activated charcoal. If consciousness is impaired, the airway
should be secured prior to lavage. Emesis is contraindicated.
Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the
best indication of the severity of the overdose. Intravenous sodium bicarbonate should
be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is
inadequate, hyperventilation may also be used. Concomitant use of hyperventilation
and sodium bicarbonate should be done with extreme caution, with frequent pH
monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias
unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine,
bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated
(e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular
instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis,
exchange transfusions, and forced diuresis generally have been reported as ineffective
in tricyclic poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the
potential for abrupt deterioration. Seizures should be controlled with benzodiazepines,
or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).
Physostigmine is not recommended except to treat life-threatening symptoms that have
been unresponsive to other therapies, and then only in consultation with a poison
control center.
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Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt
suicide by other means during the recovery phase. Psychiatric referral may be
appropriate.
Pediatric Management – The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact the local
poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION
The treatment regimens described below are based on those used in controlled clinical
trials of Anafranil in 520 adults, and 91 children and adolescents with OCD. During initial
titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal
side effects. The goal of this initial titration phase is to minimize side effects by
permitting tolerance to side effects to develop or allowing the patient time to adapt if
tolerance does not develop.
Because both CMI and its active metabolite, DMI, have long elimination half-lives, the
prescriber should take into consideration the fact that steady-state plasma levels may
not be achieved until 2 to 3 weeks after dosage change (see CLINICAL
PHARMACOLOGY). Therefore, after initial titration, it may be appropriate to wait
2 to 3 weeks between further dosage adjustments.
Initial Treatment/Dose Adjustment (Adults)
Treatment with Anafranil should be initiated at a dosage of 25 mg daily and gradually
increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial
titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal
side effects. Thereafter, the dosage may be increased gradually over the next several
weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be
given once daily at bedtime to minimize daytime sedation.
Initial Treatment/Dose Adjustment (Children and Adolescents)
As with adults, the starting dose is 25 mg daily and should be gradually increased (also
given in divided doses with meals to reduce gastrointestinal side effects) during the first
2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller.
Thereafter, the dosage may be increased gradually over the next several weeks up to a
daily maximum of 3 mg/kg or 200 mg, whichever is smaller (see PRECAUTIONS,
Pediatric Use). As with adults, after titration, the total daily dose may be given once daily
at bedtime to minimize daytime sedation.
Maintenance/Continuation Treatment (Adults, Children, and Adolescents)
While there are no systematic studies that answer the question of how long to continue
Anafranil, OCD is a chronic condition and it is reasonable to consider continuation for a
responding patient. Although the efficacy of Anafranil after 10 weeks has not been
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documented in controlled trials, patients have been continued in therapy under double-
blind conditions for up to 1 year without loss of benefit. However, dosage adjustments
should be made to maintain the patient on the lowest effective dosage, and patients
should be periodically reassessed to determine the need for treatment. During
maintenance, the total daily dose may be given once daily at bedtime.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended
to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat
psychiatric disorders and initiation of therapy with Anafranil. Conversely, at least 14
days should be allowed after stopping Anafranil before starting an MAOI intended to
treat psychiatric disorders (see CONTRAINDICATIONS).
Use of Anafranil With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Anafranil in a patient who is being treated with linezolid or intravenous
methylene blue because there is increased risk of serotonin syndrome. In a patient who
requires more urgent treatment of a psychiatric condition, other interventions, including
hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving Anafranil therapy may require urgent
treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential
benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the
risks of serotonin syndrome in a particular patient, Anafranil should be stopped
promptly, and linezolid or intravenous methylene blue can be administered. The patient
should be monitored for symptoms of serotonin syndrome for two weeks or until
24 hours after the last dose of linezolid or intravenous methylene blue, whichever
comes first. Therapy with Anafranil may be resumed 24 hours after the last dose of
linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral
tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with
Anafranil is unclear. The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use (see WARNINGS).
HOW SUPPLIED
Anafranil™ (clomipramine hydrochloride) Capsules USP
Capsules 25 mg – ivory body imprinted in black with “M” and melon-yellow cap
imprinted in black with “ANAFRANIL 25 mg”
Bottles of 30................................. NDC 0406-9906-03
Capsules 50 mg – ivory body imprinted in black with “M” and aqua blue cap imprinted in
black with “ANAFRANIL 50 mg”
Bottles of 30................................. NDC 0406-9907-03
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Capsules 75 mg – ivory body imprinted in black with “M” and yellow cap imprinted in
black with “ANAFRANIL 75 mg”
Bottles of 30................................. NDC 0406-9908-03
Storage – Store at 20º to 25ºC (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in well-closed containers with a child-resistant closure. Protect from moisture.
ANIMAL TOXICOLOGY
Phospholipidosis and testicular changes, commonly associated with tricyclic
compounds, have been observed with Anafranil. In chronic rat studies, changes related
to Anafranil consisted of systemic phospholipidosis, alterations in the testes (atrophy,
mineralization) and secondary changes in other tissues. In addition cardiac thrombosis
and dermatitis/keratitis were observed in rats treated for 2 years at doses which were 24
and 10 times the maximum recommended human daily dose (MRHD), respectively, on
a mg/kg basis, and 4 and 1.5 times the MRHD, respectively, on a mg/m2 basis.
Anafranil and M are trademarks of Mallinckrodt LLC.
Manufactured by
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
for Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Medication Guide - Anafranil™
(clomipramine hydrochloride) Capsules USP
Antidepressant Medicines, Depression and other Serious Mental Illnesses,
and Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s
antidepressant medicine. This Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your, or your family
member’s, healthcare provider about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant
medicines, depression and other serious mental illnesses, and suicidal thoughts
or actions?
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1. Antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes
of suicidal thoughts and actions. Some people may have a particularly high
risk of having suicidal thoughts or actions. These include people who have (or
have a family history of) bipolar illness (also called manic-depressive illness) or
suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself
or a family member?
Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of
the following symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling very agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
Who should not take Anafranil?
Do not take Anafranil if you:
take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
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o Do not take an MAOI within 2 weeks of stopping Anafranil unless directed
to do so by your physician.
o Do not start Anafranil if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your physician.
What else do I need to know about antidepressant medicines?
Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other
symptoms.
Antidepressants are medicines used to treat depression and other illnesses. It
is important to discuss all the risks of treating depression and also the risks of not
treating it. Patients and their families or other caregivers should discuss all treatment
choices with the healthcare provider, not just the use of antidepressants.
Antidepressant medicines have other side effects. Talk to the healthcare
provider about the side effects of the medicine prescribed for you or your family
member.
Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show
the healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
Not all antidepressant medicines prescribed for children are FDA approved for
use in children. Talk to your child’s healthcare provider for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Anafranil is a trademark of Mallinckrodt LLC.
Manufactured by
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
for Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Rev 10/2012 company logo
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|
custom-source
|
2025-02-12T13:46:16.852308
|
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|
11,837
|
Anafranil™
(clomipramine hydrochloride) Capsules USP
(25 mg, 50 mg, and 75 mg)
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of clomipramine hydrochloride or any other
antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Clomipramine hydrochloride
is not approved for use in pediatric patients except for patients with obsessive
compulsive disorder (OCD) (see WARNINGS, Clinical Worsening and Suicide
Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric
Use).
DESCRIPTION
Anafranil™ (clomipramine hydrochloride) Capsules USP is an antiobsessional drug that
belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic
antidepressants. Anafranil is available as capsules of 25, 50, and 75 mg for oral
administration.
Clomipramine hydrochloride USP is 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro
5H-dibenz[b,f ] azepine monohydrochloride, and its structural formula is:
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
C19H23ClN2 ● HCl
MW = 351.31
Clomipramine hydrochloride USP is a white to off-white crystalline powder. It is freely
soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether
and in hexane.
Inactive Ingredients. D&C Red No. 33 (25 mg capsules only), D&C Yellow No. 10,
FD&C Blue No. 1 (50 mg capsules only), FD&C Yellow No. 6, gelatin, magnesium
stearate, methylparaben, propylparaben, starch (corn), and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors
through its effects on serotonergic neuronal transmission. The actual neurochemical
mechanism is unknown, but CMI’s capacity to inhibit the reuptake of serotonin (5-HT) is
thought to be important.
Pharmacokinetics
Absorption/Bioavailability – CMI from Anafranil capsules is as bioavailable as CMI
from a solution. The bioavailability of CMI from capsules is not significantly affected by
food.
In a dose proportionality study involving multiple CMI doses, steady-state plasma
concentrations (Css) and area-under-plasma-concentration-time curves (AUC) of CMI and
CMI’s major active metabolite, desmethylclomipramine (DMI), were not proportional to dose
over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day,
although Css and AUC are approximately linearly related to dose between 100 to
150 mg/day. The relationship between dose and CMI/DMI concentrations at higher daily
doses has not been systematically assessed, but if there is significant dose dependency at
doses above 150 mg/day, there is the potential for dramatically higher Css and AUC even
for patients dosed within the recommended range. This may pose a potential risk to some
patients (see WARNINGS and PRECAUTIONS, Drug Interactions).
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After a single 50 mg oral dose, maximum plasma concentrations of CMI occur within
2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL).
After multiple daily doses of 150 mg of Anafranil, steady-state maximum plasma
concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI and from
134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for DMI. Additional information from a
rising dose study of doses up to 250 mg suggests that DMI may exhibit nonlinear
pharmacokinetics over the usual dosing range. At a dose of Anafranil 200 mg, subjects
who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours),
after the dose had plasma concentrations of up to 605 ng/mL for CMI, 781 ng/mL for
DMI, and 1386 ng/mL for both.
Distribution – CMI distributes into cerebrospinal fluid (CSF) and brain and into breast
milk. DMI also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein
binding of CMI is approximately 97%, principally to albumin, and is independent of CMI
concentration. The interaction between CMI and other highly protein-bound drugs has
not been fully evaluated, but may be important (see PRECAUTIONS, Drug
Interactions).
Metabolism – CMI is extensively biotransformed to DMI and other metabolites and their
glucuronide conjugates. DMI is pharmacologically active, but its effects on OCD
behaviors are unknown. These metabolites are excreted in urine and feces, following
biliary elimination. After a 25 mg radiolabeled dose of CMI in two subjects, 60% and
51%, respectively, of the dose were recovered in the urine and 32% and 24%,
respectively, in feces. In the same study, the combined urinary recoveries of CMI and
DMI were only about 0.8% to 1.3% of the dose administered. CMI does not induce drug-
metabolizing enzymes, as measured by antipyrine half-life.
Elimination – Evidence that the Css and AUC for CMI and DMI may increase
disproportionately with increasing oral doses suggests that the metabolism of CMI and
DMI may be capacity limited. This fact must be considered in assessing the estimates of
the pharmacokinetic parameters presented below, as these were obtained in individuals
exposed to doses of 150 mg. If the pharmacokinetics of CMI and DMI are nonlinear at
doses above 150 mg, their elimination half-lives may be considerably lengthened at
doses near the upper end of the recommended dosing range (i.e., 200 mg/day to
250 mg/day). Consequently, CMI and DMI may accumulate, and this accumulation may
increase the incidence of any dose- or plasma-concentration-dependent adverse
reactions, in particular seizures (see WARNINGS).
After a 150 mg dose, the half-life of CMI ranges from 19 hours to 37 hours (mean,
32 hr) and that of DMI ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state
levels after multiple dosing are typically reached within 7 to 14 days for CMI. Plasma
concentrations of the metabolite exceed the parent drug on multiple dosing. After
multiple dosing with 150 mg/day, the accumulation factor for CMI is approximately
2.5 and for DMI is 4.6. Importantly, it may take two weeks or longer to achieve this
extent of accumulation at constant dosing because of the relatively long elimination half-
lives of CMI and DMI (see DOSAGE AND ADMINISTRATION). The effects of hepatic
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and renal impairment on the disposition of Anafranil have not been determined.
Interactions – Co-administration of haloperidol with CMI increases plasma
concentrations of CMI. Co-administration of CMI with phenobarbital increases plasma
concentrations of phenobarbital (see PRECAUTIONS, Drug Interactions). Younger
subjects (18 to 40 years of age) tolerated CMI better and had significantly lower steady-
state plasma concentrations, compared with subjects over 65 years of age. Children
under 15 years of age had significantly lower plasma concentration/dose ratios,
compared with adults. Plasma concentrations of CMI were significantly lower in
smokers than in nonsmokers.
INDICATIONS AND USAGE
Anafranil™ (clomipramine hydrochloride) Capsules USP is indicated for the treatment of
obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD).
The obsessions or compulsions must cause marked distress, be time-consuming, or
significantly interfere with social or occupational functioning, in order to meet the DSM
III-R (circa 1989) diagnosis of OCD.
Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego
dystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in
response to an obsession or in a stereotyped fashion, and are recognized by the person as
excessive or unreasonable.
The effectiveness of Anafranil for the treatment of OCD was demonstrated in
multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in
adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients
in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the
Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean
baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH
OC). Patients taking CMI experienced a mean reduction of approximately 10 on the
YBOCS, representing an average improvement on this scale of 35% to 42% among
adults and 37% among children and adolescents. CMI-treated patients experienced a
3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical
response on either scale. The maximum dose was 250 mg/day for most adults and
3 mg/kg/day (up to 200 mg) for all children and adolescents.
The effectiveness of Anafranil for long-term use (i.e., for more than 10 weeks) has not
been systematically evaluated in placebo-controlled trials. The physician who elects to
use Anafranil for extended periods should periodically reevaluate the long-term
usefulness
of
the
drug
for
the
individual
patient
(see
DOSAGE
AND
ADMINISTRATION).
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CONTRAINDICATIONS
Anafranil is contraindicated in patients with a history of hypersensitivity to Anafranil or
other tricyclic antidepressants.
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with Anafranil or within
14 days of stopping treatment with Anafranil is contraindicated because of an increased
risk of serotonin syndrome. The use of Anafranil within 14 days of stopping an MAOI
intended to treat psychiatric disorders is also contraindicated (see WARNINGS and
DOSAGE AND ADMINISTRATION).
Starting Anafranil in a patient who is being treated with linezolid or intravenous
methylene blue is also contraindicated because of an increased risk of serotonin
syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Myocardial Infarction
Anafranil is contraindicated during the acute recovery period after a myocardial
infarction.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation and
behavior (suicidality) or unusual changes in behavior, whether or not they are taking
antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of
11 antidepressant drugs in over 77,000 patients. There was considerable variation in
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risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of
suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of
cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
18-24
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64
≥65
1 fewer case
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants can delay
the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications, both
psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who
are experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms.
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Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report such
symptoms immediately to healthcare providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for clomipramine
hydrochloride should be written for the smallest quantity of capsules consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the
initial presentation of bipolar disorder. It is generally believed (though not established in
controlled trials) that treating such an episode with an antidepressant alone may
increase the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an antidepressant,
patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that clomipramine hydrochloride is not approved for use in treating bipolar
depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported
with SNRIs and SSRIs, including Anafranil, alone but particularly with concomitant use
of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair
metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor,
rigidity,
myoclonus,
hyperreflexia,
incoordination),
seizures,
and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be
monitored for the emergence of serotonin syndrome.
The concomitant use of Anafranil with MAOIs intended to treat psychiatric disorders is
contraindicated. Anafranil should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene
blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the
administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient
taking Anafranil. Anafranil should be discontinued before initiating treatment with the
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MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Anafranil with other serotonergic drugs, including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort
is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Anafranil and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic
treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including
Anafranil may trigger an angle closure attack in a patient with anatomically narrow
angles who does not have a patent iridectomy.
Seizures
During premarket evaluation, seizure was identified as the most significant risk of
Anafranil use.
The observed cumulative incidence of seizures among patients exposed to Anafranil at
doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at
365 days. The cumulative rates correct the crude rate of 0.7% (25 of 3519 patients) for
the variable duration of exposure in clinical trials.
Although dose appears to be a predictor of seizure, there is a confounding of dose and
duration of exposure, making it difficult to assess independently the effect of either
factor alone. The ability to predict the occurrence of seizures in subjects exposed to
doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI
may be dose-dependent and may vary among subjects given the same dose.
Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in
adults and 3 mg/kg (or 200 mg) in children and adolescents (see DOSAGE AND
ADMINISTRATION).
Caution should be used in administering Anafranil to patients with a history of seizures
or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and
concomitant use with other drugs that lower the seizure threshold.
Rare reports of fatalities in association with seizures have been reported by foreign
postmarketing surveillance, but not in U.S. clinical trials. In some of these cases,
Anafranil had been administered with other epileptogenic agents; in others, the patients
involved had possibly predisposing medical conditions. Thus a causal association
between Anafranil treatment and these fatalities has not been established.
Physicians should discuss with patients the risk of taking Anafranil while engaging in
activities in which sudden loss of consciousness could result in serious injury to the
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patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.
PRECAUTIONS
General
Suicide – Since depression is a commonly associated feature of OCD, the risk of
suicide must be considered. Prescriptions for Anafranil should be written for the
smallest quantity of capsules consistent with good patient management, in order to
reduce the risk of overdose.
Cardiovascular Effects – Modest orthostatic decreases in blood pressure and modest
tachycardia were each seen in approximately 20% of patients taking Anafranil in clinical
trials; but patients were frequently asymptomatic. Among approximately 1400 patients
treated with CMI in the premarketing experience who had ECGs, 1.5% developed
abnormalities during treatment, compared with 3.1% of patients receiving active control
drugs and 0.7% of patients receiving placebo. The most common ECG changes were
PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These
changes were rarely associated with significant clinical symptoms. Nevertheless,
caution is necessary in treating patients with known cardiovascular disease, and
gradual dose titration is recommended.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena – Patients treated
with Anafranil have been reported to show a variety of neuropsychiatric signs and
symptoms including delusions, hallucinations, psychotic episodes, confusion, and
paranoia. Because of the uncontrolled nature of many of the studies, it is impossible to
provide a precise estimate of the extent of risk imposed by treatment with Anafranil. As
with tricyclic antidepressants to which it is closely related, Anafranil may precipitate an
acute psychotic episode in patients with unrecognized schizophrenia.
Mania/Hypomania – During premarketing testing of Anafranil in patients with affective
disorder, hypomania or mania was precipitated in several patients. Activation of mania
or hypomania has also been reported in a small proportion of patients with affective
disorder treated with marketed tricyclic antidepressants, which are closely related to
Anafranil.
Hepatic Changes – During premarketing testing, Anafranil was occasionally associated
with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%,
respectively) of potential clinical importance (i.e., values greater than 3 times the upper
limit of normal). In the vast majority of instances, these enzyme increases were not
associated with other clinical findings suggestive of hepatic injury; moreover, none were
jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in
foreign postmarketing experience. Caution is indicated in treating patients with known
liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such
patients.
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Hematologic Changes – Although no instances of severe hematologic toxicity were
seen in the premarketing experience with Anafranil, there have been postmarketing
reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in
association with Anafranil use. As is the case with tricyclic antidepressants to which
Anafranil is closely related, leukocyte and differential blood counts should be obtained in
patients who develop fever and sore throat during treatment with Anafranil.
Central Nervous System – More than 30 cases of hyperthermia have been recorded
by nondomestic postmarketing surveillance systems. Most cases occurred when
Anafranil was used in combination with other drugs. When Anafranil and a neuroleptic
were used concomitantly, the cases were sometimes considered to be examples of a
neuroleptic malignant syndrome.
Sexual Dysfunction – The rate of sexual dysfunction in male patients with OCD who
were treated with Anafranil in the premarketing experience was markedly increased
compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20%
experienced impotence, compared with 2.0% and 2.6%, respectively, in the placebo
group). Approximately 85% of males with sexual dysfunction chose to continue
treatment.
Weight Changes – In controlled studies of OCD, weight gain was reported in 18% of
patients receiving Anafranil, compared with 1% of patients receiving placebo. In these
studies, 28% of patients receiving Anafranil had a weight gain of at least 7% of their
initial body weight, compared with 4% of patients receiving placebo. Several patients
had weight gains in excess of 25% of their initial body weight. Conversely, 5% of
patients receiving Anafranil and 1% receiving placebo had weight losses of at least 7%
of their initial body weight.
Electroconvulsive Therapy – As with closely related tricyclic antidepressants,
concurrent administration of Anafranil with electroconvulsive therapy may increase the
risks; such treatment should be limited to those patients for whom it is essential, since
there is limited clinical experience.
Surgery – Prior to elective surgery with general anesthetics, therapy with Anafranil
should be discontinued for as long as is clinically feasible, and the anesthetist should be
advised.
Use in Concomitant Illness – As with closely related tricyclic antidepressants,
Anafranil should be used with caution in the following:
(1) Hyperthyroid patients or patients receiving thyroid medication, because of the
possibility of cardiac toxicity;
(2) Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or
urinary retention, because of the anticholinergic properties of the drug;
(3) Patients with tumors of the adrenal medulla (e.g., pheochromocytoma,
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neuroblastoma) in whom the drug may provoke hypertensive crises;
(4) Patients with significantly impaired renal function.
Withdrawal Symptoms – A variety of withdrawal symptoms have been reported in
association with abrupt discontinuation of Anafranil, including dizziness, nausea,
vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In
addition, such patients may experience a worsening of psychiatric status. While the
withdrawal effects of Anafranil have not been systematically evaluated in controlled
trials, they are well known with closely related tricyclic antidepressants, and it is
recommended that the dosage be tapered gradually and the patient monitored
carefully during discontinuation (see DRUG ABUSE AND DEPENDENCE).
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with clomipramine
hydrochloride and should counsel them in its appropriate use. A patient Medication
Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness,
and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. The
prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking clomipramine hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s prescriber
or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
Physicians are advised to discuss the following issues with patients for whom they
prescribe Anafranil:
(1) The risk of seizure (see WARNINGS);
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(2) The relatively high incidence of sexual dysfunction among males (see Sexual
Dysfunction);
(3) Since Anafranil may impair the mental and/or physical abilities required for the
performance of complex tasks, and since Anafranil is associated with a risk of
seizures, patients should be cautioned about the performance of complex and
hazardous tasks (see WARNINGS);
(4) Patients should be cautioned about using alcohol, barbiturates, or other CNS
depressants concurrently, since Anafranil may exaggerate their response to these
drugs;
(5) Patients should notify their physician if they become pregnant or intend to become
pregnant during therapy;
(6) Patients should notify their physician if they are breast-feeding.
Patients should be advised that taking Anafranil can cause mild pupillary dilation, which
in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre
existing glaucoma is almost always open-angle glaucoma because angle-closure
glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle
glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be
examined to determine whether they are susceptible to angle closure, and have a
prophylactic procedure (e.g., iridectomy), if they are susceptible.
Drug Interactions
The risks of using Anafranil in combination with other drugs have not been
systematically evaluated. Given the primary CNS effects of Anafranil, caution is advised
in using it concomitantly with other CNS-active drugs (see Information for Patients).
Anafranil should not be used with MAO inhibitors (see CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when Anafranil is
administered with anticholinergic or sympathomimetic drugs.
Several tricyclic antidepressants have been reported to block the pharmacologic effects
of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with
CMI because of its structural similarity to other tricyclic antidepressants.
The plasma concentration of CMI has been reported to be increased by the concomitant
administration of haloperidol; plasma levels of several closely related tricyclic
antidepressants have been reported to be increased by the concomitant administration
of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and
decreased by the concomitant administration of hepatic enzyme inducers (e.g.,
barbiturates, phenytoin), and such an effect may be anticipated with CMI as well.
Administration of CMI has been reported to increase the plasma levels of phenobarbital,
if given concomitantly (see CLINICAL PHARMACOLOGY, Interactions).
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Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the
Caucasian population (about 7% to 10% of Caucasians are so-called “poor
metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or quite
large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the
activity of this isozyme and make normal metabolizers resemble poor metabolizers. An
individual who is stable on a given dose of TCA may become abruptly toxic when given
one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome
P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine)
and many that are substrates for P450 2D6 (many other antidepressants,
phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all
the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline,
paroxetine, and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition.
Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA
metabolism. The extent to which SSRI-TCA interactions may pose clinical problems will
depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.
Nevertheless, caution is indicated in the co-administration of TCAs with any of the
SSRIs and also in switching from one class to the other. Of particular importance,
sufficient time must elapse before initiating TCA treatment in a patient being withdrawn
from fluoxetine, given the long half-life of the parent and active metabolite (at least
5 weeks may be necessary). Concomitant use of agents in the tricyclic antidepressant
class (which includes Anafranil) with drugs that can inhibit cytochrome P450 2D6 may
require lower doses than usually prescribed for either the tricyclic antidepressant agent
or the other drug. Furthermore, whenever one of these drugs is withdrawn from co
therapy, an increased dose of tricyclic antidepressant agent may be required. It is
desirable to monitor TCA plasma levels whenever an agent of the tricyclic
antidepressant class including Anafranil is going to be co-administered with another
drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).
Because Anafranil is highly bound to serum protein, the administration of Anafranil to
patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may
cause an increase in plasma concentrations of these drugs, potentially resulting in
adverse effects. Conversely, adverse effects may result from displacement of protein-
bound Anafranil by other highly bound drugs (see CLINICAL PHARMACOLOGY,
Distribution).
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
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Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found in two 2-year bioassays in rats at doses up to
100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose
(MRHD) on a mg/kg and mg/m2 basis, respectively, or in a 2-year bioassay in mice at
doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m2
basis, respectively.
In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg,
which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m2 basis,
respectively.
Pregnancy Category C
No teratogenic effects were observed in studies performed in rats and mice at doses up
to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD)
on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m2 basis.
Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats
given 50 and 100 mg/kg and of treated mice given 100 mg/kg.
There are no adequate or well-controlled studies in pregnant women. Withdrawal
symptoms, including jitteriness, tremor, and seizures, have been reported in neonates
whose mothers had taken Anafranil until delivery. Anafranil should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Anafranil has been found in human milk. Because of the potential for adverse reactions,
a decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in the pediatric population other than pediatric patients with
OCD have not been established (see BOX WARNING and WARNINGS, Clinical
Worsening and Suicide Risk). Anyone considering the use of Anafranil in a child or
adolescent must balance the potential risks with the clinical need.
In a controlled clinical trial in children and adolescents (10 to 17 years of age),
46 outpatients received Anafranil for up to 8 weeks. In addition, 150 adolescent patients
have received Anafranil in open-label protocols for periods of several months to several
years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were
14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE
REACTIONS) is similar to that observed in adults.
The risks, if any, that may be associated with Anafranil’s extended use in children and
adolescents with OCD have not been systematically assessed. The evidence
supporting the conclusion that Anafranil is safe for use in children and adolescents is
derived from relatively short term clinical studies and from extrapolation of experience
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gained with adult patients. In particular, there are no studies that directly evaluate the
effects of long term Anafranil use on the growth, development, and maturation of
children and adolescents. Although there is no evidence to suggest that Anafranil
adversely affects growth, development or maturation, the absence of such findings is
not adequate to rule out a potential for such effects in chronic use.
The safety and effectiveness in pediatric patients below the age of 10 have not been
established. Therefore, specific recommendations cannot be made for the use of
Anafranil in pediatric patients under the age of 10.
Geriatric Use
Clinical studies of Anafranil did not include sufficient numbers of subjects age 65 and
over to determine whether they respond differently from younger subjects;
152 patients at least 60 years of age participating in various U.S. clinical trials
received Anafranil for periods of several months to several years. No unusual age-
related adverse events were identified in this population. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function and of concomitant disease or other drug
therapy.
ADVERSE REACTIONS
Commonly Observed
The most commonly observed adverse events associated with the use of Anafranil and
not seen at an equivalent incidence among placebo-treated patients were
gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and
anorexia; nervous system complaints, including somnolence, tremor, dizziness,
nervousness, and myoclonus; genitourinary complaints, including changed libido,
ejaculatory failure, impotence, and micturition disorder; and other miscellaneous
complaints, including fatigue, sweating, increased appetite, weight gain, and visual
changes.
Leading to Discontinuation of Treatment
Approximately 20% of 3616 patients who received Anafranil in U.S. premarketing
clinical trials discontinued treatment because of an adverse event. Approximately one-
half of the patients who discontinued (9% of the total) had multiple complaints, none of
which could be classified as primary. Where a primary reason for discontinuation could
be identified, most patients discontinued because of nervous system complaints (5.4%),
primarily somnolence. The second-most-frequent reason for discontinuation was
digestive system complaints (1.3%), primarily vomiting and nausea.
There was no apparent relationship between the adverse events and elevated plasma
drug concentrations.
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Incidence in Controlled Clinical Trials
The following table enumerates adverse events that occurred at an incidence of 1% or
greater among patients with OCD who received Anafranil in adult or pediatric placebo-
controlled clinical trials. The frequencies were obtained from pooled data of clinical trials
involving either adults receiving Anafranil (N=322) or placebo (N=319) or children
treated with Anafranil (N=46) or placebo (N=44). The prescriber should be aware that
these figures cannot be used to predict the incidence of side effects in the course of
usual medical practice, in which patient characteristics and other factors differ from
those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, provide the physician
with a basis for estimating the relative contribution of drug and nondrug factors to the
incidence of side effects in the populations studied.
Incidence of Treatment-Emergent Adverse Experience
in Placebo-Controlled Clinical Trials
(Percentage of Patients Reporting Event)
Adults
Children and
Adolescents
Body System/
Adverse Event*
Anafranil
(N=322)
Placebo
(N=319)
Anafranil
(N=46)
Placebo
(N=44)
Nervous System
Somnolence
54
16
46
11
Tremor
54
2
33
2
Dizziness
54
14
41
14
Headache
52
41
28
34
Insomnia
25
15
11
7
Libido change
21
3
-
-
Nervousness
18
2
4
2
Myoclonus
13
-
2
-
Increased appetite
11
2
-
2
Paresthesia
9
3
2
2
Memory impairment
9
1
7
2
Anxiety
9
4
2
-
Twitching
7
1
4
5
Impaired concentration
5
2
-
-
Depression
5
1
-
-
Hypertonia
4
1
2
-
Sleep disorder
4
-
9
5
Psychosomatic disorder
3
-
-
-
Yawning
3
-
-
-
Confusion
3
-
2
-
Speech disorder
3
-
-
-
Abnormal dreaming
3
-
-
2
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Agitation
3
-
-
-
Migraine
3
-
-
-
Depersonalization
2
-
2
-
Irritability
2
2
2
-
Emotional lability
2
-
-
2
Panic reaction
1
-
2
-
Aggressive reaction
-
-
2
-
Paresis
-
-
2
-
Skin and Appendages
Increased sweating
29
3
9
-
Rash
8
1
4
2
Pruritus
6
-
2
2
Dermatitis
2
-
-
2
Acne
2
2
-
5
Dry skin
2
-
-
5
Urticaria
1
-
-
-
Abnormal skin odor
-
-
2
-
Digestive System
Dry mouth
84
17
63
16
Constipation
47
11
22
9
Nausea
33
14
9
11
Dyspepsia
22
10
13
2
Diarrhea
13
9
7
5
Anorexia
12
-
22
2
Abdominal pain
11
9
13
16
Vomiting
7
2
7
-
Flatulence
6
3
-
2
Tooth disorder
5
-
-
-
Gastrointestinal disorder
2
-
-
2
Dysphagia
2
-
-
-
Esophagitis
1
-
-
-
Eructation
-
-
2
2
Ulcerative stomatitis
-
-
2
-
Body as a Whole
Fatigue
39
18
35
9
Weight increase
18
1
2
-
Flushing
8
-
7
-
Hot flushes
5
-
2
-
Chest pain
4
4
7
-
Fever
4
-
2
7
Allergy
3
3
7
5
Pain
3
2
4
2
Local edema
2
4
-
-
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Chills
2
1
-
-
Weight decrease
-
-
7
-
Otitis media
-
-
4
5
Asthenia
-
-
2
-
Halitosis
-
-
2
-
Cardiovascular System
Postural hypotension
6
-
4
-
Palpitation
4
2
4
-
Tachycardia
4
-
2
-
Syncope
-
-
2
-
Respiratory System
Pharyngitis
14
9
-
5
Rhinitis
12
10
7
9
Sinusitis
6
4
2
5
Coughing
6
6
4
5
Bronchospasm
2
-
7
2
Epistaxis
2
-
-
2
Dyspnea
-
-
2
-
Laryngitis
-
1
2
-
Urogenital System
Male and Female Patients Combined
Micturition disorder
14
2
4
2
Urinary tract infection
6
1
-
-
Micturition frequency
5
3
-
-
Urinary retention
2
-
7
-
Dysuria
2
2
-
-
Cystitis
2
-
-
-
Female Patients Only
(N=182)
(N=167)
(N=10)
(N=21)
Dysmenorrhea
12
14
10
10
Lactation (nonpuerperal)
4
-
-
-
Menstrual disorder
4
2
-
-
Vaginitis
2
-
-
-
Leukorrhea
2
-
-
-
Breast enlargement
2
-
-
-
Breast pain
1
-
-
-
Amenorrhea
1
-
-
-
Male Patients Only
(N=140)
(N=152)
(N=36)
(N=23)
Ejaculation failure
42
2
6
-
Impotence
20
3
-
-
Special Senses
Abnormal vision
18
4
7
2
Taste perversion
8
-
4
-
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Tinnitus
6
-
4
-
Abnormal lacrimation
3
2
-
-
Mydriasis
2
-
-
-
Conjunctivitis
1
-
-
-
Anisocoria
-
-
2
-
Blepharospasm
-
-
2
-
Ocular allergy
-
-
2
-
Vestibular disorder
-
-
2
2
Musculoskeletal
Myalgia
13
9
-
-
Back pain
6
6
-
-
Arthralgia
3
5
-
-
Muscle weakness
1
-
2
-
Hemic and Lymphatic
Purpura
3
-
-
-
Anemia
-
-
2
2
Metabolic and
Nutritional
Thirst
2
2
-
2
*Events reported by at least 1% of Anafranil patients are included.
Other Events Observed During the Premarketing Evaluation of Anafranil
During clinical testing in the U.S., multiple doses of Anafranil were administered to
approximately 3600 subjects. Untoward events associated with this exposure were
recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion of
individuals experiencing adverse events without first grouping similar types of untoward
events into a smaller number of standardized event categories.
In the tabulations that follow, a modified World Health Organization dictionary of
terminology has been used to classify reported adverse events. The frequencies
presented, therefore, represent the proportion of the 3525 individuals exposed to
Anafranil who experienced an event of the type cited on at least one occasion while
receiving Anafranil. All events are included except those already listed in the previous
table, those reported in terms so general as to be uninformative, and those in which an
association with the drug was remote. It is important to emphasize that although the
events reported occurred during treatment with Anafranil, they were not necessarily
caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are those
occurring on one or more occasions in at least 1/100 patients; infrequent adverse
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events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring
in less than 1/1000 patients.
Body as a Whole – Infrequent - general edema, increased susceptibility to infection,
malaise. Rare - dependent edema, withdrawal syndrome.
Cardiovascular System – Infrequent - abnormal ECG, arrhythmia, bradycardia,
cardiac arrest, extrasystoles, pallor. Rare - aneurysm, atrial flutter, bundle branch block,
cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial
ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.
Digestive System – Infrequent - abnormal hepatic function, blood in stool, colitis,
duodenitis, gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis,
hemorrhoids, hepatitis, increased saliva, irritable bowel syndrome, peptic ulcer, rectal
hemorrhage, tongue ulceration, tooth caries. Rare - cheilitis, chronic enteritis, discolored
feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal
edema, paralytic ileus, salivary gland enlargement.
Endocrine System – Infrequent - hypothyroidism. Rare - goiter, gynecomastia,
hyperthyroidism.
Hemic and Lymphatic System – Infrequent - lymphadenopathy. Rare - leukemoid
reaction, lymphoma-like disorder, marrow depression.
Metabolic and Nutritional Disorder – Infrequent - dehydration, diabetes mellitus, gout,
hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia. Rare -
fat
intolerance, glycosuria.
Musculoskeletal System – Infrequent - arthrosis. Rare - dystonia, exostosis, lupus
erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.
Nervous System – Frequent - abnormal thinking, vertigo. Infrequent - abnormal
coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions,
delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria, extrapyramidal
disorder, hallucinations, hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia,
leg cramps, manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory
disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt, teeth-
grinding. Rare - anticholinergic syndrome, aphasia, apraxia, catalepsy, cholinergic
syndrome,
choreoathetosis,
generalized
spasm,
hemiparesis,
hyperesthesia,
hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism,
neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic
reaction, stupor, suicide.
Respiratory System – Infrequent - bronchitis, hyperventilation, increased sputum,
pneumonia. Rare - cyanosis, hemoptysis, hypoventilation, laryngismus.
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Skin and Appendages – Infrequent - alopecia, cellulitis, cyst, eczema, erythematous
rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular
rash, skin discoloration. Rare - chloasma, folliculitis, hypertrichosis, piloerection,
seborrhea, skin hypertrophy, skin ulceration.
Special Senses – Infrequent - abnormal accommodation, deafness, diplopia, earache,
eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste
loss. Rare -
blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos,
glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus,
visual field defect.
Urogenital System – Infrequent - endometriosis, epididymitis, hematuria, nocturia,
oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal
pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage.
Rare - albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical
dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal
cyst, uterine inflammation, vulvar disorder.
DRUG ABUSE AND DEPENDENCE
Anafranil has not been systematically studied in animals or humans for its potential for
abuse, tolerance, or physical dependence. While a variety of withdrawal symptoms
have been described in association with Anafranil discontinuation (see PRECAUTIONS,
Withdrawal Symptoms), there is no evidence for drug-seeking behavior, except for a
single report of potential Anafranil abuse by a patient with a history of dependence on
codeine, benzodiazepines, and multiple psychoactive drugs. The patient received
Anafranil for depression and panic attacks and appeared to become dependent after
hospital discharge.
Despite the lack of evidence suggesting an abuse liability for Anafranil in foreign
marketing, it is not possible to predict the extent to which Anafranil might be misused or
abused once marketed in the U.S. Consequently, physicians should carefully evaluate
patients for a history of drug abuse and follow such patients closely.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion
(including alcohol) is common in deliberate tricyclic overdose. As the management is
complex and changing, it is recommended that the physician contact a poison control
center for current information on treatment. Signs and symptoms of toxicity develop
rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as
possible.
Human Experience
In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with
Anafranil either alone or in combination with other drugs. One death involved a patient
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suspected of ingesting a dose of 7000 mg. The second death involved a patient
suspected of ingesting a dose of 5750 mg. The 10 nonfatal cases involved doses of up
to 5000 mg, accompanied by plasma levels of up to 1010 ng/mL. All 10 patients
completely recovered. Among reports from other countries of Anafranil overdose, the
lowest dose associated with a fatality was 750 mg. Based upon postmarketing reports in
the United Kingdom, CMI’s lethality in overdose is considered to be similar to that
reported for closely related tricyclic compounds marketed as antidepressants.
Manifestations
Signs and symptoms vary in severity depending upon factors such as the amount of
drug absorbed, the age of the patient, and the time elapsed since drug ingestion.
Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension,
convulsions, and CNS depression including coma. Changes in the electrocardiogram,
particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.
Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness,
agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, and
athetoid and choreiform movements. Cardiac abnormalities may include tachycardia,
signs of congestive heart failure, and in very rare cases, cardiac arrest. Respiratory
depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and oliguria or anuria
may also be present.
Management
Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway,
establish an intravenous line, and initiate gastric decontamination. A minimum of
6 hours of observation with cardiac monitoring and observation for signs of CNS or
respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks,
and seizures is necessary.
If signs of toxicity occur at any time during this period, extended monitoring is required.
There are case reports of patients succumbing to fatal dysrhythmias late after overdose;
these patients had clinical evidence of significant poisoning prior to death and most
received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels
should not guide management of the patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic overdose
should receive gastrointestinal decontamination. This should include large volume
gastric lavage followed by activated charcoal. If consciousness is impaired, the airway
should be secured prior to lavage. Emesis is contraindicated.
Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the
best indication of the severity of the overdose. Intravenous sodium bicarbonate should
be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is
inadequate, hyperventilation may also be used. Concomitant use of hyperventilation
and sodium bicarbonate should be done with extreme caution, with frequent pH
monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias
unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine,
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bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated
(e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular
instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis,
exchange transfusions, and forced diuresis generally have been reported as ineffective
in tricyclic poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the
potential for abrupt deterioration. Seizures should be controlled with benzodiazepines,
or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).
Physostigmine is not recommended except to treat life-threatening symptoms that have
been unresponsive to other therapies, and then only in consultation with a poison
control center.
Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt
suicide by other means during the recovery phase. Psychiatric referral may be
appropriate.
Pediatric Management – The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact the local
poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION
The treatment regimens described below are based on those used in controlled clinical
trials of Anafranil in 520 adults, and 91 children and adolescents with OCD. During initial
titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal
side effects. The goal of this initial titration phase is to minimize side effects by
permitting tolerance to side effects to develop or allowing the patient time to adapt if
tolerance does not develop.
Because both CMI and its active metabolite, DMI, have long elimination half-lives, the
prescriber should take into consideration the fact that steady-state plasma levels may
not be achieved until 2 to 3 weeks after dosage change (see CLINICAL
PHARMACOLOGY). Therefore, after initial titration, it may be appropriate to wait
2 to 3 weeks between further dosage adjustments.
Initial Treatment/Dose Adjustment (Adults)
Treatment with Anafranil should be initiated at a dosage of 25 mg daily and gradually
increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial
titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal
side effects. Thereafter, the dosage may be increased gradually over the next several
weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be
given once daily at bedtime to minimize daytime sedation.
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Initial Treatment/Dose Adjustment (Children and Adolescents)
As with adults, the starting dose is 25 mg daily and should be gradually increased (also
given in divided doses with meals to reduce gastrointestinal side effects) during the first
2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller.
Thereafter, the dosage may be increased gradually over the next several weeks up to a
daily maximum of 3 mg/kg or 200 mg, whichever is smaller (see PRECAUTIONS,
Pediatric Use). As with adults, after titration, the total daily dose may be given once daily
at bedtime to minimize daytime sedation.
Maintenance/Continuation Treatment (Adults, Children, and Adolescents)
While there are no systematic studies that answer the question of how long to continue
Anafranil, OCD is a chronic condition and it is reasonable to consider continuation for a
responding patient. Although the efficacy of Anafranil after 10 weeks has not been
documented in controlled trials, patients have been continued in therapy under double-
blind conditions for up to 1 year without loss of benefit. However, dosage adjustments
should be made to maintain the patient on the lowest effective dosage, and patients
should be periodically reassessed to determine the need for treatment. During
maintenance, the total daily dose may be given once daily at bedtime.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended
to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat
psychiatric disorders and initiation of therapy with Anafranil. Conversely, at least
14 days should be allowed after stopping Anafranil before starting an MAOI intended to
treat psychiatric disorders (see CONTRAINDICATIONS).
Use of Anafranil With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Anafranil in a patient who is being treated with linezolid or intravenous
methylene blue because there is increased risk of serotonin syndrome. In a patient who
requires more urgent treatment of a psychiatric condition, other interventions, including
hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving Anafranil therapy may require urgent
treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential
benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the
risks of serotonin syndrome in a particular patient, Anafranil should be stopped
promptly, and linezolid or intravenous methylene blue can be administered. The patient
should be monitored for symptoms of serotonin syndrome for two weeks or until
24 hours after the last dose of linezolid or intravenous methylene blue, whichever
comes first. Therapy with Anafranil may be resumed 24 hours after the last dose of
linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral
tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with
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Anafranil is unclear. The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use (see WARNINGS).
HOW SUPPLIED
Anafranil™ (clomipramine hydrochloride) Capsules USP
Capsules 25 mg – ivory body imprinted in black with “M” and melon-yellow cap
imprinted in black with “ANAFRANIL 25 mg”
Bottles of 30................................. NDC 0406-9906-03
Capsules 50 mg – ivory body imprinted in black with “M” and aqua blue cap imprinted in
black with “ANAFRANIL 50 mg”
Bottles of 30................................. NDC 0406-9907-03
Capsules 75 mg – ivory body imprinted in black with “M” and yellow cap imprinted in
black with “ANAFRANIL 75 mg”
Bottles of 30................................. NDC 0406-9908-03
Storage – Store at 20º to 25ºC (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in well-closed containers with a child-resistant closure. Protect from moisture.
ANIMAL TOXICOLOGY
Phospholipidosis and testicular changes, commonly associated with tricyclic
compounds, have been observed with Anafranil. In chronic rat studies, changes related
to Anafranil consisted of systemic phospholipidosis, alterations in the testes (atrophy,
mineralization) and secondary changes in other tissues. In addition cardiac thrombosis
and dermatitis/keratitis were observed in rats treated for 2 years at doses which were
24 and 10 times the maximum recommended human daily dose (MRHD), respectively,
on a mg/kg basis, and 4 and 1.5 times the MRHD, respectively, on a mg/m2 basis.
Anafranil and M are trademarks of Mallinckrodt LLC.
Manufactured by
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
for Mallinckrodt Inc.
Hazelwood, MO 63042 USA
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Medication Guide - Anafranil™
(clomipramine hydrochloride) Capsules USP
Antidepressant Medicines, Depression and other Serious Mental Illnesses,
and Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s
antidepressant medicine. This Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your, or your family
member’s, healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant
medicines, depression and other serious mental illnesses, and suicidal thoughts
or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes
of suicidal thoughts and actions. Some people may have a particularly high
risk of having suicidal thoughts or actions. These include people who have (or
have a family history of) bipolar illness (also called manic-depressive illness) or
suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself
or a family member?
• Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of
the following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• attempts to commit suicide
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• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood
Visual problems
• eye pain
• changes in vision
• swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye
examination to see if you are at risk and receive preventative treatment if you are.
Who should not take Anafranil?
Do not take Anafranil if you:
• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
o Do not take an MAOI within 2 weeks of stopping Anafranil unless directed to
do so by your physician.
o Do not start Anafranil if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your physician.
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other
symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It
is important to discuss all the risks of treating depression and also the risks of not
treating it. Patients and their families or other caregivers should discuss all treatment
choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare
provider about the side effects of the medicine prescribed for you or your family
member.
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• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show
the healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for
use in children. Talk to your child’s healthcare provider for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Anafranil is a trademark of Mallinckrodt LLC.
Manufactured by
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
for Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Rev 05/2014 company logo
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|
custom-source
|
2025-02-12T13:46:17.027595
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019906s038lbl.pdf', 'application_number': 19906, 'submission_type': 'SUPPL ', 'submission_number': 38}
|
11,838
|
Anafranil™
(clomipramine hydrochloride) Capsules USP
(25 mg, 50 mg, and 75 mg)
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of clomipramine hydrochloride or any other
antidepressant in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studies did not show an increase in the risk of
suicidality with antidepressants compared to placebo in adults beyond age 24;
there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately
and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Clomipramine hydrochloride
is not approved for use in pediatric patients except for patients with obsessive
compulsive disorder (OCD) (see WARNINGS, Clinical Worsening and Suicide
Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric
Use).
DESCRIPTION
Anafranil™ (clomipramine hydrochloride) Capsules USP is an antiobsessional drug that
belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic
antidepressants. Anafranil is available as capsules of 25, 50, and 75 mg for oral
administration.
Clomipramine hydrochloride USP is 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro
5H-dibenz[b,f] azepine monohydrochloride, and its structural formula is:
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structural formula
C19H23ClN2 ● HCl
MW = 351.31
Clomipramine hydrochloride USP is a white to off-white crystalline powder. It is freely
soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether
and in hexane.
Inactive Ingredients. D&C Red No. 33 (25 mg capsules only), D&C Yellow No. 10,
FD&C Blue No. 1 (50 mg capsules only), FD&C Yellow No. 6, gelatin, magnesium
stearate, methylparaben, propylparaben, starch (corn), and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Clomipramine (CMI) is presumed to influence obsessive and compulsive behaviors
through its effects on serotonergic neuronal transmission. The actual neurochemical
mechanism is unknown, but CMI’s capacity to inhibit the reuptake of serotonin (5-HT) is
thought to be important.
Pharmacokinetics
Absorption/Bioavailability – CMI from Anafranil capsules is as bioavailable as CMI
from a solution. The bioavailability of CMI from capsules is not significantly affected by
food.
In a dose proportionality study involving multiple CMI doses, steady-state plasma
concentrations (Css) and area-under-plasma-concentration-time curves (AUC) of CMI and
CMI’s major active metabolite, desmethylclomipramine (DMI), were not proportional to dose
over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day,
although Css and AUC are approximately linearly related to dose between 100 to
150 mg/day. The relationship between dose and CMI/DMI concentrations at higher daily
doses has not been systematically assessed, but if there is significant dose dependency at
doses above 150 mg/day, there is the potential for dramatically higher Css and AUC even
for patients dosed within the recommended range. This may pose a potential risk to some
patients (see WARNINGS and PRECAUTIONS, Drug Interactions).
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After a single 50 mg oral dose, maximum plasma concentrations of CMI occur within
2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL).
After multiple daily doses of 150 mg of Anafranil, steady-state maximum plasma
concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for CMI and from
134 ng/mL to 532 ng/mL (mean, 274 ng/mL) for DMI. Additional information from a
rising dose study of doses up to 250 mg suggests that DMI may exhibit nonlinear
pharmacokinetics over the usual dosing range. At a dose of Anafranil 200 mg, subjects
who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours),
after the dose had plasma concentrations of up to 605 ng/mL for CMI, 781 ng/mL for
DMI, and 1386 ng/mL for both.
Distribution – CMI distributes into cerebrospinal fluid (CSF) and brain and into breast
milk. DMI also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein
binding of CMI is approximately 97%, principally to albumin, and is independent of CMI
concentration. The interaction between CMI and other highly protein-bound drugs has
not been fully evaluated, but may be important (see PRECAUTIONS, Drug
Interactions).
Metabolism – CMI is extensively biotransformed to DMI and other metabolites and their
glucuronide conjugates. DMI is pharmacologically active, but its effects on OCD
behaviors are unknown. These metabolites are excreted in urine and feces, following
biliary elimination. After a 25 mg radiolabeled dose of CMI in two subjects, 60% and
51%, respectively, of the dose were recovered in the urine and 32% and 24%,
respectively, in feces. In the same study, the combined urinary recoveries of CMI and
DMI were only about 0.8% to 1.3% of the dose administered. CMI does not induce drug-
metabolizing enzymes, as measured by antipyrine half-life.
Elimination – Evidence that the Css and AUC for CMI and DMI may increase
disproportionately with increasing oral doses suggests that the metabolism of CMI and
DMI may be capacity limited. This fact must be considered in assessing the estimates of
the pharmacokinetic parameters presented below, as these were obtained in individuals
exposed to doses of 150 mg. If the pharmacokinetics of CMI and DMI are nonlinear at
doses above 150 mg, their elimination half-lives may be considerably lengthened at
doses near the upper end of the recommended dosing range (i.e., 200 mg/day to
250 mg/day). Consequently, CMI and DMI may accumulate, and this accumulation may
increase the incidence of any dose- or plasma-concentration-dependent adverse
reactions, in particular seizures (see WARNINGS).
After a 150 mg dose, the half-life of CMI ranges from 19 hours to 37 hours (mean,
32 hr) and that of DMI ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state
levels after multiple dosing are typically reached within 7 to 14 days for CMI. Plasma
concentrations of the metabolite exceed the parent drug on multiple dosing. After
multiple dosing with 150 mg/day, the accumulation factor for CMI is approximately
2.5 and for DMI is 4.6. Importantly, it may take two weeks or longer to achieve this
extent of accumulation at constant dosing because of the relatively long elimination half-
lives of CMI and DMI (see DOSAGE AND ADMINISTRATION). The effects of hepatic
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and renal impairment on the disposition of Anafranil have not been determined.
Interactions – Co-administration of haloperidol with CMI increases plasma
concentrations of CMI. Co-administration of CMI with phenobarbital increases plasma
concentrations of phenobarbital (see PRECAUTIONS, Drug Interactions). Younger
subjects (18 to 40 years of age) tolerated CMI better and had significantly lower steady-
state plasma concentrations, compared with subjects over 65 years of age. Children
under 15 years of age had significantly lower plasma concentration/dose ratios,
compared with adults. Plasma concentrations of CMI were significantly lower in
smokers than in nonsmokers.
INDICATIONS AND USAGE
Anafranil™ (clomipramine hydrochloride) Capsules USP is indicated for the treatment of
obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD).
The obsessions or compulsions must cause marked distress, be time-consuming, or
significantly interfere with social or occupational functioning, in order to meet the
DSM-III-R (circa 1989) diagnosis of OCD.
Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego
dystonic. Compulsions are repetitive, purposeful, and intentional behaviors performed in
response to an obsession or in a stereotyped fashion, and are recognized by the person as
excessive or unreasonable.
The effectiveness of Anafranil for the treatment of OCD was demonstrated in
multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in
adults and one 8-week study in children and adolescents 10 to 17 years of age. Patients
in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the
Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean
baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale
(NIMH-OC). Patients taking CMI experienced a mean reduction of approximately 10 on
the YBOCS, representing an average improvement on this scale of 35% to 42% among
adults and 37% among children and adolescents. CMI-treated patients experienced a
3.5 unit decrement on the NIMH-OC. Patients on placebo showed no important clinical
response on either scale. The maximum dose was 250 mg/day for most adults and
3 mg/kg/day (up to 200 mg) for all children and adolescents.
The effectiveness of Anafranil for long-term use (i.e., for more than 10 weeks) has not
been systematically evaluated in placebo-controlled trials. The physician who elects to
use Anafranil for extended periods should periodically reevaluate the long-term
usefulness
of
the
drug
for
the
individual
patient
(see
DOSAGE
AND
ADMINISTRATION).
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CONTRAINDICATIONS
Anafranil is contraindicated in patients with a history of hypersensitivity to Anafranil or
other tricyclic antidepressants.
Monoamine Oxidase Inhibitors (MAOIs)
The use of MAOIs intended to treat psychiatric disorders with Anafranil or within
14 days of stopping treatment with Anafranil is contraindicated because of an increased
risk of serotonin syndrome. The use of Anafranil within 14 days of stopping an MAOI
intended to treat psychiatric disorders is also contraindicated (see WARNINGS and
DOSAGE AND ADMINISTRATION).
Starting Anafranil in a patient who is being treated with linezolid or intravenous
methylene blue is also contraindicated because of an increased risk of serotonin
syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).
Myocardial Infarction
Anafranil is contraindicated during the acute recovery period after a myocardial
infarction.
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal ideation and
behavior (suicidality) or unusual changes in behavior, whether or not they are taking
antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening
of depression and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
(ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled
analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of
11 antidepressant drugs in over 77,000 patients. There was considerable variation in
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risk of suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied. There were differences in absolute risk of
suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of
cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Increases Compared to Placebo
<18
18-24
14 additional cases
5 additional cases
Decreases Compared to Placebo
25-64
≥65
1 fewer case
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond
several months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants can delay
the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of a
course of drug therapy, or at times of dose changes, either increases or
decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications, both
psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who
are experiencing emergent suicidality or symptoms that might be precursors to
worsening depression or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms.
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Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report such
symptoms immediately to healthcare providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for clomipramine
hydrochloride should be written for the smallest quantity of capsules consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder – A major depressive episode may be the
initial presentation of bipolar disorder. It is generally believed (though not established in
controlled trials) that treating such an episode with an antidepressant alone may
increase the likelihood of precipitation of a mixed/manic episode in patients at risk for
bipolar disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an antidepressant,
patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that clomipramine hydrochloride is not approved for use in treating bipolar
depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported
with SNRIs and SSRIs, including Anafranil, alone but particularly with concomitant use
of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair
metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g.,
tremor,
rigidity,
myoclonus,
hyperreflexia,
incoordination),
seizures,
and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be
monitored for the emergence of serotonin syndrome.
The concomitant use of Anafranil with MAOIs intended to treat psychiatric disorders is
contraindicated. Anafranil should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene
blue that provided information on the route of administration involved intravenous
administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the
administration of methylene blue by other routes (such as oral tablets or local tissue
injection) or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a patient
taking Anafranil. Anafranil should be discontinued before initiating treatment with the
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MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Anafranil with other serotonergic drugs, including triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort
is clinically warranted, patients should be made aware of a potential increased risk for
serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Anafranil and any concomitant serotonergic agents should be
discontinued immediately if the above events occur and supportive symptomatic
treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including
Anafranil may trigger an angle closure attack in a patient with anatomically narrow
angles who does not have a patent iridectomy.
Seizures
During premarket evaluation, seizure was identified as the most significant risk of
Anafranil use.
The observed cumulative incidence of seizures among patients exposed to Anafranil at
doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at
365 days. The cumulative rates correct the crude rate of 0.7% (25 of 3519 patients) for
the variable duration of exposure in clinical trials.
Although dose appears to be a predictor of seizure, there is a confounding of dose and
duration of exposure, making it difficult to assess independently the effect of either
factor alone. The ability to predict the occurrence of seizures in subjects exposed to
doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI
may be dose-dependent and may vary among subjects given the same dose.
Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in
adults and 3 mg/kg (or 200 mg) in children and adolescents (see DOSAGE AND
ADMINISTRATION).
Caution should be used in administering Anafranil to patients with a history of seizures
or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and
concomitant use with other drugs that lower the seizure threshold.
Rare reports of fatalities in association with seizures have been reported by foreign
postmarketing surveillance, but not in U.S. clinical trials. In some of these cases,
Anafranil had been administered with other epileptogenic agents; in others, the patients
involved had possibly predisposing medical conditions. Thus a causal association
between Anafranil treatment and these fatalities has not been established.
Physicians should discuss with patients the risk of taking Anafranil while engaging in
activities in which sudden loss of consciousness could result in serious injury to the
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patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.
PRECAUTIONS
General
Suicide – Since depression is a commonly associated feature of OCD, the risk of
suicide must be considered. Prescriptions for Anafranil should be written for the
smallest quantity of capsules consistent with good patient management, in order to
reduce the risk of overdose.
Cardiovascular Effects – Modest orthostatic decreases in blood pressure and modest
tachycardia were each seen in approximately 20% of patients taking Anafranil in clinical
trials; but patients were frequently asymptomatic. Among approximately 1400 patients
treated with CMI in the premarketing experience who had ECGs, 1.5% developed
abnormalities during treatment, compared with 3.1% of patients receiving active control
drugs and 0.7% of patients receiving placebo. The most common ECG changes were
PVCs, ST-T wave changes, and intraventricular conduction abnormalities. These
changes were rarely associated with significant clinical symptoms. Nevertheless,
caution is necessary in treating patients with known cardiovascular disease, and
gradual dose titration is recommended.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena – Patients treated
with Anafranil have been reported to show a variety of neuropsychiatric signs and
symptoms including delusions, hallucinations, psychotic episodes, confusion, and
paranoia. Because of the uncontrolled nature of many of the studies, it is impossible to
provide a precise estimate of the extent of risk imposed by treatment with Anafranil. As
with tricyclic antidepressants to which it is closely related, Anafranil may precipitate an
acute psychotic episode in patients with unrecognized schizophrenia.
Mania/Hypomania – During premarketing testing of Anafranil in patients with affective
disorder, hypomania or mania was precipitated in several patients. Activation of mania
or hypomania has also been reported in a small proportion of patients with affective
disorder treated with marketed tricyclic antidepressants, which are closely related to
Anafranil.
Hepatic Changes – During premarketing testing, Anafranil was occasionally associated
with elevations in SGOT and SGPT (pooled incidence of approximately 1% and 3%,
respectively) of potential clinical importance (i.e., values greater than 3 times the upper
limit of normal). In the vast majority of instances, these enzyme increases were not
associated with other clinical findings suggestive of hepatic injury; moreover, none were
jaundiced. Rare reports of more severe liver injury, some fatal, have been recorded in
foreign postmarketing experience. Caution is indicated in treating patients with known
liver disease, and periodic monitoring of hepatic enzyme levels is recommended in such
patients.
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Hematologic Changes – Although no instances of severe hematologic toxicity were
seen in the premarketing experience with Anafranil, there have been postmarketing
reports of leukopenia, agranulocytosis, thrombocytopenia, anemia, and pancytopenia in
association with Anafranil use. As is the case with tricyclic antidepressants to which
Anafranil is closely related, leukocyte and differential blood counts should be obtained in
patients who develop fever and sore throat during treatment with Anafranil.
Central Nervous System – More than 30 cases of hyperthermia have been recorded
by nondomestic postmarketing surveillance systems. Most cases occurred when
Anafranil was used in combination with other drugs. When Anafranil and a neuroleptic
were used concomitantly, the cases were sometimes considered to be examples of a
neuroleptic malignant syndrome.
Sexual Dysfunction – The rate of sexual dysfunction in male patients with OCD who
were treated with Anafranil in the premarketing experience was markedly increased
compared with placebo controls (i.e., 42% experienced ejaculatory failure and 20%
experienced impotence, compared with 2.0% and 2.6%, respectively, in the placebo
group). Approximately 85% of males with sexual dysfunction chose to continue
treatment.
Weight Changes – In controlled studies of OCD, weight gain was reported in 18% of
patients receiving Anafranil, compared with 1% of patients receiving placebo. In these
studies, 28% of patients receiving Anafranil had a weight gain of at least 7% of their
initial body weight, compared with 4% of patients receiving placebo. Several patients
had weight gains in excess of 25% of their initial body weight. Conversely, 5% of
patients receiving Anafranil and 1% receiving placebo had weight losses of at least 7%
of their initial body weight.
Electroconvulsive Therapy – As with closely related tricyclic antidepressants,
concurrent administration of Anafranil with electroconvulsive therapy may increase the
risks; such treatment should be limited to those patients for whom it is essential, since
there is limited clinical experience.
Surgery – Prior to elective surgery with general anesthetics, therapy with Anafranil
should be discontinued for as long as is clinically feasible, and the anesthetist should be
advised.
Use in Concomitant Illness – As with closely related tricyclic antidepressants,
Anafranil should be used with caution in the following:
(1) Hyperthyroid patients or patients receiving thyroid medication, because of the
possibility of cardiac toxicity;
(2) Patients with increased intraocular pressure, a history of narrow-angle glaucoma, or
urinary retention, because of the anticholinergic properties of the drug;
(3) Patients with tumors of the adrenal medulla (e.g., pheochromocytoma,
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neuroblastoma) in whom the drug may provoke hypertensive crises;
(4) Patients with significantly impaired renal function.
Withdrawal Symptoms – A variety of withdrawal symptoms have been reported in
association with abrupt discontinuation of Anafranil, including dizziness, nausea,
vomiting, headache, malaise, sleep disturbance, hyperthermia, and irritability. In
addition, such patients may experience a worsening of psychiatric status. While the
withdrawal effects of Anafranil have not been systematically evaluated in controlled
trials, they are well known with closely related tricyclic antidepressants, and it is
recommended that the dosage be tapered gradually and the patient monitored
carefully during discontinuation (see DRUG ABUSE AND DEPENDENCE).
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with clomipramine
hydrochloride and should counsel them in its appropriate use. A patient Medication
Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness,
and Suicidal Thoughts or Actions” is available for clomipramine hydrochloride. The
prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking clomipramine hydrochloride.
Clinical Worsening and Suicide Risk – Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and
when the dose is adjusted up or down. Families and caregivers of patients should be
advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient’s prescriber
or health professional, especially if they are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very close
monitoring and possibly changes in the medication.
Physicians are advised to discuss the following issues with patients for whom they
prescribe Anafranil:
(1) The risk of seizure (see WARNINGS);
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(2) The relatively high incidence of sexual dysfunction among males (see Sexual
Dysfunction);
(3) Since Anafranil may impair the mental and/or physical abilities required for the
performance of complex tasks, and since Anafranil is associated with a risk of
seizures, patients should be cautioned about the performance of complex and
hazardous tasks (see WARNINGS);
(4) Patients should be cautioned about using alcohol, barbiturates, or other CNS
depressants concurrently, since Anafranil may exaggerate their response to these
drugs;
(5) Patients should notify their physician if they become pregnant or intend to become
pregnant during therapy;
(6) Patients should notify their physician if they are breast-feeding.
Patients should be advised that taking Anafranil can cause mild pupillary dilation, which
in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre
existing glaucoma is almost always open-angle glaucoma because angle-closure
glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle
glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be
examined to determine whether they are susceptible to angle closure, and have a
prophylactic procedure (e.g., iridectomy), if they are susceptible.
Drug Interactions
The risks of using Anafranil in combination with other drugs have not been
systematically evaluated. Given the primary CNS effects of Anafranil, caution is advised
in using it concomitantly with other CNS-active drugs (see Information for Patients).
Anafranil should not be used with MAO inhibitors (see CONTRAINDICATIONS).
Close supervision and careful adjustment of dosage are required when Anafranil is
administered with anticholinergic or sympathomimetic drugs.
Several tricyclic antidepressants have been reported to block the pharmacologic effects
of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with
CMI because of its structural similarity to other tricyclic antidepressants.
The plasma concentration of CMI has been reported to be increased by the concomitant
administration of haloperidol; plasma levels of several closely related tricyclic
antidepressants have been reported to be increased by the concomitant administration
of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and
decreased by the concomitant administration of hepatic enzyme inducers (e.g.,
barbiturates, phenytoin), and such an effect may be anticipated with CMI as well.
Administration of CMI has been reported to increase the plasma levels of phenobarbital,
if given concomitantly (see CLINICAL PHARMACOLOGY, Interactions).
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Drugs Metabolized by P450 2D6 – The biochemical activity of the drug metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the
Caucasian population (about 7% to 10% of Caucasians are so-called “poor
metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of tricyclic
antidepressants (TCAs) when given usual doses. Depending on the fraction of drug
metabolized by P450 2D6, the increase in plasma concentration may be small, or quite
large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the
activity of this isozyme and make normal metabolizers resemble poor metabolizers. An
individual who is stable on a given dose of TCA may become abruptly toxic when given
one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome
P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine)
and many that are substrates for P450 2D6 (many other antidepressants,
phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all
the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline,
paroxetine, and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition.
Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA
metabolism. The extent to which SSRI-TCA interactions may pose clinical problems will
depend on the degree of inhibition and the pharmacokinetics of the SSRI involved.
Nevertheless, caution is indicated in the co-administration of TCAs with any of the
SSRIs and also in switching from one class to the other. Of particular importance,
sufficient time must elapse before initiating TCA treatment in a patient being withdrawn
from fluoxetine, given the long half-life of the parent and active metabolite (at least
5 weeks may be necessary). Concomitant use of agents in the tricyclic antidepressant
class (which includes Anafranil) with drugs that can inhibit cytochrome P450 2D6 may
require lower doses than usually prescribed for either the tricyclic antidepressant agent
or the other drug. Furthermore, whenever one of these drugs is withdrawn from co
therapy, an increased dose of tricyclic antidepressant agent may be required. It is
desirable to monitor TCA plasma levels whenever an agent of the tricyclic
antidepressant class including Anafranil is going to be co-administered with another
drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).
Because Anafranil is highly bound to serum protein, the administration of Anafranil to
patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may
cause an increase in plasma concentrations of these drugs, potentially resulting in
adverse effects. Conversely, adverse effects may result from displacement of protein-
bound Anafranil by other highly bound drugs (see CLINICAL PHARMACOLOGY,
Distribution).
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
Serotonergic Drugs
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.)
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Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found in two 2-year bioassays in rats at doses up to
100 mg/kg, which is 24 and 4 times the maximum recommended human daily dose
(MRHD) on a mg/kg and mg/m2 basis, respectively, or in a 2-year bioassay in mice at
doses up to 80 mg/kg, which is 20 and 1.5 times the MRHD on a mg/kg and mg/m2
basis, respectively.
In reproduction studies, no effects on fertility were found in rats given up to 24 mg/kg,
which is 6 times, and approximately equal to, the MRHD on a mg/kg and mg/m2 basis,
respectively.
Pregnancy Category C
No teratogenic effects were observed in studies performed in rats and mice at doses up
to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD)
on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m2 basis.
Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats
given 50 and 100 mg/kg and of treated mice given 100 mg/kg.
There are no adequate or well-controlled studies in pregnant women. Withdrawal
symptoms, including jitteriness, tremor, and seizures, have been reported in neonates
whose mothers had taken Anafranil until delivery. Anafranil should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Anafranil has been found in human milk. Because of the potential for adverse reactions,
a decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in the pediatric population other than pediatric patients with
OCD have not been established (see BOX WARNING and WARNINGS, Clinical
Worsening and Suicide Risk). Anyone considering the use of Anafranil in a child or
adolescent must balance the potential risks with the clinical need.
In a controlled clinical trial in children and adolescents (10 to 17 years of age),
46 outpatients received Anafranil for up to 8 weeks. In addition, 150 adolescent patients
have received Anafranil in open-label protocols for periods of several months to several
years. Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were
14 to 17 years of age. The adverse reaction profile in this age group (see ADVERSE
REACTIONS) is similar to that observed in adults.
The risks, if any, that may be associated with Anafranil’s extended use in children and
adolescents with OCD have not been systematically assessed. The evidence
supporting the conclusion that Anafranil is safe for use in children and adolescents is
derived from relatively short term clinical studies and from extrapolation of experience
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gained with adult patients. In particular, there are no studies that directly evaluate the
effects of long term Anafranil use on the growth, development, and maturation of
children and adolescents. Although there is no evidence to suggest that Anafranil
adversely affects growth, development or maturation, the absence of such findings is
not adequate to rule out a potential for such effects in chronic use.
The safety and effectiveness in pediatric patients below the age of 10 have not been
established. Therefore, specific recommendations cannot be made for the use of
Anafranil in pediatric patients under the age of 10.
Geriatric Use
Clinical studies of Anafranil did not include sufficient numbers of subjects age 65 and
over to determine whether they respond differently from younger subjects;
152 patients at least 60 years of age participating in various U.S. clinical trials
received Anafranil for periods of several months to several years. No unusual age-
related adverse events were identified in this population. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function and of concomitant disease or other drug
therapy.
ADVERSE REACTIONS
Commonly Observed
The most commonly observed adverse events associated with the use of Anafranil and
not seen at an equivalent incidence among placebo-treated patients were
gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and
anorexia; nervous system complaints, including somnolence, tremor, dizziness,
nervousness, and myoclonus; genitourinary complaints, including changed libido,
ejaculatory failure, impotence, and micturition disorder; and other miscellaneous
complaints, including fatigue, sweating, increased appetite, weight gain, and visual
changes.
Leading to Discontinuation of Treatment
Approximately 20% of 3616 patients who received Anafranil in U.S. premarketing
clinical trials discontinued treatment because of an adverse event. Approximately one-
half of the patients who discontinued (9% of the total) had multiple complaints, none of
which could be classified as primary. Where a primary reason for discontinuation could
be identified, most patients discontinued because of nervous system complaints (5.4%),
primarily somnolence. The second-most-frequent reason for discontinuation was
digestive system complaints (1.3%), primarily vomiting and nausea.
There was no apparent relationship between the adverse events and elevated plasma
drug concentrations.
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Incidence in Controlled Clinical Trials
The following table enumerates adverse events that occurred at an incidence of 1% or
greater among patients with OCD who received Anafranil in adult or pediatric placebo-
controlled clinical trials. The frequencies were obtained from pooled data of clinical trials
involving either adults receiving Anafranil (N=322) or placebo (N=319) or children
treated with Anafranil (N=46) or placebo (N=44). The prescriber should be aware that
these figures cannot be used to predict the incidence of side effects in the course of
usual medical practice, in which patient characteristics and other factors differ from
those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, provide the physician
with a basis for estimating the relative contribution of drug and nondrug factors to the
incidence of side effects in the populations studied.
Incidence of Treatment-Emergent Adverse Experience
in Placebo-Controlled Clinical Trials
(Percentage of Patients Reporting Event)
Adults
Children and
Adolescents
Body System/
Adverse Event*
Anafranil
(N=322)
Placebo
(N=319)
Anafranil
(N=46)
Placebo
(N=44)
Nervous System
Somnolence
54
16
46
11
Tremor
54
2
33
2
Dizziness
54
14
41
14
Headache
52
41
28
34
Insomnia
25
15
11
7
Libido change
21
3
-
-
Nervousness
18
2
4
2
Myoclonus
13
-
2
-
Increased appetite
11
2
-
2
Paresthesia
9
3
2
2
Memory impairment
9
1
7
2
Anxiety
9
4
2
-
Twitching
7
1
4
5
Impaired concentration
5
2
-
-
Depression
5
1
-
-
Hypertonia
4
1
2
-
Sleep disorder
4
-
9
5
Psychosomatic disorder
3
-
-
-
Yawning
3
-
-
-
Confusion
3
-
2
-
Speech disorder
3
-
-
-
Abnormal dreaming
3
-
-
2
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Agitation
3
-
-
-
Migraine
3
-
-
-
Depersonalization
2
-
2
-
Irritability
2
2
2
-
Emotional lability
2
-
-
2
Panic reaction
1
-
2
-
Aggressive reaction
-
-
2
-
Paresis
-
-
2
-
Skin and Appendages
Increased sweating
29
3
9
-
Rash
8
1
4
2
Pruritus
6
-
2
2
Dermatitis
2
-
-
2
Acne
2
2
-
5
Dry skin
2
-
-
5
Urticaria
1
-
-
-
Abnormal skin odor
-
-
2
-
Digestive System
Dry mouth
84
17
63
16
Constipation
47
11
22
9
Nausea
33
14
9
11
Dyspepsia
22
10
13
2
Diarrhea
13
9
7
5
Anorexia
12
-
22
2
Abdominal pain
11
9
13
16
Vomiting
7
2
7
-
Flatulence
6
3
-
2
Tooth disorder
5
-
-
-
Gastrointestinal disorder
2
-
-
2
Dysphagia
2
-
-
-
Esophagitis
1
-
-
-
Eructation
-
-
2
2
Ulcerative stomatitis
-
-
2
-
Body as a Whole
Fatigue
39
18
35
9
Weight increase
18
1
2
-
Flushing
8
-
7
-
Hot flushes
5
-
2
-
Chest pain
4
4
7
-
Fever
4
-
2
7
Allergy
3
3
7
5
Pain
3
2
4
2
Local edema
2
4
-
-
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Chills
2
1
-
-
Weight decrease
-
-
7
-
Otitis media
-
-
4
5
Asthenia
-
-
2
-
Halitosis
-
-
2
-
Cardiovascular System
Postural hypotension
6
-
4
-
Palpitation
4
2
4
-
Tachycardia
4
-
2
-
Syncope
-
-
2
-
Respiratory System
Pharyngitis
14
9
-
5
Rhinitis
12
10
7
9
Sinusitis
6
4
2
5
Coughing
6
6
4
5
Bronchospasm
2
-
7
2
Epistaxis
2
-
-
2
Dyspnea
-
-
2
-
Laryngitis
-
1
2
-
Urogenital System
Male and Female Patients Combined
Micturition disorder
14
2
4
2
Urinary tract infection
6
1
-
-
Micturition frequency
5
3
-
-
Urinary retention
2
-
7
-
Dysuria
2
2
-
-
Cystitis
2
-
-
-
Female Patients Only
Dysmenorrhea
(N=182)
12
(N=167)
14
(N=10)
10
(N=21)
10
Lactation (nonpuerperal)
4
-
-
-
Menstrual disorder
4
2
-
-
Vaginitis
2
-
-
-
Leukorrhea
2
-
-
-
Breast enlargement
2
-
-
-
Breast pain
1
-
-
-
Amenorrhea
1
-
-
-
Male Patients Only
Ejaculation failure
(N=140)
42
(N=152)
2
(N=36)
6
(N=23)
-
Impotence
20
3
-
-
Special Senses
Abnormal vision
18
4
7
2
Taste perversion
8
-
4
-
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Tinnitus
6
-
4
-
Abnormal lacrimation
3
2
-
-
Mydriasis
2
-
-
-
Conjunctivitis
1
-
-
-
Anisocoria
-
-
2
-
Blepharospasm
-
-
2
-
Ocular allergy
-
-
2
-
Vestibular disorder
-
-
2
2
Musculoskeletal
Myalgia
13
9
-
-
Back pain
6
6
-
-
Arthralgia
3
5
-
-
Muscle weakness
1
-
2
-
Hemic and Lymphatic
Purpura
3
-
-
-
Anemia
-
-
2
2
Metabolic and
Nutritional
Thirst
2
2
-
2
*Events reported by at least 1% of Anafranil patients are included.
Other Events Observed During the Premarketing Evaluation of Anafranil
During clinical testing in the U.S., multiple doses of Anafranil were administered to
approximately 3600 subjects. Untoward events associated with this exposure were
recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion of
individuals experiencing adverse events without first grouping similar types of untoward
events into a smaller number of standardized event categories.
In the tabulations that follow, a modified World Health Organization dictionary of
terminology has been used to classify reported adverse events. The frequencies
presented, therefore, represent the proportion of the 3525 individuals exposed to
Anafranil who experienced an event of the type cited on at least one occasion while
receiving Anafranil. All events are included except those already listed in the previous
table, those reported in terms so general as to be uninformative, and those in which an
association with the drug was remote. It is important to emphasize that although the
events reported occurred during treatment with Anafranil, they were not necessarily
caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency according to the following definitions: frequent adverse events are those
occurring on one or more occasions in at least 1/100 patients; infrequent adverse
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events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring
in less than 1/1000 patients.
Body as a Whole – Infrequent - general edema, increased susceptibility to infection,
malaise. Rare - dependent edema, withdrawal syndrome.
Cardiovascular System – Infrequent - abnormal ECG, arrhythmia, bradycardia,
cardiac arrest, extrasystoles, pallor. Rare - aneurysm, atrial flutter, bundle branch block,
cardiac failure, cerebral hemorrhage, heart block, myocardial infarction, myocardial
ischemia, peripheral ischemia, thrombophlebitis, vasospasm, ventricular tachycardia.
Digestive System – Infrequent - abnormal hepatic function, blood in stool, colitis,
duodenitis, gastric ulcer, gastritis, gastroesophageal reflux, gingivitis, glossitis,
hemorrhoids, hepatitis, increased saliva, irritable bowel syndrome, peptic ulcer, rectal
hemorrhage, tongue ulceration, tooth caries. Rare - cheilitis, chronic enteritis, discolored
feces, gastric dilatation, gingival bleeding, hiccup, intestinal obstruction, oral/pharyngeal
edema, paralytic ileus, salivary gland enlargement.
Endocrine System – Infrequent - hypothyroidism. Rare - goiter, gynecomastia,
hyperthyroidism.
Hemic and Lymphatic System – Infrequent - lymphadenopathy. Rare - leukemoid
reaction, lymphoma-like disorder, marrow depression.
Metabolic and Nutritional Disorder – Infrequent - dehydration, diabetes mellitus, gout,
hypercholesterolemia, hyperglycemia, hyperuricemia, hypokalemia. Rare -
fat
intolerance, glycosuria.
Musculoskeletal System – Infrequent - arthrosis. Rare - dystonia, exostosis, lupus
erythematosus rash, bruising, myopathy, myositis, polyarteritis nodosa, torticollis.
Nervous System – Frequent - abnormal thinking, vertigo. Infrequent - abnormal
coordination, abnormal EEG, abnormal gait, apathy, ataxia, coma, convulsions,
delirium, delusion, dyskinesia, dysphonia, encephalopathy, euphoria, extrapyramidal
disorder, hallucinations, hostility, hyperkinesia, hypnagogic hallucinations, hypokinesia,
leg cramps, manic reaction, neuralgia, paranoia, phobic disorder, psychosis, sensory
disturbance, somnambulism, stimulation, suicidal ideation, suicide attempt, teeth-
grinding. Rare - anticholinergic syndrome, aphasia, apraxia, catalepsy, cholinergic
syndrome,
choreoathetosis,
generalized
spasm,
hemiparesis,
hyperesthesia,
hyperreflexia, hypoesthesia, illusion, impaired impulse control, indecisiveness, mutism,
neuropathy, nystagmus, oculogyric crisis, oculomotor nerve paralysis, schizophrenic
reaction, stupor, suicide.
Respiratory System – Infrequent - bronchitis, hyperventilation, increased sputum,
pneumonia. Rare - cyanosis, hemoptysis, hypoventilation, laryngismus.
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Skin and Appendages – Infrequent - alopecia, cellulitis, cyst, eczema, erythematous
rash, genital pruritus, maculopapular rash, photosensitivity reaction, psoriasis, pustular
rash, skin discoloration. Rare - chloasma, folliculitis, hypertrichosis, piloerection,
seborrhea, skin hypertrophy, skin ulceration.
Special Senses – Infrequent - abnormal accommodation, deafness, diplopia, earache,
eye pain, foreign body sensation, hyperacusis, parosmia, photophobia, scleritis, taste
loss. Rare -
blepharitis, chromatopsia, conjunctival hemorrhage, exophthalmos,
glaucoma, keratitis, labyrinth disorder, night blindness, retinal disorder, strabismus,
visual field defect.
Urogenital System – Infrequent - endometriosis, epididymitis, hematuria, nocturia,
oliguria, ovarian cyst, perineal pain, polyuria, prostatic disorder, renal calculus, renal
pain, urethral disorder, urinary incontinence, uterine hemorrhage, vaginal hemorrhage.
Rare - albuminuria, anorgasmy, breast engorgement, breast fibroadenosis, cervical
dysplasia, endometrial hyperplasia, premature ejaculation, pyelonephritis, pyuria, renal
cyst, uterine inflammation, vulvar disorder.
Postmarketing Experience
The following adverse drug reaction has been reported during post-approval use of
Anafranil. Because this reaction is reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate frequency.
Eye Disorders – angle-closure glaucoma.
DRUG ABUSE AND DEPENDENCE
Anafranil has not been systematically studied in animals or humans for its potential for
abuse, tolerance, or physical dependence. While a variety of withdrawal symptoms
have been described in association with Anafranil discontinuation (see PRECAUTIONS,
Withdrawal Symptoms), there is no evidence for drug-seeking behavior, except for a
single report of potential Anafranil abuse by a patient with a history of dependence on
codeine, benzodiazepines, and multiple psychoactive drugs. The patient received
Anafranil for depression and panic attacks and appeared to become dependent after
hospital discharge.
Despite the lack of evidence suggesting an abuse liability for Anafranil in foreign
marketing, it is not possible to predict the extent to which Anafranil might be misused or
abused once marketed in the U.S. Consequently, physicians should carefully evaluate
patients for a history of drug abuse and follow such patients closely.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion
(including alcohol) is common in deliberate tricyclic overdose. As the management is
complex and changing, it is recommended that the physician contact a poison control
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center for current information on treatment. Signs and symptoms of toxicity develop
rapidly after tricyclic overdose. Therefore, hospital monitoring is required as soon as
possible.
Human Experience
In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with
Anafranil either alone or in combination with other drugs. One death involved a patient
suspected of ingesting a dose of 7000 mg. The second death involved a patient
suspected of ingesting a dose of 5750 mg. The 10 nonfatal cases involved doses of up
to 5000 mg, accompanied by plasma levels of up to 1010 ng/mL. All 10 patients
completely recovered. Among reports from other countries of Anafranil overdose, the
lowest dose associated with a fatality was 750 mg. Based upon postmarketing reports in
the United Kingdom, CMI’s lethality in overdose is considered to be similar to that
reported for closely related tricyclic compounds marketed as antidepressants.
Manifestations
Signs and symptoms vary in severity depending upon factors such as the amount of
drug absorbed, the age of the patient, and the time elapsed since drug ingestion.
Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension,
convulsions, and CNS depression including coma. Changes in the electrocardiogram,
particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity.
Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness,
agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, and
athetoid and choreiform movements. Cardiac abnormalities may include tachycardia,
signs of congestive heart failure, and in very rare cases, cardiac arrest. Respiratory
depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and oliguria or anuria
may also be present.
Management
Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway,
establish an intravenous line, and initiate gastric decontamination. A minimum of
6 hours of observation with cardiac monitoring and observation for signs of CNS or
respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks,
and seizures is necessary.
If signs of toxicity occur at any time during this period, extended monitoring is required.
There are case reports of patients succumbing to fatal dysrhythmias late after overdose;
these patients had clinical evidence of significant poisoning prior to death and most
received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels
should not guide management of the patient.
Gastrointestinal Decontamination – All patients suspected of tricyclic overdose
should receive gastrointestinal decontamination. This should include large volume
gastric lavage followed by activated charcoal. If consciousness is impaired, the airway
should be secured prior to lavage. Emesis is contraindicated.
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Cardiovascular – A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the
best indication of the severity of the overdose. Intravenous sodium bicarbonate should
be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is
inadequate, hyperventilation may also be used. Concomitant use of hyperventilation
and sodium bicarbonate should be done with extreme caution, with frequent pH
monitoring. A pH >7.60 or a pCO2 <20 mmHg is undesirable. Dysrhythmias
unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine,
bretylium, or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated
(e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular
instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis,
exchange transfusions, and forced diuresis generally have been reported as ineffective
in tricyclic poisoning.
CNS – In patients with CNS depression, early intubation is advised because of the
potential for abrupt deterioration. Seizures should be controlled with benzodiazepines,
or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin).
Physostigmine is not recommended except to treat life-threatening symptoms that have
been unresponsive to other therapies, and then only in consultation with a poison
control center.
Psychiatric Follow-up – Since overdosage is often deliberate, patients may attempt
suicide by other means during the recovery phase. Psychiatric referral may be
appropriate.
Pediatric Management – The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact the local
poison control center for specific pediatric treatment.
DOSAGE AND ADMINISTRATION
The treatment regimens described below are based on those used in controlled clinical
trials of Anafranil in 520 adults, and 91 children and adolescents with OCD. During initial
titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal
side effects. The goal of this initial titration phase is to minimize side effects by
permitting tolerance to side effects to develop or allowing the patient time to adapt if
tolerance does not develop.
Because both CMI and its active metabolite, DMI, have long elimination half-lives, the
prescriber should take into consideration the fact that steady-state plasma levels may
not be achieved until 2 to 3 weeks after dosage change (see CLINICAL
PHARMACOLOGY). Therefore, after initial titration, it may be appropriate to wait
2 to 3 weeks between further dosage adjustments.
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Initial Treatment/Dose Adjustment (Adults)
Treatment with Anafranil should be initiated at a dosage of 25 mg daily and gradually
increased, as tolerated, to approximately 100 mg during the first 2 weeks. During initial
titration, Anafranil should be given in divided doses with meals to reduce gastrointestinal
side effects. Thereafter, the dosage may be increased gradually over the next several
weeks, up to a maximum of 250 mg daily. After titration, the total daily dose may be
given once daily at bedtime to minimize daytime sedation.
Initial Treatment/Dose Adjustment (Children and Adolescents)
As with adults, the starting dose is 25 mg daily and should be gradually increased (also
given in divided doses with meals to reduce gastrointestinal side effects) during the first
2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller.
Thereafter, the dosage may be increased gradually over the next several weeks up to a
daily maximum of 3 mg/kg or 200 mg, whichever is smaller (see PRECAUTIONS,
Pediatric Use). As with adults, after titration, the total daily dose may be given once daily
at bedtime to minimize daytime sedation.
Maintenance/Continuation Treatment (Adults, Children, and Adolescents)
While there are no systematic studies that answer the question of how long to continue
Anafranil, OCD is a chronic condition and it is reasonable to consider continuation for a
responding patient. Although the efficacy of Anafranil after 10 weeks has not been
documented in controlled trials, patients have been continued in therapy under double-
blind conditions for up to 1 year without loss of benefit. However, dosage adjustments
should be made to maintain the patient on the lowest effective dosage, and patients
should be periodically reassessed to determine the need for treatment. During
maintenance, the total daily dose may be given once daily at bedtime.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended
to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat
psychiatric disorders and initiation of therapy with Anafranil. Conversely, at least
14 days should be allowed after stopping Anafranil before starting an MAOI intended to
treat psychiatric disorders (see CONTRAINDICATIONS).
Use of Anafranil With Other MAOIs, Such as Linezolid or Methylene Blue
Do not start Anafranil in a patient who is being treated with linezolid or intravenous
methylene blue because there is increased risk of serotonin syndrome. In a patient who
requires more urgent treatment of a psychiatric condition, other interventions, including
hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving Anafranil therapy may require urgent
treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential
benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the
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risks of serotonin syndrome in a particular patient, Anafranil should be stopped
promptly, and linezolid or intravenous methylene blue can be administered. The patient
should be monitored for symptoms of serotonin syndrome for two weeks or until
24 hours after the last dose of linezolid or intravenous methylene blue, whichever
comes first. Therapy with Anafranil may be resumed 24 hours after the last dose of
linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral
tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with
Anafranil is unclear. The clinician should, nevertheless, be aware of the possibility of
emergent symptoms of serotonin syndrome with such use (see WARNINGS).
HOW SUPPLIED
Anafranil™ (clomipramine hydrochloride) Capsules USP
Capsules 25 mg – ivory body imprinted in black with “M” and melon-yellow cap
imprinted in black with “ANAFRANIL 25 mg”
Bottles of 30................................. NDC 0406-9906-03
Capsules 50 mg – ivory body imprinted in black with “M” and aqua blue cap imprinted in
black with “ANAFRANIL 50 mg”
Bottles of 30................................. NDC 0406-9907-03
Capsules 75 mg – ivory body imprinted in black with “M” and yellow cap imprinted in
black with “ANAFRANIL 75 mg”
Bottles of 30................................. NDC 0406-9908-03
Storage – Store at 20º to 25ºC (68° to 77°F) [see USP Controlled Room Temperature].
Dispense in well-closed containers with a child-resistant closure. Protect from moisture.
ANIMAL TOXICOLOGY
Phospholipidosis and testicular changes, commonly associated with tricyclic
compounds, have been observed with Anafranil. In chronic rat studies, changes related
to Anafranil consisted of systemic phospholipidosis, alterations in the testes (atrophy,
mineralization) and secondary changes in other tissues. In addition cardiac thrombosis
and dermatitis/keratitis were observed in rats treated for 2 years at doses which were
24 and 10 times the maximum recommended human daily dose (MRHD), respectively,
on a mg/kg basis, and 4 and 1.5 times the MRHD, respectively, on a mg/m2 basis.
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo, M and other
brands are trademarks of a Mallinckrodt company.
© 2014 Mallinckrodt.
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Reference ID: 3600048
This label may not be the latest approved by FDA.
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Manufactured by
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
for Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Page 26 of 29
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Reference ID: 3600048
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Medication Guide - Anafranil™
(clomipramine hydrochloride) Capsules USP
Antidepressant Medicines, Depression and other Serious Mental Illnesses,
and Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member’s
antidepressant medicine. This Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your, or your family
member’s, healthcare provider about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant
medicines, depression and other serious mental illnesses, and suicidal thoughts
or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some
children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes
of suicidal thoughts and actions. Some people may have a particularly high
risk of having suicidal thoughts or actions. These include people who have (or
have a family history of) bipolar illness (also called manic-depressive illness) or
suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself
or a family member?
Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of
the following symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
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new or worse depression
new or worse anxiety
feeling very agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
Visual problems
eye pain
changes in vision
swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye
examination to see if you are at risk and receive preventative treatment if you are.
Who should not take Anafranil?
Do not take Anafranil if you:
take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
o Do not take an MAOI within 2 weeks of stopping Anafranil unless directed to
do so by your physician.
o Do not start Anafranil if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your physician.
What else do I need to know about antidepressant medicines?
Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other
symptoms.
Antidepressants are medicines used to treat depression and other illnesses. It
is important to discuss all the risks of treating depression and also the risks of not
treating it. Patients and their families or other caregivers should discuss all treatment
choices with the healthcare provider, not just the use of antidepressants.
Antidepressant medicines have other side effects. Talk to the healthcare
provider about the side effects of the medicine prescribed for you or your family
member.
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Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show
the healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
Not all antidepressant medicines prescribed for children are FDA approved for
use in children. Talk to your child’s healthcare provider for more information.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other
brands are trademarks of a Mallinckrodt company.
© 2014 Mallinckrodt.
Manufactured by
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5
for Mallinckrodt Inc.
Hazelwood, MO 63042 USA
Rev 06/2014 company logo
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Reference ID: 3600048
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:17.177437
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019906s039lbl.pdf', 'application_number': 19906, 'submission_type': 'SUPPL ', 'submission_number': 39}
|
11,840
|
NDA 19908 S027 FDA approved labeling 4.23.08
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AMBIEN safely and effectively. See full prescribing information for
AMBIEN
Ambien® (zolpidem tartrate) tablets
Initial US Approval: 1992 logo
----------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1)
03/2007
Warnings and Precautions
Severe anaphylactic and anaphylactoid reactions (5.2)
03/2007
Abnormal thinking and behavioral changes (5.3)
03/2007
Special populations (5.6)
03/2007
----------------------------INDICATIONS AND USAGE---------------------------
Ambien is indicated for the short-term treatment of insomnia characterized by
difficulties with sleep initiation. Ambien has been shown to decrease sleep
latency for up to 35 days in controlled clinical studies. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
• Adult dose: 10 mg once daily immediately before bedtime (2.1)
• Elderly/debilitated patients/hepatically impaired: 5 mg once daily
immediately before bedtime (2.2)
• Downward dosage adjustment may be necessary when used with CNS
depressants (2.3)
• Should not be taken with or immediately after a meal (2.4)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
5 mg and 10 mg tablets. Tablets not scored. (3)
-------------------------------CONTRAINDICATIONS------------------------------
Known hypersensitivity to zolpidem tartrate or to any of the inactive
ingredients in the formulation (4.1)
----------------------WARNINGS AND PRECAUTIONS-------------------------
• Need to evaluate for co-morbid diagnosis: Reevaluate if insomnia persists
after 7 to 10 days of use (5.1)
• Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis
have been reported. Do not rechallenge if such reactions occur. (5.2)
• Abnormal thinking, behavioral changes and complex behaviors: May
include “sleep-driving” and hallucinations. Immediately evaluate any new
onset behavioral changes. (5.3)
• Depression: Worsening of depression or, suicidal thinking may occur.
Prescribe the least amount feasible to avoid intentional overdose (5.3, 5.6)
• Withdrawal effects: Symptoms may occur with rapid dose reduction or
discontinuation (5.4, 9.3)
• CNS depressant effects: Use can impair alertness and motor coordination.
If used in combination with other CNS depressants, dose reductions may be
needed due to additive effects. Do not use with alcohol (2.3, 5.5)
• Elderly/debilitated patients: Use lower dose due to impaired motor,
cognitive performance and increased sensitivity (2.2, 5.6)
• Patients with hepatic impairment, mild to moderate COPD, impaired drug
metabolism or hemodynamic responses, mild to moderate sleep apnea: Use
with caution and monitor closely. (5.6)
-----------------------------ADVERSE REACTIONS--------------------------------
Most commonly observed adverse reactions were:
Short-term (< 10 nights): Drowsiness, dizziness, and diarrhea
Long-term (28 - 35 nights): Dizziness and drugged feelings (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088, or
http://www.fda.gov/medwatch
------------------------------DRUG INTERACTIONS-------------------------------
• CNS depressants: Enhanced CNS-depressant effects with combination use.
Use with alcohol causes additive psychomotor impairment (7.1)
• Imipramine: Decreased alertness observed with combination use. (7.1)
• Chlorpromazine: Impaired alertness and psychomotor performance
observed with combination use (7.1)
• Rifampin: Combination use decreases exposure to and effects of zolpidem
(7.2)
• Ketoconazole: Combination use increases exposure to and effect of
zolpidem (7.2)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
•
Pregnancy: Crosses the placenta. No studies in pregnant women. (8.1)
•
Nursing mothers: Infant exposure via breast milk. (8.3)
•
Pediatric use: Safety and effectiveness not established. Hallucinations
(incidence rate 7.4%) and other psychiatric and/or nervous system
adverse reactions were observed frequently in a study of pediatric
patients with Attention-Deficit/Hyperactivity Disorder (5.6, 8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 2/2008
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
9
DRUG ABUSE AND DEPENDENCE
2.1
Dosage in adults
9.1
Controlled substance
2.2
Special populations
9.2
Abuse
2.3
Use with CNS depressants
9.3
Dependence
2.4
Administration
10
OVERDOSAGE
3
DOSAGE FORMS AND STRENGTHS
10.1
Signs and symptoms
4
CONTRAINDICATIONS
10.2
Recommended treatment
5
WARNINGS AND PRECAUTIONS
11
DESCRIPTION
5.1
Need to evaluate for co-morbid diagnoses
12
CLINICAL PHARMACOLOGY
5.2
Severe anaphylactic and anaphylactoid reactions
12.1
Mechanism of action
5.3
Abnormal thinking and behavioral changes
12.3
Pharmacokinetics
5.4
Withdrawal effects
13
NONCLINICAL TOXICOLOGY
5.5
CNS depressant effects
13.1
Carcinogenesis, mutagenesis, impairment of fertility
5.6
Special populations
14
CLINICAL STUDIES
6
ADVERSE REACTIONS
14.1
Transient insomnia
6.1
Clinical trials experience
14.2
Chronic insomnia
7
DRUG INTERACTIONS
14.3
Studies pertinent to safety concerns for sedatives/hypnotic
7.1
CNS active drugs
drugs
7.2
Drugs that affect drug metabolism via cytochrome P450
16
HOW SUPPLIED/STORAGE AND HANDLING
7.3
Other drugs with no interaction with zolpidem
17
PATIENT COUNSELING INFORMATION
7.4
Drug–laboratory tests interactions
17.1
Severe anaphylactoid reactions
8
USE IN SPECIFIC POPULATIONS
17.2
Sleep-driving and other complex behaviors
8.1
Pregnancy
17.3
Administration Instructions
8.2
Labor and delivery
17.4
Medication Guide
8.3
Nursing mothers
*Sections or subsections omitted from the full prescribing information are not
8.4
Pediatric use
listed.
8.5
Geriatric use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Ambien (zolpidem tartrate) is indicated for the short-term treatment of insomnia characterized by
difficulties with sleep initiation. Ambien has been shown to decrease sleep latency for up to 35
days in controlled clinical studies [see Clinical Studies (14)].
The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final
formal assessments of sleep latency performed at the end of treatment.
2 DOSAGE AND ADMINISTRATION
The dose of Ambien should be individualized.
2.1 Dosage in adults
The recommended dose for adults is 10 mg once daily immediately before bedtime. The total
Ambien dose should not exceed 10 mg per day.
2.2 Special populations
Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate.
Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The
recommended dose of Ambien in both of these patient populations is 5 mg once daily
immediately before bedtime [see Warnings and Precautions (5.6)].
2.3 Use with CNS depressants
Dosage adjustment may be necessary when Ambien is combined with other CNS depressant
drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].
2.4 Administration
The effect of Ambien may be slowed by ingestion with or immediately after a meal.
3 DOSAGE FORMS AND STRENGTHS
Ambien is available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not
scored.
Ambien 5 mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed on one side
and 5401 on the other.
Ambien 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one
side and 5421 on the other.
4 CONTRAINDICATIONS
Ambien is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any
of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and
angioedema [see Warnings and Precautions (5.2)].
2
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NDA 19908 FDA SLR 027 Approved labeling 4.23.08
5 WARNINGS AND PRECAUTIONS
5.1 Need to evaluate for co-morbid diagnoses
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric
disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of
the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate
the presence of a primary psychiatric and/or medical illness that should be evaluated.
Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the
consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged
during the course of treatment with sedative/hypnotic drugs, including zolpidem.
5.2 Severe anaphylactic and anaphylactoid reactions
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients
after taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some
patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting
that suggest anaphylaxis. Some patients have required medical therapy in the emergency
department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur
and be fatal. Patients who develop angioedema after treatment with zolpidem should not be
rechallenged with the drug.
5.3 Abnormal thinking and behavioral changes
A variety of abnormal thinking and behavior changes have been reported to occur in association
with the use of sedative/hypnotics. Some of these changes may be characterized by decreased
inhibition (e.g., aggressiveness and extroversion that seemed out of character), similar to effects
produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been
reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization.
In controlled trials, < 1% of adults with insomnia who received zolpidem reported hallucinations.
In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention
deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [see Use
in Specific Populations (8.4)].
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of
a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics,
including zolpidem. These events can occur in sedative-hypnotic-naive as well as in
sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur
with Ambien alone at therapeutic doses, the use of alcohol and other CNS depressants with
Ambien appears to increase the risk of such behaviors, as does the use of Ambien at doses
exceeding the maximum recommended dose. Due to the risk to the patient and the community,
discontinuation of Ambien should be strongly considered for patients who report a
“sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making
phone calls, or having sex) have been reported in patients who are not fully awake after taking a
sedative-hypnotic. As with “sleep-driving”, patients usually do not remember these events.
Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.
3
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In primarily depressed patients, worsening of depression, including suicidal thoughts and actions
(including completed suicides), has been reported in association with the use of
sedative/hypnotics.
It can rarely be determined with certainty whether a particular instance of the abnormal
behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying
psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or
symptom of concern requires careful and immediate evaluation.
5.4 Withdrawal effects
Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have
been reports of signs and symptoms similar to those associated with withdrawal from other
CNS-depressant drugs [see Drug Abuse and Dependence (9)].
5.5 CNS depressant effects
Ambien, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset
of action, Ambien should only be taken immediately prior to going to bed. Patients should be
cautioned against engaging in hazardous occupations requiring complete mental alertness or
motor coordination such as operating machinery or driving a motor vehicle after ingesting the
drug, including potential impairment of the performance of such activities that may occur the day
following ingestion of Ambien. Ambien showed additive effects when combined with alcohol
and should not be taken with alcohol. Patients should also be cautioned about possible combined
effects with other CNS-depressant drugs. Dosage adjustments may be necessary when Ambien
is administered with such agents because of the potentially additive effects.
5.6 Special populations
Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive performance
after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the
treatment of elderly and/or debilitated patients. Therefore, the recommended Ambien dosage is
5 mg in such patients to decrease the possibility of side effects [see Dosage and Administration
(2.2)]. These patients should be closely monitored.
Use in patients with concomitant illness: Clinical experience with Ambien (zolpidem
tartrate) in patients with concomitant systemic illness is limited. Caution is advisable in using
Ambien in patients with diseases or conditions that could affect metabolism or hemodynamic
responses.
Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem in
normal subjects or in patients with mild to moderate chronic obstructive pulmonary disease
(COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen
saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in
patients with mild-to-moderate sleep apnea when treated with Ambien (10 mg) when compared
to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions
should be taken if Ambien is prescribed to patients with compromised respiratory function.
Post-marketing reports of respiratory insufficiency, most of which involved patients with
4
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pre-existing respiratory impairment, have been received. Ambien should be used with caution in
patients with sleep apnea syndrome or myasthenia gravis.
Data in end-stage renal failure patients repeatedly treated with Ambien did not demonstrate drug
accumulation or alterations in pharmacokinetic parameters. No dosage adjustment in renally
impaired patients is required; however, these patients should be closely monitored [see Clinical
Pharmacology (12.3)].
A study in subjects with hepatic impairment did reveal prolonged elimination in this group;
therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they
should be closely monitored [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)].
Use in patients with depression: As with other sedative/hypnotic drugs, Ambien should be
administered with caution to patients exhibiting signs or symptoms of depression. Suicidal
tendencies may be present in such patients and protective measures may be required. Intentional
over-dosage is more common in this group of patients; therefore, the least amount of drug that is
feasible should be prescribed for the patient at any one time.
Use in pediatric patients: Safety and effectiveness of zolpidem have not been established in
pediatric patients. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia
associated with ADHD, zolpidem did not decrease sleep latency compared to placebo.
Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of
the pediatric patients who received placebo reported hallucinations [see Use in Specific
Populations (8.4)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the
labeling:
• Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.2)]
• Abnormal thinking, behavior changes, and complex behaviors [see Warnings and Precautions
(5.3)]
• Withdrawal effects [see Warnings and Precautions (5.4)]
• CNS-depressant effects [see Warnings and Precautions (5.5)]
6.1 Clinical trials experience
Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who
received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued
treatment because of an adverse reaction. Reactions most commonly associated with
discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache
(0.5%), nausea (0.6%), and vomiting (0.5%).
Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar
foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly
5
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associated with discontinuation from these trials were daytime drowsiness (1.1%),
dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).
Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients
were given zolpidem revealed that four of the seven discontinuations during double-blind
treatment with zolpidem (n=95) were associated with impaired concentration, continuing or
aggravated depression, and manic reaction; one patient treated with placebo (n =97) was
discontinued after an attempted suicide.
Most commonly observed adverse reactions in controlled trials: During short-term
treatment (up to 10 nights) with Ambien at doses up to 10 mg, the most commonly observed
adverse reactions associated with the use of zolpidem and seen at statistically significant
differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem
patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights)
with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated
with the use of zolpidem and seen at statistically significant differences from placebo-treated
patients were dizziness (5%) and drugged feelings (3%).
Adverse reactions observed at an incidence of ≥ 1% in controlled trials: The following
tables enumerate treatment-emergent adverse reactions frequencies that were observed at an
incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate
and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by
investigators were classified utilizing a modified World Health Organization (WHO) dictionary
of preferred terms for the purpose of establishing event frequencies. The prescriber should be
aware that these figures cannot be used to predict the incidence of side effects in the course of
usual medical practice, in which patient characteristics and other factors differ from those that
prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical investigators involving related drug products and uses, since
each group of drug trials is conducted under a different set of conditions. However, the cited
figures provide the physician with a basis for estimating the relative contribution of drug and
nondrug factors to the incidence of side effects in the population studied.
The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy
trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from
doses up to and including 10 mg, the highest dose recommended for use.
Incidence of Treatment-Emergent Adverse Experiences in
Placebo-Controlled Clinical Trials Lasting up to 10 Nights
(Percentage of patients reporting)
Zolpidem
Body System/
(≤10mg)
Placebo
Adverse Event*
(N=685)
(N=473)
Central and Peripheral Nervous System
Headache
7
6
Drowsiness
2
-
Dizziness
1
-
6
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Gastrointestinal System
Diarrhea
1
-
*Reactions reported by at least 1% of patients treated with Ambien and at a greater
frequency than placebo.
The following table was derived from results of three placebo-controlled long-term efficacy trials
involving Ambien (zolpidem tartrate). These trials involved patients with chronic insomnia who
were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to
data from doses up to and including 10 mg, the highest dose recommended for use. The table
includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.
Incidence of Treatment-Emergent Adverse Experiences in
Placebo-Controlled Clinical Trials Lasting up to 35 Nights
(Percentage of patients reporting)
Zolpidem
Body System/
(≤10mg)
Placebo
Adverse Event*
(N=152)
(N=161)
Autonomic Nervous System
Dry mouth
3
1
Body as a Whole
Allergy
4
1
Back Pain
3
2
Influenza-like symptoms
2
-
Chest pain
1
-
Cardiovascular System
Palpitation
2
-
Central and Peripheral Nervous System
Drowsiness
8
5
Dizziness
5
1
Lethargy
3
1
Drugged feeling
3
-
Lightheadedness
2
1
Depression
2
1
Abnormal dreams
1
-
Amnesia
1
-
Sleep disorder
1
-
Gastrointestinal System
Diarrhea
3
2
Abdominal pain
2
2
Constipation
2
1
Respiratory System
Sinusitis
4
2
Pharyngitis
3
1
Skin and Appendages
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Rash
2
1
*Reactions reported by at least 1% of patients treated with Ambien and at a greater
frequency than placebo.
Dose relationship for adverse reactions: There is evidence from dose comparison trials
suggesting a dose relationship for many of the adverse reactions associated with zolpidem use,
particularly for certain CNS and gastrointestinal adverse events.
Adverse event incidence across the entire preapproval database: Ambien was
administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe.
Treatment-emergent adverse events associated with clinical trial participation were recorded by
clinical investigators using terminology of their own choosing. To provide a meaningful
estimate of the proportion of individuals experiencing treatment-emergent adverse events,
similar types of untoward events were grouped into a smaller number of standardized event
categories and classified utilizing a modified World Health Organization (WHO) dictionary of
preferred terms.
The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed
to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion
while receiving zolpidem. All reported treatment-emergent adverse events are included, except
those already listed in the table above of adverse events in placebo-controlled studies, those
coding terms that are so general as to be uninformative, and those events where a drug cause was
remote. It is important to emphasize that, although the events reported did occur during
treatment with Ambien, they were not necessarily caused by it.
Adverse events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in
1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension,
syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension,
impotence, increased saliva, tenesmus.
Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fatigue, fever, malaise,
trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes,
increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.
Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia.
Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension
aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose
veins, ventricular tachycardia.
Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, headache,
insomnia, vertigo. Infrequent: agitation, anxiety, decreased cognition, detached, difficulty
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concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps,
migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor,
tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased,
decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia,
hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis,
panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.
Gastrointestinal system: Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia,
constipation, dysphagia, flatulence, gastroenteritis, vomiting. Rare: enteritis, eructation,
esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.
Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia,
lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis
externa, otitis media.
Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare:
bilirubinemia, increased SGOT.
Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia,
hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.
Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis,
muscle weakness, sciatica, tendinitis.
Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis,
breast neoplasm, breast pain.
Respiratory system: Frequent: upper respiratory infection. Infrequent: bronchitis, coughing,
dyspnea, rhinitis. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.
Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis,
furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.
Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain,
scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation
abnormal, parosmia, photopsia.
Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence.
Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal
pain, urinary retention.
7 DRUG INTERACTIONS
9
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7.1 CNS-active drugs
Since the systematic evaluations of zolpidem in combination with other CNS-active drugs have
been limited, careful consideration should be given to the pharmacology of any CNS-active drug
to be used with zolpidem. Any drug with CNS-depressant effects could potentially enhance the
CNS-depressant effects of zolpidem.
Ambien was evaluated in healthy subjects in single-dose interaction studies for several CNS
drugs. Imipramine in combination with zolpidem produced no pharmacokinetic interaction other
than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased
alertness. Similarly, chlorpromazine in combination with zolpidem produced no
pharmacokinetic interaction, but there was an additive effect of decreased alertness and
psychomotor performance. A study involving haloperidol and zolpidem revealed no effect of
haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug
interaction following single-dose administration does not predict a lack following chronic
administration.
An additive effect on psychomotor performance between alcohol and zolpidem was
demonstrated [see Warnings and Precautions (5.5)].
A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels
in male volunteers did not demonstrate any clinically significant pharmacokinetic or
pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady-state
concentrations were evaluated in healthy females, the only significant change was a 17%
increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor
performance.
Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg
(17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was
significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of
sertraline and N-desmethylsertraline were unaffected by zolpidem.
7.2 Drugs that affect drug metabolism via cytochrome P450
Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of
inhibitors of other P450 enzymes has not been carefully evaluated.
A randomized, double-blind, crossover interaction study in ten healthy volunteers between
itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours
after the last dose of itraconazole resulted in a 34% increase in AUC0-∞ of zolpidem. There were
no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or
psychomotor performance.
A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects
between five consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem
(20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC
(–73%), Cmax (–58%), and T1/2 (–36%) of zolpidem together with significant reductions in the
pharmacodynamic effects of zolpidem.
10
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A randomized double-blind crossover interaction study in twelve healthy subjects showed that
co-administration of a single 5 mg dose of zolpidem tartrate with ketoconazole, a potent
CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem by a
factor of 1.3 and increased the total AUC of zolpidem by a factor of 1.7 compared to zolpidem
alone and prolonged the elimination half-life by approximately 30% along with an increase in
the pharmacodynamic effects of zolpidem. Caution should be used when ketoconazole is given
with zolpidem and consideration should be given to using a lower dose of zolpidem when
ketoconazole and zolpidem are given together. Patients should be advised that use of Ambien
with ketoconazole may enhance the sedative effects.
7.3 Other drugs with no interaction with zolpidem
A study involving cimetidine/zolpidem and ranitidine/zolpidem combinations revealed no effect
of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.
Zolpidem had no effect on digoxin pharmacokinetics and did not affect prothrombin time when
given with warfarin in normal subjects.
7.4 Drug-laboratory test interactions
Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In
addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates,
barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Ambien should be used
during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Oral studies of zolpidem in pregnant rats and rabbits showed adverse effects on the development
of offspring only at doses greater than the maximum recommended human dose (MRHD of 10
mg/day). These doses were also maternally toxic in animals. A teratogenic effect was not
observed in these studies. Administration to pregnant rats during the period of organogenesis
produced dose-related maternal toxicity and decreases in fetal skull ossification at doses 25 to
125 times the MRHD. The no-effect dose for embryo-fetal toxicity was between 4 and 5 times
the MRHD. Treatment of pregnant rabbits during organogenesis resulted in maternal toxicity at
all doses studied and increased post-implantation embryo-fetal loss and under-ossification of
fetal sternebrae at the highest dose (over 35 times the MRHD). The no-effect level for embryo-
fetal toxicity was between 9 and 10 times the MRHD. Administration to rats during the latter
part of pregnancy and throughout lactation produced maternal toxicity and decreased pup growth
and survival at doses approximately 25 to 125 times the MRHD. The no-effect dose for
offspring toxicity was between 4 and 5 times the MRHD.
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Studies to assess the effects on children whose mothers took zolpidem during pregnancy have
not been conducted. There is a published case report documenting the presence of zolpidem in
human umbilical cord blood. Children born of mothers taking sedative/hypnotic drugs may be at
some risk for withdrawal symptoms from the drug during the postnatal period. In addition,
neonatal flaccidity has been reported in infants born of mothers who received sedative/hypnotic
drugs during pregnancy.
8.2 Labor and delivery
Ambien has no established use in labor and delivery [see Pregnancy (8.1)].
8.3 Nursing mothers
Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in young
normal subjects (2.6 ± 0.3 hr). Between 0.004% and 0.019% of the total administered dose is
excreted into milk. The effect of zolpidem on the nursing infant is not known. Caution should be
exercised when Ambien is administered to a nursing mother.
8.4 Pediatric use
Safety and effectiveness of zolpidem have not been established in pediatric patients.
In an 8-week controlled study, 201 pediatric patients (aged 6-17 years) with insomnia associated
with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics)
were treated with an oral solution of zolpidem (n=136), or placebo (n=65). Zolpidem did not
significantly decrease latency to persistent sleep, compared to placebo, as measured by
polysomnography after 4 weeks of treatment. Psychiatric and nervous system disorders
comprised the most frequent (> 5%) treatment emergent adverse reactions observed with
zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%),
and hallucinations (7.4% vs. 0%) [see Warnings and Precautions(5.6)]. Ten patients on
zolpidem (7.4%) discontinued treatment due to an adverse reaction.
8.5 Geriatric use
A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials
who received zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving zolpidem at
doses of ≤ 10 mg or placebo, there were three adverse reactions occurring at an incidence of at
least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo
incidence (i.e., they could be considered drug related).
Adverse Event
Zolpidem
Placebo
Dizziness
3%
0%
Drowsiness
5%
2%
Diarrhea
3%
1%
A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30
(93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem
doses > 10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported
confusion, including 18/24 (75%) who were ≥ 70 years of age. Of these 18 patients, 14 (78%)
were receiving zolpidem doses > 10 mg.
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The dose of Ambien in elderly patients is 5 mg to minimize adverse effects related to impaired
motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see
Warnings and Precautions (5.6)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled substance
Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.
9.2 Abuse
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of the drug for non-medical purposes, often in combination with other
psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces
changes that result in a diminution of one or more of the drug effects over time. Tolerance may
occur to both desired and undesired effects of drugs and may develop at different rates for
different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use, compulsive
use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a
multidisciplinary approach, but relapse is common.
Studies of abuse potential in former drug abusers found that the effects of single doses of
zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem
tartrate 10 mg was difficult to distinguish from placebo.
Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk
for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving
zolpidem or any other hypnotic.
9.3 Dependence
Physical dependence is a state of adaptation that is manifested by a specific withdrawal
syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level
of the drug, and/or administration of an antagonist.
Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt
discontinuation. These reported symptoms range from mild dysphoria and insomnia to a
withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating,
tremors, and convulsions. The following adverse events which are considered to meet the
DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S.
clinical trials following placebo substitution occurring within 48 hours following last zolpidem
treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach
cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events
occurred at an incidence of 1% or less. However, available data cannot provide a reliable
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
estimate of the incidence, if any, of dependence during treatment at recommended doses.
Post-marketing reports of abuse, dependence and withdrawal have been received.
10 OVERDOSAGE
10.1 Signs and symptoms
In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with
CNS-depressant agents, impairment of consciousness ranging from somnolence to coma,
cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.
10.2 Recommended treatment
General symptomatic and supportive measures should be used along with immediate gastric
lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s
sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful;
however, flumazenil administration may contribute to the appearance of neurological symptoms
(convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other
appropriate signs should be monitored and general supportive measures employed. Hypotension
and CNS depression should be monitored and treated by appropriate medical intervention.
Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs.
The value of dialysis in the treatment of overdosage has not been determined, although
hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated
that zolpidem is not dialyzable.
As with the management of all overdosage, the possibility of multiple drug ingestion should be
considered. The physician may wish to consider contacting a poison control center for
up-to-date information on the management of hypnotic drug product overdosage.
11 DESCRIPTION
Ambien (zolpidem tartrate) is a non-benzodiazepine hypnotic of the imidazopyridine class and is
available in 5 mg and 10 mg strength tablets for oral administration.
Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide
L-(+)-tartrate (2:1). It has the following structure: chemical structure
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water,
alcohol, and propylene glycol. It has a molecular weight of 764.88.
Each Ambien tablet includes the following inactive ingredients: hydroxypropyl methylcellulose,
lactose, magnesium stearate, micro-crystalline cellulose, polyethylene glycol, sodium starch
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
glycolate, and titanium dioxide. The 5 mg tablet also contains FD&C Red No. 40, iron oxide
colorant, and polysorbate 80.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
Subunit modulation of the GABAA receptor chloride channel macromolecular complex is
hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug
properties. The major modulatory site of the GABAA receptor complex is located on its alpha
(α) subunit and is referred to as the benzodiazepine (BZ) or omega (ω) receptor. At least three
subtypes of the (ω) receptor have been identified.
Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure
unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs
with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some
of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines,
which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the
(BZ1) receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. The (BZ1)
receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia
nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex,
pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the (BZ1)
receptor is not absolute, but it may explain the relative absence of myorelaxant and
anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4)
in human studies of zolpidem at hypnotic doses.
12.3 Pharmacokinetics
The pharmacokinetic profile of Ambien is characterized by rapid absorption from the
gastrointestinal tract and a short elimination half-life (T1/2) in healthy subjects.
In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem
tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range:
58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean
Ambien elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the
5 and 10 mg tablets, respectively. Ambien is converted to inactive metabolites that are
eliminated primarily by renal excretion. Ambien demonstrated linear kinetics in the dose range
of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant,
independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in
young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.
A food-effect study in 30 healthy male subjects compared the pharmacokinetics of Ambien
10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that
with food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax
was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results
suggest that, for faster sleep onset, Ambien should not be administered with or immediately after
a meal.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
Special Populations
Elderly:
In the elderly, the dose for Ambien should be 5 mg [see Warnings and Precautions (5) and
Dosage and Administration (2)]. This recommendation is based on several studies in which the
mean Cmax, T1/2, and AUC were significantly increased when compared to results in young
adults. In one study of eight elderly subjects (> 70 years), the means for Cmax, T1/2, and AUC
significantly increased by 50% (255 vs. 384 ng/mL), 32% (2.2 vs. 2.9 hr), and 64% (955 vs.
1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single
20 mg oral dose. Ambien did not accumulate in elderly subjects following nightly oral dosing of
10 mg for 1 week.
Hepatic Impairment:
The pharmacokinetics of Ambien in eight patients with chronic hepatic insufficiency were
compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose,
mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs.
4,203 ng·hr/mL) higher, respectively, in hepatically -compromised patients. Tmax did not change.
The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that
observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified
accordingly in patients with hepatic insufficiency [see Dosage and Administration (2.2) and
Warnings and Precautions (5.6)].
Renal Impairment:
The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal
failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were
dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant
differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of
drug administration when baseline concentration adjustments were made. On day 1, Cmax was
172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203
± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr);
after repeated dosing Tmax was 0.8 ± 0.2 hr (range: 0.5 to 2.0 hr). This variation is accounted for
by noting that last-day serum sampling began 10 hours after the previous dose, rather than after
24 hours. This resulted in residual drug concentration and a shorter period to reach maximal
serum concentration. On day 1, T1/2 was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated
dosing, T1/2 was 2.5 ± 0.4 hr (range: 0.7 to 4.2 hr). AUC was 796 ± 159 ng·hr/mL after the first
dose and 818 ± 170 ng·hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No
accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were
not significantly different in renally impaired patients. No dosage adjustment is necessary in
patients with compromised renal function. However, as a general precaution, these patients
should be closely monitored.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, mutagenesis, impairment of fertility
Carcinogenesis:
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
Zolpidem was administered to rats and mice for 2 years at dietary dosages of 4, 18, and
80 mg/kg/day. In mice, these doses are 26 to 520 times or 2 to 35 times the maximum 10 mg
human dose on a mg/kg or mg/m2 basis, respectively. In rats these doses are 43 to 876 times or 6
to 115 times the maximum 10 mg human dose on a mg/kg or mg/m2 basis, respectively. No
evidence of carcinogenic potential was observed in mice. Renal liposarcomas were seen in
4/100 rats (3 males, 1 female) receiving 80 mg/kg/day and a renal lipoma was observed in one
male rat at the 18 mg/kg/day dose. Incidence rates of lipoma and liposarcoma for zolpidem were
comparable to those seen in historical controls and the tumor findings are thought to be a
spontaneous occurrence.
Mutagenesis:
Zolpidem did not have mutagenic activity in several tests including the Ames test, genotoxicity
in mouse lymphoma cells in vitro, chromosomal aberrations in cultured human lymphocytes,
unscheduled DNA synthesis in rat hepatocytes in vitro, and the micronucleus test in mice.
Impairment of fertility:
In a rat reproduction study, the high dose (100 mg base/kg) of zolpidem resulted in irregular
estrus cycles and prolonged precoital intervals, but there was no effect on male or female fertility
after daily oral doses of 4 to 100 mg base/kg or 5 to 130 times the recommended human dose
in mg/m2. No effects on any other fertility parameters were noted.
14 CLINICAL STUDIES
14.1 Transient insomnia
Normal adults experiencing transient insomnia (n = 462) during the first night in a sleep
laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two
doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo
on objective (polysomnographic) measures of sleep latency, sleep duration, and number of
awakenings.
Normal elderly adults (mean age 68) experiencing transient insomnia (n = 35) during the first
two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial
comparing four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were
superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all
four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and
sleep quality).
14.2 Chronic insomnia
Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic
insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and
Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n
= 75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of
zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and
sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks
and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of
awakenings at both doses studied.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel
group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was
superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective
measures of total sleep time, number of awakenings, and sleep quality for the first treatment
week.
Increased wakefulness during the last third of the night as measured by polysomnography has not
been observed in clinical trials with Ambien.
14.3 Studies pertinent to safety concerns for sedative/hypnotic drugs
Next-day residual effects: Next-day residual effects of Ambien were evaluated in seven
studies involving normal subjects. In three studies in adults (including one study in a phase
advance model of transient insomnia) and in one study in elderly subjects, a small but
statistically significant decrease in performance was observed in the Digit Symbol Substitution
Test (DSST) when compared to placebo. Studies of Ambien in non-elderly patients with
insomnia did not detect evidence of next-day residual effects using the DSST, the Multiple Sleep
Latency Test (MSLT), and patient ratings of alertness.
Rebound effects: There was no objective (polysomnographic) evidence of rebound insomnia
at recommended doses seen in studies evaluating sleep on the nights following discontinuation of
Ambien (zolpidem tartrate). There was subjective evidence of impaired sleep in the elderly on
the first post-treatment night at doses above the recommended elderly dose of 5 mg.
Memory impairment: Controlled studies in adults utilizing objective measures of memory
yielded no consistent evidence of next-day memory impairment following the administration of
Ambien. However, in one study involving zolpidem doses of 10 and 20 mg, there was a
significant decrease in next-morning recall of information presented to subjects during peak drug
effect (90 minutes post-dose), i.e., these subjects experienced anterograde amnesia. There was
also subjective evidence from adverse event data for anterograde amnesia occurring in
association with the administration of Ambien, predominantly at doses above 10 mg.
Effects on sleep stages: In studies that measured the percentage of sleep time spent in each
sleep stage, Ambien has generally been shown to preserve sleep stages. Sleep time spent in
stages 3 and 4 (deep sleep) was found comparable to placebo with only inconsistent, minor
changes in REM (paradoxical) sleep at the recommended dose.
16 HOW SUPPLIED/STORAGE AND HANDLING
Ambien 5 mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed on one side
and 5401 on the other and supplied as:
NDC Number
Size
0024-5401-31
bottle of 100
0024-5401-34
carton of 100 unit dose
0024-5401-50
bottle of 500
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
Ambien 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one
side and 5421 on the other and supplied as:
NDC Number
Size
0024-5421-31
bottle of 100
0024-5421-34
carton of 100 unit dose
0024-5421-50
bottle of 500
Store at controlled room temperature 20°–25°C (68°–77°F).
17 PATIENT COUNSELING INFORMATION
Prescribers or other healthcare professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with sedative-hypnotics, should
counsel them in its appropriate use, and should instruct them to read the accompanying
Medication Guide [see Medication Guide (17.4)].
17.1 Severe anaphylactic and anaphylactoid reactions
Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with
zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical
attention immediately if any of them occur.
17.2 Sleep-driving and other complex behaviors
There have been reports of people getting out of bed after taking a sedative-hypnotic and driving
their cars while not fully awake, often with no memory of the event. If a patient experiences
such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can
be dangerous. This behavior is more likely to occur when Ambien is taken with alcohol or other
central nervous system depressants [see Warnings and Precautions (5.3)]. Other complex
behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been
reported in patients who are not fully awake after taking a sedative-hypnotic. As with
“sleep-driving”, patients usually do not remember these events.
In addition, patients should be advised to report all concomitant medications to the prescriber.
Patients should be instructed to report events such as “sleep-driving” and other complex
behaviors immediately to the prescriber.
17.3 Administration instructions
Patients should be counseled to take Ambien right before they get into bed and only when they
are able to stay in bed a full night (7-8 hours) before being active again. Ambien tablets should
not be taken with or immediately after a meal. Advise patients NOT to take Ambien when
drinking alcohol.
17.4 Medication Guide
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
MEDICATION GUIDE
AMBIEN® (ām'bē-ən) Tablets C-IV
(zolpidem tartrate)
Read the Medication Guide that comes with AMBIEN before you start taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the
place of talking to your doctor about your medical condition or treatment.
What is the most important information I should
know about AMBIEN?
After taking AMBIEN, you may get up out of bed
while not being fully awake and do an activity
that you do not know you are doing. The next
morning, you may not remember that you did
anything during the night. You have a higher
chance for doing these activities if you drink alcohol
or take other medicines that make you sleepy with
AMBIEN. Reported activities include:
•
driving a car ("sleep-driving")
•
making and eating food
•
talking on the phone
•
having sex
•
sleep-walking
Call your doctor right away if you find out that
you have done any of the above activities after
taking AMBIEN.
Important:
1. Take AMBIEN exactly as prescribed
•
Do not take more AMBIEN than prescribed.
•
Take AMBIEN right before you get in bed, not
sooner.
2. Do not take AMBIEN if you:
•
drink alcohol
•
take other medicines that can make you sleepy.
Talk to your doctor about all of your medicines.
Your doctor will tell you if you can take AMBIEN
with your other medicines.
•
cannot get a full night’s sleep
What is AMBIEN?
AMBIEN is a sedative-hypnotic (sleep) medicine.
AMBIEN is used in adults for the short-term
treatment of a sleep problem called insomnia.
Symptoms of insomnia include:
• trouble falling asleep
AMBIEN is not for children.
AMBIEN is a federally controlled substance
(C-IV) because it can be abused or lead to
dependence. Keep AMBIEN in a safe place to
prevent misuse and abuse. Selling or giving
away AMBIEN may harm others, and is
against the law. Tell your doctor if you have
ever abused or have been dependent on
alcohol, prescription medicines or street drugs.
Who should not take AMBIEN?
Do not take AMBIEN if you are allergic to
anything in it.
See the end of this Medication Guide for a
complete list of ingredients in AMBIEN.
AMBIEN may not be right for you. Before
starting AMBIEN, tell your doctor about all
of your health conditions, including if you:
•
have a history of depression, mental
illness, or suicidal thoughts
•
have a history of drug or alcohol abuse or
addiction
•
have kidney or liver disease
•
have a lung disease or breathing
problems
•
are pregnant, planning to become
pregnant, or breastfeeding
Tell your doctor about all of the medicines you
take including prescription and nonprescription
medicines, vitamins and herbal supplements.
Medicines can interact with each other,
sometimes causing serious side effects. Do
not take AMBIEN with other medicines that
can make you sleepy.
Know the medicines you take. Keep a list of
your medicines with you to show your doctor
and pharmacist each time you get a new
medicine.
How should I take AMBIEN?
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
•
Take AMBIEN exactly as prescribed. Do not
take more AMBIEN than prescribed for you.
•
Take AMBIEN right before you get into bed.
•
Do not take AMBIEN unless you are able to
stay in bed a full night (7-8 hours) before you
must be active again.
•
For faster sleep onset, AMBIEN should NOT be
taken with or immediately after a meal.
•
Call your doctor if your insomnia worsens or is
not better within 7 to 10 days. This may mean
that there is another condition causing your
sleep problem.
•
If you take too much AMBIEN or overdose, call
your doctor or poison control center right away,
or get emergency treatment.
What are the possible side effects of AMBIEN?
Serious side effects of AMBIEN include:
•
getting out of bed while not being fully
awake and do an activity that you do not
know you are doing. (See “What is the most
important information I should know about
AMBIEN?)
•
abnormal thoughts and behavior. Symptoms
include more outgoing or aggressive behavior
than normal, confusion, agitation, hallucinations,
worsening of depression, and suicidal thoughts
or actions.
•
memory loss
•
anxiety
•
severe allergic reactions. Symptoms include
swelling of the tongue or throat, trouble
breathing, and nausea and vomiting. Get
emergency medical help if you get these
symptoms after taking AMBIEN.
Call your doctor right away if you have any of the
above side effects or any other side effects that
worry you while using AMBIEN.
The most common side effects of AMBIEN are:
•
drowsiness
•
dizziness
•
diarrhea
•
“drugged feelings”
•
You may still feel drowsy the next day after
taking AMBIEN. Do not drive or do other
dangerous activities after taking AMBIEN
until you feel fully awake.
After you stop taking a sleep medicine, you
may have symptoms for 1 to 2 days such as:
trouble
sleeping,
nausea,
flushing,
lightheadedness,
uncontrolled
crying,
vomiting, stomach cramps, panic attack,
nervousness, and stomach area pain.
These are not all the side effects of AMBIEN.
Ask your doctor or pharmacist for more
information.
Call your doctor for medical advice about side
effects. You may report side effects to FDA at
1–800–FDA–1088.
How should I store AMBIEN?
•
Store AMBIEN at room temperature, 68°
to 77°F (20° to 25°C).
•
Keep AMBIEN and all medicines out of
reach of children.
General Information about AMBIEN
•
Medicines are sometimes prescribed for
purposes other than those listed in a
Medication Guide.
•
Do not use AMBIEN for a condition for
which it was not prescribed.
•
Do not share AMBIEN with other people,
even if you think they have the same
symptoms that you have. It may harm
them and it is against the law.
This Medication Guide summarizes the most
important information about AMBIEN. If you
would like more information, talk with your
doctor. You can ask your doctor or
pharmacist for information about AMBIEN that
is written for healthcare professionals. For
more information about AMBIEN, call
1-800-633-1610.
What are the ingredients in AMBIEN?
Active Ingredient: Zolpidem tartrate
Inactive Ingredients: hydroxypropyl
methylcellulose, lactose, magnesium stearate,
micro-crystalline cellulose, polyethylene glycol,
sodium starch glycolate, and titanium dioxide.
In addition, the 5 mg tablet contains FD&C
Red No. 40, iron oxide colorant, and
polysorbate 80.
Rx Only
This Medication Guide has been approved by
the U.S. Food and Drug Administration.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19908 FDA SLR 027 Approved labeling 4.23.08
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
February 2008
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:17.313482
|
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|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AMBIEN safely and effectively. See full prescribing information for
AMBIEN
Ambien® (zolpidem tartrate) tablets for oral administration
Initial US Approval: 1992
----------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1)
03/2007
Warnings and Precautions (5)
03/2007
----------------------------INDICATIONS AND USAGE---------------------------
Ambien (zolpidem tartrate) is indicated for the short-term treatment of
insomnia characterized by difficulties with sleep initiation. Ambien has been
shown to decrease sleep latency for up to 35 days in controlled clinical
studies. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
•
Adult dose: 10 mg immediately before bedtime (2.1)
•
Elderly/Debilitated patients/Hepatic Impairment: Initial dose of 5 mg
(2.2)
•
Downward dosage adjustment may be necessary when used with CNS
depressants (2.3)
•
Total daily dose should not exceed 10 mg (2.4)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
5 mg and 10 mg tablets (3)
-------------------------------CONTRAINDICATIONS------------------------------
Hypersensitivity to zolpidem tartrate or inactive ingredients (4.1)
----------------------WARNINGS AND PRECAUTIONS-------------------------
•
Reevaluate if insomnia persists after 7 to 10 days of use (5.1)
•
Severe anaphylactic and anaphylactoid reactions have been reported
(5.2)
•
Abnormal thinking, behavior changes and complex behaviors such as
sleep-driving have been reported (5.3)
•
Pediatric patients with attention-deficit/hyperactivity disorder (ADHD):
Hallucinations (7.4%) and other psychiatric and /or nervous system
adverse events were observed frequently (5.6, 8.4)
•
Depression: Worsening of depression or, suicidal thinking may occur.
Prescribe the least amount feasible to avoid intentional overdose (5.3,
5.6)
•
Withdrawal symptoms may occur with rapid dose reduction or
discontinuation (5.4)
•
CNS depressant effects, additive effects with CNS depressants (2.3, 5.5)
•
Potential impairment of activities requiring complete mental alertness
such as operating machinery or driving a motor vehicle, after ingesting
the drug and the following day (5.5)
•
Additive effects with alcohol; should not be taken with alcohol (5.5)
•
Elderly/debilitated patients: Impaired motor, cognitive performance after
repeated exposure, increased sensitivity (2.2, 5.6)
•
Caution advised in patients with hepatic impairment, mild to moderate
COPD, impaired drug metabolism or hemodynamic responses, mild to
moderate sleep apnea (5.6)
-----------------------------ADVERSE REACTIONS--------------------------------
•
Most commonly observed adverse events in studies with zolpidem (up to
10 mg) at statistically significant differences from placebo were:
Short-term (<10 nights): Drowsiness, dizziness, and diarrhea
Long-term (28 - 35 nights): Dizziness and drugged feelings (6.1)
•
Dose relationship observed for adverse events especially CNS and GI
events (6.1)
•
Other adverse reactions, including serious adverse reactions, have been
reported (6)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088, or
http://www.fda.gov
------------------------------DRUG INTERACTIONS-------------------------------
•
Imipramine: decreased alertness (7.1)
•
Chlorpromazine: impaired alertness and psychomotor performance (7.1)
•
Alcohol causes additive psychomotor impairment (7.1)
•
Rifampin (CYP450) decreases exposure to, and effects of zolpidem (7.2)
•
Sedative/hypnotic effect reversed by flumazenil (7.3, 10.2)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
•
Labor and delivery: No established use (8.2)
•
Nursing mothers: Not recommended (8.3)
•
Pediatric use: Safety and effectiveness have not been established (8.4)
•
Geriatric use: Reduced dose in elderly to decrease side effects (8.5)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
{Revision date}
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Dosage in adults
2.2
Special populations
2.3
Administration with CNS depressants
2.4
Maximum daily dose
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1
Hypersensitivity
5
WARNINGS AND PRECAUTIONS
5.1
General
5.2
Severe anaphylactic and anaphylactoid reactions
5.3
Abnormal thinking and behavioral changes
5.4
Withdrawal effects
5.5
CNS depressant effects
5.6
Special populations
5.7
Laboratory tests
6
ADVERSE REACTIONS
6.1
Incidence in controlled clinical trials
7
DRUG INTERACTIONS
7.1
CNS active drugs
7.2
Drugs that affect drug metabolism via cytochrome P450
7.3
Other drugs
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and delivery
8.3
Nursing mothers
8.4
Pediatric use
8.5
Geriatric use
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled substance
9.2
Abuse
9.3
Dependence
10
OVERDOSAGE
10.1
Signs and symptoms
10.2
Recommended treatment
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, mutagenesis, impairment of fertility
14
CLINICAL STUDIES
14.1
Transient insomnia
14.2
Chronic insomnia
14.3
Studies pertinent to safety concerns for sedatives/hypnotic
drugs
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How supplied
16.2
Storage and handling
17
PATIENT COUNSELING INFORMATION
17.1
General
17.2
FDA-approved patient labeling
*Sections or subsections omitted from the full prescribing information are not
listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Ambien (zolpidem tartrate) is indicated for the short-term treatment of insomnia characterized by
difficulties with sleep initiation. Ambien has been shown to decrease sleep latency for up to 35
days in controlled clinical studies [see Clinical Studies (14)].
The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final
formal assessments of sleep latency performed at the end of treatment.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage in adults
The dose of Ambien should be individualized.
The recommended dose for adults is 10 mg immediately before bedtime.
2.2 Special Populations
Elderly or debilitated patients may be especially sensitive to the effects of Ambien (zolpidem
tartrate). Patients with hepatic insufficiency do not clear the drug as rapidly as normals. An
initial 5 mg dose is recommended in these patients [see Warnings and Precautions (5)].
2.3 Administration with CNS depressants:
Downward dosage adjustment may be necessary when Ambien is administered with agents
having known CNS-depressant effects because of the potentially additive effects [see Warnings
and Precautions (5)].
2.4 Maximum daily dose:
The total Ambien dose should not exceed 10 mg per day.
3 DOSAGE FORMS AND STRENGTHS
Ambien is available in 5 mg and 10 mg strength tablets for oral administration.
Ambien 5 mg tablets are capsule-shaped, pink, film coated, with, AMB 5 debossed on one side
and 5401 on the other. The 10 mg tablets are capsule-shaped, white, film coated, with AMB 10
debossed on one side and 5421 on the other. Tablets are not scored.
4 CONTRAINDICATIONS
4.1 Hypersensitivity
Ambien is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any
of the inactive ingredients in the formulation.
5 WARNINGS AND PRECAUTIONS
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3
5.1 General
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric
disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of
the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate
the presence of a primary psychiatric and/or medical illness that should be evaluated.
Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the
consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged
during the course of treatment with sedative/hypnotic drugs, including Ambien. Because some
of the important adverse effects of Ambien appear to be dose related [see Dosage and
Administration (2)], it is important to use the smallest possible effective dose, especially in the
elderly.
5.2 Severe anaphylactic and anaphylactoid reactions
Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients
after taking the first or subsequent doses of sedative-hypnotics, including Ambien. Some patients
have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that
suggest anaphylaxis. Some patients have required medical therapy in the emergency department.
If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal.
Patients who develop angioedema after treatment with Ambien should not be rechallenged with
the drug.
5.3 Abnormal Thinking and Behavioral Changes
A variety of abnormal thinking and behavior changes have been reported to occur in association
with the use of sedative/hypnotics. Some of these changes may be characterized by decreased
inhibition (eg, aggressiveness and extroversion that seemed out of character), similar to effects
produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been
reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization.
[In controlled trials, <1% of adults with insomnia who received zolpidem reported
hallucinations. In a clinical trial, 7.4 % of pediatric patients with insomnia associated with
attention-deficit/hyperactivity disorder (ADHD), who received zolpidem reported
hallucinations.]
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of
a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in
sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although
behaviors such as “sleep-driving” may occur with Ambien alone at therapeutic doses, the use of
alcohol and other CNS depressants with Ambien appears to increase the risk of such behaviors,
as does the use of Ambien at doses exceeding the maximum recommended dose. Due to the risk
to the patient and the community, discontinuation of Ambien should be strongly considered for
patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and
eating food, making phone calls, or having sex) have been reported in patients who are not fully
awake after taking a sedative-hypnotic. As with “sleep-driving”, patients usually do not
remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur
unpredictably. In primarily depressed patients, worsening of depression, including suicidal
thinking, has been reported in association with the use of sedative/hypnotics.
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4
It can rarely be determined with certainty whether a particular instance of the abnormal
behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying
psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or
symptom of concern requires careful and immediate evaluation.
5.4 Withdrawal effects
Following the rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have
been reports of signs and symptoms similar to those associated with withdrawal from other CNS-
depressant drugs [see Drug Abuse and Dependence (9)].
5.5 CNS depressant effects
Ambien, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset
of action, Ambien should only be ingested immediately prior to going to bed. Patients should be
cautioned against engaging in hazardous occupations requiring complete mental alertness or
motor coordination such as operating machinery or driving a motor vehicle after ingesting the
drug, including potential impairment of the performance of such activities that may occur the day
following ingestion of Ambien. Ambien showed additive effects when combined with alcohol
and should not be taken with alcohol. Patients should also be cautioned about possible combined
effects with other CNS-depressant drugs. Dosage adjustments may be necessary when Ambien
is administered with such agents because of the potentially additive effects.
5.6 Special Populations
Use in the elderly and/or debilitated patients: Impaired motor and/or cognitive
performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a
concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended
Ambien dosage is 5 mg in such patients [see Dosage and Administration (2)] to decrease the
possibility of side effects. These patients should be closely monitored.
Use in patients with concomitant illness: Clinical experience with Ambien (zolpidem
tartrate) in patients with concomitant systemic illness is limited. Caution is advisable in using
Ambien in patients with diseases or conditions that could affect metabolism or hemodynamic
responses. Although studies did not reveal respiratory depressant effects at hypnotic doses of
Ambien in normals or in patients with mild to moderate chronic obstructive pulmonary disease
(COPD), a reduction in the Total Arousal Index together with a reduction in lowest oxygen
saturation and increase in the times of oxygen desaturation below 80% and 90% was observed in
patients with mild-to-moderate sleep apnea when treated with Ambien (10 mg) when compared
to placebo. However, precautions should be observed if Ambien is prescribed to patients with
compromised respiratory function, since sedative/hypnotics have the capacity to depress
respiratory drive. Post-marketing reports of respiratory insufficiency, most of which involved
patients with pre-existing respiratory impairment, have been received. Data in end-stage renal
failure patients repeatedly treated with Ambien did not demonstrate drug accumulation or
alterations in pharmacokinetic parameters. No dosage adjustment in renally impaired patients is
required; however, these patients should be closely monitored [see Pharmacokinetics (12.3)]. A
study in subjects with hepatic impairment did reveal prolonged elimination in this group;
therefore, treatment should be initiated with 5 mg in patients with hepatic compromise, and they
should be closely monitored.
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5
Use in depression: As with other sedative/hypnotic drugs, Ambien should be administered
with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be
present in such patients and protective measures may be required. Intentional over-dosage is
more common in this group of patients; therefore, the least amount of drug that is feasible should
be prescribed for the patient at any one time.
Pediatric patients: Safety and effectiveness of zolpidem has not been established in pediatric
patients. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with
ADHD, zolpidem did not decrease sleep latency compared to placebo. Hallucinations were
reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients
who received placebo reported hallucinations [see Use in Specific Populations: Pediatric Use
(8.4)].
5.7 Laboratory tests
Monitoring: There are no specific laboratory tests recommended to monitor zolpidem levels.
Interference with laboratory tests: Zolpidem is not known to interfere with commonly
employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not
cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines
in two standard urine drug screens.
6 ADVERSE REACTIONS
Serious adverse reactions including severe anaphylactic and anaphylactoid reactions, abnormal
thinking and behavior, complex behaviors, withdrawal effects, amnesia, anxiety, other neuro-
psychiatric symptoms and CNS-depressant effects have been reported with zolpidem [see
Warnings and Precautions (5)].
6.1 Incidence in controlled clinical trials
Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who
received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued
treatment because of an adverse clinical event. Events most commonly associated with
discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache
(0.5%), nausea (0.6%), and vomiting (0.5%).
Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar
foreign trials discontinued treatment because of an adverse event. Events most commonly
associated with discontinuation from these trials were daytime drowsiness (1.1%),
dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).
Data from a clinical study in which selective serotonin reuptake inhibitor- (SSRI) treated patients
were given zolpidem revealed that four of the seven discontinuations during double-blind
treatment with zolpidem (n=95) were associated with impaired concentration, continuing or
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6
aggravated depression, and manic reaction; one patient treated with placebo (n =97) was
discontinued after an attempted suicide.
Most commonly observed adverse events in controlled trials: During short-term
treatment (up to 10 nights) with Ambien at doses up to 10 mg, the most commonly observed
adverse events associated with the use of zolpidem and seen at statistically significant
differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem
patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights)
with zolpidem at doses up to 10 mg, the most commonly observed adverse events associated
with the use of zolpidem and seen at statistically significant differences from placebo-treated
patients were dizziness (5%) and drugged feelings (3%).
Adverse events observed at an incidence of ≥1% in controlled trials: The following
tables enumerate treatment-emergent adverse event frequencies that were observed at an
incidence equal to 1% or greater among patients with insomnia who received Ambien in U.S.
placebo-controlled trials. Events reported by investigators were classified utilizing a modified
World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing
event frequencies. The prescriber should be aware that these figures cannot be used to predict
the incidence of side effects in the course of usual medical practice, in which patient
characteristics and other factors differ from those that prevailed in these clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigators
involving related drug products and uses, since each group of drug trials is conducted under a
different set of conditions. However, the cited figures provide the physician with a basis for
estimating the relative contribution of drug and nondrug factors to the incidence of side effects in
the population studied.
The following table was derived from a pool of 11 placebo-controlled short-term U.S. efficacy
trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from
doses up to and including 10 mg, the highest dose recommended for use.
Incidence of Treatment-Emergent Adverse Experiences in Short-term
Placebo-Controlled Clinical Trials
(Percentage of patients reporting)
Body System/
Adverse Event*
Zolpidem
(≤10mg)
(N=685)
Placebo
(N=473)
Central and Peripheral Nervous System
Headache
Drowsiness
Dizziness
Gastrointestinal System
Nausea
Diarrhea
Musculoskeletal System
Myalgia
7
2
1
2
1
1
6
_
_
3
-
2
*Events reported by at least 1% of Ambien patients are included
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7
The following table was derived from a pool of three placebo-controlled long-term efficacy trials
involving Ambien (zolpidem tartrate). These trials involved patients with chronic insomnia who
were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to
data from doses up to and including 10 mg, the highest dose recommended for use. The table
includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.
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8
Incidence of Treatment-Emergent Adverse Experiences in Long-term
Placebo-Controlled Clinical Trials
(Percentage of patients reporting)
Body System/
Adverse Event*
Zolpidem
(≤10mg)
(N=152)
Placebo
(N=161)
Autonomic Nervous System
Dry mouth
Body as a Whole
Allergy
Back Pain
Influenza-like symptoms
Chest pain
Fatigue
Cardiovascular System
Palpitation
Central and Peripheral Nervous System
Headache
Drowsiness
Dizziness
Lethargy
Drugged feeling
Lightheadedness
Depression
Abnormal dreams
Amnesia
Anxiety
Nervousness
Sleep disorder
Gastrointestinal System
Nausea
Dyspepsia
Diarrhea
Abdominal pain
Constipation
Anorexia
Vomiting
3
4
3
2
1
1
2
19
8
5
3
3
2
2
1
1
1
1
1
6
5
3
2
2
1
1
1
1
2
-
-
2
-
22
5
1
1
-
1
1
-
-
1
3
-
6
6
2
2
1
1
1
*Events reported by at least 1% of patients treated with Ambien.
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9
Incidence of Treatment-Emergent Adverse Experiences in Long-term
Placebo-Controlled Clinical Trials (continued)
(Percentage of patients reporting)
Body System/
Adverse Event*
Zolpidem
(≤10mg)
(N=152)
Placebo
(N=161)
Immunologic System
Infection
Musculoskeletal System
Myalgia
Arthralgia
Respiratory System
Upper respiratory infection
Sinusitis
Pharyngitis
Rhinitis
Skin and Appendages
Rash
Urogenital System
Urinary tract infection
1
7
4
5
4
3
1
2
2
1
7
4
6
2
1
3
1
2
*Events reported by at least 1% of patients treated with Ambien
Dose relationship for adverse events: There is evidence from dose comparison trials
suggesting a dose relationship for many of the adverse events associated with zolpidem use,
particularly for certain CNS and gastrointestinal adverse events.
Adverse event incidence across the entire preapproval database: Ambien (zolpidem
tartrate) was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and
Europe. Treatment-emergent adverse events associated with clinical trial participation were
recorded by clinical investigators using terminology of their own choosing. To provide a
meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse
events, similar types of untoward events were grouped into a smaller number of standardized
event categories and classified utilizing a modified World Health Organization (WHO)
dictionary of preferred terms. The frequencies presented, therefore, represent the proportions of
the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type
cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse
events are included, except those already listed in the table above of adverse events in placebo-
controlled studies, those coding terms that are so general as to be uninformative, and those
events where a drug cause was remote. It is important to emphasize that, although the events
reported did occur during treatment with Ambien, they were not necessarily caused by it.
Adverse events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
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10
those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in
1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension,
syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension,
impotence, increased saliva, tenesmus.
Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fever, malaise, trauma. Rare:
allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR,
pain, restless legs, rigors, tolerance increased, weight decrease.
Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia.
Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension
aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose
veins, ventricular tachycardia.
Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, insomnia,
vertigo. Infrequent: agitation, decreased cognition, detached, difficulty concentrating,
dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine,
paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal
gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido,
delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia,
hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic
attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.
Gastrointestinal system: Frequent: hiccup. Infrequent: constipation, dysphagia, flatulence,
gastroenteritis. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal
obstruction, rectal hemorrhage, tooth caries.
Hematologic and lymphatic system: Rare: anemia, hyperhemoglo-binemia, leukopenia,
lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Immunologic system: Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.
Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare:
bilirubinemia, increased SGOT.
Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia,
hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.
Musculoskeletal system: Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica,
tendinitis.
Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis,
breast neoplasm, breast pain.
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Respiratory system: Infrequent: bronchitis, coughing, dyspnea. Rare: bronchospasm,
epistaxis, hypoxia, laryngitis, pneumonia.
Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis,
furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.
Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain,
scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation
abnormal, parosmia, photopsia.
Urogenital system: Infrequent: cystitis, urinary incontinence. Rare: acute renal failure,
dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.
7 DRUG INTERACTIONS
7.1 CNS-active drugs
Ambien was evaluated in healthy volunteers in single-dose interaction studies for several CNS
drugs. A study involving haloperidol and zolpidem revealed no effect of haloperidol on the
pharmacokinetics or pharmacodynamics of zolpidem. Imipramine in combination with zolpidem
produced no pharmacokinetic interaction other than a 20% decrease in peak levels of
imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in
combination with zolpidem produced no pharmacokinetic interaction, but there was an additive
effect of decreased alertness and psychomotor performance. The lack of a drug interaction
following single-dose administration does not predict a lack following chronic administration.
An additive effect on psychomotor performance between alcohol and zolpidem was
demonstrated [see Warnings and Precautions: CNS depressant effects (5.5)].
A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels
in male volunteers did not demonstrate any clinically significant pharmacokinetic or
pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady-state
concentrations were evaluated in healthy females, the only significant change was a 17%
increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor
performance.
Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg
(17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was
significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of
sertraline and N-desmethylsertraline were unaffected by zolpidem.
Since the systematic evaluations of Ambien (zolpidem tartrate) in combination with other CNS-
active drugs have been limited, careful consideration should be given to the pharmacology of any
CNS-active drug to be used with zolpidem. Any drug with CNS-depressant effects could
potentially enhance the CNS-depressant effects of zolpidem.
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7.2 Drugs that affect drug metabolism via cytochrome P450
A randomized, double-blind, crossover interaction study in ten healthy volunteers between
itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours
after the last dose of itraconazole resulted in a 34% increase in AUC0-∞ of zolpidem. There were
no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or
psychomotor performance.
A randomized, placebo-controlled, crossover interaction study in eight healthy female volunteers
between 5 consecutive daily doses of rifampin (600 mg) and a single dose of zolpidem (20 mg)
given 17 hours after the last dose of rifampin showed significant reductions of the AUC (–73%),
Cmax (–58%), and T1/2 (–36%) of zolpidem together with significant reductions in the
pharmacodynamic effects of zolpidem.
7.3 Other drugs
A study involving cimetidine/zolpidem and ranitidine/ zolpidem combinations revealed no effect
of either drug on the pharmacokinetics or pharmacodynamics of zolpidem. Zolpidem had no
effect on digoxin kinetics and did not affect prothrombin time when given with warfarin in
normal subjects. Zolpidem’s sedative/hypnotic effect was reversed by flumazenil; however, no
significant alterations in zolpidem pharmacokinetics were found.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic effects: Pregnancy Category C
Zolpidem tartrate was administered to pregnant Sprague-Dawley rats by oral gavage during the
period of organogenesis at doses of 4, 20, or 100 mg based/kg/day. Adverse maternal and
embryo/fetal effects occurred at doses of 20 mg base/kg and higher, manifesting as dose-related
lethargy and ataxia in pregnant rats while examination of fetal skull bones revealed a dose-
related trend toward incomplete ossification. Teratogenicity was not observed at any dose level.
The no-effect dose of zolpidem for maternal and embryofetal toxicity was 4 mg base/kg/day
(between 4 to 5 times the MRHD of Ambien on a mg/m2 basis).
Administration of zolpidem tartrate to pregnant Himalayan Albino rabbits at doses of 1, 4, or 16
mg base/kg/day by oral gavage (over 35 times the MRHD of Ambien on a mg/m2 basis) during
the period of organogenesis produced dose-related maternal sedation and decreased maternal
body weight gain at all doses. At the high dose of 16 mg base/kg, there was an increase in
postimplantation fetal loss and under-ossification of sternebrae in viable fetuses. Teratogenicity
was not observed at any dose level. The no-effect dose of zolpidem for maternal toxicity was
below 1 mg base/kg/day (< 2-times the MRHD of Ambien on a mg/m2 basis). The no-effect
dose for embryofetal toxicity was 4 mg base/kg/day (between 9 and 10 times the MRHD of
Ambien on a mg/m2 basis).
Administration of zolpidem tartrate at doses of 4, 20, or 100 mg base/kg/day to pregnant
Sprague-Dawley rats starting on Day 15 of gestation and continuing through Day 21 of the
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postnatal lactation period produced dose-dependent lethargy and ataxia in dams at doses of 20
mg base/kg and higher. Decreased maternal body weight gain as well as evidence on non-
secreting mammary glands and a single incidence of maternal death was observed at 100 mg
base/kg. Effects observed on rat pups included decreased body weight with maternal doses of 20
mg base/kg and higher and decreased pup survival at maternal doses of 100 mg base/kg. The no-
effect dose for maternal and offspring toxicity was 4 mg base/kg (between 4 to 5 times the
MRHD of Ambien on a mg/m2 basis).
There are no adequate and well-controlled studies in pregnant women. Ambien should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus
Nonteratogenic effects. Studies to assess the effects on children whose mothers took zolpidem
during pregnancy have not been conducted. However, children born of mothers taking
sedative/hypnotic drugs may be at some risk for withdrawal symptoms from the drug during the
postnatal period. In addition, neonatal flaccidity has been reported in infants born of mothers
who received sedative/hypnotic drugs during pregnancy.
8.2 Labor and delivery
Ambien (zolpidem tartrate) has no established use in labor and delivery.
8.3 Nursing mothers
Studies in lactating mothers indicate that the half-life of zolpidem is similar to that in young
normal volunteers (2.6± 0.3 hr). Between 0.004 and 0.019% of the total administered dose is
excreted into milk, but the effect of zolpidem on the infant is unknown.
In addition, in a rat study, zolpidem inhibited the secretion of milk. The no-effect dose was 4 mg
base/kg or 6 times the recommended human dose in mg/m2.
The use of Ambien in nursing mothers is not recommended.
8.4 Pediatric use
Safety and effectiveness of zolpidem have not been established in pediatric patients.
In an 8-week controlled study, 201 pediatric patients (aged 6-17 years) with insomnia associated
with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics),
were treated with an oral solution of zolpidem, 0.25 mg/kg/day, up to a maximum of 10 mg/day
(n=136), or placebo (n = 65). Zolpidem did not significantly decrease latency to persistent sleep,
compared to placebo, as measured by polysomnography after 4 weeks of treatment. Psychiatric
and nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse
events observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%),
headache (12.5% vs. 9.2%), and hallucinations (7.4% vs. 0%) [see Warnings and Precautions:
Special Populations (5.6)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an
adverse event.
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8.5 Geriatric use
A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials
who received zolpidem were ≥60 years of age. For a pool of U.S. patients receiving zolpidem at
doses of ≤10 mg or placebo, there were three adverse events occurring at an incidence of at least
3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence
(ie, they could be considered drug related).
Adverse Event
Zolpidem
Placebo
Dizziness
Drowsiness
Diarrhea
3%
5%
3%
0%
2%
1%
A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30
(93%) who were ≥70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem
doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported
confusion, including 18/24 (75%) who were ≥70 years of age. Of these 18 patients, 14 (78%)
were receiving zolpidem doses >10 mg.
The recommended dose of Ambien is 5 mg in elderly to decrease the possibility of side effects
[see Dosage and Administration (2) and Warnings and Precautions (5)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled substance
Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.
9.2 Abuse
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of the drug for non-medical purposes, often in combination with other
psychoactive substances. Physical dependence is a state of adaptation that is manifested by a
specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction,
decreasing blood level of the drug, and/or administration of an antagonist. Tolerance is a state of
adaptation in which exposure to a drug induces changes that result in a diminution of one or
more of the drug effects over time. Tolerance may occur to both desired and undesired effects of
drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use, compulsive
use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a
multidisciplinary approach, but relapse is common
Studies of abuse potential in former drug abusers found that the effects of single doses of
Ambien (zolpidem tartrate) 40 mg were similar, but not identical, to diazepam 20 mg, while
zolpidem tartrate 10 mg was difficult to distinguish from placebo.
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9.3 Dependence
Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt
discontinuation. These reported symptoms range from mild dysphoria and insomnia to a
withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating,
tremors, and convulsions. The U.S. clinical trial experience from zolpidem does not reveal any
clear evidence for withdrawal syndrome. Nevertheless, the following adverse events included in
DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S.
clinical trials following placebo substitution occurring within 48 hours following last zolpidem
treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach
cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events
occurred at an incidence of 1% or less. However, available data cannot provide a reliable
estimate of the incidence, if any, of dependence during treatment at recommended doses. Rare
post-marketing reports of abuse, dependence and withdrawal have been received.
Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk
of habituation and dependence, they should be under careful surveillance when receiving
zolpidem or any other hypnotic.
10 OVERDOSAGE
10.1 Signs and symptoms
In European postmarketing reports of overdose with zolpidem alone, impairment of
consciousness has ranged from somnolence to light coma. There was one case each of
cardiovascular and respiratory compromise. Individuals have fully recovered from zolpidem
tartrate overdoses up to 400 mg (40 times the maximum recommended dose). Overdose cases
involving multiple CNS-depressant agents, including zolpidem, have resulted in more severe
symptomatology, including fatal outcomes.
10.2 Recommended treatment
General symptomatic and supportive measures should be used along with immediate gastric
lavage where appropriate. Intravenous fluids should be administered as needed. Flumazenil may
be useful. As in all cases of drug overdose, respiration, pulse, blood pressure, and other
appropriate signs should be monitored and general supportive measures employed. Hypotension
and CNS depression should be monitored and treated by appropriate medical intervention.
Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs.
The value of dialysis in the treatment of overdosage has not been determined, although
hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated
that zolpidem is not dialyzable.
Poison control center: As with the management of all overdosage, the possibility of
multiple drug ingestion should be considered. The physician may wish to consider contacting a
poison control center for up-to-date information on the management of hypnotic drug product
overdosage.
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11 DESCRIPTION
Ambien (zolpidem tartrate) is a non-benzodiazepine hypnotic of the imidazopyridine class and is
available in 5 mg and 10 mg strength tablets for oral administration.
Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-
tartrate (2:1). It has the following structure:
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water,
alcohol, and propylene glycol. It has a molecular weight of 764.88.
Each Ambien tablet includes the following inactive ingredients: hydroxypropyl methylcellulose,
lactose, magnesium stearate, micro-crystalline cellulose, polyethylene glycol, sodium starch
glycolate, and titanium dioxide; the 5 mg tablet also contains FD&C Red No. 40, iron oxide
colorant, and polysorbate 80.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
Subunit modulation of the GABAA receptor chloride channel macromolecular complex is
hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug
properties. The major modulatory site of the GABAA receptor complex is located on its alpha
(α) subunit and is referred to as the benzodiazepine (BZ) or omega (ω) receptor. At least three
subtypes of the (ω) receptor have been identified.
While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines,
barbiturates, or other drugs with known hypnotic properties, it interacts with a GABA-BZ
receptor complex and shares some of the pharmacological properties of the benzodiazepines. In
contrast to the benzodiazepines, which non-selectively bind to and activate all omega receptor
subtypes, zolpidem in vitro binds the (ω1) receptor preferentially with a high affinity ratio of the
alpha1/alpha5 subunits. The (ω1) receptor is found primarily on the Lamina IV of the
sensorimotor cortical regions, substantia nigra (parsreticulata), cerebellum molecular layer,
olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This
selective binding of zolpidem on the (ω1) receptor is not absolute, but it may explain the relative
absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation
of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.
12.3 Pharmacokinetics
The pharmacokinetic profile of Ambien is characterized by rapid absorption from the GI tract
and a short elimination half-life (T1/2) in healthy subjects.
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In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem
tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range:
58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean
Ambien elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the
5 and 10 mg tablets, respectively. Ambien is converted to inactive metabolites that are
eliminated primarily by renal excretion. Ambien demonstrated linear kinetics in the dose range
of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant,
independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in
young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.
A food-effect study in 30 healthy male volunteers compared the pharmacokinetics of Ambien 10
mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with
food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was
prolonged by 60% (from 1.4 to 2.2hr). The half-life remained unchanged. These results suggest
that, for faster sleep onset, Ambien should not be administered with or immediately after a meal.
In the elderly, the dose for Ambien should be 5 mg [see Warnings and Precautions (5) and
Dosage and Administration (2)]. This recommendation is based on several studies in which the
mean Cmax, T1/2, and AUC were significantly increased when compared to results in young
adults. In one study of eight elderly subjects (>70 years), the means for Cmax, T1/2, and AUC
significantly increased by 50% (255 vs 384 ng/mL), 32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562
ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg
oral dose. Ambien did not accumulate in elderly subjects following nightly oral dosing of 10 mg
for 1 week.
The pharmacokinetics of Ambien in eight patients with chronic hepatic insufficiency were
compared to results in healthy subjects. Following a single 20 mg oral zolpidem dose, mean
Cmax and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203
ng·hr/mL) higher, respectively, in hepatically com-promised patients. Tmax did not change. The
mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed
in normals of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients
with hepatic insufficiency [see Warnings and Precautions (5) and Dosage and Administration
(2)].
The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal
failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were
dosed with zolpidem 10 mg orally each day for 14 or 21 days. No statistically significant
differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of
drug administration when baseline concentration adjustments were made. On day 1, Cmax was
172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203
± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr);
after repeated dosing Tmax was 0.8 ± 0.2 hr (range: 0.5 to 2.0 hr). This variation is accounted for
by noting that last-day serum sampling began 10 hours after the previous dose, rather than after
24 hours. This resulted in residual drug concentration and a shorter period to reach maximal
serum concentration. On day 1, T1/2 was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated
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dosing, T1/2 was 2.5 ± 0.4 hr (range: 0.7 to 4.2 hr). AUC was 796 ± 159 ng·hr/mL after the first
dose and 818 ± 170 ng·hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No
accumulation of unchanged drug appeared after 14 or 21 days. Ambien (zolpidem tartrate)
pharmacokinetics were not significantly different in renally impaired patients. No dosage
adjustment is necessary in patients with compromised renal function. As a general precaution,
these patients should be closely monitored.
Postulated relationship between elimination rate of hypnotics and their profile of
common untoward effects: The type and duration of hypnotic effects and the profile of
unwanted effects during administration of hypnotic drugs may be influenced by the biologic
half-life of administered drug and any active metabolites formed. When half-lives are long, drug
or metabolites may accumulate during periods of nightly administration and be associated with
impairment of cognitive and/or motor performance during waking hours; the possibility of
interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives,
including half-lives of active metabolites, are short, drug and metabolites will be cleared before
the next dose is ingested, and carryover effects related to excessive sedation or CNS depression
should be minimal or absent. Ambien has a short half-life and no active metabolites. During
nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of
hypnotics may develop. If the drug has a short elimination half-life, it is possible that a relative
deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur
at some point in the interval between each night’s use. This sequence of events may account for
two clinical findings reported to occur after several weeks of nightly use of other rapidly
eliminated hypnotics, namely, increased wakefulness during the last third of the night, and the
appearance of increased signs of daytime anxiety. Increased wakefulness during the last third of
the night as measured by polysomnography has not been observed in clinical trials with Ambien.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, mutagenesis, impairment of fertility
Carcinogenesis: Zolpidem was administered to rats and mice for 2 years at dietary dosages
of 4, 18, and 80 mg/kg/day. In mice, these doses are 26 to 520 times or 2 to 35 times the
maximum 10 mg human dose on a mg/kg or mg/m2 basis, respectively. In rats these doses are 43
to 876 times or 6 to 115 times the maximum 10 mg human dose on a mg/kg or mg/m2 basis,
respectively. No evidence of carcinogenic potential was observed in mice. Renal liposarcomas
were seen in 4/100 rats (3 males, 1 female) receiving 80 mg/kg/day and a renal lipoma was
observed in one male rat at the 18 mg/kg/day dose. Incidence rates of lipoma and liposarcoma
for zolpidem were comparable to those seen in historical controls and the tumor findings are
thought to be a spontaneous occurrence.
Mutagenesis: Zolpidem did not have mutagenic activity in several tests including the Ames
test, genotoxicity in mouse lymphoma cells in vitro, chromosomal aberrations in cultured human
lymphocytes, unscheduled DNA synthesis in rat hepatocytes in vitro, and the micronucleus test
in mice.
Impairment of fertility: In a rat reproduction study, the high dose (100 mg base/kg) of
zolpidem resulted in irregular estrus cycles and prolonged precoital intervals, but there was no
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effect on male or female fertility after daily oral doses of 4 to 100 mg base/kg or 5 to 130 times
the recommended human dose in mg/m2. No effects on any other fertility parameters were
noted.
14 CLINICAL STUDIES
14.1 Transient insomnia
Normal adults experiencing transient insomnia (n = 462) during the first night in a sleep
laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two
doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo
on objective (polysomnographic) measures of sleep latency, sleep duration, and number of
awakenings.
Normal elderly adults (mean age 68) experiencing transient insomnia (n = 35) during the first
two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial
comparing four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were
superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all
four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and
sleep quality).
14.2 Chronic insomnia
Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic
insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and
Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n
= 75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of
zolpidem tartrate (10 and 15 mg) and placebo. On objective (polysomnographic) measures of
sleep latency and sleep efficiency, zolpidem 15 mg was superior to placebo for all 5 weeks;
zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep
efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at
both doses studied.
Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel
group, 4-week trial comparing two doses of zolpidem (10 and 15 mg) and placebo. Zolpidem 10
mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on
subjective measures of total sleep time, number of awakenings, and sleep quality for the first
treatment week. Zolpidem 15 mg was superior to placebo on a subjective measure of total sleep
latency for the first 3 weeks, on a subjective measure of total sleep time for the first week, and on
number of awakenings and sleep quality for the first 2 weeks.
14.3 Studies Pertinent To Safety Concerns For Sedative/Hypnotic Drugs
Next-day residual effects: Next-day residual effects of Ambien were evaluated in seven
studies involving normal volunteers. In three studies in adults (including one study in a phase
advance model of transient insomnia) and in one study in elderly subjects, a small but
statistically significant decrease in performance was observed in the Digit Symbol Substitution
Test (DSST) when compared to placebo. Studies of Ambien in non-elderly patients with
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insomnia did not detect evidence of next-day residual effects using the DSST, the Multiple Sleep
Latency Test (MSLT), and patient ratings of alertness.
Rebound effects: There was no objective (polysomnographic) evidence of rebound insomnia
at recommended doses seen in studies evaluating sleep on the nights following discontinuation of
Ambien (zolpidem tartrate). There was subjective evidence of impaired sleep in the elderly on
the first post-treatment night at doses above the recommended elderly dose of 5 mg.
Memory impairment: Controlled studies in adults utilizing objective measures of memory
yielded no consistent evidence of next-day memory impairment following the administration of
Ambien. However, in one study involving zolpidem doses of 10 and 20 mg, there was a
significant decrease in next-morning recall of information presented to subjects during peak drug
effect (90 minutes post-dose), ie, these subjects experienced anterograde amnesia. There was
also subjective evidence from adverse event data for anterograde amnesia occurring in
association with the administration of Ambien, predominantly at doses above 10 mg.
Effects on sleep stages: In studies that measured the percentage of sleep time spent in each
sleep stage, Ambien has generally been shown to preserve sleep stages. Sleep time spent in
stages 3 and 4 (deep sleep) was found comparable to placebo with only inconsistent, minor
changes in REM (paradoxical) sleep at the recommended dose.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Ambien 5 mg tablets are capsule-shaped, pink, film coated, with, AMB 5 debossed on one side
and 5401 on the other and supplied as:
NDC Number
Size
0024-5401-31
bottle of 100
0024-5401-34
carton of 100 unit dose
0024-5401-50
bottle of 500
0024-5401-10
Ambien PAK™ unit-of-use blister of 30
Ambien 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one
side and 5421 on the other and supplied as:
NDC Number
Size
0024-5421-31
bottle of 100
0024-5421-34
carton of 100 unit dose
0024-5421-50
bottle of 500
0024-5421-10
Ambien PAK™ unit-of-use blister of 30
16.2 Storage and handling
Store at controlled room temperature 20°–25° C (68°–77°F).
17 PATIENT COUNSELING INFORMATION
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17.1 General:
Patient information is printed at the end of this insert. To assure safe and effective use of
Ambien, this information and instructions provided in the patient information section should be
discussed with patients.
17.2 FDA-approved patient labeling
Your doctor has prescribed Ambien to help you sleep. The following information is intended to
guide you in the safe use of this medicine. It is not meant to take the place of your doctor’s
instructions. If you have any questions about Ambien tablets be sure to ask your doctor or
pharmacist.
Ambien is used to treat different types of sleep problems in adults, such as:
•
trouble falling asleep
•
waking up too early in the morning
•
waking up often during the night
Some people may have more than one of these problems
Ambien belongs to a group of medicines known as the “sedative/hypnotics,” or simply, sleep
medicines. There are many different sleep medicines available to help people sleep better. Sleep
problems are usually temporary, requiring treatment for only a short time, usually 1 or 2 days up
to 1 or 2 weeks. Some people have chronic sleep problems that may require more prolonged use
of sleep medicine. However, you should not use these medicines for long periods without
talking with your doctor about the risks and benefits of prolonged use.
SIDE EFFECTS
Most common side effects: All medicines have side effects. Most common side effects of
sleep medicines include
•
drowsiness
•
dizziness
•
lightheadedness
•
difficulty with coordination
You may find that these medicines make you sleepy during the day. How drowsy you feel
depends upon how your body reacts to the medicine, which sleep medicine you are taking, and
how large a dose your doctor has prescribed. Daytime drowsiness is best avoided by taking the
lowest dose possible that will still help you sleep at night. Your doctor will work with you to
find the dose of Ambien that is best for you.
To manage these side effects while you are taking this medicine:
•
When you first start taking Ambien or any other sleep medicine until you know whether
the medicine will still have some carryover effect in you the next day, use extreme care while
doing anything that requires complete alertness, such as driving a car, operating machinery, or
piloting an aircraft.
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•
NEVER drink alcohol while you are being treated with Ambien or any sleep medicine.
Alcohol can increase the side effects of Ambien or any other sleep medicine.
•
Do not take any other medicines without asking your doctor first. This includes
medicines you can buy without a prescription. Some medicines can cause drowsiness and are
best avoided while taking Ambien.
•
Always take the exact dose of Ambien prescribed by your doctor. Never change your
dose without talking to your doctor first.
SPECIAL CONCERNS
There are some special problems that may occur while taking sleep medicines.
“Sleep-Driving” and other complex behaviors: There have been reports of people
getting out of bed after taking a sleep medicine and driving their cars while not fully awake,
often with no memory of the event. If you experience such an event, it should be reported to
your doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely
to occur when Ambien is taken with alcohol or other drugs such as those for the treatment of
depression or anxiety. Other behaviors such as preparing and eating food, making phone calls,
or having sex have been reported in people who are not fully awake after taking a sleep
medicine. As with “sleep-driving”, people usually do not remember these events.
Memory problems: Sleep medicines may cause a special type of memory loss or “amnesia.”
When this occurs, a person may not remember what has happened for several hours after taking
the medicine. This is usually not a problem since most people fall asleep after taking the
medicine.
Memory loss can be a problem, however, when sleep medicines are taken while traveling, such
as during an airplane flight and the person wakes up before the effect of the medicine is gone.
This has been called “traveler’s amnesia.”
Memory problems are not common while taking Ambien. In most instances memory problems
can be avoided if you take Ambien only when you are able to get a full night’s sleep (7 to 8
hours) before you need to be active again. Be sure to talk to your doctor if you think you are
having memory problems.
Tolerance: When sleep medicines are used every night for more than a few weeks, they may
lose their effectiveness to help you sleep. This is known as “tolerance.’’ Sleep medicines
should, in most cases, be used only for short periods of time, such as 1 or 2 days and generally
no longer than 1 or 2 weeks. If your sleep problems continue, consult your doctor, who will
determine whether other measures are needed to overcome your sleep problems.
Dependence: Sleep medicines can cause dependence, especially when these medicines are
used regularly for longer than a few weeks or at high doses. Some people develop a need to
continue taking their medicines. This is known as dependence or “addiction.”
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When people develop dependence, they may have difficulty stopping the sleep medicine. If the
medicine is suddenly stopped, the body is not able to function normally and unpleasant
symptoms (see Withdrawal) may occur. They may find they have to keep taking the medicine
either at the prescribed dose or at increasing doses just to avoid withdrawal symptoms.
All people taking sleep medicines have some risk of becoming dependent on the medicine.
However, people who have been dependent on alcohol or other drugs in the past may have a
higher chance of becoming addicted to sleep medicines. This possibility must be considered
before using these medicines for more than a few weeks.
If you have been addicted to alcohol or drugs in the past, it is important to tell your doctor before
starting Ambien or any sleep medicine.
Withdrawal: Withdrawal symptoms may occur when sleep medicines are stopped suddenly
after being used daily for a long time. In some cases, these symptoms can occur even if the
medicine has been used for only a week or two.
In mild cases, withdrawal symptoms may include unpleasant feelings. In more severe cases,
abdominal and muscle cramps, vomiting, sweating, shakiness, and rarely, seizures may occur.
These more severe withdrawal symptoms are very uncommon.
Another problem that may occur when sleep medicines are stopped is known as “rebound
insomnia.” This means that a person may have more trouble sleeping the first few nights after
the medicine is stopped than before starting the medicine. If you should experience rebound
insomnia, do not get discouraged. This problem usually goes away on its own after 1 or 2 nights.
If you have been taking Ambien or any other sleep medicine for more than 1 or 2 weeks, do not
stop taking it on your own. Always follow your doctor’s directions.
Changes in behavior and thinking: Some people using sleep medicines have experienced
unusual changes in their thinking and/or behavior. These effects are not common. However,
they have included:
•
more outgoing or aggressive behavior than normal
•
loss of personal identity
•
confusion
•
strange behavior
•
agitation
•
hallucinations
•
worsening of depression
•
suicidal thoughts
How often these effects occur depends on several factors, such as a person’s general health, the
use of other medicines, and which sleep medicine is being used. Clinical experience with
Ambien suggests that it is uncommonly associated with these behavior changes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
It is also important to realize that it is rarely clear whether these behavior changes are caused by
the medicine, an illness, or occur on their own. In fact, sleep problems that do not improve may
be due to illnesses that were present before the medicine was used. If you or your family notice
any changes in your behavior, or if you have any unusual or disturbing thoughts, call your doctor
immediately.
Pregnancy: Sleep medicines may cause sedation of the unborn baby when used during the last
weeks of pregnancy.
Be sure to tell your doctor if you are pregnant, if you are planning to become pregnant, or if you
become pregnant while taking Ambien.
Children: Ambien has not been shown to help children fall asleep. Hallucinations, headache
and dizziness have all been reported as side effects in children who were given Ambien.
SAFE USE OF SLEEPING MEDICINES
To ensure the safe and effective use of Ambien or any other sleep medicine, you should observe
the following cautions:
1. Ambien is a prescription medicine and should be used ONLY as directed by your doctor.
Follow your doctor’s instructions about how to take, when to take, and how long to take
Ambien.
2. Never use Ambien or any other sleep medicine for longer than directed by your doctor.
3. If you develop an allergic reaction such as a rash, hives, shortness of breath, or swelling of
your tongue or throat when using Ambien or any other sleep medicine, discontinue Ambien
or other sleep medicine immediately and contact your doctor.
4. If you notice any unusual and/or disturbing thoughts or behavior during treatment with
Ambien or any other sleep medicine, contact your doctor.
5. Tell your doctor about any medicines you may be taking, including medicines you may buy
without a prescription. You should also tell your doctor if you drink alcohol. DO NOT use
alcohol while taking Ambien or any other sleep medicine.
6. Do not take Ambien unless you are able to get a full night’s sleep before you must be active
again. For example, Ambien should not be taken on an overnight airplane flight of less than
7 to 8 hours since “traveler’s amnesia” may occur.
7. Do not increase the prescribed dose of Ambien or any other sleep medicine unless instructed
by your doctor.
8. When you first start taking Ambien or any other sleep medicine until you know whether the
medicine will still have some carryover effect in you the next day, use extreme care while
doing anything that requires complete alertness, such as driving a car, operating machinery,
or piloting an aircraft.
9. Be aware that you may have more sleeping problems the first night or two after stopping
Ambien or any other sleep medicine.
10. Be sure to tell your doctor if you are pregnant, if you are planning to become pregnant, or if
you become pregnant while taking Ambien.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
11. As with all prescription medicines, never share Ambien or any other sleep medicine with
anyone else. Always store Ambien or any other sleep medicine in the original container out
of reach of children.
12. Ambien works very quickly. You should only take Ambien right before going to bed and
are ready to go to sleep.
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Revised XXXXXX
Copyright, sanofi-aventis U.S. LLC 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:17.387646
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019908s022lbl.pdf', 'application_number': 19908, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
11,843
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NDA 18-828/SLR-029
NDA 19-909/SLR-019
NDA 20-089/SLR-018
Page 3
PRESCRIBING INFORMATION
ZOVIRAX®
(acyclovir)
Capsules
ZOVIRAX®
(acyclovir)
Tablets
ZOVIRAX®
(acyclovir)
Suspension
DESCRIPTION
ZOVIRAX is the brand name for acyclovir, a synthetic nucleoside analogue active against
herpesviruses. ZOVIRAX Capsules, Tablets, and Suspension are formulations for oral administration.
Each capsule of ZOVIRAX contains 200 mg of acyclovir and the inactive ingredients corn starch,
lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell consists of gelatin, FD&C
Blue No. 2, and titanium dioxide. May contain one or more parabens. Printed with edible black ink.
Each 800-mg tablet of ZOVIRAX contains 800 mg of acyclovir and the inactive ingredients FD&C
Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.
Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive ingredients
magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.
Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 200 mg of acyclovir and the inactive
ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives),
carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol.
Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular
weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of acyclovir are 2.27
and 9.25.
The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-
one; it has the following structural formula:
VIROLOGY
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NDA 18-828/SLR-029
NDA 19-909/SLR-019
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Page 4
Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with in vitro
and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and
varicella-zoster virus (VZV). The inhibitory activity of acyclovir is highly selective due to its affinity
for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts
acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further
converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular
enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished
in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of
the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral
activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the
viral TK.
Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes
viruses to antivirals and the clinical response to therapy has not been established in humans, and virus
sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration
of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending
upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates
ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for
acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to
10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean
IC50 of 1.35 mcg/mL.
Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and
quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with
reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially
with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from
immunocompromised patients have been found to be TK-deficient mutants, other mutants involving
the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative
mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral
resistance to acyclovir should be considered in patients who show poor clinical response during
therapy.
CLINICAL PHARMACOLOGY
Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration have been evaluated
in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster
virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1.
Table 1. Acyclovir Pharmacokinetic Characteristics (Range)
Parameter
Range
Plasma protein binding
9% to 33%
Plasma elimination half-life
2.5 to 3.3 hr
Average oral bioavailability
10% to 20%*
*Bioavailability decreases with increasing dose.
In one multiple-dose, crossover study in healthy subjects (n = 23), it was shown that increases in
plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in
Table 2. The decrease in bioavailability is a function of the dose and not the dosage form.
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Page 5
Table 2. Acyclovir Peak and Trough Concentrations at Steady State
Parameter
200 mg
400 mg
800 mg
max
SS
C
0.83 mcg/mL
1.21 mcg/mL
1.61 mcg/mL
trough
SS
C
0.46 mcg/mL
0.63 mcg/mL
0.83 mcg/mL
There was no effect of food on the absorption of acyclovir (n = 6); therefore, ZOVIRAX Capsules,
Tablets, and Suspension may be administered with or without food.
The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine.
Special Populations: Adults with Impaired Renal Function: The half-life and total body
clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for
patients with reduced renal function (see DOSAGE AND ADMINISTRATION).
Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to younger
adults, in part due to age-related changes in renal function. Dosage reduction may be required in
geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use).
Pediatrics: In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of
adults. Mean half-life after oral doses of 300 mg/m2 and 600 mg/m2 in pediatric patients aged 7 months
to 7 years was 2.6 hours (range 1.59 to 3.74 hours).
Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown to
increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary
excretion and renal clearance were correspondingly reduced.
Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have
demonstrated that orally administered ZOVIRAX significantly reduced the duration of acute infection
and duration of lesion healing. The duration of pain and new lesion formation was decreased in some
patient groups.
Recurrent Genital Herpes: Double-blind, placebo-controlled studies in patients with frequent
recurrences (6 or more episodes per year) have shown that orally administered ZOVIRAX given daily
for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences in greater
than 95% of patients.
In a study of patients who received ZOVIRAX 400 mg twice daily for 3 years, 45%, 52%, and 63%
of patients remained free of recurrences in the first, second, and third years, respectively. Serial
analyses of the 3-month recurrence rates for the patients showed that 71% to 87% were recurrence free
in each quarter.
Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent
patients with localized cutaneous zoster infection, ZOVIRAX (800 mg 5 times daily for 10 days)
shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the
duration of viral shedding and the duration of new lesion formation.
In a similar double-blind, placebo-controlled study, ZOVIRAX (800 mg 5 times daily for 7 days)
shortened the times to complete lesion scabbing, healing, and cessation of pain; reduced the duration of
new lesion formation; and reduced the prevalence of localized zoster-associated neurologic symptoms
(paresthesia, dysesthesia, or hyperesthesia).
Treatment was begun within 72 hours of rash onset and was most effective if started within the first
48 hours.
Adults greater than 50 years of age showed greater benefit.
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NDA 18-828/SLR-029
NDA 19-909/SLR-019
NDA 20-089/SLR-018
Page 6
Chickenpox: Three randomized, double-blind, placebo-controlled trials were conducted in
993 pediatric patients aged 2 to 18 years with chickenpox. All patients were treated within 24 hours
after the onset of rash. In 2 trials, ZOVIRAX was administered at 20 mg/kg 4 times daily (up to
3,200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were administered 4 times
daily for 5 to 7 days. Treatment with ZOVIRAX shortened the time to 50% healing; reduced the
maximum number of lesions; reduced the median number of vesicles; decreased the median number of
residual lesions on day 28; and decreased the proportion of patients with fever, anorexia, and lethargy
by day 2. Treatment with ZOVIRAX did not affect varicella-zoster virus-specific humoral or cellular
immune responses at 1 month or 1 year following treatment.
INDICATIONS AND USAGE
Herpes Zoster Infections: ZOVIRAX is indicated for the acute treatment of herpes zoster
(shingles).
Genital Herpes: ZOVIRAX is indicated for the treatment of initial episodes and the management of
recurrent episodes of genital herpes.
Chickenpox: ZOVIRAX is indicated for the treatment of chickenpox (varicella).
CONTRAINDICATIONS
ZOVIRAX is contraindicated for patients who develop hypersensitivity to acyclovir or valacyclovir.
WARNINGS
ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion only. Renal failure, in
some cases resulting in death, has been observed with acyclovir therapy (see ADVERSE
REACTIONS: Observed During Clinical Practice and OVERDOSAGE). Thrombotic
thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has
occurred in immunocompromised patients receiving acyclovir therapy.
PRECAUTIONS
Dosage adjustment is recommended when administering ZOVIRAX to patients with renal
impairment (see DOSAGE AND ADMINISTRATION). Caution should also be exercised when
administering ZOVIRAX to patients receiving potentially nephrotoxic agents since this may increase
the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as
those that have been reported in patients treated with intravenous acyclovir.
Information for Patients: Patients are instructed to consult with their physician if they experience
severe or troublesome adverse reactions, they become pregnant or intend to become pregnant, they
intend to breastfeed while taking orally administered ZOVIRAX, or they have any other questions.
Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the
zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of
herpes zoster.
Genital Herpes Infections: Patients should be informed that ZOVIRAX is not a cure for genital
herpes. There are no data evaluating whether ZOVIRAX will prevent transmission of infection to
others. Because genital herpes is a sexually transmitted disease, patients should avoid contact with
lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital
herpes can also be transmitted in the absence of symptoms through asymptomatic viral shedding. If
medical management of a genital herpes recurrence is indicated, patients should be advised to initiate
therapy at the first sign or symptom of an episode.
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NDA 18-828/SLR-029
NDA 19-909/SLR-019
NDA 20-089/SLR-018
Page 7
Chickenpox: Chickenpox in otherwise healthy children is usually a self-limited disease of mild to
moderate severity. Adolescents and adults tend to have more severe disease. Treatment was initiated
within 24 hours of the typical chickenpox rash in the controlled studies, and there is no information
regarding the effects of treatment begun later in the disease course.
Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include
references to peak steady-state plasma acyclovir concentrations observed in humans treated with
800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg given
orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug concentrations in
animal studies are expressed as multiples of human exposure to acyclovir at the higher and lower
dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to 450 mg/kg
administered by gavage. There was no statistically significant difference in the incidence of tumors
between treated and control animals, nor did acyclovir shorten the latency of tumors. Maximum
plasma concentrations were 3 to 6 times human levels in the mouse bioassay and 1 to 2 times human
levels in the rat bioassay.
Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was positive in 5
of the assays.
Acyclovir did not impair fertility or reproduction in mice (450 mg/kg/day, p.o.) or in rats
(25 mg/kg/day, s.c.). In the mouse study, plasma levels were 9 to 18 times human levels, while in the
rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg/day, s.c.) in rats and rabbits
(11 to 22 and 16 to 31 times human levels, respectively) implantation efficacy, but not litter size, was
decreased. In a rat peri- and post-natal study at 50 mg/kg/day, s.c., there was a statistically significant
decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.
No testicular abnormalities were seen in dogs given 50 mg/kg/day, IV for 1 month (21 to 41 times
human levels) or in dogs given 60 mg/kg/day orally for 1 year (6 to 12 times human levels). Testicular
atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Acyclovir administered during
organogenesis was not teratogenic in the mouse (450 mg/kg/day, p.o.), rabbit (50 mg/kg/day, s.c. and
IV), or rat (50 mg/kg/day, s.c.). These exposures resulted in plasma levels 9 and 18, 16 and 106, and 11
and 22 times, respectively, human levels.
There are no adequate and well-controlled studies in pregnant women. A prospective epidemiologic
registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There
were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of
pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in
the general population. However, the small size of the registry is insufficient to evaluate the risk for
less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in
pregnant women and their developing fetuses. Acyclovir should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Acyclovir concentrations have been documented in breast milk in 2 women
following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corresponding plasma
levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to
0.3 mg/kg/day. ZOVIRAX should be administered to a nursing mother with caution and only when
indicated.
Pediatric Use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients
younger than 2 years of age have not been established.
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NDA 18-828/SLR-029
NDA 19-909/SLR-019
NDA 20-089/SLR-018
Page 8
Geriatric Use: Of 376 subjects who received ZOVIRAX in a clinical study of herpes zoster treatment
in immunocompetent subjects ≥50 years of age, 244 were 65 and over while 111 were 75 and over. No
overall differences in effectiveness for time to cessation of new lesion formation or time to healing
were reported between geriatric subjects and younger adult subjects. The duration of pain after healing
was longer in patients 65 and over. Nausea, vomiting, and dizziness were reported more frequently in
elderly subjects. Elderly patients are more likely to have reduced renal function and require dose
reduction. Elderly patients are also more likely to have renal or CNS adverse events. With respect to
CNS adverse events observed during clinical practice, somnolence, hallucinations, confusion, and
coma were reported more frequently in elderly patients (see CLINICAL PHARMACOLOGY,
ADVERSE REACTIONS: Observed During Clinical Practice, and DOSAGE AND
ADMINISTRATION).
ADVERSE REACTIONS
Herpes Simplex: Short-Term Administration: The most frequent adverse events reported during
clinical trials of treatment of genital herpes with ZOVIRAX 200 mg administered orally 5 times daily
every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient treatments (2.7%). Nausea
and/or vomiting occurred in 2 of 287 (0.7%) patients who received placebo.
Long-Term Administration: The most frequent adverse events reported in a clinical trial for the
prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules) 2 times
daily for 1 year in 586 patients treated with ZOVIRAX were nausea (4.8%) and diarrhea (2.4%). The
589 control patients receiving intermittent treatment of recurrences with ZOVIRAX for 1 year reported
diarrhea (2.7%), nausea (2.4%), and headache (2.2%).
Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of
herpes zoster (shingles) with 800 mg of oral ZOVIRAX 5 times daily for 7 to 10 days in 323 patients
was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%).
Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of
chickenpox with oral ZOVIRAX at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or 800 mg
4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving placebo
reported diarrhea (2.2%).
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during post-approval use of ZOVIRAX. Because they are
reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These
events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential
causal connection to ZOVIRAX, or a combination of these factors.
General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema.
Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness,
delirium, dizziness, dysarthria, encephalopathy, hallucinations, paresthesia, psychosis, seizure,
somnolence, tremors. These symptoms may be marked, particularly in older adults or in patients with
renal impairment (see PRECAUTIONS).
Digestive: Diarrhea, gastrointestinal distress, nausea.
Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia,
lymphadenopathy, thrombocytopenia.
Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia,
jaundice.
Musculoskeletal: Myalgia.
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NDA 18-828/SLR-029
NDA 19-909/SLR-019
NDA 20-089/SLR-018
Page 9
Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson
syndrome, toxic epidermal necrolysis, urticaria.
Special Senses: Visual abnormalities.
Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria (see
WARNINGS).
OVERDOSAGE
Overdoses involving ingestion of up to 100 capsules (20 g) have been reported. Adverse events that
have been reported in association with overdosage include agitation, coma, seizures, and lethargy.
Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in
the intratubular fluid. Overdosage has been reported following bolus injections or inappropriately high
doses and in patients whose fluid and electrolyte balance were not properly monitored. This has
resulted in elevated BUN and serum creatinine and subsequent renal failure. In the event of acute renal
failure and anuria, the patient may benefit from hemodialysis until renal function is restored (see
DOSAGE AND ADMINISTRATION).
DOSAGE AND ADMINISTRATION
Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days.
Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for
10 days.
Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to
12 months, followed by re-evaluation. Alternative regimens have included doses ranging from 200 mg
3 times daily to 200 mg 5 times daily.
The frequency and severity of episodes of untreated genital herpes may change over time. After
1 year of therapy, the frequency and severity of the patient’s genital herpes infection should be re-
evaluated to assess the need for continuation of therapy with ZOVIRAX.
Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be
initiated at the earliest sign or symptom (prodrome) of recurrence.
Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally
4 times daily (80 mg/kg/day) for 5 days. Children over 40 kg should receive the adult dose for
chickenpox.
Adults and Children over 40 kg: 800 mg 4 times daily for 5 days.
Intravenous ZOVIRAX is indicated for the treatment of varicella-zoster infections in
immunocompromised patients.
When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox.
There is no information about the efficacy of therapy initiated more than 24 hours after onset of signs
and symptoms.
Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the dose
of ZOVIRAX Capsules, Tablets, or Suspension should be modified as shown in Table 3:
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NDA 18-828/SLR-029
NDA 19-909/SLR-019
NDA 20-089/SLR-018
Page 10
Table 3. Dosage Modification for Renal Impairment
Creatinine
Adjusted Dosage Regimen
Normal Dosage
Regimen
Clearance
(mL/min/1.73 m2)
Dose
(mg)
Dosing Interval
200 mg every 4 hours
>10
200
every 4 hours, 5x daily
0-10
200
every 12 hours
400 mg every 12 hours
>10
0-10
400
200
every 12 hours
every 12 hours
800 mg every 4 hours
>25
800
every 4 hours, 5x daily
10-25
800
every 8 hours
0-10
800
every 12 hours
Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir during
hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma concentrations
following a 6-hour dialysis period. Therefore, the patient’s dosing schedule should be adjusted so that
an additional dose is administered after each dialysis.
Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the dosing
interval.
Bioequivalence of Dosage Forms: ZOVIRAX Suspension was shown to be bioequivalent to
ZOVIRAX Capsules (n = 20) and 1 ZOVIRAX 800-mg tablet was shown to be bioequivalent to 4
ZOVIRAX 200-mg capsules (n = 24).
HOW SUPPLIED
ZOVIRAX Capsules (blue, opaque cap and body) containing 200 mg acyclovir and printed with
“Wellcome ZOVIRAX 200.”
Bottle of 100 (NDC 0173-0991-55).
Unit dose pack of 100 (NDC 0173-0991-56).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
ZOVIRAX Tablets (light blue, oval) containing 800 mg acyclovir and engraved with “ZOVIRAX
800.”
Bottle of 100 (NDC 0173-0945-55).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
ZOVIRAX Tablets (white, shield-shaped) containing 400 mg acyclovir and engraved with
"ZOVIRAX" on one side and a triangle on the other side.
Bottle of 100 (NDC 0173-0949-55).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
ZOVIRAX Suspension (off-white, banana-flavored) containing 200 mg acyclovir in each
teaspoonful (5 mL).
Bottle of 1 pint (473 mL) (NDC 0173-0953-96).
Store at 15° to 25°C (59° to 77°F).
GlaxoSmithKline
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-828/SLR-029
NDA 19-909/SLR-019
NDA 20-089/SLR-018
Page 11
Research Triangle Park, NC 27709
2003, GlaxoSmithKline. All rights reserved.
November 2003
RL-2049
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18828slr029,19909slr019,20089slr018_zovirax_lbl.pdf', 'application_number': 19909, 'submission_type': 'SUPPL ', 'submission_number': 19}
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NDA 18-828/S-026, S-027
NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 3
PRODUCT INFORMATION
ZOVIRAX® (acyclovir) Capsules
ZOVIRAX® (acyclovir) Tablets
ZOVIRAX® (acyclovir) Suspension
DESCRIPTION: ZOVIRAX is the brand name for acyclovir, a synthetic nucleoside analogue
active against herpesviruses. ZOVIRAX Capsules, Tablets, and Suspension are formulations for
oral administration. Each capsule of ZOVIRAX contains 200 mg of acyclovir and the inactive
ingredients corn starch, lactose, magnesium stearate, and sodium lauryl sulfate. The capsule shell
consists of gelatin, FD&C Blue No. 2, and titanium dioxide. May contain one or more parabens.
Printed with edible black ink.
Each 800-mg tablet of ZOVIRAX contains 800 mg of acyclovir and the inactive ingredients
FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch
glycolate.
Each 400-mg tablet of ZOVIRAX contains 400 mg of acyclovir and the inactive ingredients
magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.
Each teaspoonful (5 mL) of ZOVIRAX Suspension contains 200 mg of acyclovir and the
inactive ingredients methylparaben 0.1% and propylparaben 0.02% (added as preservatives),
carboxymethylcellulose sodium, flavor, glycerin, microcrystalline cellulose, and sorbitol.
Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a
molecular weight of 225. The maximum solubility in water at 37°C is 2.5 mg/mL. The pka’s of
acyclovir are 2.27 and 9.25.
The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-
purin-6-one; it has the following structural formula:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-828/S-026, S-027
NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 4
VIROLOGY:
Mechanism of Antiviral Action: Acyclovir is a synthetic purine nucleoside analogue with
in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2),
and varicella-zoster virus (VZV).
The inhibitory activity of acyclovir is highly selective due
to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral
enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The
monophosphate is further converted into diphosphate by cellular guanylate kinase and into
triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of
herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA
polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3)
inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV
compared to VZV is due to its more efficient phosphorylation by the viral TK.
Antiviral Activities: The quantitative relationship between the in vitro susceptibility of herpes
viruses to antivirals and the clinical response to therapy has not been established in humans, and
virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the
concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary
greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against
herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to
9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical
isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against
the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.
Drug Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and
quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV
with reduced susceptibility to acyclovir have been recovered from immunocompromised patients,
especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated
thus far from immunocompromised patients have been found to be TK-deficient mutants, other
mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been
isolated. TK-negative mutants may cause severe disease in infants and immunocompromised
adults. The possibility of viral resistance to acyclovir should be considered in patients who show
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 5
poor clinical response during therapy.
CLINICAL PHARMACOLOGY:
Pharmacokinetics: The pharmacokinetics of acyclovir after oral administration have been
evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or
varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in
Table 1.
Table 1: Acyclovir Pharmacokinetic Characteristics (Range)
Parameter
Range
Plasma protein binding
9% to 33%
Plasma elimination half-life
2.5 to 3.3 h
Average oral bioavailability
10% to 20%*
*Bioavailability decreases with increasing dose.
In one multiple-dose, cross-over study in healthy subjects (n = 23), it was shown that increases
in plasma acyclovir concentrations were less than dose proportional with increasing dose, as
shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage
form.
Table 2: Acyclovir Peak and Trough Concentrations at Steady State
Parameter
200 mg
400 mg
800 mg
max
SS
C
0.83 mcg/mL
1.21 mcg/mL
1.61 mcg/mL
trough
SS
C
0.46 mcg/mL
0.63 mcg/mL
0.83 mcg/mL
There was no effect of food on the absorption of acyclovir (n = 6); therefore, ZOVIRAX
Capsules, Tablets, and Suspension may be administered with or without food.
The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine.
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Page 6
Special Populations: Adults with Impaired Renal Function: The half-life and total body
clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for
patients with reduced renal function (see DOSAGE AND ADMINISTRATION).
Geriatrics: Acyclovir plasma concentrations are higher in geriatric patients compared to
younger adults, in part due to age-related changes in renal function. Dosage reduction may be
required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric
Use).
Pediatrics: In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that
of adults. Mean half-life after oral doses of 300 mg/m2 and 600 mg/m2 in pediatric patients ages
7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours).
Drug Interactions: Coadministration of probenecid with intravenous acyclovir has been shown
to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary
excretion and renal clearance were correspondingly reduced.
Clinical Trials: Initial Genital Herpes: Double-blind, placebo-controlled studies have
demonstrated that orally administered ZOVIRAX significantly reduced the duration of acute
infection and duration of lesion healing. The duration of pain and new lesion formation was
decreased in some patient groups.
Recurrent Genital Herpes: Double-blind, placebo-controlled studies in patients with frequent
recurrences (6 or more episodes per year) have shown that orally administered ZOVIRAX given
daily for 4 months to 10 years prevented or reduced the frequency and/or severity of recurrences
in greater than 95% of patients.
In a study of patients who received ZOVIRAX 400 mg twice daily for 3 years, 45%, 52%, and
63% of patients remained free of recurrences in the first, second, and third years, respectively.
Serial analyses of the 3-month recurrence rates for the patients showed that 71% to 87% were
recurrence free in each quarter.
Herpes Zoster Infections: In a double-blind, placebo-controlled study of immunocompetent
patients with localized cutaneous zoster infection, ZOVIRAX (800 mg 5 times daily for 10 days)
shortened the times to lesion scabbing, healing, and complete cessation of pain, and reduced the
duration of viral shedding and the duration of new lesion formation.
In a similar double-blind, placebo-controlled study, ZOVIRAX (800 mg 5 times daily for
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NDA 18-828/S-026, S-027
NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 7
7 days) shortened the times to complete lesion scabbing, healing, and cessation of pain, reduced
the duration of new lesion formation, and reduced the prevalence of localized zoster-associated
neurologic symptoms (paresthesia, dysesthesia, or hyperesthesia).
Treatment was begun within 72 hours of rash onset and was most effective if started within
the first 48 hours.
Adults greater than 50 years of age showed greater benefit.
Chickenpox: Three randomized, double-blind, placebo-controlled trials were conducted in
993 pediatric patients ages 2 to 18 years with chickenpox. All patients were treated within
24 hours after the onset of rash. In 2 trials, ZOVIRAX was administered at 20 mg/kg 4 times
daily (up to 3200 mg per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were
administered 4 times daily for 5 to 7 days. Treatment with ZOVIRAX shortened the time to 50%
healing, reduced the maximum number of lesions, reduced the median number of vesicles,
decreased the median number of residual lesions on day 28, and decreased the proportion of
patients with fever, anorexia, and lethargy by day 2. Treatment with ZOVIRAX did not affect
varicella-zoster virus-specific humoral or cellular immune responses at 1 month or 1 year
following treatment.
INDICATIONS AND USAGE:
Herpes Zoster Infections: ZOVIRAX is indicated for the acute treatment of herpes zoster
(shingles).
Genital Herpes: ZOVIRAX is indicated for the treatment of initial episodes and the
management of recurrent episodes of genital herpes.
Chickenpox: ZOVIRAX is indicated for the treatment of chickenpox (varicella).
CONTRAINDICATIONS: ZOVIRAX is contraindicated for patients who develop
hypersensitivity to acyclovir or valacyclovir.
WARNINGS: ZOVIRAX Capsules, Tablets, and Suspension are intended for oral ingestion
only. Renal failure, in some cases resulting in death, has been observed with acyclovir therapy
(see ADVERSE REACTIONS: Observed During Clinical Practice and OVERDOSAGE).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-828/S-026, S-027
NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 8
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has
resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.
PRECAUTIONS: Dosage adjustment is recommended when administering ZOVIRAX to
patients with renal impairment (see DOSAGE AND ADMINISTRATION). Caution should also
be exercised when administering ZOVIRAX to patients receiving potentially nephrotoxic agents
since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous
system symptoms such as those that have been reported in patients treated with intravenous
acyclovir.
Information for Patients: Patients are instructed to consult with their physician if they
experience severe or troublesome adverse reactions, they become pregnant or intend to become
pregnant, they intend to breastfeed while taking orally administered ZOVIRAX, or they have any
other questions.
Herpes Zoster: There are no data on treatment initiated more than 72 hours after onset of the
zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis
of herpes zoster.
Genital Herpes Infections: Patients should be informed that ZOVIRAX is not a cure for
genital herpes. There are no data evaluating whether ZOVIRAX will prevent transmission of
infection to others. Because genital herpes is a sexually transmitted disease, patients should avoid
contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting
partners. Genital herpes can also be transmitted in the absence of symptoms through
asymptomatic viral shedding. If medical management of a genital herpes recurrence is indicated,
patients should be advised to initiate therapy at the first sign or symptom of an episode.
Chickenpox: Chickenpox in otherwise healthy children is usually a self-limited disease of
mild to moderate severity. Adolescents and adults tend to have more severe disease. Treatment
was initiated within 24 hours of the typical chickenpox rash in the controlled studies, and there is
no information regarding the effects of treatment begun later in the disease course.
Drug Interactions: See CLINICAL PHARMACOLOGY: Pharmacokinetics.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The data presented below include
references to peak steady-state plasma acyclovir concentrations observed in humans treated with
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NDA 19-909/S-016, S-017
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Page 9
800 mg given orally 5 times a day (dosing appropriate for treatment of herpes zoster) or 200 mg
given orally 5 times a day (dosing appropriate for treatment of genital herpes). Plasma drug
concentrations in animal studies are expressed as multiples of human exposure to acyclovir at the
higher and lower dosing schedules (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Acyclovir was tested in lifetime bioassays in rats and mice at single daily doses of up to
450 mg/kg administered by gavage. There was no statistically significant difference in the
incidence of tumors between treated and control animals, nor did acyclovir shorten the latency of
tumors. Maximum plasma concentrations were 3 to 6 times human levels in the mouse bioassay
and 1 to 2 times human levels in the rat bioassay.
Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclvoir was positive
in 5 of the assays.
Acyclovir did not impair fertility or reproduction in mice (450 mg/kg per day, PO) or in rats
(25 mg/kg per day, SC). In the mouse study, plasma levels were 9 to 18 times human levels,
while in the rat study, they were 8 to 15 times human levels. At higher doses (50 mg/kg per day,
SC) in rats and rabbits (11 to 22 and 16 to 31 times human levels, respectively) implantation
efficacy, but not litter size, was decreased. In a rat peri- and post-natal study at 50 mg/kg per day,
SC, there was a statistically significant decrease in group mean numbers of corpora lutea, total
implantation sites, and live fetuses.
No testicular abnormalities were seen in dogs given 50 mg/kg per day, IV for 1 month (21 to
41 times human levels) or in dogs given 60 mg/kg per day orally for 1 year (6 to 12 times human
levels). Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose
levels.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Acyclovir administered during
organogenesis was not teratogenic in the mouse (450 mg/kg per day, PO), rabbit (50 mg/kg per
day, SC and IV), or rat (50 mg/kg per day, SC). These exposures resulted in plasma levels 9 and
18, 16 and 106, and 11 and 22 times, respectively, human levels.
There are no adequate and well-controlled studies in pregnant women. A prospective
epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed
in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir
during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth
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NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 10
defects approximates that found in the general population. However, the small size of the registry
is insufficient to evaluate the risk for less common defects or to permit reliable or definitive
conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.
Acyclovir should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Nursing Mothers: Acyclovir concentrations have been documented in breast milk in 2 women
following oral administration of ZOVIRAX and ranged from 0.6 to 4.1 times corresponding
plasma levels. These concentrations would potentially expose the nursing infant to a dose of
acyclovir up to 0.3 mg/kg per day. ZOVIRAX should be administered to a nursing mother with
caution and only when indicated.
Pediatric Use: Safety and effectiveness of oral formulations of acyclovir in pediatric patients
less than 2 years of age have not been established.
Geriatric Use: Of 376 subjects who received ZOVIRAX in a clinical study of herpes zoster
treatment in immunocompetent subjects greater than or equal to 50 years of age, 244 were 65 and
over while 111 were 75 and over. No overall differences in effectiveness for time to cessation of
new lesion formation or time to healing were reported between geriatric subjects and younger
adult subjects. The duration of pain after healing was longer in patients 65 and over. Nausea,
vomiting, and dizziness were reported more frequently in elderly subjects. Elderly patients are
more likely to have reduced renal function and require dose reduction. Elderly patients are also
more likely to have renal or CNS adverse events. With respect to CNS adverse events observed
during clinical practice, somnolence, hallucinations, confusion, and coma were reported more
frequently in elderly patients (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS:
Observed During Clinical Practice, and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS:
Herpes Simplex: Short-Term Administration: The most frequent adverse events reported
during clinical trials of treatment of genital herpes with ZOVIRAX 200 mg administered orally
5 times daily every 4 hours for 10 days were nausea and/or vomiting in 8 of 298 patient
treatments (2.7%). Nausea and/or vomiting occurred in 2 of 287 (0.7%) patients who received
placebo.
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NDA 19-909/S-016, S-017
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Page 11
Long-Term Administration: The most frequent adverse events reported in a clinical trial for
the prevention of recurrences with continuous administration of 400 mg (two 200-mg capsules)
2 times daily for 1 year in 586 patients treated with ZOVIRAX were nausea (4.8%) and diarrhea
(2.4%). The 589 control patients receiving intermittent treatment of recurrences with ZOVIRAX
for 1 year reported diarrhea (2.7%), nausea (2.4%), and headache (2.2%).
Herpes Zoster: The most frequent adverse event reported during 3 clinical trials of treatment of
herpes zoster (shingles) with 800 mg of oral ZOVIRAX 5 times daily for 7 to 10 days in
323 patients was malaise (11.5%). The 323 placebo recipients reported malaise (11.1%).
Chickenpox: The most frequent adverse event reported during 3 clinical trials of treatment of
chickenpox with oral ZOVIRAX at doses of 10 to 20 mg/kg 4 times daily for 5 to 7 days or
800 mg 4 times daily for 5 days in 495 patients was diarrhea (3.2%). The 498 patients receiving
placebo reported diarrhea (2.2%).
Observed During Clinical Practice: In addition to adverse events reported from clinical trials,
the following events have been identified during post-approval use of ZOVIRAX. Because they
are reported voluntarily from a population of unknown size, estimates of frequency cannot be
made. These events have been chosen for inclusion due to either their seriousness, frequency of
reporting, potential causal connection to ZOVIRAX, or a combination of these factors.
General: Anaphylaxis, angioedema, fever, headache, pain, peripheral edema.
Nervous: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness,
delirium, dizziness, encephalopathy, hallucinations, paresthesia, psychosis, seizure, somnolence,
tremors. These symptoms may be marked, particularly in older adults or in patients with renal
impairment (see PRECAUTIONS).
Digestive: Diarrhea, gastrointestinal distress, nausea.
Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia,
lymphadenopathy, thrombocytopenia.
Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis,
hyperbilirubinemia, jaundice.
Musculoskeletal: Myalgia.
Skin: Alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson
syndrome, toxic epidermal necrolysis, urticaria.
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NDA 18-828/S-026, S-027
NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 12
Special Senses: Visual abnormalities.
Urogenital: Renal failure, elevated blood urea nitrogen, elevated creatinine, hematuria (see
WARNINGS).
OVERDOSAGE: Overdoses involving ingestion of up to 100 capsules (20 g) have been
reported. Adverse events that have been reported in association with overdosage include
agitation, coma, convulsions, and lethargy. Precipitation of acyclovir in renal tubules may occur
when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Overdosage has been
reported following bolus injections or inappropriately high doses and in patients whose fluid and
electrolyte balance were not properly monitored. This has resulted in elevated BUN and serum
creatinine and subsequent renal failure. In the event of acute renal failure and anuria, the patient
may benefit from hemodialysis until renal function is restored (see DOSAGE AND
ADMINISTRATION).
DOSAGE AND ADMINISTRATION:
Acute Treatment of Herpes Zoster: 800 mg every 4 hours orally, 5 times daily for 7 to 10 days.
Genital Herpes: Treatment of Initial Genital Herpes: 200 mg every 4 hours, 5 times daily for
10 days.
Chronic Suppressive Therapy for Recurrent Disease: 400 mg 2 times daily for up to
12 months, followed by re-evaluation. Alternative regimens have included doses ranging from
200 mg 3 times daily to 200 mg 5 times daily.
The frequency and severity of episodes of untreated genital herpes may change over time.
After 1 year of therapy, the frequency and severity of the patient’s genital herpes infection should
be re-evaluated to assess the need for continuation of therapy with ZOVIRAX.
Intermittent Therapy: 200 mg every 4 hours, 5 times daily for 5 days. Therapy should be
initiated at the earliest sign or symptom (prodrome) of recurrence.
Treatment of Chickenpox: Children (2 years of age and older): 20 mg/kg per dose orally
4 times daily (80 mg/kg per day) for 5 days. Children over 40 kg should receive the adult dose for
chickenpox.
Adults and Children over 40 kg: 800 mg 4 times daily for 5 days.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-828/S-026, S-027
NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 13
Intravenous ZOVIRAX is indicated for the treatment of varicella-zoster infections in
immunocompromised patients.
When therapy is indicated, it should be initiated at the earliest sign or symptom of chickenpox.
There is no information about the efficacy of therapy initiated more than 24 hours after onset of
signs and symptoms.
Patients With Acute or Chronic Renal Impairment: In patients with renal impairment, the
dose of ZOVIRAX Capsules, Tablets, or Suspension should be modified as shown in Table 3:
Table 3: Dosage Modification for Renal Impairment
Creatinine
Adjusted Dosage Regimen
Normal Dosage
Regimen
Clearance
(mL/min/1.73 m2)
Dose
(mg)
Dosing Interval
>10
200
every 4 hours, 5x daily
200 mg every 4 hours
0-10
200
every 12 hours
400 mg every 12 hours
>10
0-10
400
200
every 12 hours
every 12 hours
>25
800
every 4 hours, 5x daily
800 mg every 4 hours
10-25
800
every 8 hours
0-10
800
every 12 hours
Hemodialysis: For patients who require hemodialysis, the mean plasma half-life of acyclovir
during hemodialysis is approximately 5 hours. This results in a 60% decrease in plasma
concentrations following a 6-hour dialysis period. Therefore, the patient’s dosing schedule
should be adjusted so that an additional dose is administered after each dialysis.
Peritoneal Dialysis: No supplemental dose appears to be necessary after adjustment of the
dosing interval.
Bioequivalence of Dosage Forms: ZOVIRAX Suspension was shown to be bioequivalent to
ZOVIRAX Capsules (n = 20) and 1 ZOVIRAX 800-mg tablet was shown to be bioequivalent to
4 ZOVIRAX 200-mg capsules (n = 24).
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NDA 19-909/S-016, S-017
NDA 20-089/S-015, S-016
Page 14
HOW SUPPLIED: ZOVIRAX Capsules (blue, opaque cap and body) containing 200 mg
acyclovir and printed with “Wellcome ZOVIRAX 200” – Bottle of 100 (NDC 0173-0991-55)
and unit dose pack of 100 (NDC 0173-0991-56).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
ZOVIRAX Tablets (light blue, oval) containing 800 mg acyclovir and engraved with
“ZOVIRAX 800” – Bottle of 100 (NDC 0173-0945-55) and unit dose pack of 100 (NDC 0173-
0945-56).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
ZOVIRAX Tablets (white, shield-shaped) containing 400 mg acyclovir and engraved with
"ZOVIRAX" on one side and a triangle on the other side – Bottle of 100 (NDC 0173-0949-55).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
ZOVIRAX Suspension (off-white, banana-flavored) containing 200 mg acyclovir in each
teaspoonful (5 mL) – Bottle of 1 pint (473 mL) (NDC 0173-0953-96).
Store at 15° to 25°C (59° to 77°F).
GlaxoSmithKline
Research Triangle Park, NC 27709
2001, GlaxoSmithKline
All rights reserved.
Date of Issue
RL-no.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Debra Birnkrant
11/14/01 01:57:54 PM
NDA 19-909 SLR 017, 016
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19909s16s17lbl.pdf', 'application_number': 19909, 'submission_type': 'SUPPL ', 'submission_number': 17}
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NDA 20-518/S-013
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PRESCRIBING INFORMATION
RETROVIR®
FINAL AGREED-UPON PI 05/08/2006
(zidovudine)
Tablets
RETROVIR®
(zidovudine)
Capsules
RETROVIR®
(zidovudine)
Syrup
WARNING
RETROVIR (ZIDOVUDINE) HAS BEEN ASSOCIATED WITH HEMATOLOGIC
TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA PARTICULARLY IN
PATIENTS WITH ADVANCED HUMAN IMMUNODEFICIENCY VIRUS (HIV) DISEASE
(SEE WARNINGS). PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED WITH
SYMPTOMATIC MYOPATHY.
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE
ANALOGUES ALONE OR IN COMBINATION, INCLUDING RETROVIR AND OTHER
ANTIRETROVIRALS (SEE WARNINGS).
DESCRIPTION
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
pyrimidine nucleoside analogue active against HIV.
Tablets: RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of
zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, sodium starch glycolate, and titanium dioxide.
Capsules: RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose,
and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink,
consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and
titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.
Syrup: RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup
contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a
preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to
adjust pH.
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The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural
formula:
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a
solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
MICROBIOLOGY
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is
phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The
principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation
of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and
has been reported to be incorporated into the DNA of cells in culture.
Antiviral Activity: In vitro activity of zidovudine against HIV-1 was assessed in a number of cell
lines (including monocytes and fresh human peripheral blood lymphocytes). The IC50 and IC90 values
for zidovudine were 0.01 to 0.49 µM (1 µM = 0.27 mcg/mL) and 0.1 to 9 µM, respectively.
Zidovudine had anti–HIV-1 activity in all acute virus-cell infections tested. However, zidovudine
activity was substantially less in chronically infected cell lines. The IC50 values of zidovudine against
different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from
0.00049 to 0.004 µM. In cell culture drug combination studies, zidovudine demonstrates synergistic
activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine,
and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and
nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and
additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of
zidovudine in vitro.
Resistance: Genotypic analyses of the isolates selected in vitro and recovered from
zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid
substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine
resistance. In general, higher levels of resistance were associated with greater number of mutations. In
some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine
was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with
lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.
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Cross-Resistance: In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug
resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from
patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern
of resistance-associated mutations with such combination therapies was different (A62V, V75I, F77L,
F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M mutation being most
commonly associated with multi-drug resistance. The mutation at codon 151 in combination with
mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine,
lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are
selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and
zalcitabine.
CLINICAL PHARMACOLOGY
Pharmacokinetics: Adults: The pharmacokinetic properties of zidovudine in fasting patients are
summarized in Table 1. Following oral administration, zidovudine is rapidly absorbed and extensively
distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. Binding to plasma
protein is low. Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of
zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV area under
the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and
GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second
metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following
single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one fifth of the
zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens
ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
The extent of absorption (AUC) was equivalent when zidovudine was administered as RETROVIR
Tablets or Syrup compared to RETROVIR Capsules.
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Table 1. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratio*
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)†
0.5 to 3
(n = 19)
*Median [range].
†Approximate range.
Adults With Impaired Renal Function: Zidovudine clearance was decreased resulting in
increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14)
following a single 200-mg oral dose (Table 2). Plasma concentrations of AMT were not determined. A
dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.
Table 2. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairment*
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
*Data are expressed as mean ± standard deviation.
The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in patients
undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg
5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly
elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of
that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to
have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis (see
DOSAGE AND ADMINISTRATION: Dose Adjustment).
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Adults With Impaired Hepatic Function: Data describing the effect of hepatic impairment on
the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily
by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma
concentrations would be increased following administration of the recommended adult doses to
patients with hepatic impairment (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Pediatrics: Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric patients
(Table 3).
Patients From 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
increases in plasma zidovudine concentrations were observed following administration of oral solution
from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were
comparable to adult values. As in adult patients, the major route of elimination was by metabolism to
GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged, and
about 45% of the dose was excreted as GZDV (see DOSAGE AND ADMINISTRATION: Pediatrics).
Patients Younger Than 3 Months of Age: Zidovudine pharmacokinetics have been
evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined
immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was
13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body clearance was
slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for
neonates, see DOSAGE AND ADMINISTRATION: Neonatal Dosing.
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Table 3. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]†
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life
(hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
*Data presented as mean ± standard deviation except where noted.
†Median [range].
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women during
the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation.
Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive
transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth
were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone
maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.
However, in another patient population, a potential for interaction has been identified (see
PRECAUTIONS).
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean
concentration of zidovudine was similar in human milk and serum (see PRECAUTIONS: Nursing
Mothers).
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients over 65 years
of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no
differences in zidovudine exposure (AUC) when a single dose of zidovudine was administered as the
300-mg RETROVIR Tablet.
Effect of Food on Absorption: RETROVIR may be administered with or without food. The
extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was administered
with food.
Drug Interactions: See Table 4 and PRECAUTIONS: Drug Interactions.
Zidovudine Plus Lamivudine: No clinically significant alterations in lamivudine or zidovudine
pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose
of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).
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Table 4. Effect of Coadministered Drugs on Zidovudine AUC*
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH
COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Zidovudine
Zidovudine
Concentrations
Concentration
of
Coadministered
Drug and Dose
Dose
n
AUC
Variability
Drug
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%†
↔
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%†
↔
Nelfinavir
750 mg q 8 hr x 7
to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to
170%†
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to
130%†
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus
time curve; CI = confidence interval.
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*This table is not all inclusive.
†Estimated range of percent difference.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and
zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular
triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV
virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine
(n = 10), or zidovudine (n = 6) were co-administered as part of a multi-drug regimen to HIV/HCV
co-infected patients (see WARNINGS).
INDICATIONS AND USAGE
RETROVIR in combination with other antiretroviral agents is indicated for the treatment of HIV
infection.
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of
maternal-fetal HIV transmission as part of a regimen that includes oral RETROVIR beginning between
14 and 34 weeks of gestation, intravenous RETROVIR during labor, and administration of
RETROVIR Syrup to the neonate after birth. The efficacy of this regimen for preventing HIV
transmission in women who have received RETROVIR for a prolonged period before pregnancy has
not been evaluated. The safety of RETROVIR for the mother or fetus during the first trimester of
pregnancy has not been assessed (see Description of Clinical Studies).
Description of Clinical Studies: Therapy with RETROVIR has been shown to prolong survival
and decrease the incidence of opportunistic infections in patients with advanced HIV disease and to
delay disease progression in asymptomatic HIV-infected patients.
Combination Therapy in Adults: RETROVIR in combination with other antiretroviral agents
has been shown to be superior to monotherapy for one or more of the following endpoints: delaying
death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1
RNA. The clinical efficacy of a combination regimen that includes RETROVIR was demonstrated in
study ACTG320. This study was a multi-center, randomized, double-blind, placebo-controlled trial
that compared RETROVIR 600 mg/day plus EPIVIR 300 mg/day to RETROVIR plus EPIVIR plus
indinavir 800 mg t.i.d. The incidence of AIDS-defining events or death was lower in the triple-drug–
containing arm compared to the 2-drug–containing arm (6.1% versus 10.9%, respectively).
The complete prescribing information for each drug should be consulted before combination
therapy that includes RETROVIR is initiated.
Monotherapy in Adults: In controlled studies of treatment-naive patients conducted between
1986 and 1989, monotherapy with RETROVIR, as compared to placebo, reduced the risk of HIV
disease progression, as assessed using endpoints that included the occurrence of HIV-related illnesses,
AIDS-defining events, or death. These studies enrolled patients with advanced disease (BW002), and
asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts between 200 and
500 cells/mm3 (ACTG016 and ACTG019). A survival benefit for monotherapy with RETROVIR was
not demonstrated in the latter 2 studies.
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Subsequent studies showed that the clinical benefit of monotherapy with RETROVIR was time
limited.
Pediatric Patients: ACTG300 was a multi-center, randomized, double-blind study that provided
for comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of 471 symptomatic,
HIV-infected therapy-naive pediatric patients were enrolled in these 2 treatment arms. The median age
was 2.7 years (range 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells/mm3, and
the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration that patients
remained on study was approximately 10 months. Results are summarized in Table 5.
Table 5. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or
Death)
Endpoint
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled
trial (ACTG076) conducted in HIV-infected pregnant women with CD4+ cell counts of 200 to
1,818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to
RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks
of therapy) followed by IV administration of RETROVIR during labor and delivery. Following birth,
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically significant
difference in the incidence of HIV infection in the neonates (based on viral culture from peripheral
blood) between the group receiving RETROVIR and the group receiving placebo. Of 363 neonates
evaluated in the study, the estimated risk of HIV infection was 7.8% in the group receiving
RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%.
RETROVIR was well tolerated by mothers and infants. There was no difference in pregnancy-related
adverse events between the treatment groups.
CONTRAINDICATIONS
RETROVIR Tablets, Capsules, and Syrup are contraindicated for patients who have potentially
life-threatening allergic reactions to any of the components of the formulations.
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WARNINGS
COMBIVIR and TRIZIVIR are combination product tablets that contain zidovudine as one of
their components. RETROVIR should not be administered concomitantly with COMBIVIR or
TRIZIVIR.
The incidence of adverse reactions appears to increase with disease progression; patients should
be monitored carefully, especially as disease progression occurs.
Bone Marrow Suppression: RETROVIR should be used with caution in patients who have bone
marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. In
patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant
adverse events observed. There have been reports of pancytopenia associated with the use of
RETROVIR, which was reversible in most instances after discontinuance of the drug. However,
significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or
blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other
antiretrovirals.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are
treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV
disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage
adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
disease, have been associated with prolonged use of RETROVIR.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside
analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these
cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may
be risk factors. Particular caution should be exercised when administering RETROVIR to any patient
with known risk factors for liver disease; however, cases have also been reported in patients with no
known risk factors. Treatment with RETROVIR should be suspended in any patient who develops
clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
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Use With Interferon- and Ribavirin-Based Regimens: In vitro studies have shown ribavirin
can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no
evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic
suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected
patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some
fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral
therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa
with or without ribavirin and RETROVIR should be closely monitored for treatment-associated
toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of
RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of
interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are
observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing
information for interferon and ribavirin).
PRECAUTIONS
General: Zidovudine is eliminated from the body primarily by renal excretion following metabolism
in the liver (glucuronidation). In patients with severely impaired renal function (CrCl<15 mL/min),
dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to
be increased in patients with severely impaired hepatic function which may increase the risk of
hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND
ADMINISTRATION).
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including RETROVIR. During the initial
phase of combination antiretroviral treatment, patients whose immune system responds may develop
an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium
avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
may necessitate further evaluation and treatment.
Fat Redistribution: Redistribution/accumulation of body fat, including central obesity,
dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement,
and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
mechanism and long-term consequences of these events are currently unknown. A causal relationship
has not been established.
Information for Patients: RETROVIR is not a cure for HIV infection, and patients may continue to
acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients
should be advised to seek medical care for any significant change in their health status.
The safety and efficacy of RETROVIR in women, intravenous drug users, and racial minorities is
not significantly different than that observed in white males.
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or anemia.
The frequency and severity of these toxicities are greater in patients with more advanced
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disease and in those who initiate therapy later in the course of their infection. They should be told that
if toxicity develops, they may require transfusions or drug discontinuation. They should be told of the
extreme importance of having their blood counts followed closely while on therapy, especially for
patients with advanced symptomatic HIV disease. They should be cautioned about the use of other
medications, including ganciclovir and interferon alfa, which may exacerbate the toxicity of
RETROVIR (see PRECAUTIONS: Drug Interactions). Patients should be informed that other adverse
effects of RETROVIR include nausea and vomiting. Patients should also be encouraged to contact
their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or
pancreatitis, or any other unexpected adverse events while being treated with RETROVIR.
RETROVIR Tablets, Capsules, and Syrup are for oral ingestion only. Patients should be told of the
importance of taking RETROVIR exactly as prescribed. They should be told not to share medication
and not to exceed the recommended dose. Patients should be told that the long-term effects of
RETROVIR are unknown at this time.
Pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV
transmission to their infants should be advised that transmission may still occur in some cases despite
therapy. The long-term consequences of in utero and infant exposure to RETROVIR are unknown,
including the possible risk of cancer.
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission
of HIV to a child who may not yet be infected.
Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of
transmission of HIV to others through sexual contact or blood contamination.
Patients should be informed that redistribution or accumulation of body fat may occur in patients
receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are
not known at this time.
Drug Interactions: See CLINICAL PHARMACOLOGY section (Table 4) for information on
zidovudine concentrations when coadministered with other drugs. For patients experiencing
pronounced anemia or other severe zidovudine-associated events while receiving chronic
administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4,
zidovudine dose reduction may be considered.
Antiretroviral Agents: Concomitant use of zidovudine with stavudine should be avoided since an
antagonistic relationship has been demonstrated in vitro.
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro
antiviral activity of RETROVIR against HIV; concomitant use of such drugs should be avoided.
Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an
antagonistic relationship has been demonstrated in vitro (see CLINICAL PHARMACOLOGY for
additional drug interactions).
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
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interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone
and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics
was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine
kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
Overlapping Toxicities: Coadministration of ganciclovir, interferon alfa, and other bone marrow
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered orally at
3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial
single daily doses were 30, 60, and 120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats.
The doses in mice were reduced to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related
anemia, whereas in rats only the high dose was reduced to 450 mg/kg/day on day 91 and then to
300 mg/kg/day on day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell
carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest
dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No
vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in
rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC)
was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the
recommended therapeutic dose of 100 mg every 4 hours.
Two transplacental carcinogenicity studies were conducted in mice. One study administered
zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and
lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine
employed in this study produced zidovudine exposures approximately 3 times the estimated human
exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was
noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings
are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A
second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day
(∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from
days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes,
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and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic
study in rats given a single dose.
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based
on body surface area considerations, had no effect on fertility judged by conception rates.
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to
500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted
in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given
150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after
one sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an
in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent
reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day
(very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an
increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma
concentrations 350 times peak human plasma concentrations. (Estimated area under the curve [AUC]
in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of
teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
Mutagenesis, Impairment of Fertility).
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-transmission
(see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities
occurred with similar frequency between neonates born to mothers who received RETROVIR and
neonates born to mothers who received placebo. Abnormalities were either problems in embryogenesis
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study
drug.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are
encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV. Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics:
Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
receiving RETROVIR (see Pediatric Use and INDICATIONS AND USAGE: Maternal-Fetal HIV
Transmission).
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age
who had HIV-related symptoms or who were asymptomatic with abnormal laboratory
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values indicating significant HIV-related immunosuppression. RETROVIR has also been studied in
neonates perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND
ADMINISTRATION, INDICATIONS AND USAGE: Description of Clinical Studies, and CLINICAL
PHARMACOLOGY: Pharmacokinetics).
Geriatric Use: Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Adults: The frequency and severity of adverse events associated with the use of RETROVIR are
greater in patients with more advanced infection at the time of initiation of therapy.
Table 6 summarizes events reported at a statistically significant greater incidence for patients
receiving RETROVIR in a monotherapy study:
Table 6. Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection
(ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
8.6%†
5.8%
Headache
62.5%
52.6%
Malaise
53.2%
44.9%
Gastrointestinal
Anorexia
20.1%
10.5%
Constipation
6.4%†
3.5%
Nausea
51.4%
29.9%
Vomiting
17.2%
9.8%
*Reported in ≥5% of study population.
†Not statistically significant versus placebo.
In addition to the adverse events listed in Table 6, other adverse events observed in clinical studies
were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia,
insomnia, musculoskeletal pain, myalgia, and neuropathy.
Selected laboratory abnormalities observed during a clinical study of monotherapy with
RETROVIR are shown in Table 7.
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Table 7. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with
Asymptomatic HIV Infection (ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
1.1%
0.2%
Granulocytopenia (<750 cells/mm3)
1.8%
1.6%
Thrombocytopenia (platelets<50,000/mm3)
0%
0.5%
ALT (>5 x ULN)
3.1%
2.6%
AST (>5 x ULN)
0.9%
1.6%
Alkaline phosphatase (>5 x ULN)
0%
0%
ULN = Upper limit of normal.
Pediatrics: Study ACTG300: Selected clinical adverse events and physical findings with a ≥5%
frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2 3 times daily
compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are
listed in Table 8.
Table 8. Selected Clinical Adverse Events and Physical Findings (≥5% Frequency) in Pediatric
Patients in Study ACTG300
Adverse Event
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
25%
32%
Digestive
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
5%
8%
Respiratory
Cough
15%
18%
Abnormal breath sounds/wheezing
7%
9%
Ear, Nose, and Throat
Signs or symptoms of ears*
7%
6%
Nasal discharge or congestion
8%
11%
Other
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
*Includes pain, discharge, erythema, or swelling of an ear.
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Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy)
pediatric patients are listed in Table 9.
Table 9. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in
Study ACTG300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
8%
3%
Anemia (Hgb<7.0 g/dL)
4%
2%
Thrombocytopenia (platelets<50,000/mm3)
1%
3%
ALT (>10 x ULN)
1%
3%
AST (>10 x ULN)
2%
4%
Lipase (>2.5 x ULN)
3%
3%
Total amylase (>2.5 x ULN)
3%
3%
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR
180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema,
hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
pediatric patients.
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized,
double-blind, placebo-controlled trial in HIV-infected women and their neonates conducted to
determine the utility of RETROVIR for the prevention of maternal-fetal HIV transmission,
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates beginning
within 12 hours following birth. The most commonly reported adverse experiences were anemia
(hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22% of the neonates
who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in
hemoglobin values was less than 1.0 g/dL for neonates receiving RETROVIR compared to neonates
receiving placebo. No neonates with anemia required transfusion and all hemoglobin values
spontaneously returned to normal within 6 weeks after completion of therapy with RETROVIR.
Neutropenia was reported with similar frequency in the group that received RETROVIR (21%) and in
the group that received placebo (27%). The long-term consequences of in utero and infant exposure to
RETROVIR are unknown.
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during use of RETROVIR in clinical practice. Because they are
reported voluntarily from a population of unknown size, estimates of frequency
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cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency
of reporting, potential causal connection to RETROVIR, or a combination of these factors.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Cardiovascular: Cardiomyopathy, syncope.
Endocrine: Gynecomastia.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy,
pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic
acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with
pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia,
seizures, somnolence, vertigo.
Respiratory: Cough, dyspnea, rhinitis, sinusitis.
Skin: Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic
epidermal necrolysis, sweat, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Urogenital: Urinary frequency, urinary hesitancy.
OVERDOSAGE
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved
exposures up to 50 grams. No specific symptoms or signs have been identified following acute
overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache,
vomiting, and occasional reports of hematological disturbances. All patients recovered without
permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the
removal of zidovudine while elimination of its primary metabolite, GZDV, is enhanced.
DOSAGE AND ADMINISTRATION
Adults: The recommended oral dose of RETROVIR is 600 mg per day in divided doses in
combination with other antiretroviral agents.
Pediatrics: The recommended dose in pediatric patients 6 weeks to 12 years of age is 160 mg/m2
every 8 hours (480 mg/m2/day up to a maximum of 200 mg every 8 hours) in combination with other
antiretroviral agents.
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Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to
pregnant women (>14 weeks of pregnancy) and their neonates is:
Maternal Dosing: 100 mg orally 5 times per day until the start of labor (see INDICATIONS AND
USAGE: Description of Clinical Studies). During labor and delivery, intravenous RETROVIR should
be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous
infusion of 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See
PRECAUTIONS if hepatic disease or renal insufficiency is present.)
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone marrow
reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly in
patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is
recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who experience
hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia
usually occurs after 6 to 8 weeks.
Dose Adjustment: Anemia: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of
baseline) and/or significant neutropenia (granulocyte count of <750 cells/mm3 or reduction of >50%
from baseline) may require a dose interruption until evidence of marrow recovery is observed (see
WARNINGS). In patients who develop significant anemia, dose interruption does not necessarily
eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption
in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses,
depending on hematologic indices such as serum erythropoetin level and patient tolerance.
For patients experiencing pronounced anemia while receiving chronic coadministration of
zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose
reduction may be considered.
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal dialysis,
recommended dosing is 100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Hepatic Impairment: There are insufficient data to recommend dose adjustment of RETROVIR
in patients with mild to moderate impaired hepatic function or liver cirrhosis. Since RETROVIR is
primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these
patients. Frequent monitoring for hematologic toxicities is advised (see CLINICAL
PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).
HOW SUPPLIED
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg zidovudine,
one side engraved “GX CW3” and “300” on the other side.
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Bottle of 60 (NDC 0173-0501-00).
Store at 15° to 25°C (59° to 77°F).
RETROVIR Capsules 100 mg (white, opaque cap and body with a dark blue band) containing
100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
body.
Bottles of 100 (NDC 0173-0108-55).
Unit Dose Pack of 100 (NDC 0173-0108-56).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg zidovudine in
each teaspoonful (5 mL).
Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
Store at 15° to 25°C (59° to 77°F).
GlaxoSmithKline
Research Triangle Park, NC 27709
©2006, GlaxoSmithKline. All rights reserved.
April 2006
RL-2273
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|
custom-source
|
2025-02-12T13:46:17.829373
|
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|
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PRESCRIBING INFORMATION
RETROVIR®
(zidovudine)
Tablets
RETROVIR®
(zidovudine)
Capsules
RETROVIR®
(zidovudine)
Syrup
WARNING
RETROVIR (ZIDOVUDINE) HAS BEEN ASSOCIATED WITH HEMATOLOGIC
TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA PARTICULARLY IN
PATIENTS WITH ADVANCED HIV DISEASE (SEE WARNINGS). PROLONGED USE OF
RETROVIR HAS BEEN ASSOCIATED WITH SYMPTOMATIC MYOPATHY.
LACTIC
ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL
CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES
ALONE OR IN COMBINATION, INCLUDING RETROVIR AND OTHER
ANTIRETROVIRALS (SEE WARNINGS).
DESCRIPTION
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
pyrimidine nucleoside analogue active against human immunodeficiency virus (HIV).
Tablets: RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of
zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, sodium starch glycolate, and titanium dioxide.
Capsules: RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose,
and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink,
consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and
titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.
Syrup: RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup
contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a
preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to
adjust pH.
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The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural
formula:
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a
solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
MICROBIOLOGY
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue of the naturally occurring
nucleoside, thymidine, in which the 3′-hydroxy (-OH) group is replaced by an azido (-N3) group.
Within cells, zidovudine is converted to the active metabolite, zidovudine 5′-triphosphate (AztTP), by
the sequential action of the cellular enzymes. Zidovudine 5′-triphosphate inhibits the activity of the
HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine
5′-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3′-OH group in the
incorporated nucleoside analogue prevents the formation of the 5′ to 3′ phosphodiester linkage
essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The active
metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and mitochondrial
polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture.
In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zidovudine was assessed by infecting
cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and
clinical isolates of HIV. The IC50 and IC90 values (50% and 90% inhibitory concentrations) were 0.003
to 0.013 and 0.03 to 0.13 mcg/mL, respectively (1 nM = 0.27 ng/mL). The IC50 and IC90 values of HIV
isolates recovered from 18 untreated AIDS/ARC patients were in the range of 0.003 to 0.013 mcg/mL
and 0.03 to 0.3 mcg/mL, respectively. Zidovudine showed antiviral activity in all acutely infected cell
lines; however, activity was substantially less in chronically infected cell lines. In drug combination
studies with zalcitabine, didanosine, lamivudine, saquinavir, indinavir, ritonavir, nevirapine,
delavirdine, or interferon-alpha, zidovudine showed additive to synergistic activity in cell culture. The
relationship between the in vitro susceptibility of HIV to reverse transcriptase inhibitors and the
inhibition of HIV replication in humans has not been established.
Drug Resistance: HIV isolates with reduced sensitivity to zidovudine have been selected in vitro
and were also recovered from patients treated with RETROVIR. Genetic analysis of the isolates
showed mutations that result in 5 amino acid substitutions (Met41→Leu, A67→Asn, Lys70→Arg,
Thr215→Tyr or Phe, and Lys219→Gln) in the viral reverse transcriptase. In general, higher levels of
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resistance were associated with greater number of mutations with 215 mutation being the most
significant.
Cross-Resistance: The potential for cross-resistance between HIV reverse transcriptase inhibitors
and protease inhibitors is low because of the different enzyme targets involved. Combination therapy
with zidovudine plus zalcitabine or didanosine does not appear to prevent the emergence of
zidovudine-resistant isolates. Combination therapy with RETROVIR plus EPIVIR delayed the
emergence of mutations conferring resistance to zidovudine. In some patients harboring
zidovudine-resistant virus, combination therapy with RETROVIR plus EPIVIR restored phenotypic
sensitivity to zidovudine by 12 weeks of treatment. HIV isolates with multidrug resistance to
zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of
patients treated for ≥1 year with the combination of zidovudine and didanosine or zalcitabine. The
pattern of resistant mutations in the combination therapy was different (Ala62→Val, Val75→Ile,
Phe77→116Tyr, and Gln→151Met) from monotherapy, with mutation 151 being most significant for
multidrug resistance. Site-directed mutagenesis studies showed that these mutations could also result in
resistance to zalcitabine, lamivudine, and stavudine.
CLINICAL PHARMACOLOGY
Pharmacokinetics: Adults: The pharmacokinetic properties of zidovudine in fasting patients are
summarized in Table 1. Following oral administration, zidovudine is rapidly absorbed and extensively
distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. Binding to plasma
protein is low. Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of
zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV area under
the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and
GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second
metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following
single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one fifth of the
zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens
ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
The extent of absorption (AUC) was equivalent when zidovudine was administered as RETROVIR
Tablets or Syrup compared to RETROVIR Capsules.
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Table 1. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratio*
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)†
0.5 to 3
(n = 19)
*Median [range].
†Approximate range.
Adults with Impaired Renal Function: Zidovudine clearance was decreased resulting in
increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14)
following a single 200-mg oral dose (Table 2). Plasma concentrations of AMT were not determined. A
dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.
Table 2. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairment*
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
*Data are expressed as mean ± standard deviation.
The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in
patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to
200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite
significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was
approximately 50% of that reported in patients with normal renal function. Hemodialysis and
peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV
elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis
or peritoneal dialysis (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Adults with Impaired Hepatic Function: Data describing the effect of hepatic impairment on
the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily
by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma
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concentrations would be increased following administration of the recommended adult doses to
patients with hepatic impairment (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Pediatrics: Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric patients
(Table 3).
Patients from 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
increases in plasma zidovudine concentrations were observed following administration of oral solution
from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were
comparable to adult values. As in adult patients, the major route of elimination was by metabolism to
GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged, and
about 45% of the dose was excreted as GZDV (see DOSAGE AND ADMINISTRATION: Pediatrics).
Patients Younger Than 3 Months of Age: Zidovudine pharmacokinetics have been
evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined
immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was
13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body clearance was
slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for
neonates, see DOSAGE AND ADMINISTRATION: Neonatal Dosing.
Table 3. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]†
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
*Data presented as mean ± standard deviation except where noted.
†Median [range].
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women
during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug
accumulation. Zidovudine pharmacokinetics were similar to that of nonpregnant adults. Consistent
with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal
plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are
limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine
pharmacokinetics. However, in another patient population, a potential for interaction has been
identified (see PRECAUTIONS).
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
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HIV. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean
concentration of zidovudine was similar in human milk and serum (see PRECAUTIONS: Nursing
Mothers).
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients over 65 years
of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no
differences in zidovudine exposure (AUC) when a single dose of zidovudine was administered as the
300-mg RETROVIR Tablet.
Effect of Food on Absorption: RETROVIR may be administered with or without food. The
extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was administered
with food.
Drug Interactions: See Table 4 and PRECAUTIONS: Drug Interactions.
Zidovudine Plus Lamivudine: No clinically significant alterations in lamivudine or zidovudine
pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose
of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).
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Table 4. Effect of Coadministered Drugs on Zidovudine AUC*
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH
COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Zidovudine
Zidovudine
Concentrations
Concentration
of
Coadministered
Drug and Dose
Dose
n
AUC
Variability
Drug
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%†
↔
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%†
↔
Nelfinavir
750 mg q 8 hr x 7
to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to
170%†
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to
130%†
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus
time curve; CI
= confidence interval.
*This table is not all inclusive.
†Estimated range of percent difference.
INDICATIONS AND USAGE
RETROVIR in combination with other antiretroviral agents is indicated for the treatment of HIV
infection.
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of
maternal-fetal HIV transmission as part of a regimen that includes oral RETROVIR beginning between
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14 and 34 weeks of gestation, intravenous RETROVIR during labor, and administration of
RETROVIR Syrup to the neonate after birth. The efficacy of this regimen for preventing HIV
transmission in women who have received RETROVIR for a prolonged period before pregnancy has
not been evaluated. The safety of RETROVIR for the mother or fetus during the first trimester of
pregnancy has not been assessed (see Description of Clinical Studies).
Description of Clinical Studies: Therapy with RETROVIR has been shown to prolong survival
and decrease the incidence of opportunistic infections in patients with advanced HIV disease and to
delay disease progression in asymptomatic HIV-infected patients.
Combination Therapy in Adults: RETROVIR in combination with other antiretroviral agents
has been shown to be superior to monotherapy for one or more of the following endpoints: delaying
death, delaying development of AIDS, increasing CD4 cell counts, and decreasing plasma HIV RNA.
The clinical efficacy of a combination regimen that includes RETROVIR was demonstrated in study
ACTG320. This study was a multicenter, randomized, double-blind, placebo-controlled trial that
compared RETROVIR 600 mg/day plus EPIVIR 300 mg/day to RETROVIR plus EPIVIR plus
indinavir 800 mg t.i.d. The incidence of AIDS-defining events or death was lower in the triple-drug–
containing arm compared to the 2-drug–containing arm (6.1% versus 10.9%, respectively).
The complete prescribing information for each drug should be consulted before combination
therapy that includes RETROVIR is initiated.
Monotherapy in Adults: In controlled studies of treatment-naive patients conducted between
1986 and 1989, monotherapy with RETROVIR, as compared to placebo, reduced the risk of HIV
disease progression, as assessed using endpoints that included the occurrence of HIV-related illnesses,
AIDS-defining events, or death. These studies enrolled patients with advanced disease (BW002), and
asymptomatic or mildly symptomatic disease in patients with CD4 cell counts between 200 and
500 cells/mm3 (ACTG016 and ACTG019). A survival benefit for monotherapy with RETROVIR was
not demonstrated in the latter 2 studies. Subsequent studies showed that the clinical benefit of
monotherapy with RETROVIR was time limited.
Pediatric Patients: ACTG300 was a multicenter, randomized, double-blind study that provided
for comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of 471 symptomatic,
HIV-infected therapy-naive pediatric patients were enrolled in these 2 treatment arms. The median age
was 2.7 years (range 6 weeks to 14 years), the mean baseline CD4 cell count was 868 cells/mm3, and
the mean baseline plasma HIV RNA was 5.0 log10 copies/mL. The median duration that patients
remained on study was approximately 10 months. Results are summarized in Table 5.
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Table 5. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or
Death)
Endpoint
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled
trial (ACTG076) conducted in HIV-infected pregnant women with CD4 cell counts of 200 to
1,818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to
RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks
of therapy) followed by IV administration of RETROVIR during labor and delivery. Following birth,
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically significant
difference in the incidence of HIV infection in the neonates (based on viral culture from peripheral
blood) between the group receiving RETROVIR and the group receiving placebo. Of 363 neonates
evaluated in the study, the estimated risk of HIV infection was 7.8% in the group receiving
RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%.
RETROVIR was well tolerated by mothers and infants. There was no difference in pregnancy-related
adverse events between the treatment groups.
CONTRAINDICATIONS
RETROVIR Tablets, Capsules, and Syrup are contraindicated for patients who have potentially
life-threatening allergic reactions to any of the components of the formulations.
WARNINGS
COMBIVIR and TRIZIVIR are combination product tablets that contain zidovudine as one of
their components. RETROVIR should not be administered concomitantly with COMBIVIR or
TRIZIVIR.
The incidence of adverse reactions appears to increase with disease progression; patients should
be monitored carefully, especially as disease progression occurs.
Bone Marrow Suppression: RETROVIR should be used with caution in patients who have bone
marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. In
patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant
adverse events observed. There have been reports of pancytopenia associated with the use of
RETROVIR, which was reversible in most instances after discontinuance of the drug. However,
significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or
blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other
antiretrovirals.
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Frequent blood counts are strongly recommended in patients with advanced HIV disease who are
treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV
disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage
adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
disease, have been associated with prolonged use of RETROVIR.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside
analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these
cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may
be risk factors. Particular caution should be exercised when administering RETROVIR to any patient
with known risk factors for liver disease; however, cases have also been reported in patients with no
known risk factors. Treatment with RETROVIR should be suspended in any patient who develops
clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
PRECAUTIONS
General: Zidovudine is eliminated from the body primarily by renal excretion following metabolism
in the liver (glucuronidation). In patients with severely impaired renal function (CrCl<15 mL/min),
dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to
be increased in patients with severely impaired hepatic function which may increase the risk of
hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND
ADMINISTRATION).
Fat Redistribution: Redistribution/accumulation of body fat, including central obesity,
dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement,
and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
mechanism and long-term consequences of these events are currently unknown. A causal relationship
has not been established.
Information for Patients: RETROVIR is not a cure for HIV infection, and patients may continue to
acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients
should be advised to seek medical care for any significant change in their health status.
The safety and efficacy of RETROVIR in women, intravenous drug users, and racial minorities is
not significantly different than that observed in white males.
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or anemia.
The frequency and severity of these toxicities are greater in patients with more advanced disease and in
those who initiate therapy later in the course of their infection. They should be told that if toxicity
develops, they may require transfusions or drug discontinuation. They should be told of the extreme
importance of having their blood counts followed closely while on therapy, especially for patients with
advanced symptomatic HIV disease. They should be cautioned about the use of other medications,
including ganciclovir and interferon-alpha, that may exacerbate the toxicity of RETROVIR (see
PRECAUTIONS: Drug Interactions). Patients should be informed that other adverse effects of
RETROVIR include nausea and vomiting. Patients should also be encouraged to contact their
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physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or
pancreatitis, or any other unexpected adverse events while being treated with RETROVIR.
RETROVIR Tablets, Capsules, and Syrup are for oral ingestion only. Patients should be told of the
importance of taking RETROVIR exactly as prescribed. They should be told not to share medication
and not to exceed the recommended dose. Patients should be told that the long-term effects of
RETROVIR are unknown at this time.
Pregnant women considering the use of RETROVIR during pregnancy for prevention of
HIV-transmission to their infants should be advised that transmission may still occur in some cases
despite therapy. The long-term consequences of in utero and infant exposure to RETROVIR are
unknown, including the possible risk of cancer.
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission
of HIV to a child who may not yet be infected.
Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of
transmission of HIV to others through sexual contact or blood contamination.
Patients should be informed that redistribution or accumulation of body fat may occur in patients
receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are
not known at this time.
Drug Interactions: See CLINICAL PHARMACOLOGY section (Table 4) for information on
zidovudine concentrations when coadministered with other drugs. For patients experiencing
pronounced anemia or other severe zidovudine-associated events while receiving chronic
administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4,
zidovudine dose reduction may be considered.
Antiretroviral Agents: Concomitant use of zidovudine with stavudine should be avoided since an
antagonistic relationship has been demonstrated in vitro.
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro
antiviral activity of RETROVIR against HIV; concomitant use of such drugs should be avoided.
Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an
antagonistic relationship has been demonstrated in vitro (see CLINICAL PHARMACOLOGY for
additional drug interactions).
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone
and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics
was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine
kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
Overlapping Toxicities: Coadministration of ganciclovir, interferon-alpha, and other bone
marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered orally at
3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial
single daily doses were 30, 60, and 120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats.
The doses in mice were reduced to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related
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anemia, whereas in rats only the high dose was reduced to 450 mg/kg/day on day 91 and then to
300 mg/kg/day on day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell
carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest
dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No
vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in
rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC)
was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the
recommended therapeutic dose of 100 mg every 4 hours.
Two transplacental carcinogenicity studies were conducted in mice. One study administered
zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and
lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine
employed in this study produced zidovudine exposures approximately 3 times the estimated human
exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was
noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings
are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A
second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day
(∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from
days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and
positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic
study in rats given a single dose.
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based
on body surface area considerations, had no effect on fertility judged by conception rates.
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to
500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted
in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given
150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after
one sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an
in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent
reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day
(very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an
increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma
concentrations 350 times peak human plasma concentrations. (Estimated area-under-the-curve [AUC]
in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day.) No evidence
of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
Mutagenesis, Impairment of Fertility).
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A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-transmission
(see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities
occurred with similar frequency between neonates born to mothers who received RETROVIR and
neonates born to mothers who received placebo. Abnormalities were either problems in embryogenesis
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study
drug.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are
encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV. Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics:
Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
receiving RETROVIR (see Pediatric Use and INDICATIONS AND USAGE: Maternal-Fetal HIV
Transmission).
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age
who had HIV-related symptoms or who were asymptomatic with abnormal laboratory values
indicating significant HIV-related immunosuppression. RETROVIR has also been studied in neonates
perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION,
INDICATIONS AND USAGE: Description of Clinical Studies, and CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Geriatric Use: Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Adults: The frequency and severity of adverse events associated with the use of RETROVIR are
greater in patients with more advanced infection at the time of initiation of therapy.
Table 6 summarizes events reported at a statistically significant greater incidence for patients
receiving RETROVIR in a monotherapy study:
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NDA 19-910/S-027
NDA 20-528/S-011
Page 16
Table 6. Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection
(ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
Headache
Malaise
8.6%†
62.5%
53.2%
5.8%
52.6%
44.9%
Gastrointestinal
Anorexia
Constipation
Nausea
Vomiting
20.1%
6.4%†
51.4%
17.2%
10.5%
3.5%
29.9%
9.8%
*Reported in ≥5% of study population.
†Not statistically significant versus placebo.
In addition to the adverse events listed in Table 6, other adverse events observed in clinical studies
were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia,
insomnia, musculoskeletal pain, myalgia, and neuropathy.
Selected laboratory abnormalities observed during a clinical study of monotherapy with
RETROVIR are shown in Table 7.
Table 7. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with
Asymptomatic HIV Infection (ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
1.1%
0.2%
Granulocytopenia (<750 cells/mm3)
1.8%
1.6%
Thrombocytopenia (platelets<50,000/mm3)
0%
0.5%
ALT (>5 x ULN)
3.1%
2.6%
AST (>5 x ULN)
0.9%
1.6%
Alkaline phosphatase (>5 x ULN)
0%
0%
ULN = Upper limit of normal.
Pediatrics: Study ACTG300: Selected clinical adverse events and physical findings with a ≥5%
frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2 3 times daily
compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are
listed in Table 8.
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NDA 20-528/S-011
Page 17
Table 8. Selected Clinical Adverse Events and Physical Findings (≥5% Frequency)
in Pediatric Patients in Study ACTG300
Adverse Event
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
25%
32%
Digestive
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
5%
8%
Respiratory
Cough
15%
18%
Abnormal breath sounds/wheezing
7%
9%
Ear, Nose, and Throat
Signs or symptoms of ears*
7%
6%
Nasal discharge or congestion
8%
11%
Other
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
*Includes pain, discharge, erythema, or swelling of an ear.
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy)
pediatric patients are listed in Table 9.
Table 9. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in
Study ACTG300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
8%
3%
Anemia (Hgb<7.0 g/dL)
4%
2%
Thrombocytopenia (platelets<50,000/mm3)
1%
3%
ALT (>10 x ULN)
1%
3%
AST (>10 x ULN)
2%
4%
Lipase (>2.5 x ULN)
3%
3%
Total amylase (>2.5 x ULN)
3%
3%
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR
180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema,
hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
pediatric patients.
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NDA 20-528/S-011
Page 18
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized,
double-blind, placebo-controlled trial in HIV-infected women and their neonates conducted to
determine the utility of RETROVIR for the prevention of maternal-fetal HIV transmission,
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates beginning
within 12 hours following birth. The most commonly reported adverse experiences were anemia
(hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22% of the neonates
who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in
hemoglobin values was less than 1.0 g/dL for neonates receiving RETROVIR compared to neonates
receiving placebo. No neonates with anemia required transfusion and all hemoglobin values
spontaneously returned to normal within 6 weeks after completion of therapy with RETROVIR.
Neutropenia was reported with similar frequency in the group that received RETROVIR (21%) and in
the group that received placebo (27%). The long-term consequences of in utero and infant exposure to
RETROVIR are unknown.
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during use of RETROVIR in clinical practice. Because they are
reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These
events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential
causal connection to RETROVIR, or a combination of these factors.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Cardiovascular: Cardiomyopathy, syncope.
Endocrine: Gynecomastia.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy,
pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic
acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with
pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia,
seizures, somnolence, vertigo.
Respiratory: Cough, dyspnea, rhinitis, sinusitis.
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NDA 20-528/S-011
Page 19
Skin: Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic
epidermal necrolysis, sweat, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Urogenital: Urinary frequency, urinary hesitancy.
OVERDOSAGE
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved
exposures up to 50 grams. No specific symptoms or signs have been identified following acute
overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache,
vomiting, and occasional reports of hematological disturbances. All patients recovered without
permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the
removal of zidovudine while elimination of its primary metabolite, GZDV, is enhanced.
DOSAGE AND ADMINISTRATION
Adults: The recommended oral dose of RETROVIR is 600 mg per day in divided doses in
combination with other antiretroviral agents.
Pediatrics: The recommended dose in pediatric patients 6 weeks to 12 years of age is 160 mg/m2
every 8 hours (480 mg/m2/day up to a maximum of 200 mg every 8 hours) in combination with other
antiretroviral agents.
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to
pregnant women (>14 weeks of pregnancy) and their neonates is:
Maternal Dosing: 100 mg orally 5 times per day until the start of labor (see INDICATIONS AND
USAGE: Description of Clinical Studies). During labor and delivery, intravenous RETROVIR should
be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous
infusion of 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See
PRECAUTIONS if hepatic disease or renal insufficiency is present.)
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone marrow
reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly in
patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is
recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who experience
hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia
usually occurs after 6 to 8 weeks.
Dose Adjustment: Anemia: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of
baseline) and/or significant neutropenia (granulocyte count of <750 cells/mm3 or reduction of >50%
from baseline) may require a dose interruption until evidence of marrow recovery is observed (see
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NDA 19-655/S-039
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NDA 20-528/S-011
Page 20
WARNINGS). In patients who develop significant anemia, dose interruption does not necessarily
eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption
in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses,
depending on hematologic indices such as serum erythropoetin level and patient tolerance.
For patients experiencing pronounced anemia while receiving chronic coadministration of
zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose
reduction may be considered.
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal dialysis,
recommended dosing is 100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Hepatic Impairment: There are insufficient data to recommend dose adjustment of RETROVIR
in patients with mild to moderate impaired hepatic function or liver cirrhosis. Since RETROVIR is
primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these
patients. Frequent monitoring for hematologic toxicities is advised (see CLINICAL
PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).
HOW SUPPLIED
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg zidovudine,
one side engraved “GX CW3” and “300” on the other side. Bottle of 60 (NDC 0173-0501-00).
Store at 15° to 25°C (59° to 77°F).
RETROVIR Capsules 100 mg (white, opaque cap and body with a dark blue band) containing
100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
body. Bottles of 100 (NDC 0173-0108-55) and Unit Dose Pack of 100 (NDC 0173-0108-56).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg zidovudine in
each teaspoonful (5 mL). Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
Store at 15° to 25°C (59° to 77°F).
GlaxoSmithKline
Research Triangle Park, NC 27709
2003, GlaxoSmithKline. All rights reserved.
April 2003
RL-1194
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:18.508643
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19655slr039,19910slr027,20528slr011_retrovir_lbl.pdf', 'application_number': 19910, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
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3
PRESCRIBING INFORMATION
RETROVIR®
(zidovudine)
Tablets
RETROVIR®
(zidovudine)
Capsules
RETROVIR®
(zidovudine)
Syrup
WARNING
RETROVIR (ZIDOVUDINE) HAS BEEN ASSOCIATED WITH HEMATOLOGIC
TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA PARTICULARLY
IN PATIENTS WITH ADVANCED HUMAN IMMUNODEFICIENCY VIRUS (HIV)
DISEASE (SEE WARNINGS). PROLONGED USE OF RETROVIR HAS BEEN
ASSOCIATED WITH SYMPTOMATIC MYOPATHY.
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF
NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING
RETROVIR AND OTHER ANTIRETROVIRALS (SEE WARNINGS).
DESCRIPTION
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
pyrimidine nucleoside analogue active against HIV.
Tablets: RETROVIR Tablets are for oral administration. Each film-coated tablet contains
300 mg of zidovudine and the inactive ingredients hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
Capsules: RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline
cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with
edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical
shellac, soya lecithin, and titanium dioxide. The blue band around the capsule consists of gelatin
and FD&C Blue No. 2.
Syrup: RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR
Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added
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4
as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be
added to adjust pH.
The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following
structural formula:
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24
and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
MICROBIOLOGY
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly,
zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate
(ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain
termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the
cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of
cells in culture.
Antiviral Activity: The antiviral activity of zidovudine against HIV-1 was assessed in a
number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The
EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 µM = 0.27 mcg/mL) and 0.1 to
9 µM, respectively. HIV from therapy-naive subjects with no mutations associated with
resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 93
baseline samples from COLA40263) and 0.02 µM (0.01 to 0.03 µM) from Monogram
Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against
different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from
0.00049 to 0.004 µM. In cell culture drug combination studies, zidovudine demonstrates
synergistic activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir,
didanosine, lamivudine, and zalcitabine; the non-nucleoside reverse transcriptase inhibitors
(NNRTIs) delavirdine and nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir,
ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to
inhibit the phosphorylation of zidovudine in cell culture.
Resistance: Genotypic analyses of the isolates selected in cell culture and recovered from
zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid
substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine
resistance. In general, higher levels of resistance were associated with greater number of
mutations. In some patients harboring zidovudine-resistant virus at baseline, phenotypic
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sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.
Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations
conferring resistance to zidovudine.
Cross-Resistance: In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug
resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from
patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The
pattern of resistance-associated mutations with such combination therapies was different (A62V,
V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the
Q151M mutation being most commonly associated with multi-drug resistance. The mutation at
codon 151 in combination with mutations at 62, 75, 77, and 116 results in a virus with reduced
susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine
analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir,
didanosine, stavudine, tenofovir, and zalcitabine.
CLINICAL PHARMACOLOGY
Pharmacokinetics: Adults: The pharmacokinetic properties of zidovudine in fasting patients
are summarized in Table 1. Following oral administration, zidovudine is rapidly absorbed and
extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours.
Binding to plasma protein is low. Zidovudine is primarily eliminated by hepatic metabolism. The
major metabolite of zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine
(GZDV). GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC.
Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose
following oral administration. A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has
been identified in the plasma following single-dose intravenous (IV) administration of
zidovudine. The AMT AUC was one fifth of the zidovudine AUC. Pharmacokinetics of
zidovudine were dose independent at oral dosing regimens ranging from 2 mg/kg every 8 hours
to 10 mg/kg every 4 hours.
The extent of absorption (AUC) was equivalent when zidovudine was administered as
RETROVIR Tablets or Syrup compared to RETROVIR Capsules.
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6
Table 1. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratio*
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)†
0.5 to 3
(n = 19)
*Median [range].
†Approximate range.
Adults With Impaired Renal Function: Zidovudine clearance was decreased resulting in
increased zidovudine and GZDV half-life and AUC in patients with impaired renal function
(n = 14) following a single 200-mg oral dose (Table 2). Plasma concentrations of AMT were not
determined. A dose adjustment should not be necessary for patients with creatinine clearance
(CrCl) ≥15 mL/min.
Table 2. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal
Impairment*
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
*Data are expressed as mean ± standard deviation.
The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in
patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses
up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated
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7
despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance
was approximately 50% of that reported in patients with normal renal function. Hemodialysis
and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine,
whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients
undergoing hemodialysis or peritoneal dialysis (see DOSAGE AND ADMINISTRATION: Dose
Adjustment).
Adults With Impaired Hepatic Function: Data describing the effect of hepatic
impairment on the pharmacokinetics of zidovudine are limited. However, because zidovudine is
eliminated primarily by hepatic metabolism, it is expected that zidovudine clearance would be
decreased and plasma concentrations would be increased following administration of the
recommended adult doses to patients with hepatic impairment (see DOSAGE AND
ADMINISTRATION: Dose Adjustment).
Pediatrics: Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric
patients (Table 3).
Patients From 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics
in pediatric patients greater than 3 months of age are similar to those in adult patients.
Proportional increases in plasma zidovudine concentrations were observed following
administration of oral solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability,
terminal half-life, and oral clearance were comparable to adult values. As in adult patients, the
major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of
the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV
(see DOSAGE AND ADMINISTRATION: Pediatrics).
Patients Younger Than 3 Months of Age: Zidovudine pharmacokinetics have been
evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was
determined immediately following birth in 8 neonates who were exposed to zidovudine in utero.
The half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total
body clearance was slower, and half-life was longer than in pediatric patients >14 days old. For
dose recommendations for neonates, see DOSAGE AND ADMINISTRATION: Neonatal
Dosing.
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Table 3. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]†
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life
(hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
*Data presented as mean ± standard deviation except where noted.
†Median [range].
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women
during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug
accumulation. Zidovudine pharmacokinetics were similar to those of nonpregnant adults.
Consistent with passive transmission of the drug across the placenta, zidovudine concentrations
in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.
Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear
to alter zidovudine pharmacokinetics. However, in another patient population, a potential for
interaction has been identified (see PRECAUTIONS).
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission
of HIV. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women,
the mean concentration of zidovudine was similar in human milk and serum (see
PRECAUTIONS: Nursing Mothers).
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients over
65 years of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects
showed no differences in zidovudine exposure (AUC) when a single dose of zidovudine was
administered as the 300-mg RETROVIR Tablet.
Effect of Food on Absorption: RETROVIR may be administered with or without food.
The extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was
administered with food.
Drug Interactions: See Table 4 and PRECAUTIONS: Drug Interactions.
Zidovudine Plus Lamivudine: No clinically significant alterations in lamivudine or
zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients
given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine
(300 mg every 12 hours).
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9
Table 4. Effect of Coadministered Drugs on Zidovudine AUC*
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED
WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Zidovudine
Zidovudine
Concentrations
Concentration
of
Coadministered
Drug and Dose
Dose
n
AUC
Variability
Drug
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%†
↔
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%†
↔
Nelfinavir
750 mg q 8 hr x 7
to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to
170%†
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to
130%†
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration
versus time curve; CI = confidence interval.
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10
*This table is not all inclusive.
†Estimated range of percent difference.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine,
and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular
triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV
virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18),
stavudine (n = 10), or zidovudine (n = 6) were co-administered as part of a multi-drug regimen to
HIV/HCV co-infected patients (see WARNINGS).
INDICATIONS AND USAGE
RETROVIR in combination with other antiretroviral agents is indicated for the treatment of
HIV infection.
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of
maternal-fetal HIV transmission as part of a regimen that includes oral RETROVIR beginning
between 14 and 34 weeks of gestation, intravenous RETROVIR during labor, and administration
of RETROVIR Syrup to the neonate after birth. The efficacy of this regimen for preventing HIV
transmission in women who have received RETROVIR for a prolonged period before pregnancy
has not been evaluated. The safety of RETROVIR for the mother or fetus during the first
trimester of pregnancy has not been assessed (see Description of Clinical Studies).
Description of Clinical Studies: Therapy with RETROVIR has been shown to prolong
survival and decrease the incidence of opportunistic infections in patients with advanced HIV
disease and to delay disease progression in asymptomatic HIV-infected patients.
Combination Therapy in Adults: RETROVIR in combination with other antiretroviral
agents has been shown to be superior to monotherapy for one or more of the following
endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and
decreasing plasma HIV-1 RNA. The clinical efficacy of a combination regimen that includes
RETROVIR was demonstrated in study ACTG320. This study was a multi-center, randomized,
double-blind, placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR®
300 mg/day to RETROVIR plus EPIVIR plus indinavir 800 mg t.i.d. The incidence of
AIDS-defining events or death was lower in the triple-drug–containing arm compared to the
2-drug–containing arm (6.1% versus 10.9%, respectively).
The complete prescribing information for each drug should be consulted before combination
therapy that includes RETROVIR is initiated.
Monotherapy in Adults: In controlled studies of treatment-naive patients conducted
between 1986 and 1989, monotherapy with RETROVIR, as compared to placebo, reduced the
risk of HIV disease progression, as assessed using endpoints that included the occurrence of
HIV-related illnesses, AIDS-defining events, or death. These studies enrolled patients with
advanced disease (BW002), and asymptomatic or mildly symptomatic disease in patients with
CD4+ cell counts between 200 and 500 cells/mm3 (ACTG016 and ACTG019). A survival
benefit for monotherapy with RETROVIR was not demonstrated in the latter 2 studies.
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Subsequent studies showed that the clinical benefit of monotherapy with RETROVIR was time
limited.
Pediatric Patients: ACTG300 was a multi-center, randomized, double-blind study that
provided for comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of
471 symptomatic, HIV-infected therapy-naive pediatric patients were enrolled in these
2 treatment arms. The median age was 2.7 years (range 6 weeks to 14 years), the mean baseline
CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was
5.0 log10 copies/mL. The median duration that patients remained on study was approximately
10 months. Results are summarized in Table 5.
Table 5. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease
Progression or Death)
Endpoint
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind,
placebo-controlled trial (ACTG076) conducted in HIV-infected pregnant women with CD4+ cell
counts of 200 to 1,818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or
no previous exposure to RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks
of gestation (median 11 weeks of therapy) followed by IV administration of RETROVIR during
labor and delivery. Following birth, neonates received oral RETROVIR Syrup for 6 weeks. The
study showed a statistically significant difference in the incidence of HIV infection in the
neonates (based on viral culture from peripheral blood) between the group receiving RETROVIR
and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of
HIV infection was 7.8% in the group receiving RETROVIR and 24.9% in the placebo group, a
relative reduction in transmission risk of 68.7%. RETROVIR was well tolerated by mothers and
infants. There was no difference in pregnancy-related adverse events between the treatment
groups.
CONTRAINDICATIONS
RETROVIR Tablets, Capsules, and Syrup are contraindicated for patients who have
potentially life-threatening allergic reactions to any of the components of the formulations.
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WARNINGS
COMBIVIR® and TRIZIVIR® are combination product tablets that contain zidovudine as one
of their components. RETROVIR should not be administered concomitantly with COMBIVIR or
TRIZIVIR.
The incidence of adverse reactions appears to increase with disease progression; patients
should be monitored carefully, especially as disease progression occurs.
Bone Marrow Suppression: RETROVIR should be used with caution in patients who have
bone marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin
<9.5 g/dL. In patients with advanced symptomatic HIV disease, anemia and neutropenia were the
most significant adverse events observed. There have been reports of pancytopenia associated
with the use of RETROVIR, which was reversible in most instances after discontinuance of the
drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of
RETROVIR, and/or blood transfusions, has occurred during treatment with RETROVIR alone or
in combination with other antiretrovirals.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who
are treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or
early HIV disease, periodic blood counts are recommended. If anemia or neutropenia develops,
dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
disease, have been associated with prolonged use of RETROVIR.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside
analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of
these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside
analogues may be risk factors. Particular caution should be exercised when administering
RETROVIR to any patient with known risk factors for liver disease; however, cases have also
been reported in patients with no known risk factors. Treatment with RETROVIR should be
suspended in any patient who develops clinical or laboratory findings suggestive of lactic
acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in
the absence of marked transaminase elevations).
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Use With Interferon- and Ribavirin-Based Regimens: In vitro studies have shown
ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine.
Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of
HIV/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine
in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions),
hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients
receiving combination antiretroviral therapy for HIV and interferon alfa with or without
ribavirin. Patients receiving interferon alfa with or without ribavirin and RETROVIR should be
closely monitored for treatment-associated toxicities, especially hepatic decompensation,
neutropenia, and anemia. Discontinuation of RETROVIR should be considered as medically
appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be
considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g.,
Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).
PRECAUTIONS
General: Zidovudine is eliminated from the body primarily by renal excretion following
metabolism in the liver (glucuronidation). In patients with severely impaired renal function
(CrCl<15 mL/min), dosage reduction is recommended. Although the data are limited, zidovudine
concentrations appear to be increased in patients with severely impaired hepatic function which
may increase the risk of hematologic toxicity (see CLINICAL PHARMACOLOGY:
Pharmacokinetics and DOSAGE AND ADMINISTRATION).
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including RETROVIR. During the initial
phase of combination antiretroviral treatment, patients whose immune system responds may
develop an inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or
tuberculosis), which may necessitate further evaluation and treatment.
Fat Redistribution: Redistribution/accumulation of body fat, including central obesity,
dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast
enlargement, and “cushingoid appearance,” have been observed in patients receiving
antiretroviral therapy. The mechanism and long-term consequences of these events are currently
unknown. A causal relationship has not been established.
Information for Patients: RETROVIR is not a cure for HIV infection, and patients may
continue to acquire illnesses associated with HIV infection, including opportunistic infections.
Therefore, patients should be advised to seek medical care for any significant change in their
health status.
The safety and efficacy of RETROVIR in women, intravenous drug users, and racial
minorities is not significantly different than that observed in white males.
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or
anemia. The frequency and severity of these toxicities are greater in patients with more advanced
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disease and in those who initiate therapy later in the course of their infection. They should be
told that if toxicity develops, they may require transfusions or drug discontinuation. They should
be told of the extreme importance of having their blood counts followed closely while on
therapy, especially for patients with advanced symptomatic HIV disease. They should be
cautioned about the use of other medications, including ganciclovir and interferon alfa, which
may exacerbate the toxicity of RETROVIR (see PRECAUTIONS: Drug Interactions). Patients
should be informed that other adverse effects of RETROVIR include nausea and vomiting.
Patients should also be encouraged to contact their physician if they experience muscle
weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected
adverse events while being treated with RETROVIR.
RETROVIR Tablets, Capsules, and Syrup are for oral ingestion only. Patients should be told
of the importance of taking RETROVIR exactly as prescribed. They should be told not to share
medication and not to exceed the recommended dose. Patients should be told that the long-term
effects of RETROVIR are unknown at this time.
Pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV
transmission to their infants should be advised that transmission may still occur in some cases
despite therapy. The long-term consequences of in utero and infant exposure to RETROVIR are
unknown, including the possible risk of cancer.
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal
transmission of HIV to a child who may not yet be infected.
Patients should be advised that therapy with RETROVIR has not been shown to reduce the
risk of transmission of HIV to others through sexual contact or blood contamination.
Patients should be informed that redistribution or accumulation of body fat may occur in
patients receiving antiretroviral therapy and that the cause and long-term health effects of these
conditions are not known at this time.
Drug Interactions: See CLINICAL PHARMACOLOGY section (Table 4) for information on
zidovudine concentrations when coadministered with other drugs. For patients experiencing
pronounced anemia or other severe zidovudine-associated events while receiving chronic
administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in
Table 4, zidovudine dose reduction may be considered.
Antiretroviral Agents: Concomitant use of zidovudine with stavudine should be avoided
since an antagonistic relationship has been demonstrated in vitro.
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the
in vitro antiviral activity of RETROVIR against HIV; concomitant use of such drugs should be
avoided.
Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an
antagonistic relationship has been demonstrated in vitro (see CLINICAL PHARMACOLOGY
for additional drug interactions).
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
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interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose
alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in
phenytoin kinetics was observed. Although not designed to optimally assess the effect of
phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed
with phenytoin.
Overlapping Toxicities: Coadministration of ganciclovir, interferon alfa, and other bone
marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered
orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each
group). Initial single daily doses were 30, 60, and 120 mg/kg/day in mice and 80, 220, and
600 mg/kg/day in rats. The doses in mice were reduced to 20, 30, and 40 mg/kg/day after day 90
because of treatment-related anemia, whereas in rats only the high dose was reduced to
450 mg/kg/day on day 91 and then to 300 mg/kg/day on day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous
cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given
the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a
middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell
carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or
middle dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by
AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at
the recommended therapeutic dose of 100 mg every 4 hours.
Two transplacental carcinogenicity studies were conducted in mice. One study administered
zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition
and lactation with dosing continuing in offspring for 24 months postnatally. The doses of
zidovudine employed in this study produced zidovudine exposures approximately 3 times the
estimated human exposure at recommended doses. After 24 months, an increase in incidence of
vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in
either gender. These findings are consistent with results of the standard oral carcinogenicity
study in mice, as described earlier. A second study administered zidovudine at maximum
tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg nonpregnant body weight or
∼450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There
was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the
offspring of mice receiving the higher dose level of zidovudine.
It is not known how predictive the results of rodent carcinogenicity studies may be for
humans.
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro
cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes,
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and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a
cytogenetic study in rats given a single dose.
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose
based on body surface area considerations, had no effect on fertility judged by conception rates.
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses
up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine
treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal
resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used
in the teratology studies resulted in peak zidovudine plasma concentrations (after one half of the
daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human
plasma concentrations (after one sixth of the daily dose) achieved with the recommended daily
dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine
exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional
teratology study in rats, a dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats
of 3,683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal
malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak
human plasma concentrations. (Estimated area under the curve [AUC] in rats at this dose level
was 300 times the daily AUC in humans given 600 mg/day.) No evidence of teratogenicity was
seen in this experiment at doses of 600 mg/kg/day or less.
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
Mutagenesis, Impairment of Fertility).
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
women to determine the utility of RETROVIR for the prevention of maternal-fetal
HIV-transmission (see INDICATIONS AND USAGE: Description of Clinical Studies).
Congenital abnormalities occurred with similar frequency between neonates born to mothers
who received RETROVIR and neonates born to mothers who received placebo. Abnormalities
were either problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound
before or immediately after initiation of study drug.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission
of HIV. Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY:
Pharmacokinetics: Nursing Mothers). Because of both the potential for HIV transmission and the
potential for serious adverse reactions in nursing infants, mothers should be instructed not to
breastfeed if they are receiving RETROVIR (see Pediatric Use and INDICATIONS AND
USAGE: Maternal-Fetal HIV Transmission).
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months
of age who had HIV-related symptoms or who were asymptomatic with abnormal laboratory
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values indicating significant HIV-related immunosuppression. RETROVIR has also been studied
in neonates perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND
ADMINISTRATION, INDICATIONS AND USAGE: Description of Clinical Studies, and
CLINICAL PHARMACOLOGY: Pharmacokinetics).
Geriatric Use: Clinical studies of RETROVIR did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy.
ADVERSE REACTIONS
Adults: The frequency and severity of adverse events associated with the use of RETROVIR
are greater in patients with more advanced infection at the time of initiation of therapy.
Table 6 summarizes events reported at a statistically significant greater incidence for patients
receiving RETROVIR in a monotherapy study:
Table 6. Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection
(ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
8.6%†
5.8%
Headache
62.5%
52.6%
Malaise
53.2%
44.9%
Gastrointestinal
Anorexia
20.1%
10.5%
Constipation
6.4%†
3.5%
Nausea
51.4%
29.9%
Vomiting
17.2%
9.8%
*Reported in ≥5% of study population.
†Not statistically significant versus placebo.
In addition to the adverse events listed in Table 6, other adverse events observed in clinical
studies were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue,
hyperbilirubinemia, insomnia, musculoskeletal pain, myalgia, and neuropathy.
Selected laboratory abnormalities observed during a clinical study of monotherapy with
RETROVIR are shown in Table 7.
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Table 7. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with
Asymptomatic HIV Infection (ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
1.1%
0.2%
Granulocytopenia (<750 cells/mm3)
1.8%
1.6%
Thrombocytopenia (platelets<50,000/mm3)
0%
0.5%
ALT (>5 x ULN)
3.1%
2.6%
AST (>5 x ULN)
0.9%
1.6%
Alkaline phosphatase (>5 x ULN)
0%
0%
ULN = Upper limit of normal.
Pediatrics: Study ACTG300: Selected clinical adverse events and physical findings with a
≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2
3 times daily compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy)
pediatric patients are listed in Table 8.
Table 8. Selected Clinical Adverse Events and Physical Findings (≥5% Frequency) in
Pediatric Patients in Study ACTG300
Adverse Event
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
25%
32%
Digestive
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
5%
8%
Respiratory
Cough
15%
18%
Abnormal breath sounds/wheezing
7%
9%
Ear, Nose, and Throat
Signs or symptoms of ears*
7%
6%
Nasal discharge or congestion
8%
11%
Other
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
*Includes pain, discharge, erythema, or swelling of an ear.
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Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral
therapy) pediatric patients are listed in Table 9.
Table 9. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric
Patients in Study ACTG300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
8%
3%
Anemia (Hgb<7.0 g/dL)
4%
2%
Thrombocytopenia (platelets<50,000/mm3)
1%
3%
ALT (>10 x ULN)
1%
3%
AST (>10 x ULN)
2%
4%
Lipase (>2.5 x ULN)
3%
3%
Total amylase (>2.5 x ULN)
3%
3%
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Additional adverse events reported in open-label studies in pediatric patients receiving
RETROVIR 180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG
abnormality, edema, hematuria, left ventricular dilation, macrocytosis, nervousness/irritability,
and weight loss.
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
pediatric patients.
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized,
double-blind, placebo-controlled trial in HIV-infected women and their neonates conducted to
determine the utility of RETROVIR for the prevention of maternal-fetal HIV transmission,
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates
beginning within 12 hours following birth. The most commonly reported adverse experiences
were anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in
22% of the neonates who received RETROVIR and in 12% of the neonates who received
placebo. The mean difference in hemoglobin values was less than 1.0 g/dL for neonates
receiving RETROVIR compared to neonates receiving placebo. No neonates with anemia
required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks
after completion of therapy with RETROVIR. Neutropenia was reported with similar frequency
in the group that received RETROVIR (21%) and in the group that received placebo (27%). The
long-term consequences of in utero and infant exposure to RETROVIR are unknown.
Observed During Clinical Practice: In addition to adverse events reported from clinical
trials, the following events have been identified during use of RETROVIR in clinical practice.
Because they are reported voluntarily from a population of unknown size, estimates of frequency
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cannot be made. These events have been chosen for inclusion due to either their seriousness,
frequency of reporting, potential causal connection to RETROVIR, or a combination of these
factors.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Cardiovascular: Cardiomyopathy, syncope.
Endocrine: Gynecomastia.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth
ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy,
pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice,
lactic acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis
with pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania,
paresthesia, seizures, somnolence, vertigo.
Respiratory: Cough, dyspnea, rhinitis, sinusitis.
Skin: Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic
epidermal necrolysis, sweat, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Urogenital: Urinary frequency, urinary hesitancy.
OVERDOSAGE
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These
involved exposures up to 50 grams. No specific symptoms or signs have been identified
following acute overdosage with zidovudine apart from those listed as adverse events such as
fatigue, headache, vomiting, and occasional reports of hematological disturbances. All patients
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
negligible effect on the removal of zidovudine while elimination of its primary metabolite,
GZDV, is enhanced.
DOSAGE AND ADMINISTRATION
Adults: The recommended oral dose of RETROVIR is 600 mg per day in divided doses in
combination with other antiretroviral agents.
Pediatrics: The recommended dose in pediatric patients 6 weeks to 12 years of age is
160 mg/m2 every 8 hours (480 mg/m2/day up to a maximum of 200 mg every 8 hours) in
combination with other antiretroviral agents.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to
pregnant women (>14 weeks of pregnancy) and their neonates is:
Maternal Dosing: 100 mg orally 5 times per day until the start of labor (see INDICATIONS
AND USAGE: Description of Clinical Studies). During labor and delivery, intravenous
RETROVIR should be administered at 2 mg/kg (total body weight) over 1 hour followed by a
continuous intravenous infusion of 1 mg/kg/hour (total body weight) until clamping of the
umbilical cord.
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See
PRECAUTIONS if hepatic disease or renal insufficiency is present.)
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone
marrow reserve and to dose and duration of therapy. In patients with poor bone marrow reserve,
particularly in patients with advanced symptomatic HIV disease, frequent monitoring of
hematologic indices is recommended to detect serious anemia or neutropenia (see WARNINGS).
In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as
2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks.
Dose Adjustment: Anemia: Significant anemia (hemoglobin of <7.5 g/dL or reduction of
>25% of baseline) and/or significant neutropenia (granulocyte count of <750 cells/mm3 or
reduction of >50% from baseline) may require a dose interruption until evidence of marrow
recovery is observed (see WARNINGS). In patients who develop significant anemia, dose
interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs
following dose interruption, resumption in dose may be appropriate using adjunctive measures
such as epoetin alfa at recommended doses, depending on hematologic indices such as serum
erythropoetin level and patient tolerance.
For patients experiencing pronounced anemia while receiving chronic coadministration of
zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine
dose reduction may be considered.
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal dialysis,
recommended dosing is 100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Hepatic Impairment: There are insufficient data to recommend dose adjustment of
RETROVIR in patients with mild to moderate impaired hepatic function or liver cirrhosis. Since
RETROVIR is primarily eliminated by hepatic metabolism, a reduction in the daily dose may be
necessary in these patients. Frequent monitoring for hematologic toxicities is advised (see
CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).
HOW SUPPLIED
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
zidovudine, one side engraved “GX CW3” and “300” on the other side.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Bottle of 60 (NDC 0173-0501-00).
Store at 15° to 25°C (59° to 77°F).
RETROVIR Capsules 100 mg (white, opaque cap and body with a dark blue band) containing
100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100”
on body.
Bottles of 100 (NDC 0173-0108-55).
Unit Dose Pack of 100 (NDC 0173-0108-56).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
zidovudine in each teaspoonful (5 mL).
Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
Store at 15° to 25°C (59° to 77°F).
GlaxoSmithKline
Research Triangle Park, NC 27709
©2006, GlaxoSmithKline. All rights reserved.
October 2006
RL-2324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:18.552195
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019910s032lbl.pdf', 'application_number': 19910, 'submission_type': 'SUPPL ', 'submission_number': 32}
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11,844
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RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
1
PRODUCT INFORMATION
1
RETROVIR® (zidovudine) Tablets
2
RETROVIR® (zidovudine) Capsules
3
RETROVIR® (zidovudine) Syrup
4
5
WARNING: RETROVIR (ZIDOVUDINE) MAY BE ASSOCIATED WITH
6
HEMATOLOGIC TOXICITY INCLUDING GRANULOCYTOPENIA AND SEVERE
7
ANEMIA PARTICULARLY IN PATIENTS WITH ADVANCED HIV DISEASE (SEE
8
WARNINGS). PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED WITH
9
SYMPTOMATIC MYOPATHY SIMILAR TO THAT PRODUCED BY HUMAN
10
IMMUNODEFICIENCY VIRUS.
11
RARE OCCURRENCES OF POTENTIALLY FATAL LACTIC ACIDOSIS IN THE ABSENCE OF
12
HYPOXEMIA, AND SEVERE HEPATOMEGALY WITH STEATOSIS HAVE BEEN REPORTED
13
WITH THE USE OF CERTAIN ANTIRETROVIRAL NUCLEOSIDE ANALOGUES (SEE
14
WARNINGS).
15
16
DESCRIPTION: RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]),
17
a pyrimidine nucleoside analogue active against human immunodeficiency virus (HIV).
18
Tablets: RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of
19
zidovudine and the inactive ingredients hydroxypropyl methylcellulose, magnesium stearate,
20
microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
21
Capsules: RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
22
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose,
23
and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink,
24
consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and
25
titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.
26
Syrup: RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup
27
contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a
28
preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to
29
adjust pH.
30
The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural
31
formula:
32
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
2
34
35
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a
36
solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
37
38
MICROBIOLOGY: Mechanism of Action: Zidovudine is a synthetic nucleoside analogue of the
39
naturally occurring nucleoside, thymidine, in which the 3′-hydroxy (-OH) group is replaced by an azido
40
(-N3) group. Within cells, zidovudine is converted to the active metabolite, zidovudine 5′-triphosphate
41
(AztTP), by the sequential action of the cellular enzymes. Zidovudine 5′-triphosphate inhibits the
42
activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate,
43
deoxythymidine 5′-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3′- OH
44
group in the incorporated nucleoside analogue prevents the formation of the 5′ to 3′ phosphodiester
45
linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The
46
active metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and
47
mitochondrial polymerase-gamma and has been reported to be incorporated into the DNA of cells in
48
culture.
49
In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zidovudine was assessed by infecting cell
50
lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and
51
clinical isolates of HIV. The IC50 and IC90 values (50% and 90% inhibitory concentrations) were 0.003
52
to 0.013 and 0.03 to 0.13 mcg/mL, respectively (1 nM = 0.27 ng/mL).The IC50 and IC90 values of HIV
53
isolates recovered from 18 untreated AIDS/ARC patients were in the range of 0.003 to 0.013 mcg/mL
54
and 0.03 to 0.3 mcg/mL, respectively. Zidovudine showed antiviral activity in all acutely infected cell
55
lines; however, activity was substantially less in chronically infected cell lines. In drug combination
56
studies with zalcitabine, didanosine, lamivudine, saquinavir, indinavir, ritonavir, nevirapine,
57
delavirdine, or interferon-alpha, zidovudine showed additive to synergistic activity in cell culture. The
58
relationship between the in vitro susceptibility of HIV to reverse transcriptase inhibitors and the
59
inhibition of HIV replication in humans has not been established.
60
Drug Resistance: HIV isolates with reduced sensitivity to zidovudine have been selected in vitro and
61
were also recovered from patients treated with RETROVIR. Genetic analysis of the isolates showed
62
mutations which result in five amino acid substitutions (Met41→Leu, A67→Asn, Lys70→Arg,
63
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
3
Thr215→Tyr or Phe, and Lys219→Gln) in the viral reverse transcriptase. In general, higher levels of
64
resistance were associated with greater number of mutations with 215 mutation being the most
65
significant.
66
Cross-Resistance: The potential for cross-resistance between HIV reverse transcriptase inhibitors
67
and protease inhibitors is low because of the different enzyme targets involved. Combination therapy
68
with zidovudine plus zalcitabine or didanosine does not appear to prevent the emergence of
69
zidovudine-resistant isolates. Combination therapy with RETROVIR plus EPIVIR delayed the
70
emergence of mutations conferring resistance to zidovudine. In some patients harboring
71
zidovudine-resistant virus, combination therapy with RETROVIR plus EPIVIR restored phenotypic
72
sensitivity to zidovudine by 12 weeks of treatment. HIV isolates with multidrug resistance to
73
zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number
74
of patients treated for ≥1 year with the combination of zidovudine and didanosine or zalcitabine. The
75
pattern of resistant mutations in the combination therapy was different (Ala62→Val, Val75→Ile,
76
Phe77→116Tyr, and Gln→151Met) from monotherapy, with mutation 151 being most significant for
77
multidrug resistance. Site-directed mutagenesis studies showed that these mutations could also
78
result in resistance to zalcitabine, lamivudine, and stavudine.
79
80
CLINICAL PHARMACOLOGY:
81
Pharmacokinetics: Adults: The pharmacokinetics of zidovudine has been evaluated in 22 adult
82
HIV-infected patients in a Phase 1 dose-escalation study. After oral dosing (capsules), zidovudine
83
was rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring within
84
0.5 to 1.5 hours. Dose-independent kinetics was observed over the range of 2 mg/kg every 8 hours to
85
10 mg/kg every 4 hours. The mean zidovudine half-life was approximately 1 hour and ranged from
86
0.78 to 1.93 hours following oral dosing.
87
Zidovudine is rapidly metabolized to 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine
88
(GZDV) which has an apparent elimination half-life of 1 hour (range 0.61 to 1.73 hours). Following
89
oral administration, urinary recovery of zidovudine and GZDV accounted for 14% and 74% of the
90
dose, respectively, and the total urinary recovery averaged 90% (range 63% to 95%), indicating a
91
high degree of absorption. However, as a result of first-pass metabolism, the average oral capsule
92
bioavailability of zidovudine is 65% (range 52% to 75%). A second metabolite, 3′-amino-3′-
93
deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV)
94
administration of zidovudine. AMT area-under-the-curve (AUC) was one fifth of the AUC of
95
zidovudine and had a half-life of 2.7 ± 0.7 hours. In comparison, GZDV AUC was about threefold
96
greater than the AUC of zidovudine.
97
Additional pharmacokinetic data following intravenous dosing indicated dose-independent kinetics
98
over the range of 1 to 5 mg/kg with a mean zidovudine half-life of 1.1 hours (range 0.48 to
99
2.86 hours). Total body clearance averaged 1900 mL/min per 70 kg and the apparent volume of
100
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
4
distribution was 1.6 L/kg. Renal clearance is estimated to be 400 mL/min per 70 kg, indicating
101
glomerular filtration and active tubular secretion by the kidneys. Zidovudine plasma protein binding is
102
34% to 38%, indicating that drug interactions involving binding site displacement are not anticipated.
103
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in
104
39 patients receiving chronic therapy with RETROVIR. The median ratio measured in 50 paired
105
samples drawn 1 to 8 hours after the last dose of RETROVIR was 0.6.
106
Adults with Impaired Renal Function: The pharmacokinetics of zidovudine has been evaluated
107
in patients with impaired renal function following a single 200-mg oral dose. In 14 patients (mean
108
creatinine clearance 18 ± 2 mL/min) the half-life of zidovudine was 1.4 hours compared to 1.0 hour
109
for control subjects with normal renal function; AUC values were approximately twice those of
110
controls. Additionally, GZDV half-life in these patients was 8.0 hours (vs 0.9 hours for control) and
111
AUC was 17 times higher than for control subjects. The pharmacokinetics and tolerance were
112
evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis
113
(n = 6). Patients received escalating doses of zidovudine up to 200 mg five times daily for 8 weeks.
114
Daily doses of 500 mg or less were well tolerated despite significantly elevated plasma levels of
115
GZDV. Apparent oral clearance of zidovudine was approximately 50% of that reported in patients with
116
normal renal function. The plasma concentrations of AMT are not known in patients with renal
117
insufficiency. Daily doses of 300 to 400 mg should be appropriate in HIV-infected patients with severe
118
renal dysfunction (see DOSAGE AND ADMINISTRATION: Dose Adjustment). Hemodialysis and
119
peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, whereas GZDV
120
elimination is enhanced.
121
Pediatrics: The pharmacokinetics and bioavailability of zidovudine have been evaluated in
122
21 HIV-infected pediatric patients, aged 6 months through 12 years, following intravenous doses
123
administered over the range of 80 to 160 mg/m2 every 6 hours, and following oral doses of the IV
124
solution administered over the range of 90 to 240 mg/m2 every 6 hours. After discontinuation of the IV
125
infusion, zidovudine plasma concentrations decayed biexponentially, consistent with
126
two-compartment pharmacokinetics. Proportional increases in AUC and in zidovudine concentrations
127
were observed with increasing dose, consistent with dose-independent kinetics over the dose range
128
studied. The mean terminal half-life and total body clearance across all dose levels administered
129
were 1.5 hours and 30.9 mL/min per kg, respectively. These values compare to mean half-life and
130
total body clearance in adults of 1.1 hours and 27.1 mL/min per kg.
131
The mean oral bioavailability of 65% was independent of dose. This value is the same as the
132
bioavailability in adults. Doses of 180 mg/m2 four times daily in pediatric patients produced similar
133
systemic exposure (24-hour AUC 10.7 hr•mcg/mL) as doses of 200 mg six times daily in adult
134
patients (10.9 hr•mcg/mL).
135
The pharmacokinetics of zidovudine have been studied in pediatric patients from birth to 3 months
136
of life. In one study of the pharmacokinetics of zidovudine in women during the last trimester of
137
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
5
pregnancy, zidovudine elimination was determined immediately after birth in eight neonates who were
138
exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In another study, the
139
pharmacokinetics of zidovudine were evaluated in pediatric patients (ranging in age of 1 day to
140
3 months) of normal birth weight for gestational age and with normal renal and hepatic function. In
141
neonates less than or equal to 14 days old, mean ± SD total body clearance was 10.9 ± 4.8 mL/min
142
per kg (n = 18) and half-life was 3.1 ± 1.2 hours (n = 21). In neonates and infants greater than
143
14 days old, total body clearance was 19.0 ± 4.0 mL/min per kg (n = 16) and half-life was
144
1.9 ± 0.7 hours (n = 18). Bioavailability was 89% ± 19% (n = 15) in the younger age group and
145
decreased to 61% ± 19% (n = 17) in patients older than 14 days.
146
Concentrations of zidovudine in cerebrospinal fluid were measured after both intermittent oral and
147
IV drug administration in 21 pediatric patients during Phase 1 and Phase 2 studies. The mean
148
zidovudine CSF/plasma concentration ratio measured at an average time of 2.2 hours postdose at
149
oral doses of 120 to 240 mg/m2 was 0.52 ± 0.44 (n = 28); after an IV infusion of doses of 80 to
150
160 mg/m2 over 1 hour, the mean CSF/plasma concentration ratio was 0.87 ± 0.66 (n = 23) at
151
3.2 hours after the start of the infusion. During continuous IV infusion, mean steady-state
152
CSF/plasma ratio was 0.26 ± 0.17 (n = 28).
153
As in adult patients, the major route of elimination in pediatric patients was by metabolism to
154
GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged and about 45%
155
of the dose was excreted as GZDV. Overall, the pharmacokinetics of zidovudine in pediatric patients
156
greater than 3 months of age are similar to that of zidovudine in adult patients.
157
Pregnancy: The pharmacokinetics of zidovudine have been studied in a Phase 1 study of eight
158
women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of
159
drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant adults.
160
Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in
161
infant plasma at birth were essentially equal to those in maternal plasma at delivery. Although data
162
are limited, methadone maintenance therapy in five pregnant women did not appear to alter
163
zidovudine pharmacokinetics. However, in another patient population, a potential for interaction has
164
been identified (see PRECAUTIONS).
165
Nursing Mothers: The U.S. Public Health Service Centers for Disease Control and Prevention
166
advises HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who
167
may not yet be infected. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected
168
women, the mean concentration of zidovudine was similar in human milk and serum (see
169
PRECAUTIONS: Nursing Mothers).
170
Effect of Food on Absorption: Administration of RETROVIR Capsules with food decreased
171
peak plasma concentrations by greater than 50%; however, bioavailability as determined by AUC
172
may not be affected.
173
The effect of food on the absorption of zidovudine from the tablet formulation is not known.
174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
6
Tablets: In a single-dose study of 23 healthy volunteers, the mean ± SD relative bioavailability of
175
the RETROVIR 300-mg Tablet relative to three 100-mg RETROVIR Capsules was 110 ± 18%. After
176
administration of the 300-mg RETROVIR Tablet or three 100-mg RETROVIR Capsules, the mean
177
± SD Cmax values were 1.81 ± 0.52 and 1.50 ± 0.46 mcg/mL, respectively.
178
Syrup: In a multiple-dose bioavailability study conducted in 12 HIV-infected adults receiving doses
179
of 100 or 200 mg every 4 hours, RETROVIR Syrup was demonstrated to be bioequivalent to
180
RETROVIR Capsules with respect to area under the zidovudine plasma concentration-time curve
181
(AUC). The rate of absorption of RETROVIR Syrup was greater than that of RETROVIR Capsules,
182
as indicated by mean times to peak concentration of 0.5 and 0.8 hours, respectively. Mean values for
183
steady-state peak concentration (dose-normalized to 200 mg) were 1.5 and 1.2 mcg/mL for syrup
184
and capsules, respectively.
185
186
INDICATIONS AND USAGE: RETROVIR is indicated for the treatment of HIV infection when
187
antiretroviral therapy is warranted (see Description of Clinical Studies).
188
The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in
189
antiretroviral therapy should be considered if disease progression occurs during treatment.
190
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of maternal-fetal
191
HIV transmission as part of a regimen that includes oral RETROVIR beginning between 14 and
192
34 weeks of gestation, intravenous RETROVIR during labor, and administration of RETROVIR Syrup
193
to the neonate after birth. The efficacy of this regimen for preventing HIV transmission in women who
194
have received RETROVIR for a prolonged period before pregnancy has not been evaluated. The
195
safety of RETROVIR for the mother or fetus during the first trimester of pregnancy has not been
196
assessed (see Description of Clinical Studies).
197
Description of Clinical Studies: Therapy with RETROVIR has been shown to prolong survival and
198
decrease the incidence of opportunistic infections in patients with advanced HIV disease at the
199
initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients.
200
Other randomized studies suggest that the duration of the clinical benefit of monotherapy with
201
RETROVIR is time-limited.
202
Combination Therapy-Adults: ACTG175 was a randomized, double-blind, controlled trial that
203
compared RETROVIR 200 mg t.i.d.; didanosine 200 mg b.i.d.; RETROVIR plus didanosine; and
204
RETROVIR plus zalcitabine 0.75 mg t.i.d. A total of 2467 HIV-infected adults with baseline CD4
205
counts of 200 to 500 cells/mm3 (mean = 352) and no prior AIDS-defining event enrolled with the
206
following demographics: male (82%), Caucasian (70%), mean age of 35 years, asymptomatic HIV
207
infection (81%), and prior antiretroviral use (57%, mean duration = 89.5 weeks). The overall median
208
duration of study treatment was 118 weeks. The incidence of AIDS-defining events or death is shown
209
in Table 1.
210
211
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
7
Table 1
212
First AIDS-Defining Event or Death and Death Only
213
by Study Arm and Antiretroviral Experience
214
215
Treatment
Antiretroviral
Experience
Event
RETROVIR
Didanosine
RETROVIR
plus
Didanosine
RETROVIR
plus Zalcitabine
No. of Patients
619
620
613
615
Overall
AIDS/Death
96 (16%)
71 (11%)
66 (11%)
76 (12%)
Death Only
54 (9%)
29 (5%)
31 (5%)
40 (7%)
No. of Patients
269
268
263
267
Naive
AIDS/Death
32 (12%)
23 (9%)
20 (8%)
16 (6%)
Death Only
18 (7%)
11 (4%)
11 (4%)
9 (3%)
No. of Patients
350
352
350
348
Experienced
AIDS/Death
64 (18%)
48 (14%)
45 (13%)
60 (17%)
Death Only
36 (10%)
18 (5%)
20 (6%)
31 (9%)
216
RETROVIR in combination with certain antiretroviral agents has been shown to be superior to
217
monotherapy in one or more of the following: delaying death, delaying development of AIDS,
218
increasing CD4 cell counts, and decreasing plasma HIV RNA. Use of RETROVIR in some
219
combinations is based on surrogate marker data. The complete prescribing information for each drug
220
should be consulted before combination therapy which includes RETROVIR is initiated.
221
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
222
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled
223
trial (ACTG 076) conducted in HIV-infected pregnant women with CD4 cell counts of 200
224
to1818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure
225
to RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median
226
11 weeks of therapy) followed by IV administration of RETROVIR during labor and delivery. After
227
birth, neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
228
significant difference in the incidence of HIV infection in the neonates (based on viral culture from
229
peripheral blood) between the group receiving RETROVIR and the group receiving placebo. Of
230
363 neonates evaluated in the study, the estimated risk of HIV infection was 7.8% in the group
231
receiving RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of
232
68.7%. RETROVIR was well tolerated by mothers and infants. There was no difference in
233
pregnancy-related adverse events between the treatment groups.
234
Dose-Frequency Study: A randomized, double-blind, dose-frequency study of RETROVIR in
235
320 patients with AIDS or advanced ARC was conducted to assess the safety and tolerability of
236
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
8
600 mg RETROVIR per day given as either 100 mg every 4 hours or as 300 mg every 12 hours for
237
48 weeks. No significant difference was detected between the two dose frequencies with regard to
238
adverse experiences or hematologic abnormalities. Although this study was not designed to
239
determine efficacy, no differences in the frequency of or time to opportunistic infections, neoplasms,
240
or death were noted between treatment groups. Changes in CD4 cell counts and β2-microglobulin
241
levels were similar between treatment groups.
242
243
CONTRAINDICATIONS: RETROVIR Tablets, Capsules, and Syrup are contraindicated for patients
244
who have potentially life-threatening allergic reactions to any of the components of the formulations.
245
246
WARNINGS: Before combination therapy with RETROVIR is initiated, consult the complete
247
prescribing information for each drug. The safety profile of RETROVIR plus other antiretroviral agents
248
reflects the individual safety profiles of each component.
249
The incidence of adverse reactions appears to increase with disease progression, and patients
250
should be monitored carefully, especially as disease progression occurs.
251
Bone Marrow Suppression: RETROVIR should be used with caution in patients who have bone
252
marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL. In
253
patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant
254
adverse events observed (see ADVERSE REACTIONS). There have been reports of pancytopenia
255
associated with the use of RETROVIR, which was reversible in most instances after discontinuance
256
of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation
257
of RETROVIR, and/or blood transfusions has occurred during treatment with RETROVIR alone or in
258
combination with other antiretrovirals.
259
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are
260
treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV
261
disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage
262
adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
263
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
264
disease, have been associated with prolonged use of RETROVIR.
265
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Rare occurrences of potentially fatal lactic
266
acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported
267
with the use of certain antiretroviral nucleoside analogues. Lactic acidosis should be considered
268
whenever a patient receiving therapy with RETROVIR develops unexplained tachypnea, dyspnea, or
269
fall in serum bicarbonate level. Under these circumstances, therapy with RETROVIR should be
270
suspended until the diagnosis of lactic acidosis has been excluded. Caution should be exercised
271
when administering RETROVIR to any patient, particularly obese women, with hepatomegaly,
272
hepatitis, or other known risk factor for liver disease. These patients should be followed closely while
273
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For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
9
on therapy with RETROVIR. The significance of elevated aminotransferase levels suggesting hepatic
274
injury in HIV-infected patients prior to starting RETROVIR or while on RETROVIR is unclear.
275
Treatment with RETROVIR should be suspended in the setting of rapidly elevating aminotransferase
276
levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown etiology.
277
Other Serious Adverse Reactions: Several serious adverse events have been reported with use of
278
RETROVIR in clinical practice. Reports of pancreatitis, sensitization reactions (including anaphylaxis
279
in one patient), vasculitis, and seizures have been rare. These adverse events, except for
280
sensitization, have also been associated with HIV disease. Changes in skin and nail pigmentation
281
have been associated with the use of RETROVIR.
282
283
PRECAUTIONS:
284
General: Zidovudine is eliminated from the body primarily by renal excretion following metabolism in
285
the liver (glucuronidation). In patients with severely impaired renal function, dosage reduction is
286
recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND
287
ADMINISTRATION). Although very little data are available, patients with severely impaired hepatic
288
function may be at greater risk of toxicity.
289
Information for Patients: RETROVIR is not a cure for HIV infection, and patients may continue to
290
acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients
291
should be advised to seek medical care for any significant change in their health status.
292
The safety and efficacy of RETROVIR in women, intravenous drug users, and racial minorities is
293
not significantly different than that observed in white males.
294
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or
295
anemia. The frequency and severity of these toxicities are greater in patients with more advanced
296
disease and in those who initiate therapy later in the course of their infection. They should be told that
297
if toxicity develops, they may require transfusions or dose modifications including possible
298
discontinuation. They should be told of the extreme importance of having their blood counts followed
299
closely while on therapy, especially for patients with advanced symptomatic HIV disease. They
300
should be cautioned about the use of other medications, including ganciclovir and interferon-alpha,
301
that may exacerbate the toxicity of RETROVIR (see PRECAUTIONS: Drug Interactions). Patients
302
should be informed that other adverse effects of RETROVIR include nausea and vomiting. Patients
303
should also be encouraged to contact their physician if they experience muscle weakness, shortness
304
of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being
305
treated with RETROVIR.
306
RETROVIR Tablets, Capsules, and Syrup are for oral ingestion only. Patients should be told of the
307
importance of taking RETROVIR exactly as prescribed. They should be told not to share medication
308
and not to exceed the recommended dose. Patients should be told that the long-term effects of
309
RETROVIR are unknown at this time.
310
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
10
Pregnant women considering the use of RETROVIR during pregnancy for prevention of
311
HIV-transmission to their infants should be advised that transmission may still occur in some cases
312
despite therapy. The long-term consequences of in utero and infant exposure to RETROVIR are
313
unknown, including the possible risk of cancer.
314
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission
315
of HIV to a child who may not yet be infected.
316
Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of
317
transmission of HIV to others through sexual contact or blood contamination.
318
Drug Interactions: Ganciclovir: Use of RETROVIR in combination with ganciclovir increases the
319
risk of hematologic toxicities in some patients with advanced HIV disease. Should the use of this
320
combination become necessary in the treatment of patients with HIV disease, dose reduction or
321
interruption of one or both agents may be necessary to minimize hematologic toxicity. Hematologic
322
parameters, including hemoglobin, hematocrit, and white blood cell count with differential, should be
323
monitored frequently in all patients receiving this combination.
324
Interferon-alpha: Hematologic toxicities have also been seen when RETROVIR is used
325
concomitantly with interferon-alpha. As with the concomitant use of RETROVIR and ganciclovir, dose
326
reduction or interruption of one or both agents may be necessary, and hematologic parameters
327
should be monitored frequently.
328
Bone Marrow Suppressive Agents/Cytotoxic Agents: Coadministration of RETROVIR with
329
drugs that are cytotoxic or which interfere with RBC/WBC number or function (e.g., dapsone,
330
flucytosine, vincristine, vinblastine, or adriamycin) may increase the risk of hematologic toxicity.
331
Probenecid: Limited data suggest that probenecid may increase zidovudine levels by inhibiting
332
glucuronidation and/or by reducing renal excretion of zidovudine. Some patients who have used
333
RETROVIR concomitantly with probenecid have developed flu-like symptoms consisting of myalgia,
334
malaise, and/or fever and maculopapular rash.
335
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
336
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
337
interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone
338
and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin
339
kinetics was observed. Although not designed to optimally assess the effect of phenytoin on
340
zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
341
Methadone: In a pharmacokinetic study of nine HIV-positive patients receiving
342
methadone-maintenance (30 to 90 mg daily) concurrent with 200 mg of RETROVIR every 4 hours,
343
no changes were observed in the pharmacokinetics of methadone upon initiation of therapy with
344
RETROVIR and after 14 days of treatment with RETROVIR. No adjustments in
345
methadone-maintenance requirements were reported. For four patients, the mean zidovudine AUC
346
This label may not be the latest approved by FDA.
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RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
11
was elevated twofold, while for five patients, the value was equal to that of control patients. The exact
347
mechanism and clinical significance of these data are unknown.
348
Fluconazole: The coadministration of fluconazole with RETROVIR has been reported to interfere
349
with the oral clearance and metabolism of RETROVIR. In a pharmacokinetic interaction study in
350
which 12 HIV-positive men received RETROVIR 200 mg every 8 hours alone and in combination with
351
fluconazole 400 mg daily, fluconazole increased the zidovudine AUC (74%; range 28% to 173%) and
352
the zidovudine half-life (128%; range -4% to 189%) at steady state. The clinical significance of this
353
interaction is unknown.
354
Atovaquone: Data from 14 HIV-infected volunteers who were given atovaquone tablets 750 mg
355
every 12 hours with zidovudine 200 mg every 8 hours showed a 24% ± 12% decrease in zidovudine
356
oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide
357
metabolite:parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1
358
when zidovudine was administered with atovaquone tablets. Zidovudine had no effect on atovaquone
359
pharmacokinetics.
360
Valproic Acid: The concomitant administration of valproic acid 250 mg (n = 5) or 500 mg (n = 1)
361
every 8 hours and zidovudine 100 mg orally every 8 hours for 4 days to six HIV-infected,
362
asymptomatic male volunteers resulted in a 79% ± 61% (mean ± SD) increase in the plasma
363
zidovudine AUC and a 22% ± 10% decrease in the plasma GZDV AUC as compared to the
364
administration of zidovudine in the absence of valproic acid. The GZDV/zidovudine urinary excretion
365
ratio decreased 58% ± 12%. Because no change in the zidovudine plasma half-life occurred, these
366
results suggest that valproic acid may increase the oral bioavailability of zidovudine through inhibition
367
of first-pass metabolism. Although the clinical significance of this interaction is unknown, patients
368
should be monitored more closely for a possible increase in zidovudine-related adverse effects. The
369
effect of zidovudine on the pharmacokinetics of valproic acid was not evaluated.
370
Lamivudine: RETROVIR and lamivudine were coadministered to 12 asymptomatic HIV-positive
371
patients in a single-center, open-label, randomized, crossover study. No significant differences were
372
observed in AUC∞ or total clearance for lamivudine or zidovudine when the two drugs were
373
administered together. Coadministration of RETROVIR with lamivudine resulted in an increase of
374
39% ± 62% (mean ± SD) in Cmax of zidovudine.
375
Other Agents: Preliminary data from a drug interaction study (n = 10) suggest that
376
coadministration of 200 mg RETROVIR and 600 mg rifampin decreases the area under the plasma
377
concentration curve by an average of 48% ± 34%. However, the effect of once-daily dosing of
378
rifampin on multiple daily doses of RETROVIR is unknown. Some nucleoside analogues affecting
379
DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of RETROVIR against HIV;
380
concomitant use of such drugs should be avoided.
381
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered orally at
382
three dosage levels to separate groups of mice and rats (60 females and 60 males in each group).
383
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
12
Initial single daily doses were 30, 60, and 120 mg/kg per day in mice and 80, 220, and 600 mg/kg per
384
day in rats. The doses in mice were reduced to 20, 30, and 40 mg/kg per day after day 90 because of
385
treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg per day on
386
day 91 and then to 300 mg/kg per day on day 279.
387
In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing
388
squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred in
389
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina
390
of a middle-dose animal. No vaginal tumors were found at the lowest dose.
391
In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
392
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in
393
rats. No other drug-related tumors were observed in either sex of either species.
394
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by
395
AUC) was approximately three times (mouse) and 24 times (rat) the estimated human exposure at
396
the recommended therapeutic dose of 100 mg every 4 hours.
397
Two transplacental carcinogenicity studies were conducted in mice. One study administered
398
zidovudine at doses of 20 mg/kg per day or 40 mg/kg per day from gestation day 10 through
399
parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of
400
zidovudine employed in this study produced zidovudine exposures approximately three times the
401
estimated human exposure at recommended doses. After 24 months, an increase in incidence of
402
vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either
403
gender. These findings are consistent with results of the standard oral carcinogenicity study in mice,
404
as described earlier. A second study administered zidovudine at maximum tolerated doses of
405
12.5 mg/day or 25 mg/day (∼1000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body
406
weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number
407
of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher
408
dose level of zidovudine.
409
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
410
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
411
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and
412
positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic
413
study in rats given a single dose.
414
Zidovudine, administered to male and female rats at doses up to seven times the usual adult dose
415
based on body surface area considerations, had no effect on fertility judged by conception rates.
416
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to
417
500 mg/kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment
418
resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in
419
rats given 150 or 450 mg/kg per day and rabbits given 500 mg/kg per day. The doses used in the
420
This label may not be the latest approved by FDA.
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RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
13
teratology studies resulted in peak zidovudine plasma concentrations (after one half of the daily dose)
421
in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma
422
concentrations (after one sixth of the daily dose) achieved with the recommended daily dose (100 mg
423
every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
424
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose
425
of 3000 mg/kg per day (very near the oral median lethal dose in rats of 3683 mg/kg) caused marked
426
maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak
427
zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated
428
area-under-the-curve [AUC] in rats at this dose level was 300 times the daily AUC in humans given
429
600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg
430
per day or less.
431
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
432
Mutagenesis, Impairment of Fertility).
433
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
434
women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-transmission
435
(see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities occurred
436
with similar frequency between neonates born to mothers who received RETROVIR and neonates
437
born to mothers who received placebo. Abnormalities were either problems in embryogenesis (prior
438
to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
439
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
440
exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are
441
encouraged to register patients by calling 1-800-258-4263.
442
Nursing Mothers: The U.S. Public Health Service Centers for Disease Control and Prevention
443
advises HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who
444
may not yet be infected. Zidovudine is excreted in human milk (see Pharmacokinetics).
445
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age
446
who have HIV-related symptoms or who are asymptomatic with abnormal laboratory values indicating
447
significant HIV-related immunosuppression (see ADVERSE REACTIONS, DOSAGE AND
448
ADMINISTRATION, and INDICATIONS AND USAGE: Description of Clinical Studies, and
449
Pharmacokinetics).
450
Geriatric Use: Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
451
and over to determine whether they respond differently from younger subjects. Other reported clinical
452
experience has not identified differences in responses between the elderly and younger patients. In
453
general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of
454
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
455
456
ADVERSE REACTIONS:
457
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
14
Monotherapy: Adults: The frequency and severity of adverse events associated with the use of
458
RETROVIR in adults are greater in patients with more advanced infection at the time of initiation of
459
therapy. The following table summarizes the relative incidence of hematologic adverse events
460
observed in clinical studies by severity of HIV disease present at the start of treatment:
461
462
Table 2
463
464
Stage of
Disease
RETROVIR
Daily Dose* (mg)
Granulocytopenia
(<750 cells/mm3)
Anemia
(Hgb <8.0 g/dL)
Asymptomatic
ACTG 019
500
1.8%†
1.1%†
Early HIV Disease
(CD4 >200 cells/mm3)
ACTG 016
1200
4%
4%
Advanced HIV Disease
(CD4 >200 cells/mm3)
BW 02
(CD4 ≤200 cells/mm3)
ACTG 002
BW 02
1500
600
1500
10%†
37%
47%
3%†‡
29%
29%‡
* The currently recommended dose is 500 to 600 mg daily.
465
† Not statistically significant compared to placebo.
466
‡ Anemia = Hgb <7.5 g/dL.
467
468
The anemia reported in patients with advanced HIV disease receiving RETROVIR appeared to be
469
the result of impaired erythrocyte maturation as evidenced by macrocytosis while on drug. Although
470
mean platelet counts in patients receiving RETROVIR were significantly increased compared to
471
mean baseline values, thrombocytopenia did occur in some of these patients with advanced disease.
472
Twelve percent of patients receiving RETROVIR compared to 5% of patients receiving placebo had
473
>50% decreases from baseline platelet count. Mild drug-associated elevations in total bilirubin levels
474
have been reported as an uncommon occurrence in patients treated for asymptomatic HIV infection.
475
The HIV-infected adults participating in these clinical trials often had baseline symptoms and signs
476
of HIV disease and/or experienced adverse events at some time during study. It was often difficult to
477
distinguish adverse events possibly associated with administration of RETROVIR from underlying
478
signs of HIV disease or intercurrent illnesses. The following table summarizes clinical adverse events
479
or symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with
480
1500 mg/day of RETROVIR in the original placebo-controlled study. Of the items listed in the table,
481
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For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
15
only severe headache, nausea, insomnia, and myalgia were reported at a significantly greater rate in
482
patients receiving RETROVIR.
483
484
Table 3
485
Percentage (%) of Patients with Clinical Events in Advanced HIV Disease (BW 02)
486
487
Adverse Event
RETROVIR
1500 mg/day*
(n = 144) %
Placebo
(n = 137) %
BODY AS A WHOLE
Asthenia
Diaphoresis
Fever
Headache
Malaise
19
5
16
42
8
18
4
12
37
7
GASTROINTESTINAL
Anorexia
Diarrhea
Dyspepsia
GI Pain
Nausea
Vomiting
11
12
5
20
46
6
8
18
4
19
18
3
MUSCULOSKELETAL
Myalgia
8
2
NERVOUS
Dizziness
Insomnia
Paresthesia
Somnolence
6
5
6
8
4
1
3
9
RESPIRATORY
Dyspnea
5
3
SKIN
Rash
17
15
SPECIAL SENSES
Taste Perversion
5
8
* The currently recommended dose is 500 to 600 mg daily.
488
489
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
16
All events of a severe or life-threatening nature were monitored for adults in the placebo-controlled
490
studies in early HIV disease and asymptomatic HIV infection. Data concerning the occurrence of
491
additional signs or symptoms were also collected. No distinction was made in reporting events
492
between those possibly associated with the administration of the study medication and those due to
493
the underlying disease. The following tables summarize all those events reported at a statistically
494
significant greater incidence for patients receiving RETROVIR in these studies:
495
496
Table 4
497
Percentage (%) of Patients with Adverse Events in Early HIV Disease (ACTG 016)
498
499
Adverse Event
RETROVIR
1200 mg/day*
(n = 361) %
Placebo
(n = 352) %
BODY AS A WHOLE
Asthenia
69
62
GASTROINTESTINAL
Dyspepsia
Nausea
Vomiting
6
61
25
1
41
13
* The currently recommended dose is 500 to 600 mg daily.
500
501
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
17
Table 5
502
Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection (ACTG
503
019)
504
505
Adverse Event
RETROVIR
500 mg/day
(n = 453) %
Placebo
(n = 428) %
BODY AS A WHOLE
Asthenia
Headache
Malaise
8.6†
62.5
53.2
5.8
52.6
44.9
GASTROINTESTINAL
Anorexia
Constipation
Nausea
Vomiting
20.1
6.4†
51.4
17.2
10.5
3.5
29.9
9.8
NERVOUS
Dizziness
17.9†
15.2
* Reported in ≥5% of study population.
506
† Not statistically significant versus placebo.
507
508
Several serious adverse events have been reported with the use of RETROVIR in clinical practice.
509
Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have
510
been associated with prolonged use of RETROVIR. Reports of hepatomegaly with steatosis,
511
hepatitis, pancreatitis, lactic acidosis, sensitization reactions (including anaphylaxis in one patient),
512
hyperbilirubinemia, vasculitis, and seizures have been rare. These adverse events, except for
513
sensitization, have also been associated with HIV disease. A single case of macular edema has been
514
reported with the use of RETROVIR.
515
Additional adverse events reported in clinical trials at a rate not significantly different from placebo
516
are listed below. Selected events from post-marketing clinical experience with RETROVIR are also
517
included. Many of these events may also occur as part of HIV disease. The clinical significance of the
518
association between treatment with RETROVIR and these events is unknown.
519
Body as a Whole: Abdominal pain, back pain, body odor, chest pain, chills, edema of the lip,
520
fever, flu syndrome, hyperalgesia.
521
Cardiovascular: Syncope, vasodilation.
522
Gastrointestinal: Bleeding gums, constipation, diarrhea, dysphagia, edema of the tongue,
523
eructation, flatulence, mouth ulcer, rectal hemorrhage.
524
Hemic and Lymphatic: Lymphadenopathy.
525
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RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
18
Musculoskeletal: Arthralgia, muscle spasm, tremor, twitch.
526
Nervous: Anxiety, confusion, depression, dizziness, emotional lability, loss of mental acuity,
527
nervousness, paresthesia, somnolence, vertigo.
528
Respiratory: Cough, dyspnea, epistaxis, hoarseness, pharyngitis, rhinitis, sinusitis.
529
Skin: Acne, changes in skin and nail pigmentation, pruritus, rash, sweat, urticaria.
530
Special senses: Amblyopia, hearing loss, photophobia, taste perversion.
531
Urogenital: Dysuria, polyuria, urinary frequency, urinary hesitancy.
532
Pediatrics: Anemia and granulocytopenia among pediatric patients with advanced HIV disease
533
receiving RETROVIR occurred with similar incidence to that reported for adults with AIDS or
534
advanced ARC (see above). Management of neutropenia and anemia included, in some cases, dose
535
modification and/or blood product transfusions. In the open-label studies, 17% had their dose
536
modified (generally a reduction in dose by 30%) due to anemia and 25% had their dose modified
537
(temporary discontinuation or dose reduction by 30%) for neutropenia. Four pediatric patients had
538
RETROVIR permanently discontinued for neutropenia. The following table summarizes the
539
occurrence of anemia (Hgb <7.5 g/dL) and granulocytopenia (<750 cells/mm3) among 124 pediatric
540
patients receiving RETROVIR for a mean of 267 days (range 3 to 855 days):
541
542
Table 6
543
544
Advanced
Pediatric
Granulocytopenia
(<750 cells/mm3)
Anemia
(Hgb <7.5 g/dL)
HIV Disease
n
%
n
%
(n = 124)
48
39
28*
23
* Twenty-two pediatric patients received one or more transfusions due to a decline in hemoglobin to
545
<7.5 g/dL; an additional 15 pediatric patients were transfused for hemoglobin levels >7.5 g/dL.
546
Fifty-nine percent of the patients transfused had a prestudy history of anemia or transfusion
547
requirement.
548
549
Macrocytosis was observed among the majority of pediatric patients enrolled in the studies.
550
In the open-label studies involving 124 pediatric patients, 16 clinical adverse events were reported
551
by 24 pediatric patients. No event was reported by more than 5.6% of the study populations. Due to
552
the open-label design of the studies, it was difficult to determine possible events related to the use of
553
RETROVIR versus disease-related events. Therefore, all clinical events reported as associated with
554
therapy with RETROVIR or of unknown relationship to therapy with RETROVIR are presented in the
555
following table:
556
557
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
19
Table 7
558
Percentage (%) of Pediatric Patients with Clinical Events in Open-Label Studies
559
560
Adverse Event
n
%
BODY AS A WHOLE
Fever
Phlebitis*/Bacteremia
Headache
4
2
2
3.2
1.6
1.6
GASTROINTESTINAL
Nausea
Vomiting
Abdominal Pain
Diarrhea
Weight Loss
1
6
4
1
1
0.8
4.8
3.2
0.8
0.8
NERVOUS
Insomnia
Nervousness/Irritability
Decreased Reflexes
Seizure
3
2
7
1
2.4
1.6
5.6
0.8
CARDIOVASCULAR
Left Ventricular Dilation
Cardiomyopathy
S3 Gallop
Congestive Heart Failure
Generalized Edema
ECG Abnormality
1
1
1
1
1
3
0.8
0.8
0.8
0.8
0.8
2.4
UROGENITAL
Hematuria/Viral Cystitis
1
0.8
* Peripheral vein IV catheter site.
561
562
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
563
pediatric patients.
564
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized, double-blind,
565
placebo-controlled trial in HIV-infected women and their neonates conducted to determine the utility
566
of RETROVIR for the prevention of maternal-fetal HIV transmission, RETROVIR Syrup at 2 mg/kg
567
was administered every 6 hours for 6 weeks to neonates beginning within 12 hours after birth. The
568
most commonly reported adverse experiences were anemia (hemoglobin <9.0 g/dL) and neutropenia
569
(<1000 cells/mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of
570
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
20
the neonates who received placebo. The mean difference in hemoglobin values was less than
571
1.0 g/dL for neonates receiving RETROVIR compared to neonates receiving placebo. No neonates
572
with anemia required transfusion and all hemoglobin values spontaneously returned to normal within
573
6 weeks after completion of therapy with RETROVIR. Neutropenia was reported with similar
574
frequency in the group that received RETROVIR (21%) and in the group that received placebo (27%).
575
The long-term consequences of in utero and infant exposure to RETROVIR are unknown.
576
577
OVERDOSAGE: Cases of acute overdoses in both pediatric patients and adults have been reported
578
with doses up to 50 grams. None were fatal. The only consistent finding in these cases of overdose
579
was spontaneous or induced nausea and vomiting. Hematologic changes were transient and not
580
severe. Some patients experienced nonspecific CNS symptoms such as headache, dizziness,
581
drowsiness, lethargy, and confusion. One report of a grand mal seizure possibly attributable to
582
RETROVIR occurred in a 35-year-old male 3 hours after ingesting 36 grams of RETROVIR. No other
583
cause could be identified. All patients recovered without permanent sequelae. Hemodialysis and
584
peritoneal dialysis appear to have a negligible effect on the removal of zidovudine while elimination of
585
its primary metabolite, GZDV, is enhanced.
586
587
DOSAGE AND ADMINISTRATION:
588
Adults: The recommended total oral daily dose of RETROVIR is 600 mg per day in divided doses in
589
combination with other antiretroviral agents and 500 mg (100 mg every 4 hours while awake) or
590
600 mg per day in divided doses for monotherapy. The effectiveness of this dose compared to higher
591
dosing regimens in improving the neurologic dysfunction associated with HIV disease is unknown. A
592
small randomized study found a greater effect of higher doses of RETROVIR on improvement of
593
neurological symptoms in patients with pre-existing neurological disease.
594
Pediatrics: The recommended dose in pediatric patients 3 months to 12 years of age is 180 mg/m2
595
every 6 hours (720 mg/m2 per day), not to exceed 200 mg every 6 hours.
596
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to
597
pregnant women (>14 weeks of pregnancy) and their neonates is:
598
Maternal Dosing: 100 mg orally five times per day until the start of labor (see INDICATIONS AND
599
USAGE: Description of Clinical Studies). During labor and delivery, intravenous RETROVIR
600
should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous
601
intravenous infusion of 1 mg/kg per hour (total body weight) until clamping of the umbilical cord.
602
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing
603
through 6 weeks of age. Neonates unable to receive oral dosing may be administered RETROVIR
604
intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See PRECAUTIONS if
605
hepatic disease or renal insufficiency is present.)
606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
21
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone marrow
607
reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly
608
in patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is
609
recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who
610
experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and
611
neutropenia usually occurs after 6 to 8 weeks.
612
Dose Adjustment: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of baseline)
613
and/or significant neutropenia (granulocyte count of <750 cells/mm3 or reduction of >50% from
614
baseline) may require a dose interruption until evidence of marrow recovery is observed (see
615
WARNINGS). For less severe anemia or neutropenia, a reduction in daily dose may be adequate. In
616
patients who develop significant anemia, dose modification does not necessarily eliminate the need
617
for transfusion. If marrow recovery occurs following dose modification, gradual increases in dose may
618
be appropriate depending on hematologic indices and patient tolerance.
619
In end-stage renal disease patients maintained on hemodialysis or peritoneal dialysis,
620
recommended dosing is 100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY:
621
Pharmacokinetics).
622
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
623
impaired hepatic function.
624
625
HOW SUPPLIED: RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing
626
300 mg zidovudine, one side engraved “GX CW3” and “300” on the other side. Bottle of 60 (NDC
627
0173-0501-00).
628
Store at 15° to 25°C (59° to 77°F).
629
630
RETROVIR Capsules 100 mg (white, opaque cap and body with a dark blue band) containing
631
100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
632
body. Bottles of 100 (NDC 0173-0108-55) and Unit Dose Pack of 100 (NDC 0173-0108-56).
633
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
634
635
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg zidovudine in
636
each teaspoonful (5 mL). Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
637
Store at 15° to 25°C (59° to 77°F).
638
639
US Patent Nos. 4,818,538 and 4,828,838 (Product Patents); 4,724,232; 4,833,130; and 4,837,208
640
(Use Patents)
641
642
643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
22
644
Glaxo Wellcome Inc.
645
Research Triangle Park, NC 27709
646
647
Copyright 1996, 2000, Glaxo Wellcome Inc. All rights reserved.
648
649
Date of Issue
RL-
650
651
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
--------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
--------------------------------------------------------------------------------------------------------
/s/
---------------------
Debra Birnkrant
10/5/01 03:55:05 PM
NDA 19-910 SLR 024
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:18.655365
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19910s24lbl.pdf', 'application_number': 19910, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
11,841
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AMBIEN safely and effectively. See full prescribing information for
AMBIEN
Ambien (zolpidem tartrate) tablets C-IV
Initial US Approval: 1992
----------------------------RECENT MAJOR CHANGES------------------------
Dosage and Administration (2)
4/2013
Dosage and Administration, Dosage in Adults (2.1)
4/2013
Warnings and Precautions (5)
4/2013
----------------------------INDICATIONS AND USAGE---------------------------
Ambien, a gamma-aminobutyric acid (GABA) A agonist, is indicated for the
short-term treatment of insomnia characterized by difficulties with sleep
initiation. Ambien has been shown to decrease sleep latency for up to 35 days
in controlled clinical studies. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
Use the lowest dose effective for the patient (2.1)
Recommended initial dose is 5 mg for women and 5 or 10 mg for men,
immediately before bedtime with at least 7-8 hours remaining before the
planned time of awakening (2.1)
Geriatric patients and patients with hepatic impairment: Recommended
dose is 5 mg for men and women (2.2)
Lower doses of CNS depressants may be necessary when taken
concomitantly with Ambien (2.3)
The effect of Ambien may be slowed if taken with or immediately after
a meal (2.4)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
5 mg and 10 mg tablets. Tablets not scored. (3)
-------------------------------CONTRAINDICATIONS------------------------------
Known hypersensitivity to zolpidem (4)
----------------------WARNINGS AND PRECAUTIONS-------------------------
CNS depressant effects: Impairs alertness and motor coordination. Instruct
patients on correct use. (5.1)
Need to evaluate for co-morbid diagnosis: Reevaluate if insomnia persists
after 7 to 10 days of use. (5.2)
Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis
have been reported. Do not rechallenge if such reactions occur. (5.3)
“Sleep-driving” and other complex behaviors while not fully awake. Risk
increases with dose and use with other CNS depressants and alcohol.
Immediately evaluate any new onset behavioral changes. (5.4)
Depression: Worsening of depression or suicidal thinking may occur.
Prescribe the least amount of tablets feasible to avoid intentional overdose.
(5.5)
Respiratory Depression: Consider this risk before prescribing in patients
with compromised respiratory function (5.6)
Withdrawal effects: Symptoms may occur with rapid dose reduction or
discontinuation (5.7, 9.3)
-----------------------------ADVERSE REACTIONS-------------------------------
Most commonly observed adverse reactions were:
Short-term (< 10 nights): Drowsiness, dizziness, and diarrhea
Long-term (28 - 35 nights): Dizziness and drugged feelings (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088, or
http://www.fda.gov/medwatch
------------------------------DRUG INTERACTIONS-------------------------------
CNS depressants, including alcohol: Possible adverse additive CNS-
depressant effects (5.1, 7.1)
Imipramine: Decreased alertness observed (7.1)
Chlorpromazine: Impaired alertness and psychomotor performance
observed (7.1)
Rifampin: Combination use may decrease effect (7.2)
Ketoconazole: Combination use may increase effect (7.2)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
Pregnancy: Based on animal data, may cause fetal harm (8.1)
Pediatric use: Safety and effectiveness not established. Hallucinations
(incidence rate 7%) and other psychiatric and/or nervous system adverse
reactions were observed frequently in a study of pediatric patients with
Attention-Deficit/Hyperactivity Disorder (5.4, 8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: xx/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Dosage in Adults
2.2
Special Populations
2.3
Use with CNS Depressants
2.4
Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
CNS Depressant Effects and Next-Day Impairment
5.2
Need to Evaluate for Co-morbid Diagnoses
5.3
Severe Anaphylactic and Anaphylactoid Reactions
5.4
Abnormal Thinking and Behavioral Changes
5.5
Use in Patients with Depression
5.6
Respiratory Depression
5.7
Withdrawal Effects
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
7
DRUG INTERACTIONS
7.1
CNS-active Drugs
7.2
Drugs that Affect Drug Metabolism via Cytochrome P450
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Gender Differences in Pharmacokinetics
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
9.3
Dependence
10
OVERDOSAGE
10.1
Signs and Symptoms
10.2
Recommended Treatment
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1
Transient Insomnia
14.2
Chronic Insomnia
14.3
Studies Pertinent to Safety Concerns for Sedatives/Hypnotic
Drugs
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Ambien (zolpidem tartrate) is indicated for the short-term treatment of insomnia characterized by
difficulties with sleep initiation. Ambien has been shown to decrease sleep latency for up to 35
days in controlled clinical studies [see Clinical Studies (14)].
The clinical trials performed in support of efficacy were 4-5 weeks in duration with the final
formal assessments of sleep latency performed at the end of treatment.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage in Adults
Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women
and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at
least 7-8 hours remaining before the planned time of awakening. If the 5 mg dose is not
effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels
following use of the 10 mg dose increase the risk of next day impairment of driving and other
activities that require full alertness [see Warnings and Precautions (5.1)]. The total dose of
Ambien should not exceed 10 mg once daily immediately before bedtime.
The recommended initial doses for women and men are different because zolpidem clearance is
lower in women.
2.2 Special Populations
Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate.
Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The
recommended dose of Ambien in both of these patient populations is 5 mg once daily
immediately before bedtime [see Warnings and Precautions (5.1); Use in Specific Populations
(8.5)].
2.3 Use with CNS Depressants
Dosage adjustment may be necessary when Ambien is combined with other CNS depressant
drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].
2.4 Administration
The effect of Ambien may be slowed by ingestion with or immediately after a meal.
3 DOSAGE FORMS AND STRENGTHS
Ambien is available in 5 mg and 10 mg strength tablets for oral administration. Tablets are not
scored.
Ambien 5 mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed on one side
and 5401 on the other.
Reference ID: 3295868
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ambien 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one
side and 5421 on the other.
4 CONTRAINDICATIONS
Ambien is contraindicated in patients with known hypersensitivity to zolpidem. Observed
reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.3)].
5 WARNINGS AND PRECAUTIONS
5.1 CNS Depressant Effects and Next-Day Impairment
Ambien, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant
effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic
antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of Ambien
and of other concomitant CNS depressants may be necessary when Ambien is administered with
such agents because of the potentially additive effects. The use of Ambien with other sedative-
hypnotics (including other zolpidem products) at bedtime or the middle of the night is not
recommended [see Dosage and Administration (2.3)].
The risk of next-day psychomotor impairment, including impaired driving, is increased if
Ambien is taken with less than a full night of sleep remaining (7- to 8 hours); if a higher than the
recommended dose is taken; if co-administered with other CNS depressants; or if co
administered with other drugs that increase the blood levels of zolpidem. Patients should be
cautioned against driving and other activities requiring complete mental alertness if Ambien is
taken in these circumstances [see Dosage and Administration (2) and Clinical Studies (14.3)].
5.2 Need to Evaluate for Co-morbid Diagnoses
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric
disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of
the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the
presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of
insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of
an unrecognized psychiatric or physical disorder. Such findings have emerged during the course
of treatment with sedative/hypnotic drugs, including zolpidem.
5.3 Severe Anaphylactic and Anaphylactoid Reactions
Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after
taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some patients
have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that
suggest anaphylaxis. Some patients have required medical therapy in the emergency department.
If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal.
Patients who develop angioedema after treatment with zolpidem should not be rechallenged with
the drug.
5.4 Abnormal Thinking and Behavioral Changes
Abnormal thinking and behavior changes have been reported in patients treated with
sedative/hypnotics, including Ambien. Some of these changes included decreased inhibition
3
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation
and depersonalization. Visual and auditory hallucinations have been reported.
In controlled trials of Ambien 10 mg taken at bedtime < 1% of adults with insomnia reported
hallucinations. In a clinical trial, 7% of pediatric patients treated with Ambien 0.25 mg/kg taken
at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific
Populations (8.4)].
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of
a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive
as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving”
have occurred with Ambien alone at therapeutic doses, the co-administration of Ambien with
alcohol and other CNS depressants increases the risk of such behaviors, as does the use of
Ambien at doses exceeding the maximum recommended dose. Due to the risk to the patient and
the community, discontinuation of Ambien should be strongly considered for patients who report
a “sleep-driving” episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex)
have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with
“sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other
neuro-psychiatric symptoms may also occur.
It can rarely be determined with certainty whether a particular instance of the abnormal
behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying
psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or
symptom of concern requires careful and immediate evaluation.
5.5 Use in Patients with Depression
In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and
suicidal thoughts and actions (including completed suicides), have been reported. Suicidal
tendencies may be present in such patients and protective measures may be required. Intentional
overdosage is more common in this group of patients; therefore, the lowest number of tablets that
is feasible should be prescribed for the patient at any one time.
5.6 Respiratory Depression
Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at
hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive
pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in
lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%,
was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem
compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive,
precautions should be taken if Ambien is prescribed to patients with compromised respiratory
function. Post-marketing reports of respiratory insufficiency in patients receiving 10 mg of
zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported.
The risk of respiratory depression should be considered prior to prescribing Ambien in patients
with respiratory impairment including sleep apnea and myasthenia gravis.
4
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.7 Withdrawal Effects
There have been reports of withdrawal signs and symptoms following the rapid dose decrease or
abrupt discontinuation of zolpidem. Monitor patients for tolerance, abuse, and dependence [see
Drug Abuse and Dependence (9.2) and (9.3)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the
labeling:
CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1)]
Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.3)]
Abnormal thinking and behavior changes, and complex behaviors [see Warnings and
Precautions (5.4)]
Withdrawal effects [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Associated with discontinuation of treatment: Approximately 4% of 1,701 patients who
received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued
treatment because of an adverse reaction. Reactions most commonly associated with
discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache
(0.5%), nausea (0.6%), and vomiting (0.5%).
Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar
foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly
associated with discontinuation from these trials were daytime drowsiness (1.1%),
dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).
Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients
were given zolpidem revealed that four of the seven discontinuations during double-blind
treatment with zolpidem (n=95) were associated with impaired concentration, continuing or
aggravated depression, and manic reaction; one patient treated with placebo (n =97) was
discontinued after an attempted suicide.
Most commonly observed adverse reactions in controlled trials: During short-term
treatment (up to 10 nights) with Ambien at doses up to 10 mg, the most commonly observed
adverse reactions associated with the use of zolpidem and seen at statistically significant
differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem
patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights)
with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated
with the use of zolpidem and seen at statistically significant differences from placebo-treated
patients were dizziness (5%) and drugged feelings (3%).
Adverse reactions observed at an incidence of ≥ 1% in controlled trials: The following
tables enumerate treatment-emergent adverse reactions frequencies that were observed at an
incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate
5
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by
investigators were classified utilizing a modified World Health Organization (WHO) dictionary
of preferred terms for the purpose of establishing event frequencies. The prescriber should be
aware that these figures cannot be used to predict the incidence of side effects in the course of
usual medical practice, in which patient characteristics and other factors differ from those that
prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical investigators involving related drug products and uses, since
each group of drug trials is conducted under a different set of conditions. However, the cited
figures provide the physician with a basis for estimating the relative contribution of drug and
nondrug factors to the incidence of side effects in the population studied.
The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy
trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from
doses up to and including 10 mg, the highest dose recommended for use.
Incidence of Treatment-Emergent Adverse Experiences in
Placebo-Controlled Clinical Trials Lasting up to 10 Nights
(Percentage of patients reporting)
Zolpidem
Body System/
(≤10 mg)
Placebo
Adverse Event*
(N=685)
(N=473)
Central and Peripheral Nervous System
Headache
7
6
Drowsiness
2
-
Dizziness
1
-
Gastrointestinal System
Diarrhea
1
-
*Reactions reported by at least 1% of patients treated with Ambien and at a greater
frequency than placebo.
The following table was derived from results of three placebo-controlled long-term efficacy trials
involving Ambien (zolpidem tartrate). These trials involved patients with chronic insomnia who
were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to
data from doses up to and including 10 mg, the highest dose recommended for use. The table
includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.
Incidence of Treatment-Emergent Adverse Experiences in
Placebo-Controlled Clinical Trials Lasting up to 35 Nights
(Percentage of patients reporting)
Zolpidem
Body System/
(≤10 mg)
Placebo
Adverse Event*
(N=152)
(N=161)
Autonomic Nervous System
Dry mouth
3
1
Reference ID: 3295868
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Body as a Whole
Allergy
4
1
Back Pain
3
2
Influenza-like symptoms
2
-
Chest pain
1
-
Cardiovascular System
Palpitation
2
-
Central and Peripheral Nervous System
Drowsiness
8
5
Dizziness
5
1
Lethargy
3
1
Drugged feeling
3
-
Lightheadedness
2
1
Depression
2
1
Abnormal dreams
1
-
Amnesia
1
-
Sleep disorder
1
-
Gastrointestinal System
Diarrhea
3
2
Abdominal pain
2
2
Constipation
2
1
Respiratory System
Sinusitis
4
2
Pharyngitis
3
1
Skin and Appendages
Rash
2
1
*Reactions reported by at least 1% of patients treated with Ambien and at a greater
frequency than placebo.
Dose relationship for adverse reactions: There is evidence from dose comparison trials
suggesting a dose relationship for many of the adverse reactions associated with zolpidem use,
particularly for certain CNS and gastrointestinal adverse events.
Adverse event incidence across the entire preapproval database: Ambien was
administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe.
Treatment-emergent adverse events associated with clinical trial participation were recorded by
clinical investigators using terminology of their own choosing. To provide a meaningful
estimate of the proportion of individuals experiencing treatment-emergent adverse events,
similar types of untoward events were grouped into a smaller number of standardized event
categories and classified utilizing a modified World Health Organization (WHO) dictionary of
preferred terms.
The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed
to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion
7
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while receiving zolpidem. All reported treatment-emergent adverse events are included, except
those already listed in the table above of adverse events in placebo-controlled studies, those
coding terms that are so general as to be uninformative, and those events where a drug cause was
remote. It is important to emphasize that, although the events reported did occur during
treatment with Ambien, they were not necessarily caused by it.
Adverse events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in
1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension,
syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension,
impotence, increased saliva, tenesmus.
Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fatigue, fever, malaise,
trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes,
increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.
Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia.
Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension
aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose
veins, ventricular tachycardia.
Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, headache,
insomnia, vertigo Infrequent: agitation, anxiety, decreased cognition, detached, difficulty
concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps,
migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor,
tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased,
decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia,
hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis,
panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.
Gastrointestinal system: Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia,
constipation, dysphagia, flatulence, gastroenteritis, vomiting. Rare: enteritis, eructation,
esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.
Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia,
lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis
externa, otitis media.
Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare:
bilirubinemia, increased SGOT.
8
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Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia,
hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.
Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis,
muscle weakness, sciatica, tendinitis.
Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis,
breast neoplasm, breast pain.
Respiratory system: Frequent: upper respiratory infection, lower respiratory infection.
Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, respiratory
depression, epistaxis, hypoxia, laryngitis, pneumonia.
Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis,
furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.
Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain,
scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation
abnormal, parosmia, photopsia.
Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence.
Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal
pain, urinary retention.
7 DRUG INTERACTIONS
7.1 CNS-active Drugs
Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression
[see Warnings and Precautions (5.1)]. Zolpidem tartrate was evaluated in healthy volunteers in
single-dose interaction studies for several CNS drugs.
Imipramine, Chlorpromazine
Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a
20% decrease in peak levels of imipramine, but there was an additive effect of decreased
alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic
interaction, but there was an additive effect of decreased alertness and psychomotor performance
[see Clinical Pharmacology (12.3)].
Haloperidol
A study involving haloperidol and zolpidem revealed no effect of haloperidol on the
pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following
single-dose administration does not predict the absence of an effect following chronic
administration [see Clinical Pharmacology (12.3)].
9
Reference ID: 3295868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Alcohol
An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was
demonstrated [see Warnings and Precautions (5.1)].
Sertraline
Concomitant administration of zolpidem and sertraline increases exposure to zolpidem [see
Clinical Pharmacology (12.3)].
Fluoxetine
After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life
(17%) was observed. There was no evidence of an additive effect in psychomotor performance
[see Clinical Pharmacology (12.3)].
7.2 Drugs that Affect Drug Metabolism via Cytochrome P450
Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of
drugs on other P450 enzymes on the exposure to zolpidem is not known.
Rifampin
Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic
effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of
zolpidem.
Ketoconazole
Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamic effects of zolpidem.
Consideration should be given to using a lower dose of zolpidem when ketoconazole and
zolpidem are given together.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Ambien in pregnant women.
Studies in children to assess the effects of prenatal exposure to zolpidem have not been
conducted; however, cases of severe neonatal respiratory depression have been reported when
zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants.
Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal
symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born
to mothers who received sedative-hypnotic drugs during pregnancy. Ambien should be used
during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring
development at doses greater than the Ambien maximum recommended human dose (MRHD) of
10 mg/day (approximately 8 mg/day zolpidem base); however, teratogenicity was not observed.
10
Reference ID: 3295868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats
during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at
all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis. In rabbits
treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day
increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest
dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the
MRHD on a mg/m2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg
base/kg/day during the latter part of pregnancy and throughout lactation produced decreased
offspring growth and survival at all but the lowest dose, which is approximately 5 times the
MRHD on a mg/m2 basis.
8.2 Labor and Delivery
Ambien has no established use in labor and delivery [see Pregnancy (8.1)].
8.3 Nursing Mothers
Zolpidem is excreted in human milk. Caution should be exercised when Ambien is administered
to a nursing woman.
8.4 Pediatric Use
Ambien is not recommended for use in children. Safety and effectiveness of zolpidem in
pediatric patients below the age of 18 years have not been established.
In an 8-week study, in pediatric patients (aged 6-17 years) with insomnia associated with
attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at
0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Psychiatric and
nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse
reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%),
headache (12.5% vs. 9.2%), and hallucinations were reported in 7% of the pediatric patients who
received zolpidem; none of the pediatric patients who received placebo reported hallucinations
[see Warnings and Precautions(5.4)]. Ten patients on zolpidem (7.4%) discontinued treatment
due to an adverse reaction.
8.5 Geriatric Use
A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials
who received zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving zolpidem at
doses of ≤10 mg or placebo, there were three adverse reactions occurring at an incidence of at
least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo
incidence (i.e., they could be considered drug related).
Adverse Event
Zolpidem
Placebo
Dizziness
3%
0%
Drowsiness
5%
2%
Diarrhea
3%
1%
A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem reported falls, including 28/30
(93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem
Reference ID: 3295868
11
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doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving zolpidem reported
confusion, including 18/24 (75%) who were ≥ 70 years of age. Of these 18 patients, 14 (78%)
were receiving zolpidem doses >10 mg.
The dose of Ambien in elderly patients is 5 mg to minimize adverse effects related to impaired
motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see
Warnings and Precautions (5.1)].
8.6 Gender Difference in Pharmacokinetics
Women clear zolpidem tartrate from the body at a lower rate than men. Cmax and AUC
parameters of zolpidem were approximately 45% higher at the same dose in female subjects
compared with male subjects. Given the higher blood levels of zolpidem tartrate in women
compared to men at a given dose, the recommended initial dose of Ambien for adult women is
5 mg, and the recommended dose for adult men is 5 or 10 mg.
In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose
of Ambien in geriatric patients is 5 mg regardless of gender.
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.
9.2 Abuse
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of the drug for non-medical purposes, often in combination with other
psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces
changes that result in a diminution of one or more of the drug effects over time. Tolerance may
occur to both desired and undesired effects of drugs and may develop at different rates for
different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use, compulsive
use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a
multidisciplinary approach, but relapse is common.
Studies of abuse potential in former drug abusers found that the effects of single doses of
zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem
tartrate 10 mg was difficult to distinguish from placebo.
Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk
for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving
zolpidem or any other hypnotic.
12
Reference ID: 3295868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
9.3 Dependence
Physical dependence is a state of adaptation that is manifested by a specific withdrawal
syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level
of the drug, and/or administration of an antagonist.
Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt
discontinuation. These reported symptoms range from mild dysphoria and insomnia to a
withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating,
tremors, and convulsions. The following adverse events which are considered to meet the
DSM-III-R criteria for uncomplicated sedative/hypnotic withdrawal were reported during U.S.
clinical trials following placebo substitution occurring within 48 hours following last zolpidem
treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach
cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events
occurred at an incidence of 1% or less. However, available data cannot provide a reliable
estimate of the incidence, if any, of dependence during treatment at recommended doses.
Post-marketing reports of abuse, dependence and withdrawal have been received.
10 OVERDOSAGE
10.1 Signs and Symptoms
In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with
CNS-depressant agents, impairment of consciousness ranging from somnolence to coma,
cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.
10.2 Recommended Treatment
General symptomatic and supportive measures should be used along with immediate gastric
lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s
sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful;
however, flumazenil administration may contribute to the appearance of neurological symptoms
(convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other
appropriate signs should be monitored and general supportive measures employed. Hypotension
and CNS depression should be monitored and treated by appropriate medical intervention.
Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs.
The value of dialysis in the treatment of overdosage has not been determined, although
hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated
that zolpidem is not dialyzable.
As with the management of all overdosage, the possibility of multiple drug ingestion should be
considered. The physician may wish to consider contacting a poison control center for
up-to-date information on the management of hypnotic drug product overdosage.
11 DESCRIPTION
Ambien (zolpidem tartrate) is a gamma-aminobutyric acid (GABA) A agonist of the
imidazopyridine class and is available in 5 mg and 10 mg strength tablets for oral administration.
13
Reference ID: 3295868
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Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide
L-(+)-tartrate (2:1). It has the following structure: structural formula
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water,
alcohol, and propylene glycol. It has a molecular weight of 764.88.
Each Ambien tablet includes the following inactive ingredients: hydroxypropyl methylcellulose,
lactose, magnesium stearate, micro-crystalline cellulose, polyethylene glycol, sodium starch
glycolate, and titanium dioxide. The 5 mg tablet also contains FD&C Red No. 40, iron oxide
colorant, and polysorbate 80.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure
unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It
interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties
of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and
activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a
high affinity ratio of the 1/5 subunits. This selective binding of zolpidem on the BZ1 receptor
is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects
in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of
zolpidem tartrate at hypnotic doses.
12.3 Pharmacokinetics
The pharmacokinetic profile of Ambien is characterized by rapid absorption from the
gastrointestinal tract and a short elimination half-life (T1/2) in healthy subjects.
In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem
tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range:
58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean
Ambien elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the
5 and 10 mg tablets, respectively. Ambien is converted to inactive metabolites that are
eliminated primarily by renal excretion. Ambien demonstrated linear kinetics in the dose range
of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant,
independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in
young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.
14
Reference ID: 3295868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
A food-effect study in 30 healthy male subjects compared the pharmacokinetics of Ambien 10
mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with
food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was
prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest
that, for faster sleep onset, Ambien should not be administered with or immediately after a meal.
Special Populations
Elderly:
In the elderly, the dose for Ambien should be 5 mg [see Warnings and Precautions (5) and
Dosage and Administration (2)]. This recommendation is based on several studies in which the
mean Cmax, T1/2, and AUC were significantly increased when compared to results in young
adults. In one study of eight elderly subjects (> 70 years), the means for Cmax, T1/2, and AUC
significantly increased by 50% (255 vs. 384 ng/mL), 32% (2.2 vs. 2.9 hr), and 64% (955 vs.
1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single
20 mg oral dose. Ambien did not accumulate in elderly subjects following nightly oral dosing of
10 mg for 1 week.
Hepatic Impairment:
The pharmacokinetics of Ambien in eight patients with chronic hepatic insufficiency were
compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose,
mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs.
4,203 ng·hr/mL) higher, respectively, in hepatically -compromised patients. Tmax did not change.
The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that
observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified
accordingly in patients with hepatic insufficiency [see Dosage and Administration (2.2)].
Renal Impairment:
The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal
failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were
dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant
differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of
drug administration when baseline concentration adjustments were made. Zolpidem was not
hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem
pharmacokinetics were not significantly different in renally impaired patients. No dosage
adjustment is necessary in patients with compromised renal function.
Drug Interactions
CNS-depressants
Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression
[see Warnings and Precautions (5.1)]. Zolpidem tartrate was evaluated in healthy volunteers in
single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem
produced no pharmacokinetic interaction other than a 20% decrease in peak levels of
imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in
combination with zolpidem produced no pharmacokinetic interaction, but there was an additive
effect of decreased alertness and psychomotor performance.
15
Reference ID: 3295868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
A study involving haloperidol and zolpidem revealed no effect of haloperidol on the
pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following
single-dose administration does not predict the absence of an effect following chronic
administration.
An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was
demonstrated [see Warnings and Precautions (5.1)].
Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the
presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female
volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased
(-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.
A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state
levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or
pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at
steady state and the concentrations evaluated in healthy females, an increase in the zolpidem
half-life (17%) was observed. There was no evidence of an additive effect in psychomotor
performance.
Drugs that Affect Drug Metabolism via Cytochrome P450
Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of
inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.
A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-
state levels in male volunteers resulted in a 34% increase in AUC0- of zolpidem tartrate. There
were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway,
or psychomotor performance.
A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state
levels in female subjects showed significant reductions of the AUC (-73%), Cmax (-58%), and T1/2
(-36 %) of zolpidem together with significant reductions in the pharmacodynamic effects of
zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the
pharmacodynamic effects of zolpidem.
A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4
inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem (30%) and the total
AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life
(30 %) along with an increase in the pharmacodynamic effects of zolpidem. Consideration
should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given
together.
Other Drugs with No Interactions with Zolpidem
A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations
revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.
Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time
when given with warfarin in healthy subjects.
16
Reference ID: 3295868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18,
and 80 mg base/kg. In mice, these doses are approximately 2.5, 10, and 50 times the maximum
recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) on mg/m2 basis. In
rats, these doses are approximately 5, 20, and 100 times the MRHD on a mg/m2 basis. No
evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma,
liposarcoma) were seen at the mid- and high doses.
Mutagenesis: Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma,
and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.
Impairment of fertility: Oral administration of zolpidem (doses of 4, 20, and 100 mg
base/kg/day) to rats prior to and during mating, and continuing in females through postpartum
day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose
tested. The no-effect dose for these findings is approximately 24 times the MRHD on a mg/m2
basis. There was no impairment of fertility at any dose tested.
14 CLINICAL STUDIES
14.1 Transient Insomnia
Normal adults experiencing transient insomnia (n = 462) during the first night in a sleep
laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two
doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo
on objective (polysomnographic) measures of sleep latency, sleep duration, and number of
awakenings.
Normal elderly adults (mean age 68) experiencing transient insomnia (n = 35) during the first
two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial
comparing four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were
superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all
four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and
sleep quality).
14.2 Chronic Insomnia
Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic
insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and
Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n
= 75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of
zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and
sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks
and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of
awakenings at both doses studied.
Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel
group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was
17
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective
measures of total sleep time, number of awakenings, and sleep quality for the first treatment
week.
Increased wakefulness during the last third of the night as measured by polysomnography has not
been observed in clinical trials with Ambien.
14.3 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs
Next-day residual effects: Next-day residual effects of Ambien were evaluated in seven
studies involving normal subjects. In three studies in adults (including one study in a phase
advance model of transient insomnia) and in one study in elderly subjects, a small but
statistically significant decrease in performance was observed in the Digit Symbol Substitution
Test (DSST) when compared to placebo. Studies of Ambien in non-elderly patients with
insomnia did not detect evidence of next-day residual effects using the DSST, the Multiple Sleep
Latency Test (MSLT), and patient ratings of alertness.
Rebound effects: There was no objective (polysomnographic) evidence of rebound insomnia
at recommended doses seen in studies evaluating sleep on the nights following discontinuation of
Ambien (zolpidem tartrate). There was subjective evidence of impaired sleep in the elderly on
the first post-treatment night at doses above the recommended elderly dose of 5 mg.
Memory impairment: Controlled studies in adults utilizing objective measures of memory
yielded no consistent evidence of next-day memory impairment following the administration of
Ambien. However, in one study involving zolpidem doses of 10 and 20 mg, there was a
significant decrease in next-morning recall of information presented to subjects during peak drug
effect (90 minutes post-dose), i.e., these subjects experienced anterograde amnesia. There was
also subjective evidence from adverse event data for anterograde amnesia occurring in
association with the administration of Ambien, predominantly at doses above 10 mg.
Effects on sleep stages: In studies that measured the percentage of sleep time spent in each
sleep stage, Ambien has generally been shown to preserve sleep stages. Sleep time spent in
stages 3 and 4 (deep sleep) was found comparable to placebo with only inconsistent, minor
changes in REM (paradoxical) sleep at the recommended dose.
16 HOW SUPPLIED/STORAGE AND HANDLING
Ambien 5 mg tablets are capsule-shaped, pink, film coated, with AMB 5 debossed on one side
and 5401 on the other and supplied as:
NDC Number
Size
0024-5401-31
bottle of 100
Ambien 10 mg tablets are capsule-shaped, white, film coated, with AMB 10 debossed on one
side and 5421 on the other and supplied as:
NDC Number
Size
0024-5421-31
bottle of 100
0024-5421-50
bottle of 500
Reference ID: 3295868
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Store at controlled room temperature 20°–25°C (68°–77°F).
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide).
Inform patients and their families about the benefits and risks of treatment with Ambien. Inform
patients of the availability of a Medication Guide and instruct them to read the Medication Guide
prior to initiating treatment with Ambien and with each prescription refill. Review the Ambien
Medication Guide with every patient prior to initiation of treatment. Instruct patients or
caregivers that Ambien should be taken only as prescribed.
CNS Depressant Effects and Next-Day Impairment
Tell patients that Ambien has the potential to cause next-day impairment, and that this risk is
increased if dosing instructions are not carefully followed. Tell patients to wait for at least 8
hours after dosing before driving or engaging in other activities requiring full mental alertness.
Inform patients that impairment can be present despite feeling fully awake.
Severe Anaphylactic and Anaphylactoid Reactions
Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with
zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical
attention immediately if any of them occur.
Sleep-driving and Other Complex Behaviors
Instruct patients and their families that sedative hypnotics can cause abnormal thinking and
behavior change, including “sleep driving” and other complex behaviors while not being fully
awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you
immediately if they develop any of these symptoms.
Suicide
Tell patients to immediately report any suicidal thoughts.
Alcohol and Other Drugs
Ask patients about alcohol consumption, medicines they are taking, and drugs they may be
taking without a prescription. Advise patients not to use Ambien if they drank alcohol that
evening or before bed.
Tolerance, Abuse, and Dependence
Tell patients not to increase the dose of Ambien on their own, and to inform you if they believe
the drug “does not work”.
Administration Instructions
Patients should be counseled to take Ambien right before they get into bed and only when they
are able to stay in bed a full night (7-8 hours) before being active again. Ambien tablets should
not be taken with or immediately after a meal. Advise patients NOT to take Ambien if they
drank alcohol that evening.
19
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
AMBIEN® (ām'bē-ən)
(zolpidem tartrate)
Tablets C-IV
Read the Medication Guide that comes with AMBIEN before you start taking it and each time
you get a refill. There may be new information. This Medication Guide does not take the
place of talking to your healthcare provider about your medical condition or treatment.
What is the most important information I should
know about AMBIEN?
Do not take more AMBIEN than prescribed.
Do not take AMBIEN unless you are able to
stay in bed a full night (7 to 8 hours) before
you must be active again.
Take AMBIEN right before you get in bed, not
sooner.
AMBIEN may cause serious side effects,
including:
After taking AMBIEN, you may get up out of
bed while not being fully awake and do an
activity that you do not know you are doing.
The next morning, you may not remember
that you did anything during the night. You
have a higher chance for doing these activities if
you drink alcohol or take other medicines that
make you sleepy with AMBIEN. Reported
activities include:
o driving a car ("sleep-driving")
o making and eating food
o talking on the phone
o
having sex
o
sleep-walking
Call your healthcare provider right away if you
find out that you have done any of the above
activities after taking AMBIEN.
Do not take AMBIEN if you:
drank alcohol that evening or before bed
took another medicine to help you sleep
What is AMBIEN?
AMBIEN is a sedative-hypnotic (sleep) medicine.
AMBIEN is used in adults for the short-term
treatment of a sleep problem called insomnia
(trouble falling asleep).
It is not known if AMBIEN is safe and effective in
children under the age of 18 years.
AMBIEN is a federally controlled substance
(C-IV) because it can be abused or lead to
dependence. Keep AMBIEN in a safe place to
prevent misuse and abuse. Selling or giving
away AMBIEN may harm others, and is
against the law. Tell your healthcare provider
if you have ever abused or have been
dependent on alcohol, prescription medicines
or street drugs.
Who should not take AMBIEN?
Do not take AMBIEN if you are allergic to
zolpidem or any other ingredients in
AMBIEN. See the end of this Medication
Guide for a complete list of ingredients in
AMBIEN.
Do not take AMBIEN if you have had an
allergic reaction to drugs containing
zolpidem, such as Ambien CR, Edluar,
Zolpimist, or Intermezzo.
Symptoms of a serious allergic reaction to
zolpidem can include:
swelling of your face, lips, and throat that
may cause difficulty breathing or
swallowing
What should I tell my healthcare provider
before taking AMBIEN?
AMBIEN may not be right for you. Before
starting AMBIEN, tell your healthcare
provider about all of your health
conditions, including if you:
have a history of depression, mental
illness, or suicidal thoughts
have a history of drug or alcohol abuse or
addiction
have kidney or liver disease
have a lung disease or breathing
problems
Reference ID: 3295868
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
are pregnant, planning to become pregnant. It is
not known if AMBIEN will harm your unborn
baby.
are breastfeeding or plan to breastfeed.
AMBIEN can pass into your breast milk. It is not
known if AMBIEN will harm your baby. Talk to
your healthcare provider about the best way to
feed your baby while you take AMBIEN.
Tell your healthcare provider about all of the
medicines you take, including prescription and
nonprescription medicines, vitamins and herbal
supplements.
Medicines can interact with each other, sometimes
causing serious side effects. Do not take AMBIEN
with other medicines that can make you sleepy
unless your healthcare provider tells you to.
Know the medicines you take. Keep a list of your
medicines with you to show your healthcare provider
and pharmacist each time you get a new medicine.
How should I take AMBIEN?
See “What is the most important information
I should know about AMBIEN?”
Take AMBIEN exactly as prescribed. Only take
1 AMBIEN tablet a night if needed.
Do not take AMBIEN if you drank alcohol that
evening or before bed.
You should not take AMBIEN with or right after a
meal. AMBIEN may help you fall asleep faster if
you take it on an empty stomach.
Call your healthcare provider if your insomnia
worsens or is not better within 7 to 10 days. This
may mean that there is another condition
causing your sleep problem.
If you take too much AMBIEN or overdose, get
emergency treatment.
What are the possible side effects of AMBIEN?
AMBIEN may cause serious side effects,
including:
getting out of bed while not being fully
awake and do an activity that you do not
know you are doing. See “What is the most
important information I should know about
AMBIEN?”
abnormal thoughts and behavior. Symptoms
include more outgoing or aggressive behavior
than normal, confusion, agitation, hallucinations,
worsening of depression, and suicidal
thoughts or actions.
memory loss
anxiety
severe allergic reactions. Symptoms
include swelling of the tongue or throat,
and trouble breathing. Get emergency
medical help if you get these symptoms
after taking AMBIEN.
Call your healthcare provider right away if
you have any of the above side effects or
any other side effects that worry you while
using AMBIEN.
The most common side effects of AMBIEN
are:
drowsiness
dizziness
diarrhea
grogginess or feeling as if you have been
drugged
After you stop taking a sleep medicine, you
may have symptoms for 1 to 2 days such as:
trouble sleeping
nausea
flushing
lightheadedness
uncontrolled crying
vomiting
stomach cramps
panic attack
nervousness
stomach area pain
These are not all the side effects of AMBIEN.
Ask your healthcare provider or pharmacist for
more information.
Call your healthcare provider for medical
advice about side effects. You may report side
effects to FDA at 1–800–FDA–1088.
How should I store AMBIEN?
Store AMBIEN at room temperature, 68°F
to 77°F (20°C to 25°C).
Keep AMBIEN and all medicines out of
reach of children.
21
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General Information about the safe and effective
use of AMBIEN
Medicines are sometimes prescribed for purposes
other than those listed in a Medication Guide. Do not
use AMBIEN for a condition for which it was not
prescribed. Do not share AMBIEN with other people,
even if they have the same symptoms that you have.
It may harm them and it is against the law.
This Medication Guide summarizes the most
important information about AMBIEN. If you would
like more information, talk with your healthcare
provider. You can ask your healthcare provider or
pharmacist for information about AMBIEN that is
written for healthcare professionals.
For more information, call 1-800-633-1610.
What are the ingredients in AMBIEN?
Active Ingredient: Zolpidem tartrate
Inactive Ingredients: hydroxypropyl
methylcellulose, lactose, magnesium stearate,
micro-crystalline cellulose, polyethylene glycol,
sodium starch glycolate, and titanium dioxide. In
addition, the 5 mg tablet contains FD&C Red No. 40,
iron oxide colorant, and polysorbate 80.
This Medication Guide has been approved by the
U.S. Food and Drug Administration.
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Month 2013
© 2013 sanofi-aventis U.S. LLC
Reference ID: 3295868
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Ambien CR safely and effectively. See full prescribing information for
Ambien CR.
Ambien CR (zolpidem tartrate extended-release) tablets C-IV
Initial U.S. Approval: 1992
----------------------------RECENT MAJOR CHANGES--------------------------
Dosage and Administration (2)
4/2013
Dosage and Administration, Dosage in Adults (2.1)
4/2013
Warnings and Precautions (5)
4/2013
----------------------------INDICATIONS AND USAGE---------------------------
Ambien CR, a gamma-aminobutyric acid (GABA) A agonist, is indicated for
the treatment of insomnia characterized by difficulties with sleep onset and/or
sleep maintenance. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
Use the lowest dose effective for the patient (2.1)
Recommended initial dose is 6.25 mg for women, and 6.25 or 12.5 mg for
men, immediately before bedtime with at least 7-8 hours remaining before
the planned time of awakening (2.1)
Geriatric patients and patients with hepatic impairment: Recommended
dose is 6.25 mg for men and women (2.2)
Lower doses of CNS depressants may be necessary when taken
concomitantly with Ambien CR (2.3)
Tablets to be swallowed whole, not to be crushed, divided or chewed (2.4)
The effect of Ambien CR may be slowed if taken with or immediately
after a meal (2.4)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Tablets: 6.25 mg and 12.5 mg extended-release tablets. Tablets not scored. (3)
-------------------------------CONTRAINDICATIONS------------------------------
Known hypersensitivity to zolpidem (4)
----------------------WARNINGS AND PRECAUTIONS-------------------------
CNS depressant effects: Impaired alertness and motor coordination,
including risk of morning impairment. Caution patients against driving and
other activities requiring complete mental alertness the morning after use.
(5.1)
Need to evaluate for co-morbid diagnoses: Revaluate if insomnia persists
after 7 to 10 days of use (5.2)
Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis
have been reported. Do not rechallenge if such reactions occur. (5.3)
“Sleep-driving” and other complex behaviors while not fully awake. Risk
increases with dose and use with other CNS depressants and alcohol.
Immediately evaluate any new onset behavioral changes. (5.4)
Depression: Worsening of depression or, suicidal thinking may occur.
Prescribe the least amount of tablets feasible to avoid intentional overdose.
(5.5)
Respiratory Depression: Consider this risk before prescribing in patients
with compromised respiratory function (5.6 )
Withdrawal effects: Symptoms may occur with rapid dose reduction or
discontinuation (5.7, 9.3)
-----------------------------ADVERSE REACTIONS-------------------------------
Most commonly observed adverse reactions (> 10% in either elderly or adult
patients) are: headache, next-day somnolence and dizziness (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or
http://www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
CNS depressants, including alcohol: Possible adverse additive CNS-
depressant effects (5.1, 7.1)
Imipramine: Decreased alertness observed (7.1)
Chlorpromazine: Impaired alertness and psychomotor performance
observed (7.1)
Rifampin: Combination use may decrease effect (7.2)
Ketoconazole: Combination use may increase effect (7.2)
------------------------USE IN SPECIFIC POPULATIONS----------------------
Pregnancy: Based on animal data may cause fetal harm (8.1)
Pediatric use: Safety and effectiveness not established. Hallucinations
(incidence rate 7%) and other psychiatric and/or nervous system adverse
reactions were observed frequently in a study of pediatric patients with
Attention-Deficit/Hyperactivity Disorder (5.4, 8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide
Revised Month/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
Dosage in Adults
2.2
Special Populations
2.3
Use with CNS Depressants
2.4
Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
CNS Depressant Effects and Next-Day Impairment
5.2
Need to Evaluate for Co-morbid Diagnoses
5.3
Severe Anaphylactic and Anaphylactoid Reactions
5.4
Abnormal Thinking and Behavioral Changes
5.5
Use in Patients with Depression
5.6
Respiratory Depression
5.7
Withdrawal Effects
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
7
DRUG INTERACTIONS
7.1
CNS-active Drugs
7.2
Drugs that Affect Drug Metabolism via Cytochrome P450
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Labor and Delivery
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Gender Differences in Pharmacokinetics
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2 Abuse
9.3
Dependence
10 OVERDOSAGE
10.1 Signs and Symptoms
10.2 Recommended Treatment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1
Controlled Clinical Trials
14.2
Studies Pertinent to Safety Concerns for Sedative/Hypnotic
Drugs
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Ambien CR (zolpidem tartrate extended-release tablets) is indicated for the treatment of
insomnia characterized by difficulties with sleep onset and/or sleep maintenance (as measured by
wake time after sleep onset).
The clinical trials performed in support of efficacy were up to 3 weeks (using polysomnography
measurement up to 2 weeks in both adult and elderly patients) and 24 weeks (using patient-
reported assessment in adult patients only) in duration [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosage in Adults
Use the lowest effective dose for the patient. The recommended initial dose is 6.25 mg for
women and either 6.25 or 12.5 mg for men, taken only once per night immediately before
bedtime with at least 7-8 hours remaining before the planned time of awakening. If the 6.25 mg
dose is not effective, the dose can be increased to 12.5 mg. In some patients, the higher morning
blood levels following use of the 12.5 mg dose increase the risk of next day impairment of
driving and other activities that require full alertness [see Warnings and Precautions (5.1)]. The
total dose of Ambien CR should not exceed 12.5 mg once daily immediately before bedtime.
The recommended initial doses for women and men are different because zolpidem clearance is
lower in women.
2.2 Special Populations
Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate.
Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The
recommended dose of Ambien CR in both of these patient populations is 6.25 mg once daily
immediately before bedtime [see Warnings and Precautions (5.1); Use in Specific Populations
(8.5)].
2.3 Use with CNS Depressants
Dosage adjustment may be necessary when Ambien CR is combined with other CNS depressant
drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].
2.4 Administration
Ambien CR extended-release tablets should be swallowed whole, and not be divided, crushed, or
chewed. The effect of Ambien CR may be slowed by ingestion with or immediately after a
meal.
3 DOSAGE FORMS AND STRENGTHS
Ambien CR is available as extended-release tablets containing 6.25 mg or 12.5 mg of zolpidem
tartrate for oral administration. Tablets are not scored.
2
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ambien CR 6.25 mg tablets are pink, round, bi-convex, and debossed with A~ on one side.
Ambien CR 12.5 mg tablets are blue, round, bi-convex, and debossed with A~ on one side.
4 CONTRAINDICATIONS
Ambien CR is contraindicated in patients with known hypersensitivity to zolpidem. Observed
reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.3)].
5 WARNINGS AND PRECAUTIONS
5.1 CNS Depressant Effects and Next-Day Impairment
Ambien CR is a central nervous system (CNS) depressant and can impair daytime function in
some patients even when used as prescribed. Prescribers should monitor for excess depressant
effects, but impairment can occur in the absence of subjective symptoms, and may not be
reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). While
pharmacodynamic tolerance or adaptation to some adverse depressant effects of Ambien CR may
develop, patients using Ambien CR should be cautioned against driving or engaging in other
hazardous activities or activities requiring complete mental alertness the day after use.
Additive effects occur with concomitant use of other CNS depressants (e.g. benzodiazepines,
opioids, tricyclic antidepressants, alcohol), including daytime use. Downward dose adjustment of
Ambien CR and concomitant CNS depressants should be considered [see Dosage and
Administration (2.3)].
The use of Ambien CR with other sedative-hypnotics (including other zolpidem products) at
bedtime or the middle of the night is not recommended.
The risk of next-day psychomotor impairment is increased if Ambien CR is taken with less than
a full night of sleep remaining (7- to 8 hours); if higher than the recommended dose is taken; if co
administered with other CNS depressants; or co-administered with other drugs that increase the blood
levels of zolpidem [see Dosage and Administration (2) and Clinical Studies (14.2)].
5.2 Need to Evaluate for Co-morbid Diagnoses
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric
disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of
t
i
he patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the
presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of
nsomnia or the emergence of new thinking or behavior abnormalities may be the consequence of
an unrecognized psychiatric or physical disorder. Such findings have emerged during the course
of treatment with sedative/hypnotic drugs, including zolpidem.
3
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.3 Severe Anaphylactic and Anaphylactoid Reactions
Cases of angioedema involving the tongue, glottis or larynx have been reported in patients after
taking the first or subsequent doses of sedative-hypnotics, including zolpidem. Some patients
have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that
suggest anaphylaxis. Some patients have required medical therapy in the emergency department.
If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal.
Patients who develop angioedema after treatment with zolpidem should not be rechallenged with
the drug.
5.4 Abnormal Thinking and Behavioral Changes
Abnormal thinking and behavior changes have been reported in patients treated with
sedative/hypnotics, including Ambien CR. Some of these changes included decreased inhibition
(e.g. aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation
and depersonalization. Visual and auditory hallucinations have been reported.
In controlled trials, <1% of adults with insomnia reported hallucinations. In a clinical trial, 7%
of pediatric patients treated with Ambien 0.25 mg/kg taken at bedtime reported hallucinations
versus 0% treated with placebo [see Use in Specific Populations (8.4)].
Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of
a sedative-hypnotic, with amnesia for the event) have been reported in sedative-hypnotic-naive
as well as in sedative-hypnotic-experienced persons. Although behaviors such as “sleep-driving”
have occurred with Ambien CR alone at therapeutic doses, the co-administration of alcohol and
other CNS depressants increases the risk of such behaviors, as does the use of Ambien CR at
doses exceeding the maximum recommended dose. Due to the risk to the patient and the
community, discontinuation of Ambien CR should be strongly considered for patients who report
a “sleep-driving” episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex)
have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with
“sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other
neuro-psychiatric symptoms may also occur.
It can rarely be determined with certainty whether a particular instance of the abnormal
behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying
psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or
symptom of concern requires careful and immediate evaluation.
5.5 Use in Patients with Depression
In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and
suicidal thoughts and actions (including completed suicides), have been reported. Suicidal
tendencies may be present in such patients and protective measures may be required. Intentional
overdosage is more common in this group of patients; therefore, the lowest number of tablets that
is feasible should be prescribed for the patient at any one time.
4
Reference ID: 3295868
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.6 Respiratory Depression
Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at
hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive
pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in
lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%,
was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem
compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive,
precautions should be taken if Ambien CR is prescribed to patients with compromised
respiratory function. Post-marketing reports of respiratory insufficiency in patients receiving
10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been
reported. The risk of respiratory depression should be considered prior to prescribing Ambien
CR in patients with respiratory impairment including sleep apnea and myasthenia gravis.
5.7 Withdrawal Effects
There have been reports of withdrawal signs and symptoms following the rapid dose decrease or
abrupt discontinuation of zolpidem. Monitor patients for tolerance, abuse, and dependence [see
Drug Abuse and Dependence (9.2) and (9.3)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the
labeling:
CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1)]
Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.3)]
Abnormal thinking and behavior changes, and complex behaviors [see Warnings and
Precautions (5.4)]
Withdrawal effects [see Warnings and Precautions (5.7)]
6.1 Clinical Trials Experience
Associated with discontinuation of treatment: In 3-week clinical trials in adults and elderly
patients (> 65 years), 3.5% (7/201) patients receiving Ambien CR 6.25 or 12.5 mg discontinued
treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. The
reaction most commonly associated with discontinuation in patients treated with Ambien CR was
somnolence (1%).
In a 6-month study in adult patients (18-64 years of age), 8.5% (57/669) of patients receiving
Ambien CR 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an
adverse reaction. Reactions most commonly associated with discontinuation of Ambien CR
included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as
compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression
or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of
patients on placebo.
Data from a clinical study in which selective serotonin reuptake inhibitor- (SSRI-) treated
patients were given zolpidem revealed that four of the seven discontinuations during double-
blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or
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aggravated depression, and manic reaction; one patient treated with placebo (n =97) was
discontinued after an attempted suicide.
Most commonly observed adverse reactions in controlled trials: During treatment with
Ambien CR in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for
three weeks, the most commonly observed adverse reactions associated with the use of Ambien
CR were headache, next-day somnolence, and dizziness.
In the 6-month trial evaluating Ambien CR 12.5 mg, the adverse reaction profile was consistent
with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for Ambien
CR versus 2.6% for placebo).
Adverse reactions observed at an incidence of ≥1% in controlled trials: The following
tables enumerate treatment-emergent adverse reaction frequencies that were observed at an
incidence equal to 1% or greater among patients with insomnia who received Ambien CR in
placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA
dictionary for the purpose of establishing event frequencies. The prescriber should be aware that
these figures cannot be used to predict the incidence of side effects in the course of usual medical
practice, in which patient characteristics and other factors differ from those that prevailed in
these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained
from other clinical investigators involving related drug products and uses, since each group of
drug trials is conducted under a different set of conditions. However, the cited figures provide
the physician with a basis for estimating the relative contribution of drug and nondrug factors to
the incidence of side effects in the population studied.
The following tables were derived from results of two placebo-controlled efficacy trials
involving Ambien CR. These trials involved patients with primary insomnia who were treated
for 3 weeks with Ambien CR at doses of 12.5 mg (Table 1) or 6.25 mg (Table 2), respectively.
The tables include only adverse reactions occurring at an incidence of at least 1% for
Ambien CR patients and with an incidence greater than that seen in the placebo patients.
Table 1. Incidences of Treatment-Emergent Adverse
Reactions in
a 3-Week Placebo-Controlled Clinical Trial in Adults
(percentage of patients reporting)
Body System/Adverse
Reaction *
Ambien
CR
12.5 mg
(N = 102)
Placebo
(N =
110)
Infections and infestations
Influenza
3
0
Gastroenteritis
1
0
Labyrinthitis
1
0
Metabolism and nutrition
disorders
Appetite disorder
1
0
Psychiatric disorders
Hallucinations **
4
0
Disorientation
3
2
6
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Anxiety
2
0
Depression
2
0
Psychomotor retardation
2
0
Binge eating
1
0
Depersonalization
1
0
Disinhibition
1
0
Euphoric mood
1
0
Mood swings
1
0
Stress symptoms
1
0
Nervous system disorders
Headache
19
16
Somnolence
15
2
Dizziness
12
5
Memory disorders ***
3
0
Balance disorder
2
0
Disturbance in attention
2
0
Hypoesthesia
2
1
Ataxia
1
0
Paresthesia
1
0
Eye disorders
Visual disturbance
3
0
Eye redness
2
0
Vision blurred
2
1
Altered visual depth
perception
1
0
Asthenopia
1
0
Ear and labyrinth disorders
Vertigo
2
0
Tinnitus
1
0
Respiratory, thoracic and
mediastinal disorders
Throat irritation
1
0
Gastrointestinal disorders
Nausea
7
4
Constipation
2
0
Abdominal discomfort
1
0
Abdominal tenderness
1
0
Frequent bowel movements
1
0
Gastroesophageal reflux
disease
1
0
Vomiting
1
0
Skin and subcutaneous
tissue
disorders
Rash
1
0
Skin wrinkling
1
0
Urticaria
1
0
Musculoskeletal and
connective
tissue disorders
Back pain
4
3
Myalgia
4
0
Neck pain
1
0
7
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Reproductive system and
breast
disorders
Menorrhagia
1
0
General disorders and
administration site
conditions
Fatigue
3
2
Asthenia
1
0
Chest discomfort
1
0
Investigations
Blood pressure increased
1
0
Body temperature increased
1
0
Injury, poisoning and
procedural complications
Contusion
1
0
Social circumstances
Exposure to poisonous plant
1
0
*Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group.
**Hallucinations included hallucinations NOS as well as visual and hypnogogic hallucinations.
***Memory disorders include: memory impairment, amnesia, anterograde amnesia.
Table 2. Incidences of Treatment-Emergent
Adverse Reactions in a 3-Week Placebo-Controlled
Clinical Trial in Elderly
(percentage of patients reporting)
Body System/Adverse
Reaction *
Ambien
CR
6.25 mg
(N=99)
Placebo
(N=106)
Infections and infestations
Nasopharyngitis
6
4
Lower respiratory tract
infection
1
0
Otitis externa
1
0
Upper respiratory tract
infection
1
0
Psychiatric disorders
Anxiety
3
2
Psychomotor retardation
2
0
Apathy
1
0
Depressed mood
1
0
Nervous system disorders
Headache
14
11
Dizziness
8
3
Somnolence
6
5
Burning sensation
1
0
Dizziness postural
1
0
Memory disorders **
1
0
Muscle contractions
involuntary
1
0
Paresthesia
1
0
Tremor
1
0
8
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Cardiac disorders
Palpitations
2
0
Respiratory, thoracic and
mediastinal disorders
Dry throat
1
0
Gastrointestinal disorders
Flatulence
1
0
Vomiting
1
0
Skin and subcutaneous
tissue
disorders
Rash
1
0
Urticaria
1
0
Musculoskeletal and
connective
tissue disorders
Arthralgia
2
0
Muscle cramp
2
1
Neck pain
2
0
Renal and urinary
disorders
Dysuria
1
0
Reproductive system and
breast
disorders
Vulvovaginal dryness
1
0
General disorders and
administration site
conditions
Influenza like illness
1
0
Pyrexia
1
0
Injury, poisoning and
procedural complications
Neck injury
1
0
*Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group.
**Memory disorders include: memory impairment, amnesia, anterograde amnesia.
Dose relationship for adverse reactions: There is evidence from dose comparison trials
suggesting a dose relationship for many of the adverse reactions associated with zolpidem use,
particularly for certain CNS and gastrointestinal adverse events.
Other adverse reactions observed during the premarketing evaluation of Ambien CR:
Other treatment-emergent adverse reactions associated with participation in Ambien CR studies
(those reported at frequencies of <1%) were not different in nature or frequency to those seen in
studies with immediate-release zolpidem tartrate, which are listed below.
Adverse Events Observed During the Premarketing Evaluation of Immediate-Release
Zolpidem Tartrate:
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Immediate-release zolpidem tartrate was administered to 3,660 subjects in clinical trials
throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with
clinical trial participation were recorded by clinical investigators using terminology of their own
choosing. To provide a meaningful estimate of the proportion of individuals experiencing
treatment-emergent adverse events, similar types of untoward events were grouped into a smaller
number of standardized event categories and classified utilizing a modified World Health
Organization (WHO) dictionary of preferred terms.
The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed
to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion
while receiving zolpidem. All reported treatment-emergent adverse events are included, except
those already listed in the table above of adverse events in placebo-controlled studies, those
coding terms that are so general as to be uninformative, and those events where a drug cause was
remote. It is important to emphasize that, although the events reported did occur during
treatment with Ambien, they were not necessarily caused by it.
Adverse events are further classified within body system categories and enumerated in order of
decreasing frequency using the following definitions: frequent adverse events are defined as
those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in
1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.
Autonomic nervous system: Frequent: dry mouth. Infrequent: increased sweating, pallor,
postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing,
glaucoma, hypotension, impotence, increased saliva, tenesmus.
Body as a whole: Frequent: asthenia. Infrequent: chest pain, edema, falling, fever, malaise,
trauma. Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes,
increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.
Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia.
Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension
aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose
veins, ventricular tachycardia.
Central and peripheral nervous system: Frequent: ataxia, confusion, drowsiness, drugged
feeling, euphoria, insomnia, lethargy, lightheadedness, vertigo. Infrequent: agitation, decreased
cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination,
hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime
dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive
reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization,
dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction,
neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder,
somnambulism, suicide attempts, tetany, yawning.
10
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Gastrointestinal system: Frequent: diarrhea, dyspepsia, hiccup. Infrequent: anorexia,
constipation, dysphagia, flatulence, gastroenteritis. Rare: enteritis, eructation, esophagospasm,
gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.
Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia,
lymphadenopathy, macrocytic anemia, purpura, thrombosis.
Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis
externa, otitis media.
Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare:
bilirubinemia, increased SGOT.
Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia,
hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.
Musculoskeletal system: Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica,
tendinitis.
Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis,
breast neoplasm, breast pain.
Respiratory system: Frequent: sinusitis. Infrequent: bronchitis, coughing, dyspnea. Rare:
bronchospasm, respiratory depression, epistaxis, hypoxia, laryngitis, pneumonia.
Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis,
furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.
Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain,
scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation
abnormal, parosmia, photopsia.
Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence.
Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal
pain, urinary retention.
7 DRUG INTERACTIONS
7.1 CNS-active Drugs
Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression
[see Warnings and Precautions (5.1)]. Zolpidem tartrate was evaluated in healthy volunteers in
single-dose interaction studies for several CNS drugs.
Imipramine, Chlorpromazine
Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a
20% decrease in peak levels of imipramine, but there was an additive effect of decreased
alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic
Reference ID: 3295868
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interaction, but there was an additive effect of decreased alertness and psychomotor performance
[see Clinical Pharmacology (12.3)].
Haloperidol
A study involving haloperidol and zolpidem revealed no effect of haloperidol on the
pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following
single-dose administration does not predict the absence of an effect following chronic
administration [see Clinical Pharmacology (12.3)].
Alcohol
An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was
demonstrated [see Warnings and Precautions (5.1)].
Sertraline
Concomitant administration of zolpidem and sertraline increases exposure to zolpidem [see
Clinical Pharmacology (12.3)].
Fluoxetine
After multiple doses of zolpidem tartrate and fluoxetine an increase in the zolpidem half-life
(17%) was observed. There was no evidence of an additive effect in psychomotor performance
[see Clinical Pharmacology (12.3).
7.2 Drugs that Affect Drug Metabolism via Cytochrome P450
Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of
drugs on other P450 enzymes on the exposure to zolpidem is not known.
Rifampin
Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic
effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of
zolpidem.
Ketoconazole
Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamic effects of zolpidem.
Consideration should be given to using a lower dose of zolpidem when ketoconazole and
zolpidem are given together.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Ambien CR in pregnant women. Studies in
children to assess the effects of prenatal exposure to zolpidem have not been conducted;
however, cases of severe neonatal respiratory depression have been reported when zolpidem was
used at the end of pregnancy, especially when taken with other CNS depressants. Children born
to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the
postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who
received sedative-hypnotic drugs during pregnancy. Ambien CR should be used during
pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Reference ID: 3295868
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Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring
development at doses greater than the Ambien CR maximum recommended human dose
(MRHD) of 12.5 mg/day (approximately 10 mg/day zolpidem base); however, teratogenicity was
not observed.
When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats
during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at
all but the lowest dose, which is approximately 4 times the MRHD on a mg/m2 basis. In rabbits
treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day,
increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest
dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 8 times the
MRHD on a mg/m2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg
base/kg/day during the latter part of pregnancy and throughout lactation produced decreased
offspring growth and survival at all but the lowest dose, which is approximately 4 times the
MRHD on a mg/m2 basis.
8.2 Labor and Delivery
Ambien CR has no established use in labor and delivery [see Pregnancy (8.1)].
8.3 Nursing Mothers
Zolpidem is excreted in human milk. Caution should be exercised when Ambien CR is
administered to a nursing woman.
8.4 Pediatric Use
Ambien CR is not recommended for use in children. Safety and effectiveness of zolpidem in
pediatric patients below the age of 18 years have not been established.
In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with
attention-deficit/hyperactivity disorder (ADHD) an oral solution of zolpidem tartrate dosed at
0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo.. Psychiatric and
nervous system disorders comprised the most frequent (> 5%) treatment emergent adverse
reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%),
headache (12.5% vs. 9.2%), and hallucinations were reported in 7% of the pediatric patients who
received zolpidem; none of the pediatric patients who received placebo reported hallucinations
[see Warnings and Precautions (5.4)]. Ten patients on zolpidem (7.4%) discontinued treatment
due to an adverse reaction.
FDA has not required pediatric studies of Ambien CR in the pediatric population based on these
efficacy and safety findings.
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8.5 Geriatric Use
A total of 99 elderly (≥ 65 years of age) received daily doses of 6.25 mg Ambien CR in a 3-week
placebo-controlled study. The adverse reaction profile of Ambien CR 6.25 mg in this population
was similar to that of Ambien CR 12.5 mg in younger adults (≤ 64 years of age). Dizziness was
reported in 8% of Ambien CR-treated patients compared with 3% of those treated with placebo.
The dose of Ambien CR in elderly patients is 6.25 mg to minimize adverse effects related to
impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs
[see Warnings and Precautions (5.1)].
8.6 Gender Difference in Pharmacokinetics
Women clear zolpidem tartrate from the body at a lower rate than men. Cmax and AUC
parameters of zolpidem from Ambien CR were, respectively, approximately 50% and 75%
higher at the same dose in adult female subjects compared to adult male subjects. Between 6 and
12 hours after dosing, zolpidem concentrations were 2- to 3 fold higher in adult female compared
to adult male subjects. Given the higher blood levels of zolpidem tartrate in women compared to
men at a given dose, the recommended initial dose of Ambien CR for adult women is 6.25 mg,
and the recommended dose for adult men is 6.25 or 12.5 mg.
In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose
of Ambien CR in geriatric patients is 6.25 mg regardless of gender.
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.
9.2 Abuse
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of the drug for non-medical purposes, often in combination with other
psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces
changes that result in a diminution of one or more of the drug effects over time. Tolerance may
occur to both desired and undesired effects of drugs and may develop at different rates for
different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and
environmental factors influencing its development and manifestations. It is characterized by
behaviors that include one or more of the following: impaired control over drug use, compulsive
use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a
multidisciplinary approach, but relapse is common.
Studies of abuse potential in former drug abusers found that the effects of single doses of
zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem
tartrate 10 mg effects were difficult to distinguish from placebo.
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Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk
for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving
zolpidem or any other hypnotic.
9.3 Dependence
Physical dependence is a state of adaptation that is manifested by a specific withdrawal
syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level
of the drug, and/or administration of an antagonist.
Sedative/hypnotics have produced withdrawal signs and symptoms following abrupt
discontinuation. These reported symptoms range from mild dysphoria and insomnia to a
withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating,
tremors, and convulsions. The following adverse events, which are considered to meet the DSM
III-R criteria for uncomplicated sedative/hypnotic withdrawal, were reported during U.S. clinical
trials following placebo substitution occurring within 48 hours following last zolpidem
treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach
cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events
occurred at an incidence of 1% or less. However, available data cannot provide a reliable
estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-
marketing reports of abuse, dependence and withdrawal have been received.
10 OVERDOSAGE
10.1 Signs and Symptoms
In postmarketing experience of overdose with zolpidem tartrate alone, or in combination with
CNS-depressant agents, impairment of consciousness ranging from somnolence to coma,
cardiovascular and/or respiratory compromise and fatal outcomes have been reported.
10.2 Recommended Treatment
General symptomatic and supportive measures should be used along with immediate gastric
lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s
sedative hypnotic effect was shown to be reduced by flumazenil and therefore may be useful;
however, flumazenil administration may contribute to the appearance of neurological symptoms
(convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other
appropriate signs should be monitored and general supportive measures employed. Hypotension
and CNS depression should be monitored and treated by appropriate medical intervention.
Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs.
The value of dialysis in the treatment of overdosage has not been determined, although
hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated
that zolpidem is not dialyzable.
As with the management of all overdosage, the possibility of multiple drug ingestion should be
considered. The physician may wish to consider contacting a poison control center for up-to
date information on the management of hypnotic drug product overdosage.
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11 DESCRIPTION
Ambien CR contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A agonist of the
imidazopyridine class. Ambien CR (zolpidem tartrate extended-release tablets) is available in
6.25 mg and 12.5 mg strength tablets for oral administration.
Chemically, zolpidem is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)
tartrate (2:1). It has the following structure: structural formula
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water,
alcohol, and propylene glycol. It has a molecular weight of 764.88.
Ambien CR consists of a coated two-layer tablet: one layer that releases its drug content
immediately and another layer that allows a slower release of additional drug content. The 6.25
mg Ambien CR tablet contains the following inactive ingredients: colloidal silicon dioxide,
hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, potassium bitartrate, red ferric oxide, sodium starch glycolate, and titanium
dioxide. The 12.5 mg Ambien CR tablet contains the following inactive ingredients: colloidal
silicon dioxide, FD&C Blue #2, hypromellose, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, potassium bitartrate, sodium starch glycolate,
titanium dioxide, and yellow ferric oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure
unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It
interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties
of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and
activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a
high affinity ratio of the 1/5 subunits. This selective binding of zolpidem on the BZ1 receptor
is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects
in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of
zolpidem tartrate at hypnotic doses.
12.3 Pharmacokinetics
Ambien CR exhibits biphasic absorption characteristics, which results in rapid initial absorption
from the gastrointestinal tract similar to zolpidem tartrate immediate-release, then provides
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extended plasma concentrations beyond three hours after administration. A study in 24 healthy
male subjects was conducted to compare mean zolpidem plasma concentration-time profiles
obtained after single oral administration of Ambien CR 12.5 mg and of an immediate-release
formulation of zolpidem tartrate (10 mg). The terminal elimination half-life observed with
Ambien CR (12.5 mg) was similar to that obtained with immediate-release zolpidem tartrate (10
mg). The mean plasma concentration-time profiles are shown in Figure 1.
Figure 1: Mean plasma concentration-time profiles for Ambien CR (12.5 mg) and
immediate-release zolpidem tartrate (10 mg)
gr
aph
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
Time (h)
In adult and elderly patients treated with Ambien CR, there was no evidence of accumulation
after repeated once-daily dosing for up to two weeks.
Absorption:
Following administration of Ambien CR, administered as a single 12.5 mg dose in healthy male
adult subjects, the mean peak concentration (Cmax) of zolpidem was 134 ng/mL (range: 68.9 to
197 ng/ml) occurring at a median time (Tmax) of 1.5 hours. The mean AUC of zolpidem was 740
ng·hr/mL (range: 295 to 1359 ng·hr/mL).
A food-effect study in 45 healthy subjects compared the pharmacokinetics of Ambien CR 12.5
mg when administered while fasting or within 30 minutes after a meal. Results demonstrated
that with food, mean AUC and Cmax were decreased by 23% and 30%, respectively, while
median Tmax was increased from 2 hours to 4 hours. The half-life was not changed. These
results suggest that, for faster sleep onset, Ambien CR should not be administered with or
immediately after a meal.
Distribution:
Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of
concentration between 40 and 790 ng/mL.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Metabolism:
Zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion.
Elimination:
When Ambien CR was administered as a single 12.5 mg dose in healthy male adult subjects, the
mean zolpidem elimination half-life was 2.8 hours (range: 1.62 to 4.05 hr).
Special Populations
Elderly:
In 24 elderly (≥ 65 years) healthy subjects administered a single 6.25 mg dose of Ambien CR,
the mean peak concentration (Cmax) of zolpidem was 70.6 (range: 35.0 to 161) ng/mL occurring
at a median time (Tmax) of 2.0 hours. The mean AUC of zolpidem was 413 ng·hr/mL (range: 124
to 1190 ng·hr/mL) and the mean elimination half-life was 2.9 hours (range: 1.59 to 5.50 hours).
Hepatic Impairment:
Ambien CR was not studied in patients with hepatic impairment. The pharmacokinetics of an
immediate-release formulation of zolpidem tartrate in eight patients with chronic hepatic
insufficiency were compared to results in healthy subjects. Following a single 20-mg oral
zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL)
and five times (788 vs. 4,203 ng·hr/mL) higher, respectively, in hepatically compromised
patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to
25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr). Dosing
should be modified accordingly in patients with hepatic insufficiency [see Dosage and
Administration (2.2)].
Renal Impairment:
Ambien CR was not studied in patients with renal impairment. The pharmacokinetics of an
immediate-release formulation of zolpidem tartrate were studied in 11 patients with end-stage
renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who
were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically
significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last
day of drug administration when baseline concentration adjustments were made. Zolpidem was
not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days.
Zolpidem pharmacokinetics were not significantly different in renally-impaired patients. No
dosage adjustment is necessary in patients with compromised renal function.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Interactions
CNS-depressants
Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression
[see Warnings and Precautions (5.1)]. Zolpidem tartrate was evaluated in healthy volunteers in
single-dose interaction studies for several CNS drugs. Imipramine in combination with zolpidem
produced no pharmacokinetic interaction other than a 20% decrease in peak levels of
imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in
combination with zolpidem produced no pharmacokinetic interaction, but there was an additive
effect of decreased alertness and psychomotor performance.
A study involving haloperidol and zolpidem revealed no effect of haloperidol on the
pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following
single-dose administration does not predict the absence of an effect following chronic
administration.
An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was
demonstrated [see Warnings and Precautions (5.1)].
Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 10 mg in the
presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female
volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased
(-53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.
A single-dose interaction study with zolpidem tartrate 10 mg and fluoxetine 20 mg at steady-state
levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or
pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine were given at
steady state and the concentrations evaluated in healthy females, an increase in the zolpidem
half-life (17%) was observed. There was no evidence of an additive effect in psychomotor
performance.
Drugs that Affect Drug Metabolism via Cytochrome P450
Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of
inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.
A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-
state levels in male volunteers resulted in a 34% increase in AUC0- of zolpidem tartrate. There
were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway,
or psychomotor performance.
A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state
levels in female subjects showed significant reductions of the AUC (-73%), Cmax (-58%), and T1/2
(-36 %) of zolpidem together with significant reductions in the pharmacodynamic effects of
zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the
pharmacodynamic effects of zolpidem.
A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4
inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem (30%) and the total
AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life
(30 %) along with an increase in the pharmacodynamic effects of zolpidem. Consideration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given
together.
Other Drugs with No Interactions with Zolpidem
A study involving cimetidine/zolpidem tartrate and ranitidine/zolpidem tartrate combinations
revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.
Zolpidem tartrate had no effect on digoxin pharmacokinetics and did not affect prothrombin time
when given with warfarin in healthy subjects.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18,
and 80 mg base/kg. In mice, these doses are approximately 2, 9, and 40 times the maximum
recommended human dose (MRHD) of 12.5 mg/day (10 mg zolpidem base) on mg/m2 basis. In
rats, these doses are approximately 4, 18, and 80 times the MRHD on a mg/m2 basis. No
evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma,
liposarcoma) were seen at the mid- and high doses.
Mutagenesis: Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma,
and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.
Impairment of fertility: Oral administration of zolpidem (doses of 4, 20, and 100 mg
base/kg/day) to rats prior to and during mating, and continuing in females through postpartum
day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose
tested. The no-effect dose for these findings is approximately 20 times the MRHD on a mg/m2
basis. There was no impairment of fertility at any dose tested.
14 CLINICAL STUDIES
14.1 Controlled Clinical Trials
Ambien CR was evaluated in three placebo-controlled studies for the treatment of patients with
chronic primary insomnia (as defined in the APA Diagnostic and Statistical Manual of Mental
Disorders, DSM IV).
Adult outpatients (18-64 years) with primary insomnia (N=212) were evaluated in a double-
blind, randomized, parallel-group, 3-week trial comparing Ambien CR 12.5 mg and placebo.
Ambien CR 12.5 mg decreased wake time after sleep onset (WASO) for the first 7 hours during
the first 2 nights and for the first 5 hours after 2 weeks of treatment. Ambien CR 12.5 mg was
superior to placebo on objective measures (polysomnography recordings) of sleep induction (by
decreasing latency to persistent sleep [LPS]) during the first 2 nights of treatment and after 2
weeks of treatment. Ambien CR 12.5 mg was also superior to placebo on the patient reported
global impression regarding the aid to sleep after the first 2 nights and after 3 weeks of treatment.
20
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Elderly outpatients (≥ 65 years) with primary insomnia (N=205) were evaluated in a double-
blind, randomized, parallel-group, 3-week trial comparing Ambien CR 6.25 mg and placebo.
Ambien CR 6.25 mg decreased wake time after sleep onset (WASO) for the first 6 hours during
the first 2 nights and the first 4 hours after 2 weeks of treatment. Ambien CR 6.25 mg was
superior to placebo on objective measures (polysomnography recordings) of sleep induction (by
decreasing LPS) during the first 2 nights of treatment and after 2 weeks on treatment. Ambien
CR 6.25 mg was superior to placebo on the patient reported global impression regarding the aid
to sleep after the first 2 nights and after 3 weeks of treatment.
In both studies, in patients treated with Ambien CR, polysomnography showed increased
wakefulness at the end of the night compared to placebo-treated patients.
In a 24-week double-blind, placebo controlled, randomized study in adult outpatients (18-64
years) with primary insomnia (N=1025), Ambien CR 12.5 mg administered as needed (3 to 7
nights per week) was superior to placebo over 24 weeks, on patient global impression regarding
aid to sleep, and on patient-reported specific sleep parameters for sleep induction and sleep
maintenance with no significant increased frequency of drug intake observed over time.
14.2 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs
Next-day residual effects: In five clinical studies [three controlled studies in adults (18-64
years of age) administered Ambien CR 12.5 mg and two controlled studies in the elderly (≥ 65
years of age) administered Ambien CR 6.25 mg or 12.5 mg], the effect of Ambien CR on
vigilance, memory, or motor function were assessed using neurocognitive tests. In these studies,
no significant decrease in performance was observed eight hours after a nighttime dose. In
addition, no evidence of next-day residual effects was detected with Ambien CR 12.5 mg and
6.25 mg using self-ratings of sedation.
During the 3-week studies, next-day somnolence was reported by 15% of the adult patients who
received 12.5 mg Ambien CR versus 2% of the placebo group; next-day somnolence was
reported by 6% of the elderly patients who received 6.25 mg Ambien CR versus 5% of the
placebo group [see Adverse Reactions (6)]. In a 6-month study, the overall incidence of next-day
somnolence was 5.7% in the Ambien CR group as compared to 2% in the placebo group.
Rebound effects: Rebound insomnia, defined as a dose-dependent worsening in sleep
parameters (latency, sleep efficiency, and number of awakenings) compared with baseline
following discontinuation of treatment, is observed with short- and intermediate-acting
hypnotics. In the two 3-week placebo-controlled studies in patients with primary insomnia, a
rebound effect was only observed on the first night after abrupt discontinuation of Ambien CR.
On the second night, there was no worsening compared to baseline in the Ambien CR group.
In a 6-month placebo-controlled study in which Ambien CR was taken as needed (3 to 7 nights
per week), within the first month a rebound effect was observed for Total Sleep Time (not for
WASO) during the first night off medication. After this first month period, no further rebound
insomnia was observed. After final treatment discontinuation no rebound was observed.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
Ambien CR 6.25 mg tablets are composed of two layers* and are coated, pink, round, bi-convex,
debossed with A~ on one side and supplied as:
NDC Number
Size
0024-5501-31
bottle of 100
0024-5501-10
carton of 30 unit dose
Ambien CR 12.5 mg tablets are composed of two layers* and are coated, blue, round, bi-convex,
debossed with A~ on one side and supplied as:
NDC Number
Size
0024-5521-31
bottle of 100
0024-5521-50
bottle of 500
0024-5521-10
carton of 30 unit dose
*Layers are covered by the coating and are indistinguishable.
Store between 15°-25° C (59°-77°F). Limited excursions permissible up to 30° C (86°F)
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide).
Inform patients and their families about the benefits and risks of treatment with Ambien CR.
Inform patients of the availability of a Medication Guide and instruct them to read the
Medication Guide prior to initiating treatment with Ambien CR and with each prescription refill.
Review the Ambien CR Medication Guide with every patient prior to initiation of treatment.
Instruct patients or caregivers that Ambien CR should be taken only as prescribed.
CNS Depressant Effects and Next-Day Impairment
Tell patients that Ambien CR can cause next-day impairment even when used as prescribed, and
that this risk is increased if dosing instructions are not carefully followed. Caution patients
against driving and other activities requiring complete mental alertness the day after use. Inform
patients that impairment can be present despite feeling fully awake.
Severe Anaphylactic and Anaphylactoid Reactions
Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with
zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical
attention immediately if any of them occur.
Sleep-driving and Other Complex Behaviors
Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior
change, including “sleep driving” and other complex behaviors while not being fully awake
(preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately
if they develop any of these symptoms.
Suicide
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell patients to immediately report any suicidal thoughts.
Alcohol and Other Drugs
Ask patients about alcohol consumption, medicines they are taking, and drugs they may be
taking without a prescription. Advise patients not to use Ambien CR if they drank alcohol that
evening or before bed.
Tolerance, Abuse, and Dependence
Tell patients not to increase the dose of Ambien CR on their own, and to inform you if they
believe the drug “does not work”.
Administration Instructions
Patients should be counseled to take Ambien CR right before they get into bed and only when
they are able to stay in bed a full night (7-8 hours) before being active again. Ambien CR tablets
should not be taken with or immediately after a meal. Advise patients NOT to take Ambien CR
if they drank alcohol that evening.
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MEDICATION GUIDE
AMBIEN CR® (ām'bē-ən see ahr)
(zolpidem tartrate extended-release)
Tablets C-IV
Read the Medication Guide that comes with AMBIEN CR before you start taking it and each
time you get a refill. There may be new information. This Medication Guide does not take the
place of talking to your healthcare provider about your medical condition or treatment.
What is the most important information I should know about AMBIEN CR?
Do not take more AMBIEN CR than prescribed.
Do not take AMBIEN CR unless you are able to stay in bed a full night (7 to 8
hours) before you must be active again.
Take AMBIEN CR right before you get in bed, not sooner.
AMBIEN CR may cause serious side effects that you may not know are happening to you.
These side effects include:
sleepiness during the day
not thinking clearly
act strangely, confused, or upset
“sleep-walking” or doing other activities when you are asleep like:
o eating
o talking
o having sex
o driving a car
Call your healthcare provider right away if you find out that you have done any of
the above activities after taking AMBIEN CR.
You should not drive a car or do things that require clear thinking the day after you take
AMBIEN CR.
Do not take AMBIEN CR if you:
drank alcohol that evening or before bed
take other medicines that can make you sleepy. Taking AMBIEN CR with other drugs can
cause side effects. Talk to your healthcare provider about all of your medicines. Your
healthcare provider will tell you if you can take AMBIEN CR with your other medicines.
cannot get a full night’s sleep
What is AMBIEN CR?
AMBIEN CR is a sedative-hypnotic (sleep) medicine. AMBIEN CR is used in adults for the
treatment of a sleep problem called insomnia. Symptoms of insomnia include:
trouble falling asleep
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waking up often during the night
It is not known if AMBIEN CR is safe and effective in children under the age of 18 years.
AMBIEN CR is a federally controlled substance (C-IV) because it can be abused or lead to
dependence. Keep AMBIEN CR in a safe place to prevent misuse and abuse. Selling or giving
away AMBIEN CR may harm others, and is against the law. Tell your healthcare provider if you
have ever abused or have been dependent on alcohol, prescription medicines or street drugs.
Who should not take AMBIEN CR?
Do not take AMBIEN CR if you are allergic to zolpidem or any other ingredients in AMBIEN
CR. See the end of this Medication Guide for a complete list of ingredients in AMBIEN CR.
Do not take AMBIEN CR if you have had an allergic reaction to drugs containing zolpidem,
such as Ambien, Edluar, Zolpimist, or Intermezzo.
Symptoms of a serious allergic reaction to zolpidem can include:
swelling of your face, lips, and throat that may cause difficulty breathing or swallowing
What should I tell my healthcare provider before taking AMBIEN CR?
AMBIEN CR may not be right for you. Before starting AMBIEN CR, tell your healthcare
provider about all of your health conditions, including if you:
have a history of depression, mental illness, or suicidal thoughts
have a history of drug or alcohol abuse or addiction
have kidney or liver disease
have a lung disease or breathing problems
are pregnant, planning to become pregnant. It is not known if AMBIEN CR will harm your
unborn baby.
are breastfeeding or plan to breastfeed. AMBIEN CR can pass into your breast milk. It is not
known if AMBIEN CR will harm your baby. Talk to your healthcare provider about the best way
to feed your baby while you take AMBIEN CR.
Tell your healthcare provider about all of the medicines you take, including prescription and
nonprescription medicines, vitamins and herbal supplements.
Medicines can interact with each other, sometimes causing serious side effects. Do not take
AMBIEN CR with other medicines that can make you sleepy unless your healthcare provider
tells you to.
Know the medicines you take. Keep a list of your medicines with you to show your healthcare
provider and pharmacist each time you get a new medicine.
How should I take AMBIEN CR?
See “What is the most important information I should know about AMBIEN CR?”
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Take AMBIEN CR exactly as prescribed. Only take 1 AMBIEN CR tablet a night if needed.
Do not take AMBIEN CR if you drank alcohol that evening or before bed.
You should not take AMBIEN CR with or right after a meal. AMBIEN CR may help you fall
asleep faster if you take it on an empty stomach.
Take AMBIEN CR Tablets whole. Do not break, crush, dissolve or chew AMBIEN CR tablets
before swallowing. If you cannot swallow AMBIEN CR tablets whole, tell your healthcare
provider. You may need a different medicine.
Call your healthcare provider if your insomnia worsens or is not better within 7 to 10 days. This
may mean that there is another condition causing your sleep problems.
If you take too much AMBIEN CR or overdose, get emergency treatment.
What are the possible side effects of AMBIEN CR?
AMBIEN CR may cause serious side effects including:
getting out of bed while not being fully awake and doing an activity that you do not know
you are doing. (See “What is the most important information I should know about
AMBIEN CR?”)
abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior
than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal
thoughts or actions.
memory loss
anxiety
severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble
breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms
after taking AMBIEN CR.
Call your healthcare provider right away if you have any of the above side effects or any
other side effects that worry you while using AMBIEN CR.
The most common side effects of AMBIEN CR are:
headache
sleepiness
dizziness
drowsiness the next day after you take AMBIEN CR
After you stop taking a sleep medicine, you may have symptoms for 1 to 2 days such as:
trouble sleeping
nausea
flushing
lightheadedness
uncontrolled crying
vomiting
stomach cramps
panic attack
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nervousness
stomach area pain
These are not all the side effects of AMBIEN CR. Ask your healthcare provider or pharmacist
for more information.
Call your healthcare provider for medical advice about side effects. You may report side effects
to FDA at 1–800–FDA–1088.
How should I store AMBIEN CR?
Store AMBIEN CR at room temperature, 59°F to 77°F (15°C to 25° C).
Keep AMBIEN CR and all medicines out of reach of children.
General Information about the safe and effective use of AMBIEN CR
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use AMBIEN CR for a condition for which it was not prescribed. Do not share AMBIEN
CR with other people, even if you think they have the same symptoms that you have. It may harm
them and it is against the law.
This Medication Guide summarizes the most important information about AMBIEN CR. If you
would like more information, talk with your healthcare provider. You can ask your healthcare
provider or pharmacist for information about AMBIEN CR that is written for healthcare
professionals.
For more information, go to www.ambiencr.com or call 1-800-633-1610.
What are the ingredients in AMBIEN CR?
Active Ingredient: Zolpidem tartrate
Inactive Ingredients:
The 6.25 mg tablets contain: colloidal silicon dioxide, hypromellose, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium bitartrate, red ferric
oxide, sodium starch glycolate, and titanium dioxide.
The 12.5 mg tablets contain: colloidal silicon dioxide, FD&C Blue #2, hypromellose, lactose
monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, potassium
bitartrate, sodium starch glycolate, titanium dioxide, and yellow ferric oxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
Month 2013
Reference ID: 3295868
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
© 2013 sanofi-aventis U.S. LLC
Reference ID: 3295868
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:18.748089
|
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11,851
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NIZORAL® (KETOCONAZOLE) 2% SHAMPOO
DESCRIPTION
NIZORAL® (ketoconazole) 2% Shampoo is a red-orange liquid for topical application,
containing the broad spectrum synthetic antifungal agent ketoconazole in a concentration of 2%
in an aqueous suspension. It also contains: coconut fatty acid diethanolamide, disodium
monolauryl ether sulfosuccinate, F.D.&C. Red No. 40, hydrochloric acid, imidurea,
laurdimonium hydrolyzed animal collagen, macrogol 120 methyl glucose dioleate, perfume
bouquet, sodium chloride, sodium hydroxide, sodium lauryl ether sulfate, and purified water.
Ketoconazole is cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3
dioxolan-4-yl]methoxy]phenyl]piperazine and has the following structural formula: chemical stucture
CLINICAL PHARMACOLOGY
Tinea (pityriasis) versicolor is a non-contagious infection of the skin caused by Pityrosporum
orbiculare (Malassezia furfur). This commensal organism is part of the normal skin flora. In
susceptible individuals the condition is often recurrent and may give rise to hyperpigmented or
hypopigmented patches on the trunk which may extend to the neck, arms and upper thighs.
Treatment of the infection may not immediately result in restoration of pigment to the affected
sites. Normalization of pigment following successful therapy is variable and may take months,
depending on individual skin type and incidental skin exposure. The rate of recurrence of
infection is variable.
NIZORAL® (ketoconazole) was not detected in plasma in 39 patients who shampooed 4
10 times per week for 6 months, or in 33 patients who shampooed 2-3 times per week for 3
26 months (mean: 16 months).
An exaggerated use washing test on the sensitive antecubital skin of 10 subjects twice daily for
five consecutive days showed that the irritancy potential of ketoconazole 2% shampoo was
significantly less than that of 2.5% selenium sulfide shampoo.
A human sensitization test, a phototoxicity study, and a photoallergy study conducted in
38 male and 22 female volunteers showed no contact sensitization of the delayed
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Reference ID: 3223896
hypersensitivity type, no phototoxicity and no photoallergenic potential due to NIZORAL®
(ketoconazole) 2% Shampoo.
Mode of Action: Interpretations of in vivo studies suggest that ketoconazole impairs the
synthesis of ergosterol, which is a vital component of fungal cell membranes. It is postulated,
but not proven, that the therapeutic effect of ketoconazole in tinea (pityriasis) versicolor is due
to the reduction of Pityrosporum orbiculare (Malassezia furfur) and that the therapeutic effect
in dandruff is due to the reduction of Pityrosporum ovale. Support for the therapeutic effect in
tinea versicolor comes from a three-arm, parallel, double-blind, placebo controlled study in
patients who had moderately severe tinea (pityriasis) versicolor. Successful response rates in
the primary efficacy population for each of both three-day and single-day regimens of
ketoconazole 2% shampoo were statistically significantly greater (73% and 69%, respectively)
than a placebo regimen (5%). There had been mycological confirmation of fungal disease in all
cases at baseline. Mycological clearing rates were 84% and 78%, respectively, for the three-day
and one-day regimens of the 2% shampoo and 11% in the placebo regimen. While the
differences in the rates of successful response between either of the two active treatments and
placebo were statistically significant, the difference between the two active regimens was not.
Microbiology: NIZORAL® (ketoconazole) is a broad spectrum synthetic antifungal agent
which inhibits the growth of the following common dermatophytes and yeasts by altering the
permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes,
T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum;
yeasts: Candida albicans, C. tropicalis, Pityrosporum ovale (Malassezia ovale) and
Pityrosporum orbiculare (M. furfur). Development of resistance by these microorganisms to
ketoconazole has not been reported.
INDICATIONS AND USAGE
NIZORAL® (ketoconazole) 2% Shampoo is indicated for the treatment of tinea (pityriasis)
versicolor caused by or presumed to be caused by Pityrosporum orbiculare (also known as
Malassezia furfur or M. orbiculare).
Note: Tinea (pityriasis) versicolor may give rise to hyperpigmented or hypopigmented patches
on the trunk which may extend to the neck, arms and upper thighs. Treatment of the infection
may not immediately result in normalization of pigment to the affected sites. Normalization of
pigment following successful therapy is variable and may take months, depending on
individual skin type and incidental sun exposure. Although tinea versicolor is not contagious, it
may recur because the organism that causes the disease is part of the normal skin flora.
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Reference ID: 3223896
CONTRAINDICATIONS
NIZORAL® (ketoconazole) 2% Shampoo is contraindicated in persons who have known
hypersensitivity to the active ingredient or excipients of this formulation.
PRECAUTIONS
Severe hypersensitivity reactions, including anaphylaxis, have been reported during post-
marketing use of NIZORAL® (ketoconazole) Shampoo. If a reaction suggesting sensitivity or
chemical irritation should occur, use of the medication should be discontinued.
Information for Patients:
Patients should be advised of the following:
NIZORAL® (ketoconazole) 2% Shampoo may be irritating to mucous membranes of
the eyes and contact with this area should be avoided.
The following have been reported with the use of NIZORAL® (ketoconazole) 2%
Shampoo: hair discoloration and abnormal hair texture, removal of the curl from
permanently waved hair, itching, skin burning sensation and contact dermatitis,
hypersensitivity, alopecia, rash, urticaria, skin irritation, dry skin, and application site
reactions.
Patients who develop allergic reactions, such as generalized rash, skin reactions,
severe swelling, or shortness of breath should discontinue NIZORAL® and contact
their physician immediately.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long-term studies to assess the carcinogenic potential of NIZORAL® (ketoconazole) 2%
Shampoo have not been conducted. A long-term feeding study of ketoconazole in Swiss Albino
mice and in Wistar rats showed no evidence of oncogenic activity. The dominant lethal
mutation test in male and female mice revealed that single oral doses of ketoconazole as high
as 80 mg/kg were not genotoxic. The Ames Salmonella microsomal activator assay was also
negative.
Pregnancy: Teratogenic effects: Pregnancy Category C:
There are no adequate and well-controlled studies in pregnant women. Ketoconazole should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In
humans, ketoconazole is not detected in plasma after chronic shampooing on the scalp.
Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in the rat when
given orally in the diet at 80 mg/kg/day (a dose 10 times the maximum recommended human
oral dose). However, these effects may be related to maternal toxicity, which was seen at this
and higher dose levels.
Reference ID: 3223896
3
Nursing mothers: There are no adequate and well-controlled studies in nursing women.
Ketoconazole is not detected in plasma after chronic shampooing on the scalp. Caution should
be exercised when NIZORAL® (ketoconazole) 2% Shampoo is administered to a nursing
woman.
Pediatric Use: Safety and effectiveness in children have not been established.
ADVERSE REACTIONS
In 11 double-blind trials in 264 patients using ketoconazole 2% shampoo for the treatment of
dandruff or seborrheic dermatitis, an increase in normal hair loss and irritation occurred in less
than 1% of patients. In three open-label safety trials in which 41 patients shampooed 4-10 times
weekly for six months, the following adverse experiences each occurred once: abnormal hair
texture, scalp pustules, mild dryness of the skin, and itching. As with other shampoos, oiliness
and dryness of hair and scalp have been reported. In a double-blind, placebo-controlled trial in
which patients with tinea versicolor were treated with either a single application of NIZORAL®
(ketoconazole) 2% Shampoo (n=106), a daily application for three consecutive days (n=107),
or placebo (n=105), drug-related adverse events occurred in 5 (5%), 7 (7%) and 4 (4%) of
patients, respectively. The only events that occurred in more than one patient in any one of the
three treatment groups were pruritus, application site reaction, and dry skin; none of these
events occurred in more than 3% of the patients in any one of the three groups.
In worldwide experience with NIZORAL® (ketoconazole) Shampoo there have been reports of
hair discoloration and abnormal hair texture, itching, skin burning sensation, contact dermatitis,
hypersensitivity, angioedema, alopecia, rash, urticaria, skin irritation, dry skin, and application
site reactions. Because these reactions are reported voluntarily from a population of uncertain
size, it is not possible to reliably estimate their frequency.
OVERDOSAGE
NIZORAL® (ketoconazole) 2% Shampoo is intended for external use only. In the event of
accidental ingestion, supportive measures should be employed. Induced emesis and gastric
lavage should usually be avoided.
DOSAGE AND ADMINISTRATION
Apply the shampoo to the damp skin of the affected area and a wide margin surrounding this
area. Lather, leave in place for 5 minutes, and then rinse off with water.
One application of the shampoo should be sufficient.
4
Reference ID: 3223896
HOW SUPPLIED
NIZORAL® (ketoconazole) 2% Shampoo is a red-orange liquid supplied in a 4-fluid ounce
(120 mL) nonbreakable plastic bottle (NDC 50458-680-08).
Storage conditions: Store at a temperature not above 25°C (77°F). Protect from light.
Product of Belgium
Manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
©Janssen Pharmaceuticals, Inc. 2004
Revised: December 2012
Reference ID: 3223896
5
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019927s031lbl.pdf', 'application_number': 19927, 'submission_type': 'SUPPL ', 'submission_number': 31}
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EN-1179 Page 1 of 6
PRESERVATIVE-FREE
MORPHINE
SULFATE
Injection, USP Rx only
WARNING: MAY BE HABIT FORMING.
PCA Vial
Protect from light
ONLY FOR USE WITH A COMPATIBLE HOSPIRA PCA PUMP SET WITH
INJECTOR AND A COMPATIBLE HOSPIRA INFUSION DEVICE.
DESCRIPTION
Morphine, the most important alkaloid of opium, is classified pharmacologically as a narcotic
analgesic. Morphine Sulfate, USP (pentahydrate), is chemically designated 7, 8-didehydro-4, 5α-
epoxy-17-methylmorphinan-3, 6α-diol sulfate (2:1) (salt), pentahydrate, a white crystalline powder,
soluble in water. It has the following structural formula:
Preservative-free Morphine Sulfate Injection, USP, is a sterile, nonpyrogenic solution of
morphine sulfate in water for injection. This product was designed to be administered by the
intravenous route with a compatible Hospira infusion device.
For 0.5 mg or 1 mg presentation, each mL contains morphine sulfate, USP (pentahydrate)
0.5 mg or 1 mg, respectively, and sodium chloride, USP, 9 mg in water for injection, USP. May
contain sodium hydroxide and/or hydrochloric acid for pH adjustments. For 5 mg presentation,
each mL contains morphine sulfate, USP (pentahydrate), 5 mg, sodium chloride, USP, 7.6 mg, with
citric acid, USP, anhydrous 0.4 mg and sodium citrate, USP, dihydrate 0.2 mg added as buffers in
water for injection, USP. May contain additional citric acid and/or sodium citrate for pH
adjustment. The pH range for all preservative-free Morphine Sulfate Injection, USP presentations is
2.5 to 6.5. Morphine Sulfate Injection, USP, contains no antioxidant, bacteriostatic or antimicrobial
agent, and is intended only as a single-dose unit, to provide analgesia via the intravenous route,
using a compatible Hospira infusion device. Each vial is intended for SINGLE USE ONLY. When
the dosing requirement is completed, the unused portion should be discarded in an appropriate
manner.
DO NOT HEAT STERILIZE. Do not use the injection if its color is darker than pale
yellow, if it is discolored in any other way, or if it contains a precipitate.
CLINICAL PHARMACOLOGY
Morphine produces a wide spectrum of pharmacologic effects including analgesia, dysphoria,
euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, and physical
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1179 Page 2 of 6
dependence. Opiate analgesia involves at least three anatomical areas of the central nervous system:
the periaqueductal-periventricular gray matter, the ventromedial medulla, and the spinal cord. A
systemically administered opiate may produce analgesia by acting at any, all, or some combination
of these distinct regions. Morphine interacts predominantly with the μ-receptor. The μ-binding sites
of opioids are very discretely distributed in the human brain, with high densities of sites found in
the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical
areas. They are also found on the terminal axons of primary afferents within laminae I and II
(substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.
Pharmacokinetics
Morphine has an apparent volume of distribution ranging from 1 to 4.7 L/kg after intravenous
dosage. Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. When
morphine is introduced outside of the CNS, plasma concentrations of morphine remain higher than
the corresponding CSF morphine levels.
Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h
(liters/kilogram/hour) in postoperative patients, but shows considerable interindividual variation.
The major pathway of clearance is hepatic glucuronidation to morphine-3-glucuronide, which is
pharmacologically inactive. The major excretion path of the conjugate is through the kidneys, with
about 10% in the feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted
unchanged in the urine. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours,
although the longer half-lives were obtained when morphine levels were monitored over protracted
periods with very sensitive radioimmunoassay methods. The accepted elimination half-life in
normal subjects is 1.5 to 2 hours.
The minimum analgesic morphine plasma concentration during Patient-Controlled Analgesia
(PCA) has been reported as 20-40 ng/mL, corresponding to a self-administration rate of 1.5 to
3 mg/h.
Clinical Trials
Morphine is the most frequently-used opioid administered by PCA, and has been studied in
controlled clinical trials in both acute postoperative settings and the chronic pain of malignancy.
PCA morphine was administered to opioid-naive postoperative patients using a 1-2 mg bolus size
and a six minute lockout interval. This resulted in an average self-administration rate of 2-3 mg/h,
and average blood level of 30-70 ng/mL, and an analgesic efficacy similar to that observed with
conventional dosing.
In opioid-tolerant patients with pain from malignancy, most patients were studied with a bolus size
of 1-3 mg, a lockout of six minutes, and self-administered at a rate of 3-10 mg/h. In a minority of
cases, patients were studied using subcutaneous route of administration, and in such cases a bolus
size of 10 mg was used with a lockout of 30 minutes. PCA analgesia was rated as effective as
conventional therapy by both patients and physicians.
Individualization of Dosage
The mean morphine self-administration rate observed in controlled clinical trials ranged from
1-10 mg/h, depending on the nature of the pain, the degree of opioid tolerance developed by the
patient, and the individual patient factors. Most patients will achieve adequate analgesia with a
1 mg bolus and a six minute lockout, although patients with a high degree of opioid tolerance may
require a larger bolus size to be comfortable without excessively frequent triggering of the device.
In such patients, a bolus size of 2-3 mg is usually adequate, although up to a 5 mg bolus has been
used in opioid-tolerant patients in some studies. Although the lockout interval may be varied, most
investigators have left it at 6 minutes to facilitate easy calculation of the maximal dosing rate.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1179 Page 3 of 6
For opioid-naive patients, the combination of dosing rate and lockout should not permit a
maximal dosing rate greater than 10 mg/h (1 mg possible every 6 minutes), while for opioid-
tolerant patients maximal dosing rates up to 30 mg/h are common (3 mg every 6 minutes) and
greater rates may be needed in selected patients.
INDICATIONS AND USAGE
Preservative-free Morphine Sulfate Injection is indicated for the management of pain where use of
an opioid analgesic by PCA is appropriate. It was developed for administration via a compatible
Hospira infusion device.
CONTRAINDICATIONS
The only absolute contraindication for Preservative-free Morphine Sulfate Injection is allergy to
morphine or other opiates. Relative contraindications to its use are acute bronchial asthma and
upper airway obstruction (see PRECAUTIONS).
WARNINGS
NALOXONE
INJECTION
AND
RESUSCITATIVE
EQUIPMENT
SHOULD
BE
IMMEDIATELY AVAILABLE FOR USE IN CASE OF LIFE-THREATENING OR
INTOLERABLE SIDE EFFECTS AND WHENEVER MORPHINE THERAPY IS BEING
INITIATED.
Intravenous Preservative-free Morphine Sulfate Injection should be used only by those familiar
with managing respiratory depression. Rapid intravenous administration may result in chest wall
rigidity. Morphine sulfate may be habit forming. (See DRUG ABUSE AND DEPENDENCE.)
PRECAUTIONS
PCA Analgesia:
Although self-administration of opioids by PCA may allow each patient to individually titrate to an
acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of
respiratory depression. Health care providers and family members monitoring patients receiving
PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation,
respiratory depression, or other adverse effects of opioid medications.
Use in Patients with Increased Intracranial Pressure or with Head Injury: Preservative-free
Morphine Sulfate Injection, USP, should be used with extreme caution in patients with increased
intracranial pressure or with head injury. Pupillary changes (miosis) from morphine may obscure
the existence, extent, and course of intracranial pathology. Clinicians should maintain a high index
of suspicion for adverse drug reactions when evaluating altered mental status in patients receiving
this treatment.
Use in Chronic Pulmonary Disease:
Care is urged in using this drug in patients who have a decreased respiratory reserve (e.g.,
emphysema, severe obesity, kyphoscoliosis, or paralysis of the phrenic nerve). Preservative-free
Morphine Sulfate Injection, USP, should not be given in cases of chronic asthma, upper airway
obstruction, or in any other chronic pulmonary disorder without due consideration of the known
risk of acute respiratory failure following morphine administration in such patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1179 Page 4 of 6
Use in Hepatic or Renal Disease:
The elimination half-life of morphine may be prolonged in patients with reduced metabolic rates
and with hepatic and/or renal dysfunction. Hence, care should be exercised in administering
morphine to patients with these conditions, since high blood morphine levels, due to reduced
clearance, may take several days to develop.
Use in Patients with Disorders of the Biliary Tract:
Care should be exercised in patients with disorders of the biliary tract because circulating morphine
may induce smooth muscle hypertonicity resulting in biliary colic.
Use with Other Central Nervous System Depressants:
The depressant effects of morphine sulfate are potentiated by the presence of other CNS
depressants such as alcohol, sedatives or antihistaminics. The minimum effective dose of such
agents should be chosen for patients who are receiving PCA morphine to minimize the risk of
respiratory depression.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Studies of morphine sulfate in animals to evaluate the carcinogenic and mutagenic potential or the
effect on fertility have not been conducted.
Pregnancy Category C:
Morphine sulfate is not teratogenic in rats at 35 mg/kg/day (thirty-five times the usual human dose),
but does result in increased pup mortality and growth retardation at doses that narcotize the animal
(> 10 mg/kg/day, ten times the usual human dose). Preservative-free Morphine Sulfate Injection
should only be given to pregnant women when clearly needed and means are at hand to manage the
delivery and perinatal care of the opiate-dependent infant.
Labor and Delivery:
Intravenous morphine readily passes into the fetal circulation and may result in respiratory
depression in the neonate. Naloxone and resuscitative equipment should be available for reversal of
narcotic-induced respiratory depression in the neonate. In addition, intravenous morphine may
reduce the strength, duration and frequency of uterine contraction resulting in prolonged labor.
Nursing Mothers:
Morphine is excreted in maternal milk in amounts that may cause sedation of a nursing infant. Use
in nursing mothers should be individualized based on the clinical situation.
Pediatric Use:
Adequate studies, to establish the safety and effectiveness of PCA-administered morphine in
children, have not been performed, and usage in this population is not recommended.
Geriatric Use:
The pharmacodynamic effects of morphine in the aged are more variable than in the younger
population. Patients will vary widely in the effective initial dose, rate of development of tolerance,
and the frequency and magnitude of associated adverse effects as the dose is increased.
ADVERSE REACTIONS
The most serious side effect is respiratory depression (see WARNINGS). Because of delay in
maximum CNS effect with intravenously administered drug (30 min), rapid administration may
result in overdosing. The depression may be severe and could require intervention (see
WARNINGS and OVERDOSAGE).
While low doses of intravenously administered morphine have little effect on cardiovascular
stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in
circulating catecholamines. Excitation of the central nervous system, resulting in convulsions, may
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1179 Page 5 of 6
accompany high doses of morphine given intravenously. Dysphoric reactions may occur after any
size dose and toxic psychoses have been reported.
Constipation: Constipation is frequently encountered during PCA-administration of morphine;
this can usually be managed by conventional therapy.
Other side effects include: dizziness, euphoria, anxiety, depression of cough reflex, interference
with thermal regulation, and oliguria. Evidence of histamine release such as urticaria, wheals,
and/or local tissue irritation may occur.
DRUG ABUSE AND DEPENDENCE
Morphine sulfate is a Schedule II narcotic under the United States Controlled Substance Act
(21 U.S.C. 801-886).
Morphine is the most commonly cited prototype for narcotic substances that possess an
addiction-forming or addiction-sustaining liability. All patients are at risk for developing a
dependence to morphine. As with all potent opioids which are μ-agonists, tolerance as well as
psychological and physical dependence to morphine may develop irrespective of the route of
administration (intravenous, intramuscular, intrathecal, epidural or oral). Individuals with a prior
history of opioid or other substance abuse or dependence, being more apt to respond to the
euphorogenic and reinforcing properties of morphine, would be considered to be at greater risk.
Withdrawal symptoms may occur when morphine is discontinued abruptly or upon
administration of a narcotic antagonist.
OVERDOSAGE
Overdosage of morphine is characterized by respiratory depression, with or without concomitant
CNS depression. Since respiratory arrest may result either through direct depression of the
respiratory center, or as the result of hypoxia, primary attention should be given to the
establishment of adequate respiratory exchange through provision of a patent airway and institution
of assisted, or controlled, ventilation. The narcotic antagonist, naloxone, is a specific antidote. An
initial dose of 0.4 mg of naloxone should be administered intravenously, simultaneously with
respiratory resuscitation. If the desired degree of counteraction and improvement in respiratory
function is not obtained, naloxone may be repeated at 2 to 3 minute intervals. If no response is
observed after 10 mg of naloxone has been administered, the diagnosis of narcotic-induced, or
partial narcotic-induced, toxicity should be questioned. Intramuscular or subcutaneous
administration may be used if the intravenous route is not available.
DOSAGE AND ADMINISTRATION
PHYSICIANS SHOULD COMPLETELY FAMILIARIZE THEMSELVES WITH THE
HOSPIRA INFUSION DEVICE BEFORE PRESCRIBING PRESERVATIVE-FREE MORPHINE
SULFATE INJECTION, USP.
Preservative-free Morphine Sulfate Injection was developed for intravenous administration
with a compatible Hospira infusion device.
Parenteral drug products should be inspected for particulate matter and discoloration prior to
administration, whenever solution and container permit. Do not use if color is darker than pale
yellow, if it is discolored in any other way, or if it contains a precipitate.
Intravenous Administration
For use in a compatible Hospira infusion device, dosage should be adjusted according to the
severity of the pain and the response of the patient. Patients must be closely monitored because of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EN-1179 Page 6 of 6
the considerable variability in both the dosage requirements and patient response. Following are
recommendations that have to be individualized for each patient.
Intravenous Adult Dosage: The usual dose for administration to adults, via a compatible
Hospira infusion device, is a 1 mg bolus, with a range of 0.2 to 3 mg per incremental dose for the
0.5 mg/mL and 1 mg/mL concentrations and a range of 0.5 to 3 mg per incremental dose for the
5 mg/mL concentration. The recommended Lockout Interval is 6 minutes. The physician may
adjust the dosage either upward or downward (see INDIVIDUALIZATION OF DOSAGE);
depending on patient response. Occasionally, it may be necessary to exceed the usual dosage in
cases of exceptionally severe pain or in those patients who become tolerant.
SAFETY AND HANDLING INSTRUCTIONS
Preservative-free Morphine Sulfate Injection is supplied in sealed PCA vials. Accidental dermal
exposure should be treated by the removal of any contaminated clothing and rinsing the affected
area with water. Each vial of Preservative-free Morphine Sulfate Injection contains a potent
narcotic which has been associated with abuse and dependence among health care providers. Due
to the limited indications for this product, the risk of overdosage and the risk of its diversion and
abuse, it is recommended that special measures be taken to control this product within the hospital
or clinic. Preservative-free Morphine Sulfate Injection should be subject to rigid accounting,
rigorous control of wastage and restricted access.
HOW SUPPLIED
Preservative-free Morphine Sulfate Injection, USP, is supplied in single-dose 30 mL PCA vials as
follows:
Concentration
Total Morphine
List No.
(mg/mL)
(mg/30 mL)
2028
0.5
15
2029
1
30
6028
5
150
This vial is only for use with a compatible Hospira PCA pump set with injector and a
compatible Hospira infusion device (see directions for use supplied with the set or infuser).
NOTE: Vial injector and PCA set are sold separately.
CONTAINS NO PRESERVATIVES. DISCARD UNUSED PORTION. DO NOT HEAT-
STERILIZE.
Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from
freezing. Protect from light. Store in carton until time of use.
Revised: April, 2006
©Hospira 2006
EN-1179 Printed in USA
HOSPIRA, INC., LAKE FOREST, IL 60045 USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CAUTION: Liquid in glass. Handle
with care. Inspect vial for damage
prior to assembly.
USE ASEPTIC TECHNIQUE
Do not assemble until ready to use.
1. Remove caps from vial and vial
injector.
2. Insert injector into vial and rotate
vial clockwise about 3 turns or until
vial stopper is pierced by metal
cannula.
3. To prime set, see PCA set
instructions.
NOTE: Vial injector and PCA set are
sold separately.
PRESS AND PULL TO OPEN
OP EN
NDC 0409-6028-04
30 mL Single-dose
(01) 0 030409 602804 8
Printed in USA
Hospira, Inc.
Lake Forest, IL 60045 USA
Single-dose unit. Discard unused portion.
For intravenous administration only. Not for
intrathecal or epidural use. Usual dosage: See
insert. Do not use the injection if it is darker
than pale yellow or discolored in any other way,
or if it contains a precipitate. Store at 20 to 25°C
(68 to 77°F). [See USP Controlled Room
Temperature.]
Each mL contains morphine sulfate,
pentahydrate 5 mg; sodium chloride
7.6 mg; citric acid, anhydrous 0.4 mg and
sodium citrate, dihydrate 0.2 mg added as
buffers. May contain additional citric acid
and/or sodium citrate for pH adjustment.
Medication and fluid path are sterile and
nonpyrogenic if caps are in place and
package is intact.
CA-1405 (10/06)
PMS Black
PMS 368
COLOR
PMS 199
CAUTION: TO PREVENT
OVERDOSE, VIAL AND INJECTOR
MUST BE SECURELY LOCKED
INTO THE INFUSER.
ONLY FOR USE WITH A COMPATIBLE
HOSPIRA PCA PUMP SET WITH
INJECTOR AND A COMPATIBLE
HOSPIRA INFUSION DEVICE.
MORPHINE
SULFATE
Injection, USP
5 mg/mL (150 mg/30 mL)
Make sure the pump is
programmed for
MORPHINE 5 mg/mL
before starting infusion.
2
Glass Vial
Protect from light.
Intravenous Administration Only
Program pump for
MORPHINE
5 mg/mL before start.
HIGH STRENGTH
only
Label Control 095N, Approval
Approved By
Date
*Not Valid Unless Final
Proofs Carry 095N
Approval Signature
Packaging
Graphics Art
List
Commodity
CR
Editor
Date
Artist
CA-1405v1
06-5488
KA
MW
6028
10/05/06
BWR 2 MIL
PRESERVATIVE-FREE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
125
100
75
50
25
0
25
20
15
10
5
0
RL-1862 (10/06)
(01) 0 030409 602804 8
MORPHINE*
5 mg/mL (150 mg/30 mL)
30 mL Single-dose
NDC 0409-6028-04
Hospira, Inc., Lake Forest, IL 60045 USA
mg ApproxmL
mg
mL
Each mL contains *morphine sulfate, pentahydrate 5 mg; sodium chloride
7.6 mg; citric acid, anhydrous 0.4 mg and sodium citrate, dihydrate 0.2 mg added
as buffers. May contain additional citric acid and/or sodium citrate
for pH adjustment.
2
5 mg/mL
5 mg/mL
5 mg/mL
5 mg/mL
5 mg/mL
PMS Black
PMS 368
COLOR
PMS 802
White
Label Control 095N, Approval
Approved By
Date
*Not Valid Unless Final
Proofs Carry 095N
Approval Signature
Packaging
Graphics Art
List
Commodity
CR
Editor
Date
Artist
RL-1862v1
06-5488
KA
MW
6028
10/05/06
BWR 2.5 MIL
Caution: To prevent
overdose, vial and
injector must be
securely locked into
the infuser.
Protect from light.
Sterile, nonpyrogenic.
For intravenous
administration only.
Usual dosage: See
insert.
Only for use with
Hospira infusion system.
WARNING: MAY BE
HABIT FORMING.
PRESERVATIVE-FREE
only
HIGH STRENGTH
HIGH STRENGTH
MORPHINE SULFATE
Injection, USP 5 mg/mL (150 mg/30 mL)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RETROVIR safely and effectively. See full prescribing information for
RETROVIR.
RETROVIR (zidovudine) Tablets, Capsules, and Syrup
Initial U.S. Approval: 1987
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
• Hematologic toxicity including neutropenia and severe anemia have
been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine.
(5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues
including RETROVIR. Suspend treatment if clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity
occur. (5.3)
---------------------------RECENT MAJOR CHANGES -------------------
Dosage and Administration, Pediatric Patients (2.1)
November 2009
----------------------------INDICATIONS AND USAGE--------------------
RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for:
• Treatment of Human Immunodeficiency Virus (HIV-1) infection in
combination with other antiretroviral agents. (1.1)
• Prevention of maternal-fetal HIV-1 transmission. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
• Treatment of HIV-1 infection:
Adults: 600 mg/day in divided doses with other antiretroviral agents.
Pediatric patients (4 weeks to <18 years of age): Dosage should be
calculated based on body weight not to exceed adult dose. (2.1)
• Prevention of maternal-fetal HIV-1 transmission:
Specific dosage instructions for mother and infant. (2.2)
• Patients with severe anemia and/or neutropenia:
Dosage interruption may be necessary. (2.3)
• Renal Impairment: Recommended dosage in hemodialysis or peritoneal
dialysis patients is 100 mg every 6 to 8 hours. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS -------------
Tablets: 300 mg (3)
Capsules: 100 mg (3)
Syrup: 50 mg/5 mL (3)
-------------------------------CONTRAINDICATIONS-----------------------
Hypersensitivity to zidovudine (e.g., anaphylaxis, Stevens-Johnson
syndrome). (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
• Hematologic toxicity/bone marrow suppression including neutropenia and
severe anemia have been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine. (5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues including
RETROVIR. Suspend treatment if clinical or laboratory findings
suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3)
• Exacerbation of anemia has been reported in HIV-1/HCV co-infected
patients receiving ribavirin and zidovudine. Coadministration of ribavirin
and zidovudine is not advised. (5.4)
• Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV
co-infected patients receiving combination antiretroviral therapy and
interferon alfa with/without ribavirin. Discontinue zidovudine as medically
appropriate and consider dose reduction or discontinuation of interferon
alfa, ribavirin, or both. (5.4)
• RETROVIR should not be administered with other zidovudine-containing
combination products. (5.5)
• Immune reconstitution syndrome (5.6) and redistribution/accumulation of
body fat (5.7) have been reported in patients treated with combination
antiretroviral therapy.
------------------------------ ADVERSE REACTIONS ----------------------
• Most commonly reported adverse reactions (incidence ≥15%) in adult
HIV-1 clinical studies were headache, malaise, nausea, anorexia, and
vomiting. (6.1)
• Most commonly reported adverse reactions (incidence ≥15%) in pediatric
HIV-1 clinical studies were fever, cough, and digestive disorders. (6.1)
• Most commonly reported adverse reactions in neonates (incidence ≥15%)
in the prevention of maternal-fetal transmission of HIV-1 clinical trial
were anemia and neutropenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS-----------------------
• Stavudine: Concomitant use with zidovudine should be avoided. (7.1)
• Doxorubicin: Use with zidovudine should be avoided. (7.2)
• Bone marrow suppressive/cytotoxic agents: May increase the hematologic
toxicity of zidovudine. (7.3)
----------------------- USE IN SPECIFIC POPULATIONS ---------------
Pregnancy: Physicians are encouraged to register patients in the Antiretroviral
Pregnancy Registry by calling 1-800-258-4263. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: May 2010
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
2
DOSAGE AND ADMINISTRATION
2.1
Treatment of HIV-1 Infection
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
2.3
Patients With Severe Anemia and/or Neutropenia
2.4
Patients With Renal Impairment
2.5
Patients With Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
5.2
Myopathy
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
5.4
Use With Interferon- and Ribavirin-Based Regimens in
HIV-1/HCV Co-Infected Patients
5.5
Use With Other Zidovudine-Containing Products
5.6
Immune Reconstitution Syndrome
5.7
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
7.2
Doxorubicin
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic
Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Reproductive and Developmental Toxicology Studies
14 CLINICAL STUDIES
14.1 Adults
14.2 Pediatric Patients
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
17.1 Information About Therapy With RETROVIR
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________
1
FULL PRESCRIBING INFORMATION
2
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC
3
ACIDOSIS
4
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup have been associated with
5
hematologic toxicity including neutropenia and severe anemia, particularly in patients with
6
advanced HIV-1 disease [see Warnings and Precautions (5.1)].
7
Prolonged use of RETROVIR has been associated with symptomatic myopathy [see
8
Warnings and Precautions (5.2)].
9
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
10
been reported with the use of nucleoside analogues alone or in combination, including
11
RETROVIR and other antiretrovirals. Suspend treatment if clinical or laboratory findings
12
suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and
13
Precautions (5.3)].
14
1
INDICATIONS AND USAGE
15
1.1
Treatment of HIV-1
16
RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with
17
other antiretroviral agents for the treatment of HIV-1 infection.
18
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
19
RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see
20
Dosage and Administration (2.2)]. The indication is based on a dosing regimen that included
21
3 components:
22
1.
antepartum therapy of HIV-1 infected mothers
23
2.
intrapartum therapy of HIV-1 infected mothers
24
3.
post-partum therapy of HIV-1 exposed neonate.
25
Points to consider prior to initiating RETROVIR in pregnant women for the prevention of
26
maternal-fetal HIV-1 transmission include:
27
• In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be
28
given in combination with other antiretroviral drugs.
29
• Prevention of HIV-1 transmission in women who have received RETROVIR for a prolonged
30
period before pregnancy has not been evaluated.
31
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the
32
first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are
33
not fully known, women in the first trimester of pregnancy who do not require immediate
34
initiation of antiretroviral therapy for their own health may consider delaying use; this
35
indication is based on use after 14 weeks gestation.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
2
DOSAGE AND ADMINISTRATION
37
2.1
Treatment of HIV-1 Infection
38
Adults: The recommended oral dose of RETROVIR is 600 mg/day in divided doses in
39
combination with other antiretroviral agents.
40
Pediatric Patients (4 Weeks to <18 Years of Age): Healthcare professionals should
41
pay special attention to accurate calculation of the dose of RETROVIR, transcription of the
42
medication order, dispensing information, and dosing instructions to minimize risk for
43
medication dosing errors.
44
Prescribers should calculate the appropriate dose of RETROVIR for each child based on
45
body weight (kg) and should not exceed the recommended adult dose.
46
Before prescribing RETROVIR Capsules or Tablets, children should be assessed for the
47
ability to swallow capsules or tablets. If a child is unable to reliably swallow a RETROVIR
48
Capsule or Tablet, the RETROVIR Syrup formulation should be prescribed.
49
The recommended dosage in pediatric patients 4 weeks of age and older and weighing
50
≥4 kg is provided in Table 1. RETROVIR Syrup should be used to provide accurate dosage
51
when whole tablets or capsules are not appropriate.
52
53
Table 1: Recommended Pediatric Dosage of RETROVIR
Body Weight
(kg)
Total Daily Dose
Dosage Regimen and Dose
b.i.d.
t.i.d.
4 to <9
24 mg/kg/day
12 mg/kg
8 mg/kg
≥9 to <30
18 mg/kg/day
9 mg/kg
6 mg/kg
≥30
600 mg/day
300 mg
200 mg
54
55
Alternatively, dosing for RETROVIR can be based on body surface area (BSA) for each
56
child. The recommended oral dose of RETROVIR is 480 mg/m2/day in divided doses
57
(240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by
58
mg/kg will not be the same as that calculated by BSA.
59
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
60
The recommended dosage regimen for administration to pregnant women (>14 weeks of
61
pregnancy) and their neonates is:
62
Maternal Dosing: 100 mg orally 5 times per day until the start of labor [see Clinical
63
Studies (14.3)]. During labor and delivery, intravenous RETROVIR should be administered at
64
2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of
65
1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
66
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
67
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
68
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours.
69
2.3
Patients With Severe Anemia and/or Neutropenia
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
70
Significant anemia (hemoglobin <7.5 g/dL or reduction >25% of baseline) and/or
71
significant neutropenia (granulocyte count <750 cells/mm3 or reduction >50% from baseline)
72
may require a dose interruption until evidence of marrow recovery is observed [see Warnings
73
and Precautions (5.1)]. In patients who develop significant anemia, dose interruption does not
74
necessarily eliminate the need for transfusion. If marrow recovery occurs following dose
75
interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin
76
alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level
77
and patient tolerance.
78
2.4
Patients With Renal Impairment
79
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal
80
dialysis, the recommended dosage is 100 mg every 6 to 8 hours [see Clinical Pharmacology
81
(12.3)].
82
2.5
Patients With Hepatic Impairment
83
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
84
mild to moderate impaired hepatic function or liver cirrhosis.
85
3
DOSAGE FORMS AND STRENGTHS
86
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
87
zidovudine, one side engraved “GX CW3” and “300” on the other side.
88
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
89
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
90
body.
91
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
92
zidovudine in each teaspoonful (5 mL).
93
4
CONTRAINDICATIONS
94
RETROVIR Tablets, Capsules, and Syrup are contraindicated in patients who have had
95
potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to
96
any of the components of the formulations.
97
5
WARNINGS AND PRECAUTIONS
98
5.1
Hematologic Toxicity/Bone Marrow Suppression
99
RETROVIR should be used with caution in patients who have bone marrow compromise
100
evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. Hematologic
101
toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of
102
therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the
103
most significant adverse events observed. In patients who experience hematologic toxicity, a
104
reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after
105
6 to 8 weeks. There have been reports of pancytopenia associated with the use of RETROVIR,
106
which was reversible in most instances after discontinuance of the drug. However, significant
107
anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
108
transfusions, has occurred during treatment with RETROVIR alone or in combination with other
109
antiretrovirals.
110
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia
111
in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease
112
who are treated with RETROVIR. For HIV-1-infected individuals and patients with
113
asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or
114
neutropenia develops, dosage interruption may be needed [see Dosage and Administration
115
(2.3)].
116
5.2
Myopathy
117
Myopathy and myositis with pathological changes, similar to that produced by HIV-1
118
disease, have been associated with prolonged use of RETROVIR.
119
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
120
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
121
reported with the use of nucleoside analogues alone or in combination, including zidovudine and
122
other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged
123
exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be
124
exercised when administering RETROVIR to any patient with known risk factors for liver
125
disease; however, cases have also been reported in patients with no known risk factors.
126
Treatment with RETROVIR should be suspended in any patient who develops clinical or
127
laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
128
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
129
5.4
Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV
130
Co-Infected Patients
131
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine
132
nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or
133
pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when
134
ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected patients [see Clinical
135
Pharmacology (12.3)], exacerbation of anemia due to ribavirin has been reported when
136
zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not
137
advised. Consideration should be given to replacing zidovudine in established combination
138
HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
139
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
140
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
141
ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be
142
closely monitored for treatment-associated toxicities, especially hepatic decompensation,
143
neutropenia, and anemia.
144
Discontinuation of zidovudine should be considered as medically appropriate. Dose
145
reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if
146
worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh
147
>6) (see the complete prescribing information for interferon and ribavirin).
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
148
5.5
Use With Other Zidovudine-Containing Products
149
RETROVIR should not be administered with combination products that contain
150
zidovudine as one of their components (e.g., COMBIVIR® [lamivudine and zidovudine] Tablets
151
or TRIZIVIR® [abacavir sulfate, lamivudine, and zidovudine] Tablets).
152
5.6
Immune Reconstitution Syndrome
153
Immune reconstitution syndrome has been reported in patients treated with combination
154
antiretroviral therapy, including RETROVIR. During the initial phase of combination
155
antiretroviral treatment, patients whose immune systems respond may develop an inflammatory
156
response to indolent or residual opportunistic infections (such as Mycobacterium avium
157
infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
158
may necessitate further evaluation and treatment.
159
5.7
Fat Redistribution
160
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat
161
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
162
“cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
163
mechanism and long-term consequences of these events are currently unknown. A causal
164
relationship has not been established.
165
6
ADVERSE REACTIONS
166
6.1
Clinical Trials Experience
167
The following adverse reactions are discussed in greater detail in other sections of the
168
labeling:
169
• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and
170
Precautions (5.1)].
171
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].
172
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
173
Precautions (5.3)].
174
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings
175
and Precautions (5.4)].
176
Because clinical trials are conducted under widely varying conditions, adverse reaction
177
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
178
trials of another drug and may not reflect the rates observed in practice.
179
Adults: The frequency and severity of adverse reactions associated with the use of
180
RETROVIR are greater in patients with more advanced infection at the time of initiation of
181
therapy.
182
Table 2 summarizes events reported at a statistically significant greater incidence for
183
patients receiving RETROVIR in a monotherapy study.
184
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
185
Table 2. Percentage (%) of Patients With Adverse Reactionsa in Asymptomatic HIV-1
186
Infection (ACTG 019)
Adverse Reaction
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
Headache
Malaise
Gastrointestinal
Anorexia
Constipation
Nausea
Vomiting
9%
b
63%
53%
20%
6%
b
51%
17%
6%
53%
45%
11%
4%
30%
10%
187
a Reported in ≥5% of study population.
188
b Not statistically significant versus placebo.
189
190
In addition to the adverse reactions listed in Table 2, adverse reactions observed at an
191
incidence of ≥5% in any treatment arm in clinical studies (NUCA3001, NUCA3002,
192
NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills,
193
dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in
194
these studies hyperbilirubinemia was reported at an incidence of ≤0.8%.
195
Selected laboratory abnormalities observed during a clinical study of monotherapy with
196
RETROVIR are shown in Table 3.
197
198
Table 3. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients With
199
Asymptomatic HIV-1 Infection (ACTG 019)
Test
(Abnormal Level)
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
Granulocytopenia (<750 cells/mm3)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>5 x ULN)
AST (>5 x ULN)
1%
2%
0%
3%
1%
<1%
2%
<1%
3%
2%
200
ULN = Upper limit of normal.
201
202
Pediatrics: The clinical adverse reactions reported among adult recipients of
203
RETROVIR may also occur in pediatric patients.
204
Study ACTG 300: Selected clinical adverse reactions and physical findings with a
205
≥5% frequency during therapy with EPIVIR® (lamivudine) Oral Suspension 4 mg/kg twice daily
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
206
plus RETROVIR 160 mg/m2 3 times daily compared with didanosine in therapy-naive (≤56 days
207
of antiretroviral therapy) pediatric patients are listed in Table 4.
208
209
Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in
210
Pediatric Patients in Study ACTG 300
Adverse Reaction
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
Digestive
25%
32%
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
Respiratory
5%
8%
Cough
15%
18%
Abnormal breath sounds/wheezing
Ear, Nose, and Throat
7%
9%
Signs or symptoms of earsa
7%
6%
Nasal discharge or congestion
Other
8%
11%
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
211
a Includes pain, discharge, erythema, or swelling of an ear.
212
213
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of
214
antiretroviral therapy) pediatric patients are listed in Table 5.
215
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
216
Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric
217
Patients in Study ACTG 300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
Anemia (Hgb<7.0 g/dL)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>10 x ULN)
AST (>10 x ULN)
Lipase (>2.5 x ULN)
Total amylase (>2.5 x ULN)
8%
4%
1%
1%
2%
3%
3%
3%
2%
3%
3%
4%
3%
3%
218
ULN = Upper limit of normal.
219
ANC = Absolute neutrophil count.
220
221
Macrocytosis was reported in the majority of pediatric patients receiving RETROVIR
222
180 mg/m2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an
223
incidence of <6% in these studies were congestive heart failure, decreased reflexes, ECG
224
abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
225
Use for the Prevention of Maternal-Fetal Transmission of HIV-1: In a randomized,
226
double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to
227
determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission,
228
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates
229
beginning within 12 hours following birth. The most commonly reported adverse reactions were
230
anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22%
231
of the neonates who received RETROVIR and in 12% of the neonates who received placebo.
232
The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving
233
RETROVIR compared with neonates receiving placebo. No neonates with anemia required
234
transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after
235
completion of therapy with RETROVIR. Neutropenia in neonates was reported with similar
236
frequency in the group that received RETROVIR (21%) and in the group that received placebo
237
(27%). The long-term consequences of in utero and infant exposure to RETROVIR are
238
unknown.
239
6.2
Postmarketing Experience
240
In addition to adverse reactions reported from clinical trials, the following reactions have
241
been identified during postmarketing use of RETROVIR. Because they are reported voluntarily
242
from a population of unknown size, estimates of frequency cannot be made. These reactions have
243
been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or
244
potential causal connection to RETROVIR.
245
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
246
redistribution/accumulation of body fat [see Warnings and Precautions (5.7)].
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
247
Cardiovascular: Cardiomyopathy, syncope.
248
Endocrine: Gynecomastia.
249
Eye: Macular edema.
250
Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
251
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
252
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia,
253
lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
254
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice,
255
lactic acidosis, pancreatitis.
256
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and
257
myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis,
258
tremor.
259
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania,
260
paresthesia, seizures, somnolence, vertigo.
261
Respiratory: Dyspnea, rhinitis, sinusitis.
262
Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic
263
epidermal necrolysis, sweat, urticaria.
264
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
265
Urogenital: Urinary frequency, urinary hesitancy.
266
7
DRUG INTERACTIONS
267
7.1
Antiretroviral Agents
268
Stavudine: Concomitant use of zidovudine with stavudine should be avoided since an
269
antagonistic relationship has been demonstrated in vitro.
270
Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues
271
affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of
272
RETROVIR against HIV-1; concomitant use of such drugs should be avoided.
273
7.2
Doxorubicin
274
Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic
275
relationship has been demonstrated in vitro.
276
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
277
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow
278
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
279
8
USE IN SPECIFIC POPULATIONS
280
8.1
Pregnancy
281
Pregnancy Category C.
282
In humans, treatment with RETROVIR during pregnancy reduced the rate of
283
maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to
284
7.8% for infants born to mothers treated with RETROVIR [see Clinical Studies (14.3)]. There
285
were no differences in pregnancy-related adverse events between the treatment groups. Animal
10
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For current labeling information, please visit https://www.fda.gov/drugsatfda
286
reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal
287
malformations.
288
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected
289
pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal
290
HIV-1-transmission [see Clinical Studies (14.3)]. Congenital abnormalities occurred with similar
291
frequency between neonates born to mothers who received RETROVIR and neonates born to
292
mothers who received placebo. The observed abnormalities included problems in embryogenesis
293
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of
294
study drug.
295
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of
296
zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times
297
(rabbits) the mean steady-state peak human plasma concentration following a single 100-mg
298
dose of zidovudine. There were no other reported developmental anomalies. In another
299
developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that
300
produced peak plasma concentrations 350 times peak human plasma concentrations (300 times
301
the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated
302
with marked maternal toxicity and an increased incidence of fetal malformations. However, there
303
were no signs of teratogenicity at doses up to one fifth the lethal dose [see Nonclinical
304
Toxicology (13.2)].
305
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
306
women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established.
307
Physicians are encouraged to register patients by calling 1-800-258-4263.
308
8.3
Nursing Mothers
309
Zidovudine is excreted in human milk [see Clinical Pharmacology (12.3)].
310
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers
311
in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1
312
infection. Because of both the potential for HIV-1 transmission and the potential for serious
313
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
314
receiving RETROVIR.
315
8.4
Pediatric Use
316
RETROVIR has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who
317
had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values
318
indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in
319
neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.1), Adverse Reactions
320
(6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2), (14.3)].
321
8.5
Geriatric Use
322
Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
323
and over to determine whether they respond differently from younger subjects. Other reported
324
clinical experience has not identified differences in responses between the elderly and younger
325
patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater
11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
326
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
327
drug therapy.
328
8.6
Renal Impairment
329
In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is
330
recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
331
8.7
Hepatic Impairment
332
Zidovudine is eliminated from the body primarily by renal excretion following
333
metabolism in the liver (glucuronidation). Although the data are limited, zidovudine
334
concentrations appear to be increased in patients with severely impaired hepatic function, which
335
may increase the risk of hematologic toxicity [see Dosage and Administration (2.5), Clinical
336
Pharmacology (12.3)].
337
10
OVERDOSAGE
338
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These
339
involved exposures up to 50 grams. No specific symptoms or signs have been identified
340
following acute overdosage with zidovudine apart from those listed as adverse events such as
341
fatigue, headache, vomiting, and occasional reports of hematological disturbances. All patients
342
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
343
negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3′
344
azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.
345
11
DESCRIPTION
346
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
347
pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′
348
Chemical structure of Retrovir
12
349
350
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of
351
267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
352
RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg
353
of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline
354
cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
355
RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
356
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline
357
cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
358
edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical
359
shellac, soya lecithin, and titanium dioxide.
360
RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR
361
Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added
362
as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be
363
added to adjust pH.
364
12
CLINICAL PHARMACOLOGY
365
12.1 Mechanism of Action
366
Zidovudine is an antiviral agent [see Clinical Pharmacology (12.4)].
367
12.3 Pharmacokinetics
368
Absorption and Bioavailability: In adults, following oral administration, zidovudine is
369
rapidly absorbed and extensively distributed, with peak serum concentrations occurring within
370
0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as RETROVIR
371
Tablets or Syrup compared with RETROVIR Capsules. The pharmacokinetic properties of
372
zidovudine in fasting adult patients are summarized in Table 6.
373
374
Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratioa
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)b
0.5 to 3
(n = 19)
375
a Median [range].
376
b Approximate range.
377
378
Distribution: The apparent volume of distribution of zidovudine, following oral
379
administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (Table 6).
13
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380
Metabolism and Elimination: Zidovudine is primarily eliminated by hepatic
381
metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater
382
than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and
383
74%, respectively, of the dose following oral administration. A second metabolite, 3′-amino-3′
384
deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous
385
(IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC.
386
Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from
387
2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
388
Effect of Food on Absorption: RETROVIR may be administered with or without food.
389
The zidovudine AUC was similar when a single dose of zidovudine was administered with food.
390
Special Populations: Renal Impairment: Zidovudine clearance was decreased
391
resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal
392
function (n = 14) following a single 200-mg oral dose (Table 7). Plasma concentrations of AMT
393
were not determined. A dose adjustment should not be necessary for patients with creatinine
394
clearance (CrCl) ≥15 mL/min.
395
396
Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal
397
Impairmenta
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
398
a Data are expressed as mean ± standard deviation.
399
400
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of
401
zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5)
402
or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks.
403
Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma
404
concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in
405
patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a
406
negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
407
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis
408
[see Dosage and Administration (2.4)].
409
Hepatic Impairment: Data describing the effect of hepatic impairment on the
410
pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated
411
primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased
412
and plasma concentrations would be increased following administration of the recommended
413
adult doses to patients with hepatic impairment [see Dosage and Administration (2.5)].
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
414
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in
415
HIV-1-infected pediatric patients (Table 8).
416
Patients 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in
417
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
418
increases in plasma zidovudine concentrations were observed following administration of oral
419
solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral
420
clearance were comparable to adult values. As in adult patients, the major route of elimination
421
was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in
422
the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and
423
Administration (2.1)].
424
Patients <3 Months of Age: Zidovudine pharmacokinetics have been evaluated in
425
pediatric patients from birth to 3 months of life. Zidovudine elimination was determined
426
immediately following birth in 8 neonates who were exposed to zidovudine in utero. The
427
half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body
428
clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose
429
recommendations for neonates [see Dosage and Administration (2.2)].
430
431
Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patientsa
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]b
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
432
a Data presented as mean ± standard deviation except where noted.
433
b Median [range].
434
435
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I study of
436
8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to
437
those of nonpregnant adults. Consistent with passive transmission of the drug across the
438
placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in
439
maternal plasma at delivery [see Use in Specific Populations (8.1)].
440
Although data are limited, methadone maintenance therapy in 5 pregnant women did not
441
appear to alter zidovudine pharmacokinetics.
442
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
443
HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
444
HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women,
445
the mean concentration of zidovudine was similar in human milk and serum [see Use in Specific
446
Populations (8.3)].
447
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients
448
over 65 years of age.
449
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12)
450
subjects showed no differences in zidovudine AUC when a single dose of zidovudine was
451
administered as the 300-mg RETROVIR Tablet.
452
Drug Interactions: [See Drug Interactions (7)].
453
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
454
Table 9. Effect of Coadministered Drugs on Zidovudine AUCa
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED
WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Drug and Dose
Zidovudine
Dose
n
Zidovudine
Concentrations
Concentration of
Coadministered
Drug
AUC
Variability
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%b
↔
Clarithromycin
500 mg twice daily
100 mg q 4 hr
x 7 days
4
↓AUC
12%
Range
↓34% to ↑14%
Not Reported
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Lamivudine
300 mg q 12 hr
single 200 mg
12
↑AUC
13%
90% CI:
2% to 27%
↔
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%b
↔
Nelfinavir
750 mg q 8 hr x
7 to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to 170%b
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to 130%b
Not Assessed
455
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration
456
versus time curve; CI = confidence interval.
457
a This table is not all inclusive.
458
b Estimated range of percent difference.
459
460
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients
461
receiving RETROVIR, while in one case a high level was documented. However, in a
462
pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single
17
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For current labeling information, please visit https://www.fda.gov/drugsatfda
463
300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every
464
4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally
465
assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine
466
clearance was observed with phenytoin.
467
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine,
468
stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or
469
intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss
470
of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine
471
(n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug
472
regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.4)].
473
12.4 Microbiology
474
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly,
475
zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate
476
(ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT)
477
via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak
478
inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into
479
the DNA of cells in culture.
480
Antiviral Activity: The antiviral activity of zidovudine against HIV-1 was assessed in a
481
number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The
482
EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to
483
9 μM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with
484
resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92
485
baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram
486
Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against
487
different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against HIV-2 isolates from
488
0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates
489
synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and
490
lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and
491
the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with
492
interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell
493
culture.
494
Resistance: Genotypic analyses of the isolates selected in cell culture and recovered
495
from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino
496
acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer
497
zidovudine resistance. In general, higher levels of resistance were associated with greater number
498
of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline,
499
phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and
500
zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of
501
substitutions conferring resistance to zidovudine.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
502
Cross-Resistance: In a study of 167 HIV-1-infected patients, isolates (n = 2) with
503
multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were
504
recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus
505
zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination
506
therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine
507
monotherapy, with the Q151M substitution being most commonly associated with multi-drug
508
resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116
509
results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine,
510
and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer
511
cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
512
13
NONCLINICAL TOXICOLOGY
513
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
514
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats
515
(60 females and 60 males in each group). Initial single daily doses were 30, 60, and
516
120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced
517
to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats
518
only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on
519
day 279.
520
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing
521
squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in
522
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the
523
vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
524
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell
525
carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or
526
middle dose in rats. No other drug-related tumors were observed in either sex of either species.
527
At doses that produced tumors in mice and rats, the estimated drug exposure (as
528
measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human
529
exposure at the recommended therapeutic dose of 100 mg every 4 hours.
530
It is not known how predictive the results of rodent carcinogenicity studies may be for
531
humans.
532
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in
533
vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human
534
lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was
535
negative in a cytogenetic study in rats given a single dose.
536
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult
537
dose based on body surface area, had no effect on fertility judged by conception rates.
538
Two transplacental carcinogenicity studies were conducted in mice. One study
539
administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10
540
through parturition and lactation with dosing continuing in offspring for 24 months postnatally.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
541
The doses of zidovudine administered in this study produced zidovudine exposures
542
approximately 3 times the estimated human exposure at recommended doses. After 24 months,
543
an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or
544
lung or any other organ in either gender. These findings are consistent with results of the
545
standard oral carcinogenicity study in mice, as described earlier. A second study administered
546
zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg
547
nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12
548
through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
549
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
550
13.2 Reproductive and Developmental Toxicology Studies
551
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed
552
no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal
553
toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or
554
450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
555
resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
556
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations
557
(after one sixth of the daily dose) achieved with the recommended daily dose (100 mg every
558
4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
559
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a
560
dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused
561
marked maternal toxicity and an increase in the incidence of fetal malformations. This dose
562
resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations.
563
(Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given
564
600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of
565
600 mg/kg/day or less.
566
14
CLINICAL STUDIES
567
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence
568
of opportunistic infections in patients with advanced HIV-1 disease and to delay disease
569
progression in asymptomatic HIV-1-infected patients.
570
14.1 Adults
571
Combination Therapy: RETROVIR in combination with other antiretroviral agents has
572
been shown to be superior to monotherapy for one or more of the following endpoints: delaying
573
death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma
574
HIV-1 RNA.
575
The clinical efficacy of a combination regimen that includes RETROVIR was
576
demonstrated in study ACTG 320. This study was a multi-center, randomized, double-blind,
577
placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR 300 mg/day to
578
RETROVIR plus EPIVIR plus indinavir 800 mg t.i.d. The incidence of AIDS-defining events or
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
579
death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm
580
(6.1% versus 10.9%, respectively).
581
Monotherapy: In controlled studies of treatment-naive patients conducted between 1986
582
and 1989, monotherapy with RETROVIR, as compared with placebo, reduced the risk of HIV-1
583
disease progression, as assessed using endpoints that included the occurrence of HIV-1-related
584
illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease
585
(BW 002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts
586
between 200 and 500 cells/mm3 (ACTG 016 and ACTG 019). A survival benefit for
587
monotherapy with RETROVIR was not demonstrated in the latter 2 studies. Subsequent studies
588
showed that the clinical benefit of monotherapy with RETROVIR was time limited.
589
14.2 Pediatric Patients
590
ACTG 300 was a multi-center, randomized, double-blind study that provided for
591
comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of
592
471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these
593
2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline
594
CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was
595
5.0 log10 copies/mL. The median duration that patients remained on study was approximately
596
10 months. Results are summarized in Table 10.
597
598
Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease
599
Progression or Death)
EPIVIR plus RETROVIR
Didanosine
Endpoint
(n = 236)
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
600
601
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
602
The utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission was
603
demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in
604
HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in
605
the treated group: 560 cells/mm3) who had little or no previous exposure to RETROVIR. Oral
606
RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy)
607
followed by IV administration of RETROVIR during labor and delivery. Following birth,
608
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
609
significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture
610
from peripheral blood) between the group receiving RETROVIR and the group receiving
611
placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8%
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
612
in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in
613
transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was
614
no difference in pregnancy-related adverse events between the treatment groups.
615
16
HOW SUPPLIED/STORAGE AND HANDLING
616
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
617
zidovudine, one side engraved “GX CW3” and “300” on the other side.
618
Bottle of 60 (NDC 0173-0501-00).
619
Store at 15° to 25°C (59° to 77°F).
620
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
621
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
622
body.
623
Bottles of 100 (NDC 0173-0108-55).
624
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
625
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
626
zidovudine in each teaspoonful (5 mL).
627
Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
628
Store at 15° to 25°C (59° to 77°F).
629
17
PATIENT COUNSELING INFORMATION
630
17.1 Information About Therapy With RETROVIR
631
Neutropenia and Anemia: Patients should be informed that the major toxicities of
632
RETROVIR are neutropenia and/or anemia. The frequency and severity of these toxicities are
633
greater in patients with more advanced disease and in those who initiate therapy later in the
634
course of their infection. Patients should be informed that if toxicity develops, they may require
635
transfusions or drug discontinuation. Patients should be informed of the extreme importance of
636
having their blood counts followed closely while on therapy, especially for patients with
637
advanced symptomatic HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.1)].
638
Myopathy: Patients should be informed that myopathy and myositis with pathological
639
changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of
640
RETROVIR [see Boxed Warning, Warnings and Precautions (5.2)].
641
Lactic Acidosis/Hepatomegaly: Patients should be informed that some HIV medicines,
642
including RETROVIR, can cause a rare, but serious condition called lactic acidosis with liver
643
enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.3)].
644
HIV-1/HCV Co-Infection: Patients with HIV-1/HCV co-infection should be informed
645
that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
646
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
647
ribavirin [see Warnings and Precautions (5.4)].
648
Redistribution/Accumulation of Body Fat: Patients should be informed that
649
redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
650
and that the cause and long-term health effects of these conditions are not known at this time
651
[see Warnings and Precautions (5.7)].
652
Common Adverse Reactions: Patients should be informed that the most commonly
653
reported adverse reactions in adult patients being treated with RETROVIR were headache,
654
malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in
655
pediatric patients receiving RETROVIR were fever, cough, and digestive disorders. Patients also
656
should be encouraged to contact their physician if they experience muscle weakness, shortness of
657
breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being
658
treated with RETROVIR [see Adverse Reactions (6)].
659
Drug Interactions: Patients should be cautioned about the use of other medications,
660
including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of
661
RETROVIR [see Drug Interactions (7)].
662
Pregnancy: Pregnant women considering the use of RETROVIR during pregnancy for
663
prevention of HIV-1 transmission to their infants should be informed that transmission may still
664
occur in some cases despite therapy. The long-term consequences of in utero and infant exposure
665
to RETROVIR are unknown, including the possible risk of cancer [see Use in Specific
666
Populations (8.1)].
667
HIV-1-infected pregnant women should be informed not to breastfeed to avoid postnatal
668
transmission of HIV to a child who may not yet be infected [see Use in Specific Populations
669
(8.3)].
670
Information About Therapy With RETROVIR: RETROVIR is not a cure for HIV-1
671
infection, and patients may continue to acquire illnesses associated with HIV-1 infection,
672
including opportunistic infections. Therefore, patients should be informed to seek medical care
673
for any significant change in their health status.
674
Patients should be informed of the importance of taking RETROVIR exactly as
675
prescribed. They should be informed not to share medication and not to exceed the
676
recommended dose. Patients should be informed that the long-term effects of RETROVIR are
677
unknown at this time.
678
Patients should be informed that therapy with RETROVIR has not been shown to reduce
679
the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
680
681
RETROVIR, COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of
682
GlaxoSmithKline.
683
684
685
686
GlaxoSmithKline
687
Research Triangle Park, NC 27709
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
688
689
©2010, GlaxoSmithKline. All rights reserved.
690
691
May 2010
692
RTT:xPI
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019910s036lbl.pdf', 'application_number': 19910, 'submission_type': 'SUPPL ', 'submission_number': 36}
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11,852
|
NIZORAL® (KETOCONAZOLE) 2% SHAMPOO
DESCRIPTION
NIZORAL® (ketoconazole) 2% Shampoo is a red-orange liquid for topical
application, containing the broad spectrum synthetic antifungal agent ketoconazole
in a concentration of 2% in an aqueous suspension. It also contains: coconut fatty
acid diethanolamide, disodium monolauryl ether sulfosuccinate, F.D.&C. Red
No. 40, hydrochloric acid, imidurea, laurdimonium hydrolyzed animal collagen,
macrogol 120 methyl glucose dioleate, perfume bouquet, sodium chloride, sodium
hydroxide, sodium lauryl ether sulfate, and purified water.
Ketoconazole
is
cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine and has the following
structural formula: structural formula
CLINICAL PHARMACOLOGY
Tinea (pityriasis) versicolor is a non-contagious infection of the skin caused by
Pityrosporum orbiculare (Malassezia furfur). This commensal organism is part of
the normal skin flora. In susceptible individuals the condition is often recurrent and
may give rise to hyperpigmented or hypopigmented patches on the trunk which may
extend to the neck, arms and upper thighs. Treatment of the infection may not
immediately result in restoration of pigment to the affected sites. Normalization of
pigment following successful therapy is variable and may take months, depending
on individual skin type and incidental skin exposure. The rate of recurrence of
infection is variable.
NIZORAL® (ketoconazole) was not detected in plasma in 39 patients who
shampooed 4-10 times per week for 6 months, or in 33 patients who shampooed 2
3 times per week for 3-26 months (mean: 16 months).
An exaggerated use washing test on the sensitive antecubital skin of 10 subjects
twice daily for five consecutive days showed that the irritancy potential of
ketoconazole 2% shampoo was significantly less than that of 2.5% selenium sulfide
shampoo.
1
Reference ID: 3397646
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A human sensitization test, a phototoxicity study, and a photoallergy study
conducted in 38 male and 22 female volunteers showed no contact sensitization of
the delayed hypersensitivity type, no phototoxicity and no photoallergenic potential
due to NIZORAL® (ketoconazole) 2% Shampoo.
Mode of Action: Interpretations of in vivo studies suggest that ketoconazole impairs
the synthesis of ergosterol, which is a vital component of fungal cell membranes. It
is postulated, but not proven, that the therapeutic effect of ketoconazole in tinea
(pityriasis) versicolor is due to the reduction of Pityrosporum orbiculare
(Malassezia furfur) and that the therapeutic effect in dandruff is due to the reduction
of Pityrosporum ovale. Support for the therapeutic effect in tinea versicolor comes
from a three-arm, parallel, double-blind, placebo controlled study in patients who
had moderately severe tinea (pityriasis) versicolor. Successful response rates in the
primary efficacy population for each of both three-day and single-day regimens of
ketoconazole 2% shampoo were statistically significantly greater (73% and 69%,
respectively) than a placebo regimen (5%). There had been mycological
confirmation of fungal disease in all cases at baseline. Mycological clearing rates
were 84% and 78%, respectively, for the three-day and one-day regimens of the 2%
shampoo and 11% in the placebo regimen. While the differences in the rates of
successful response between either of the two active treatments and placebo were
statistically significant, the difference between the two active regimens was not.
Microbiology: NIZORAL® (ketoconazole) is a broad spectrum synthetic antifungal
agent which inhibits the growth of the following common dermatophytes and yeasts
by altering the permeability of the cell membrane: dermatophytes: Trichophyton
rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M.
gypseum and Epidermophyton floccosum; yeasts: Candida albicans, C. tropicalis,
Pityrosporum ovale (Malassezia ovale) and Pityrosporum orbiculare (M. furfur).
Development of resistance by these microorganisms to ketoconazole has not been
reported.
INDICATIONS AND USAGE
NIZORAL® (ketoconazole) 2% Shampoo is indicated for the treatment of tinea
(pityriasis) versicolor caused by or presumed to be caused by Pityrosporum
orbiculare (also known as Malassezia furfur or M. orbiculare).
Note: Tinea (pityriasis) versicolor may give rise to hyperpigmented or
hypopigmented patches on the trunk which may extend to the neck, arms and upper
thighs. Treatment of the infection may not immediately result in normalization of
pigment to the affected sites. Normalization of pigment following successful
therapy is variable and may take months, depending on individual skin type and
Reference ID: 3397646
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
incidental sun exposure. Although tinea versicolor is not contagious, it may recur
because the organism that causes the disease is part of the normal skin flora.
CONTRAINDICATIONS
NIZORAL® (ketoconazole) 2% Shampoo is contraindicated in persons who have
known hypersensitivity to the active ingredient or excipients of this formulation.
PRECAUTIONS
Severe hypersensitivity reactions, including anaphylaxis, have been reported during
post-marketing use of NIZORAL® (ketoconazole) Shampoo. If a reaction
suggesting sensitivity or chemical irritation should occur, use of the medication
should be discontinued.
Information for Patients:
Patients should be advised of the following:
NIZORAL® (ketoconazole) 2% Shampoo may be irritating to mucous
membranes of the eyes and contact with this area should be avoided.
The following have been reported with the use of NIZORAL®
(ketoconazole) 2% Shampoo: hair discoloration and abnormal hair texture,
removal of the curl from permanently waved hair, itching, skin burning
sensation and contact dermatitis, hypersensitivity, angioedema, alopecia,
rash, urticaria, skin irritation, dry skin, and application site reactions.
Patients who develop allergic reactions, such as generalized rash, skin
reactions, severe swelling, angioedema, or shortness of breath should
discontinue NIZORAL® (ketoconazole) 2% Shampoo and contact their
physician immediately.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long-term studies to assess the carcinogenic potential of NIZORAL®
(ketoconazole) 2% Shampoo have not been conducted. A long-term feeding study
of ketoconazole in Swiss Albino mice and in Wistar rats showed no evidence of
oncogenic activity. The dominant lethal mutation test in male and female mice
revealed that single oral doses of ketoconazole as high as 80 mg/kg were not
genotoxic. The Ames Salmonella microsomal activator assay was also negative.
Pregnancy: Teratogenic effects: Pregnancy Category C:
There are no adequate and well-controlled studies in pregnant women.
Ketoconazole should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus. In humans, ketoconazole is not detected in plasma
after chronic shampooing on the scalp.
Reference ID: 3397646
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ketoconazole has been shown to be teratogenic (syndactylia and oligodactylia) in
the rat when given orally in the diet at 80 mg/kg/day (a dose 10 times the maximum
recommended human oral dose). However, these effects may be related to maternal
toxicity, which was seen at this and higher dose levels.
Nursing mothers: There are no adequate and well-controlled studies in nursing
women. Ketoconazole is not detected in plasma after chronic shampooing on the
scalp. Caution should be exercised when NIZORAL® (ketoconazole) 2% Shampoo
is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children have not been established.
ADVERSE REACTIONS
Clinical Trials Experience
In 11 double-blind trials in 264 patients using ketoconazole 2% shampoo for the
treatment of dandruff or seborrheic dermatitis, an increase in normal hair loss and
irritation occurred in less than 1% of patients. In three open-label safety trials in
which 41 patients shampooed 4-10 times weekly for six months, the following
adverse experiences each occurred once: abnormal hair texture, scalp pustules, mild
dryness of the skin, and itching. As with other shampoos, oiliness and dryness of
hair and scalp have been reported. In a double-blind, placebo-controlled trial in
which patients with tinea versicolor were treated with either a single application of
NIZORAL® (ketoconazole) 2% Shampoo (n=106), a daily application for three
consecutive days (n=107), or placebo (n=105), drug-related adverse events occurred
in 5 (5%), 7 (7%) and 4 (4%) of patients, respectively. The only events that
occurred in more than one patient in any one of the three treatment groups were
pruritus, application site reaction, and dry skin; none of these events occurred in
more than 3% of the patients in any one of the three groups.
Post-marketing Experience
Because these reactions are reported voluntarily from a population of uncertain size,
it is not possible to reliably estimate their frequency. The following adverse drug
reactions have been identified during post-marketing experience with NIZORAL®
(ketoconazole) Shampoo: there have been reports of hair discoloration and
abnormal hair texture, itching, skin burning sensation, contact dermatitis,
hypersensitivity, angioedema, alopecia, rash, urticaria, skin irritation, dry skin, and
application site reactions.
OVERDOSAGE
NIZORAL® (ketoconazole) 2% Shampoo is intended for external use only. In the
event of accidental ingestion, supportive and symptomatic measures should be
Reference ID: 3397646
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
employed. Induced emesis and gastric lavage should not be performed to avoid
aspiration.
DOSAGE AND ADMINISTRATION
Apply the shampoo to the damp skin of the affected area and a wide margin
surrounding this area. Lather, leave in place for 5 minutes, and then rinse off with
water.
One application of the shampoo should be sufficient.
HOW SUPPLIED
NIZORAL® (ketoconazole) 2% Shampoo is a red-orange liquid supplied in a 4-fluid
ounce (120 mL) nonbreakable plastic bottle (NDC 50458-680-08).
Storage conditions: Store at a temperature not above 25°C (77°F). Protect from
light.
Product of Belgium
Manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
©Janssen Pharmaceuticals, Inc. 2004
Revised: October 2013
Reference ID: 3397646
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019927s032lbl.pdf', 'application_number': 19927, 'submission_type': 'SUPPL ', 'submission_number': 32}
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11,848
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RETROVIR safely and effectively. See full prescribing information for
RETROVIR.
RETROVIR (zidovudine) Tablets, Capsules, and Syrup
Initial U.S. Approval: 1987
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
• Hematologic toxicity including neutropenia and severe anemia have
been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine.
(5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues
including RETROVIR. Suspend treatment if clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity
occur. (5.3)
---------------------------RECENT MAJOR CHANGES -------------------
Dosage and Administration, Pediatric Patients (2.1)
November 2009
----------------------------INDICATIONS AND USAGE--------------------
RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for:
• Treatment of Human Immunodeficiency Virus (HIV-1) infection in
combination with other antiretroviral agents. (1.1)
• Prevention of maternal-fetal HIV-1 transmission. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
• Treatment of HIV-1 infection:
Adults: 600 mg/day in divided doses with other antiretroviral agents.
Pediatric patients (4 weeks to <18 years of age): Dosage should be
calculated based on body weight not to exceed adult dose. (2.1)
• Prevention of maternal-fetal HIV-1 transmission:
Specific dosage instructions for mother and infant. (2.2)
• Patients with severe anemia and/or neutropenia:
Dosage interruption may be necessary. (2.3)
• Renal Impairment – Recommended dosage in hemodialysis or peritoneal
dialysis patients is 100 mg every 6 to 8 hours. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS -------------
Tablets: 300 mg (3)
Capsules: 100 mg (3)
Syrup: 50 mg/5 mL (3)
-------------------------------CONTRAINDICATIONS-----------------------
Hypersensitivity to zidovudine (e.g., anaphylaxis, Stevens-Johnson
syndrome). (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
• Hematologic toxicity/bone marrow suppression including neutropenia and
severe anemia have been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine. (5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues including
RETROVIR. Suspend treatment if clinical or laboratory findings
suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3)
• Exacerbation of anemia has been reported in HIV-1/HCV co-infected
patients receiving ribavirin and zidovudine. Coadministration of ribavirin
and zidovudine is not advised. (5.4)
• Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV
co-infected patients receiving combination antiretroviral therapy and
interferon alfa with/without ribavirin. Discontinue zidovudine as medically
appropriate and consider dose reduction or discontinuation of interferon
alfa, ribavirin, or both. (5.4)
• RETROVIR should not be administered with other zidovudine-containing
combination products. (5.5)
• Immune reconstitution syndrome (5.6) and redistribution/accumulation of
body fat (5.7) have been reported in patients treated with combination
antiretroviral therapy.
------------------------------ ADVERSE REACTIONS ----------------------
• The most commonly reported adverse reactions (incidence ≥15%) in adult
HIV-1 clinical studies were headache, malaise, nausea, anorexia, and
vomiting. (6.1)
• The most commonly reported adverse reactions (incidence ≥15%) in
pediatric HIV-1 clinical studies were fever, cough, and digestive disorders.
(6.1)
• The most commonly reported adverse reactions in neonates (incidence
≥15%) in the prevention of maternal-fetal transmission of HIV-1 clinical
trial were anemia and neutropenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS-----------------------
• Stavudine: Concomitant use with zidovudine should be avoided. (7.1)
• Doxorubicin: Use with zidovudine should be avoided. (7.2)
• Bone marrow suppressive/cytotoxic agents: May increase the hematologic
toxicity of zidovudine. (7.3)
----------------------- USE IN SPECIFIC POPULATIONS ---------------
Pregnancy: Physicians are encouraged to register patients in the Antiretroviral
Pregnancy Registry by calling 1-800-258-4263. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: November 2009
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
2
DOSAGE AND ADMINISTRATION
2.1
Treatment of HIV-1 Infection
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
2.3
Patients With Severe Anemia and/or Neutropenia
2.4
Patients With Renal Impairment
2.5
Patients With Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
5.2
Myopathy
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
5.4
Use With Interferon- and Ribavirin-Based Regimens in
HIV-1/HCV Co-Infected Patients
5.5
Use With Other Zidovudine-Containing Products
5.6
Immune Reconstitution Syndrome
5.7
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
7.2
Doxorubicin
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Reproductive and Developmental Toxicology Studies
14 CLINICAL STUDIES
14.1 Adults
14.2 Pediatric Patients
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Information About Therapy With RETROVIR
*Sections or subsections omitted from the full prescribing information are not listed.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________
1
FULL PRESCRIBING INFORMATION
2
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC
3
ACIDOSIS
4
RETROVIR® (zidovudine) has been associated with hematologic toxicity including
5
neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease [see
6
Warnings and Precautions (5.1)].
7
Prolonged use of RETROVIR has been associated with symptomatic myopathy [see
8
Warnings and Precautions (5.2)].
9
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
10
been reported with the use of nucleoside analogues alone or in combination, including
11
RETROVIR and other antiretrovirals. Suspend treatment if clinical or laboratory findings
12
suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and
13
Precautions (5.3)].
14
1
INDICATIONS AND USAGE
15
1.1
Treatment of HIV-1
16
RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with
17
other antiretroviral agents for the treatment of HIV-1 infection.
18
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
19
RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see
20
Dosage and Administration (2.2)]. The indication is based on a dosing regimen that included
21
3 components:
22
1.
antepartum therapy of HIV-1 infected mothers
23
2.
intrapartum therapy of HIV-1 infected mothers
24
3.
post-partum therapy of HIV-1 exposed neonate.
25
Points to consider prior to initiating RETROVIR in pregnant women for the prevention of
26
maternal-fetal HIV-1 transmission include:
27
• In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be
28
given in combination with other antiretroviral drugs.
29
• Prevention of HIV-1 transmission in women who have received RETROVIR for a prolonged
30
period before pregnancy has not been evaluated.
31
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the
32
first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are
33
not fully known, women in the first trimester of pregnancy who do not require immediate
34
initiation of antiretroviral therapy for their own health may consider delaying use; this
35
indication is based on use after 14 weeks gestation.
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
36
2
DOSAGE AND ADMINISTRATION
37
2.1
Treatment of HIV-1 Infection
38
Adults: The recommended oral dose of RETROVIR is 600 mg/day in divided doses in
39
combination with other antiretroviral agents.
40
Pediatric Patients (4 weeks to <18 years of age): Healthcare professionals should
41
pay special attention to accurate calculation of the dose of RETROVIR, transcription of the
42
medication order, dispensing information, and dosing instructions to minimize risk for
43
medication dosing errors.
44
Prescribers should calculate the appropriate dose of RETROVIR for each child based on
45
body weight (kg) and should not exceed the recommended adult dose.
46
Before prescribing RETROVIR capsules or tablets, children should be assessed for the
47
ability to swallow capsules or tablets. If a child is unable to reliably swallow a RETROVIR
48
capsule or tablet, the RETROVIR syrup formulation should be prescribed.
49
The recommended dosage in pediatric patients 4 weeks of age and older and weighing
50
≥4 kg is provided in Table 1. RETROVIR Syrup should be used to provide accurate dosage
51
when whole tablets or capsules are not appropriate.
52
53
Table 1: Recommended Pediatric Dosage of RETROVIR
Body
Weight
(kg)
Total Daily
Dose
Dosage Regimen and Dose
b.i.d.
t.i.d.
4 to <9
24 mg/kg/day
12 mg/kg
8 mg/kg
≥9 to <30
18 mg/kg/day
9 mg/kg
6 mg/kg
≥30
600 mg/day
300 mg
200 mg
54
55
Alternatively, dosing for RETROVIR can be based on body surface area (BSA) for each
56
child. The recommended oral dose of RETROVIR is 480 mg/m2/day in divided doses
57
(240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by
58
mg/kg will not be the same as that calculated by BSA.
59
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
60
The recommended dosage regimen for administration to pregnant women (>14 weeks of
61
pregnancy) and their neonates is:
62
Maternal Dosing: 100 mg orally 5 times per day until the start of labor [see Clinical
63
Studies (14.3)]. During labor and delivery, intravenous RETROVIR should be administered at
64
2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of
65
1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
66
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
67
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
68
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours.
69
2.3
Patients With Severe Anemia and/or Neutropenia
3
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70
Significant anemia (hemoglobin <7.5 g/dL or reduction >25% of baseline) and/or
71
significant neutropenia (granulocyte count <750 cells/mm3 or reduction >50% from baseline)
72
may require a dose interruption until evidence of marrow recovery is observed [see Warnings
73
and Precautions (5.1)]. In patients who develop significant anemia, dose interruption does not
74
necessarily eliminate the need for transfusion. If marrow recovery occurs following dose
75
interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin
76
alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level
77
and patient tolerance.
78
2.4
Patients With Renal Impairment
79
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal
80
dialysis, the recommended dosage is 100 mg every 6 to 8 hours [see Clinical Pharmacology
81
(12.3)].
82
2.5
Patients With Hepatic Impairment
83
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
84
mild to moderate impaired hepatic function or liver cirrhosis.
85
3
DOSAGE FORMS AND STRENGTHS
86
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
87
zidovudine, one side engraved “GX CW3” and “300” on the other side.
88
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
89
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
90
body.
91
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
92
zidovudine in each teaspoonful (5 mL).
93
4
CONTRAINDICATIONS
94
RETROVIR Tablets, Capsules, and Syrup are contraindicated in patients who have had
95
potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to
96
any of the components of the formulations.
97
5
WARNINGS AND PRECAUTIONS
98
5.1
Hematologic Toxicity/Bone Marrow Suppression
99
RETROVIR should be used with caution in patients who have bone marrow compromise
100
evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. Hematologic
101
toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of
102
therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the
103
most significant adverse events observed. In patients who experience hematologic toxicity, a
104
reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after
105
6 to 8 weeks. There have been reports of pancytopenia associated with the use of RETROVIR,
106
which was reversible in most instances after discontinuance of the drug. However, significant
107
anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood
4
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108
transfusions, has occurred during treatment with RETROVIR alone or in combination with other
109
antiretrovirals.
110
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia
111
in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease
112
who are treated with RETROVIR. For HIV-1-infected individuals and patients with
113
asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or
114
neutropenia develops, dosage interruption may be needed [see Dosage and Administration
115
(2.3)].
116
5.2
Myopathy
117
Myopathy and myositis with pathological changes, similar to that produced by HIV-1
118
disease, have been associated with prolonged use of RETROVIR.
119
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
120
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
121
reported with the use of nucleoside analogues alone or in combination, including zidovudine and
122
other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged
123
exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be
124
exercised when administering RETROVIR to any patient with known risk factors for liver
125
disease; however, cases have also been reported in patients with no known risk factors.
126
Treatment with RETROVIR should be suspended in any patient who develops clinical or
127
laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
128
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
129
5.4
Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV
130
Co-Infected Patients
131
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine
132
nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or
133
pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when
134
ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected patients [see Clinical
135
Pharmacology (12.3)], exacerbation of anemia due to ribavirin has been reported when
136
zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not
137
advised. Consideration should be given to replacing zidovudine in established combination
138
HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
139
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
140
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
141
ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be
142
closely monitored for treatment-associated toxicities, especially hepatic decompensation,
143
neutropenia, and anemia.
144
Discontinuation of zidovudine should be considered as medically appropriate. Dose
145
reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if
146
worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh
147
>6) (see the complete prescribing information for interferon and ribavirin).
5
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148
5.5
Use With Other Zidovudine-Containing Products
149
RETROVIR should not be administered with combination products that contain
150
zidovudine as one of their components (e.g., COMBIVIR® or TRIZIVIR®).
151
5.6
Immune Reconstitution Syndrome
152
Immune reconstitution syndrome has been reported in patients treated with combination
153
antiretroviral therapy, including RETROVIR. During the initial phase of combination
154
antiretroviral treatment, patients whose immune systems respond may develop an inflammatory
155
response to indolent or residual opportunistic infections (such as Mycobacterium avium
156
infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
157
may necessitate further evaluation and treatment.
158
5.7
Fat Redistribution
159
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat
160
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
161
“cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
162
mechanism and long-term consequences of these events are currently unknown. A causal
163
relationship has not been established.
164
6
ADVERSE REACTIONS
165
6.1
Clinical Trials Experience
166
The following adverse reactions are discussed in greater detail in other sections of the
167
labeling:
168
• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and
169
Precautions (5.1)].
170
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].
171
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
172
Precautions (5.3)].
173
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings
174
and Precautions (5.4)].
175
Because clinical trials are conducted under widely varying conditions, adverse reaction
176
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
177
trials of another drug and may not reflect the rates observed in practice.
178
Adults: The frequency and severity of adverse reactions associated with the use of
179
RETROVIR are greater in patients with more advanced infection at the time of initiation of
180
therapy.
181
Table 2 summarizes events reported at a statistically significant greater incidence for
182
patients receiving RETROVIR in a monotherapy study.
183
6
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184
Table 2. Percentage (%) of Patients With Adverse Reactionsa in Asymptomatic HIV-1
185
Infection (ACTG 019)
Adverse Reaction
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
Headache
Malaise
Gastrointestinal
Anorexia
Constipation
Nausea
Vomiting
9%
b
63%
53%
20%
6%
b
51%
17%
6%
53%
45%
11%
4%
30%
10%
186
a Reported in ≥5% of study population.
187
b Not statistically significant versus placebo.
188
189
In addition to the adverse reactions listed in Table 2, adverse reactions observed at an
190
incidence of ≥5% in any treatment arm in clinical studies (NUCA3001, NUCA3002,
191
NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills,
192
dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in
193
these studies hyperbilirubinemia was reported at an incidence of ≤0.8%.
194
Selected laboratory abnormalities observed during a clinical study of monotherapy with
195
RETROVIR are shown in Table 3.
196
197
Table 3. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients With
198
Asymptomatic HIV-1 Infection (ACTG 019)
Test
(Abnormal Level)
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
Granulocytopenia (<750 cells/mm3)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>5 x ULN)
AST (>5 x ULN)
1%
2%
0%
3%
1%
<1%
2%
<1%
3%
2%
199
ULN = Upper limit of normal.
200
201
Pediatrics: The clinical adverse reactions reported among adult recipients of
202
RETROVIR may also occur in pediatric patients.
203
Study ACTG300: Selected clinical adverse reactions and physical findings with a
204
≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2
7
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205
3 times daily compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy)
206
pediatric patients are listed in Table 4.
207
208
Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in
209
Pediatric Patients in Study ACTG300
Adverse Reaction
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
Digestive
25%
32%
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
Respiratory
5%
8%
Cough
15%
18%
Abnormal breath sounds/wheezing
Ear, Nose, and Throat
7%
9%
Signs or symptoms of earsa
7%
6%
Nasal discharge or congestion
Other
8%
11%
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
210
a Includes pain, discharge, erythema, or swelling of an ear.
211
212
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of
213
antiretroviral therapy) pediatric patients are listed in Table 5.
214
8
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215
Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric
216
Patients in Study ACTG300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
Anemia (Hgb<7.0 g/dL)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>10 x ULN)
AST (>10 x ULN)
Lipase (>2.5 x ULN)
Total amylase (>2.5 x ULN)
8%
4%
1%
1%
2%
3%
3%
3%
2%
3%
3%
4%
3%
3%
217
ULN = Upper limit of normal.
218
ANC = Absolute neutrophil count.
219
220
Macrocytosis was reported in the majority of pediatric patients receiving RETROVIR
221
180 mg/m2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an
222
incidence of <6% in these studies were congestive heart failure, decreased reflexes, ECG
223
abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
224
Use for the Prevention of Maternal-Fetal Transmission of HIV-1: In a randomized,
225
double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to
226
determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission,
227
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates
228
beginning within 12 hours following birth. The most commonly reported adverse reactions were
229
anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22%
230
of the neonates who received RETROVIR and in 12% of the neonates who received placebo.
231
The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving
232
RETROVIR compared with neonates receiving placebo. No neonates with anemia required
233
transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after
234
completion of therapy with RETROVIR. Neutropenia in neonates was reported with similar
235
frequency in the group that received RETROVIR (21%) and in the group that received placebo
236
(27%). The long-term consequences of in utero and infant exposure to RETROVIR are
237
unknown.
238
6.2
Postmarketing Experience
239
In addition to adverse reactions reported from clinical trials, the following reactions have
240
been identified during postmarketing use of RETROVIR. Because they are reported voluntarily
241
from a population of unknown size, estimates of frequency cannot be made. These reactions have
242
been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or
243
potential causal connection to RETROVIR.
244
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
245
redistribution/accumulation of body fat [see Warnings and Precautions (5.6)].
9
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246
Cardiovascular: Cardiomyopathy, syncope.
247
Endocrine: Gynecomastia.
248
Eye: Macular edema.
249
Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
250
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
251
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia,
252
lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
253
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice,
254
lactic acidosis, pancreatitis.
255
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and
256
myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis,
257
tremor.
258
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania,
259
paresthesia, seizures, somnolence, vertigo.
260
Respiratory: Dyspnea, rhinitis, sinusitis.
261
Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic
262
epidermal necrolysis, sweat, urticaria.
263
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
264
Urogenital: Urinary frequency, urinary hesitancy.
265
7
DRUG INTERACTIONS
266
7.1
Antiretroviral Agents
267
Stavudine: Concomitant use of zidovudine with stavudine should be avoided since an
268
antagonistic relationship has been demonstrated in vitro.
269
Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues
270
affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of
271
RETROVIR against HIV-1; concomitant use of such drugs should be avoided.
272
7.2
Doxorubicin
273
Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic
274
relationship has been demonstrated in vitro.
275
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
276
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow
277
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
278
8
USE IN SPECIFIC POPULATIONS
279
8.1
Pregnancy
280
Pregnancy Category C.
281
In humans, treatment with RETROVIR during pregnancy reduced the rate of
282
maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to
283
7.8% for infants born to mothers treated with RETROVIR [see Clinical Studies (14.3)]. There
284
were no differences in pregnancy-related adverse events between the treatment groups. Animal
10
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285
reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal
286
malformations.
287
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected
288
pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal
289
HIV-1-transmission [see Clinical Studies (14.3)]. Congenital abnormalities occurred with similar
290
frequency between neonates born to mothers who received RETROVIR and neonates born to
291
mothers who received placebo. The observed abnormalities included problems in embryogenesis
292
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of
293
study drug.
294
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of
295
zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times
296
(rabbits) the mean steady-state peak human plasma concentration following a single 100-mg
297
dose of zidovudine. There were no other reported developmental anomalies. In another
298
developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that
299
produced peak plasma concentrations 350 times peak human plasma concentrations (300 times
300
the daily AUC in humans given 600 mg/day zidovudine). This dose was associated with marked
301
maternal toxicity and an increased incidence of fetal malformations. However, there were no
302
signs of teratogenicity at doses up to one fifth the lethal dose [see Nonclinical Toxicology
303
(13.2)].
304
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
305
women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established.
306
Physicians are encouraged to register patients by calling 1-800-258-4263.
307
8.3
Nursing Mothers
308
Zidovudine is excreted in human milk [see Clinical Pharmacology (12.3)].
309
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers
310
in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1
311
infection. Because of both the potential for HIV-1 transmission and the potential for serious
312
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
313
receiving RETROVIR.
314
8.4
Pediatric Use
315
RETROVIR has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who
316
had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values
317
indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in
318
neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.1), Adverse Reactions
319
(6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2), (14.3)].
320
8.5
Geriatric Use
321
Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
322
and over to determine whether they respond differently from younger subjects. Other reported
323
clinical experience has not identified differences in responses between the elderly and younger
324
patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater
11
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325
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
326
drug therapy.
327
8.6
Renal Impairment
328
In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is
329
recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
330
8.7
Hepatic Impairment
331
Zidovudine is eliminated from the body primarily by renal excretion following
332
metabolism in the liver (glucuronidation). Although the data are limited, zidovudine
333
concentrations appear to be increased in patients with severely impaired hepatic function which
334
may increase the risk of hematologic toxicity [see Dosage and Administration (2.5), Clinical
335
Pharmacology (12.3)].
336
10
OVERDOSAGE
337
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These
338
involved exposures up to 50 grams. No specific symptoms or signs have been identified
339
following acute overdosage with zidovudine apart from those listed as adverse events such as
340
fatigue, headache, vomiting, and occasional reports of hematological disturbances. All patients
341
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
342
negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3′
343
azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.
344
11
DESCRIPTION
345
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
346
pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′
347
Structural Formula
12
348
349
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of
350
267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
351
RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg
352
of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline
353
cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
354
RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
355
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline
356
cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
357
edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical
358
shellac, soya lecithin, and titanium dioxide.
359
RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR
360
Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added
361
as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be
362
added to adjust pH.
363
12
CLINICAL PHARMACOLOGY
364
12.1 Mechanism of Action
365
Zidovudine is an antiviral agent [see Clinical Pharmacology (12.4)].
366
12.3 Pharmacokinetics
367
Absorption and Bioavailability: In adults, following oral administration, zidovudine is
368
rapidly absorbed and extensively distributed, with peak serum concentrations occurring within
369
0.5 to 1.5 hours. The extent of absorption (AUC) was equivalent when zidovudine was
370
administered as RETROVIR Tablets or Syrup compared with RETROVIR Capsules. The
371
pharmacokinetic properties of zidovudine in fasting adult patients are summarized in Table 6.
372
373
Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratioa
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)b
0.5 to 3
(n = 19)
374
a Median [range].
375
b Approximate range.
376
377
Distribution: The apparent volume of distribution of zidovudine, following oral
378
administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (Table 6).
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
379
Metabolism and Elimination: Zidovudine is primarily eliminated by hepatic
380
metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater
381
than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and
382
74%, respectively, of the dose following oral administration. A second metabolite, 3′-amino-3′
383
deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous
384
(IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC.
385
Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from
386
2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
387
Effect of Food on Absorption: RETROVIR may be administered with or without food.
388
The extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was
389
administered with food.
390
Special Populations: Renal Impairment: Zidovudine clearance was decreased
391
resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal
392
function (n = 14) following a single 200-mg oral dose (Table 7). Plasma concentrations of AMT
393
were not determined. A dose adjustment should not be necessary for patients with creatinine
394
clearance (CrCl) ≥15 mL/min.
395
396
Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal
397
Impairmenta
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
398
a Data are expressed as mean ± standard deviation.
399
400
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of
401
zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5)
402
or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks.
403
Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma
404
concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in
405
patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a
406
negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
407
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis
408
[see Dosage and Administration (2.4)].
409
Hepatic Impairment: Data describing the effect of hepatic impairment on the
410
pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated
411
primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
412
and plasma concentrations would be increased following administration of the recommended
413
adult doses to patients with hepatic impairment [see Dosage and Administration (2.5)].
414
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in
415
HIV-1-infected pediatric patients (Table 8).
416
Patients 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in
417
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
418
increases in plasma zidovudine concentrations were observed following administration of oral
419
solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral
420
clearance were comparable to adult values. As in adult patients, the major route of elimination
421
was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in
422
the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and
423
Administration (2.1)].
424
Patients <3 Months of Age: Zidovudine pharmacokinetics have been evaluated in
425
pediatric patients from birth to 3 months of life. Zidovudine elimination was determined
426
immediately following birth in 8 neonates who were exposed to zidovudine in utero. The
427
half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body
428
clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose
429
recommendations for neonates [see Dosage and Administration (2.2)].
430
431
Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patientsa
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]b
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
432
a Data presented as mean ± standard deviation except where noted.
433
b Median [range].
434
435
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I study of
436
8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to
437
those of nonpregnant adults. Consistent with passive transmission of the drug across the
438
placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in
439
maternal plasma at delivery [see Use in Specific Populations (8.1)].
440
Although data are limited, methadone maintenance therapy in 5 pregnant women did not
441
appear to alter zidovudine pharmacokinetics.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
442
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
443
HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
444
HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women,
445
the mean concentration of zidovudine was similar in human milk and serum [see Use In Specific
446
Populations (8.3)].
447
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients
448
over 65 years of age.
449
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12)
450
subjects showed no differences in zidovudine exposure (AUC) when a single dose of zidovudine
451
was administered as the 300-mg RETROVIR Tablet.
452
Drug Interactions: [See Drug Interactions (7)].
453
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
454
Table 9. Effect of Coadministered Drugs on Zidovudine AUCa
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED
WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Drug and Dose
Zidovudine
Dose
n
Zidovudine
Concentrations
Concentration
of
Coadministered
Drug
AUC
Variability
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%b
↔
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Lamivudine
300 mg q 12 hr
single 200 mg
12
↑AUC
13%
90% CI:
2% to 27%
↔
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%b
↔
Nelfinavir
750 mg q 8 hr x
7 to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to
170%b
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to
130%b
Not Assessed
455
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration
456
versus time curve; CI = confidence interval.
457
a This table is not all inclusive.
458
b Estimated range of percent difference.
459
460
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients
461
receiving RETROVIR, while in one case a high level was documented. However, in a
462
pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single
463
300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
464
4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally
465
assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine
466
clearance was observed with phenytoin.
467
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine,
468
stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or
469
intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss
470
of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine
471
(n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug
472
regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.4)].
473
12.4 Microbiology
474
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly,
475
zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate
476
(ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT)
477
via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak
478
inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into
479
the DNA of cells in culture.
480
Antiviral Activity: The antiviral activity of zidovudine against HIV-1 was assessed in a
481
number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The
482
EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to
483
9 μM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with
484
resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92
485
baseline samples from COLA40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram
486
Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against
487
different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against HIV-2 isolates from
488
0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates
489
synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and
490
lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and
491
the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with
492
interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell
493
culture.
494
Resistance: Genotypic analyses of the isolates selected in cell culture and recovered
495
from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino
496
acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer
497
zidovudine resistance. In general, higher levels of resistance were associated with greater number
498
of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline,
499
phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and
500
zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of
501
substitutions conferring resistance to zidovudine.
502
Cross-Resistance: In a study of 167 HIV-1-infected patients, isolates (n = 2) with
503
multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
504
recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus
505
zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination
506
therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine
507
monotherapy, with the Q151M substitution being most commonly associated with multi-drug
508
resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116
509
results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine,
510
and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer
511
cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
512
13
NONCLINICAL TOXICOLOGY
513
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
514
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats
515
(60 females and 60 males in each group). Initial single daily doses were 30, 60, and
516
120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced
517
to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats
518
only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on
519
day 279.
520
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing
521
squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in
522
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the
523
vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
524
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell
525
carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or
526
middle dose in rats. No other drug-related tumors were observed in either sex of either species.
527
At doses that produced tumors in mice and rats, the estimated drug exposure (as
528
measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human
529
exposure at the recommended therapeutic dose of 100 mg every 4 hours.
530
It is not known how predictive the results of rodent carcinogenicity studies may be for
531
humans.
532
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in
533
vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human
534
lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was
535
negative in a cytogenetic study in rats given a single dose.
536
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult
537
dose based on body surface area, had no effect on fertility judged by conception rates.
538
Two transplacental carcinogenicity studies were conducted in mice. One study
539
administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10
540
through parturition and lactation with dosing continuing in offspring for 24 months postnatally.
541
The doses of zidovudine administered in this study produced zidovudine exposures
542
approximately 3 times the estimated human exposure at recommended doses. After 24 months,
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
543
an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or
544
lung or any other organ in either gender. These findings are consistent with results of the
545
standard oral carcinogenicity study in mice, as described earlier. A second study administered
546
zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg
547
nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12
548
through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
549
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
550
13.2 Reproductive and Developmental Toxicology Studies
551
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed
552
no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal
553
toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or
554
450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
555
resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
556
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations
557
(after one sixth of the daily dose) achieved with the recommended daily dose (100 mg every
558
4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
559
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a
560
dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused
561
marked maternal toxicity and an increase in the incidence of fetal malformations. This dose
562
resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations.
563
(Estimated area under the curve [AUC] in rats at this dose level was 300 times the daily AUC in
564
humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses
565
of 600 mg/kg/day or less.
566
14
CLINICAL STUDIES
567
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence
568
of opportunistic infections in patients with advanced HIV-1 disease and to delay disease
569
progression in asymptomatic HIV-1-infected patients.
570
14.1 Adults
571
Combination Therapy: RETROVIR in combination with other antiretroviral agents has
572
been shown to be superior to monotherapy for one or more of the following endpoints: delaying
573
death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma
574
HIV-1 RNA.
575
The clinical efficacy of a combination regimen that includes RETROVIR was
576
demonstrated in study ACTG320. This study was a multi-center, randomized, double-blind,
577
placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR® 300 mg/day to
578
RETROVIR plus EPIVIR plus indinavir 800 mg t.i.d. The incidence of AIDS-defining events or
579
death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm
580
(6.1% versus 10.9%, respectively).
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
581
Monotherapy: In controlled studies of treatment-naive patients conducted between 1986
582
and 1989, monotherapy with RETROVIR, as compared with placebo, reduced the risk of HIV-1
583
disease progression, as assessed using endpoints that included the occurrence of HIV-1-related
584
illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease
585
(BW002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts
586
between 200 and 500 cells/mm3 (ACTG016 and ACTG019). A survival benefit for monotherapy
587
with RETROVIR was not demonstrated in the latter 2 studies. Subsequent studies showed that
588
the clinical benefit of monotherapy with RETROVIR was time limited.
589
14.2 Pediatric Patients
590
ACTG300 was a multi-center, randomized, double-blind study that provided for
591
comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of
592
471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these
593
2 treatment arms. The median age was 2.7 years (range 6 weeks to 14 years), the mean baseline
594
CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was
595
5.0 log10 copies/mL. The median duration that patients remained on study was approximately
596
10 months. Results are summarized in Table 10.
597
598
Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease
599
Progression or Death)
EPIVIR plus
RETROVIR
Didanosine
Endpoint
(n = 236)
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
600
601
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
602
The utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission was
603
demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG076) conducted in
604
HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in
605
the treated group: 560 cells/mm3) who had little or no previous exposure to RETROVIR. Oral
606
RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy)
607
followed by IV administration of RETROVIR during labor and delivery. Following birth,
608
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
609
significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture
610
from peripheral blood) between the group receiving RETROVIR and the group receiving
611
placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8%
612
in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
613
transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was
614
no difference in pregnancy-related adverse events between the treatment groups.
615
16
HOW SUPPLIED/STORAGE AND HANDLING
616
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
617
zidovudine, one side engraved “GX CW3” and “300” on the other side.
618
Bottle of 60 (NDC 0173-0501-00).
619
Store at 15° to 25°C (59° to 77°F).
620
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
621
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
622
body.
623
Bottles of 100 (NDC 0173-0108-55).
624
Unit Dose Pack of 100 (NDC 0173-0108-56).
625
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
626
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
627
zidovudine in each teaspoonful (5 mL).
628
Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
629
Store at 15° to 25°C (59° to 77°F).
630
17
PATIENT COUNSELING INFORMATION
631
17.1 Information About Therapy With RETROVIR
632
Neutropenia and Anemia: Patients should be informed that the major toxicities of
633
RETROVIR are neutropenia and/or anemia. The frequency and severity of these toxicities are
634
greater in patients with more advanced disease and in those who initiate therapy later in the
635
course of their infection. Patients should be informed that if toxicity develops, they may require
636
transfusions or drug discontinuation. Patients should be informed of the extreme importance of
637
having their blood counts followed closely while on therapy, especially for patients with
638
advanced symptomatic HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.1)].
639
Myopathy: Patients should be informed that myopathy and myositis with pathological
640
changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of
641
RETROVIR [see Boxed Warning, Warnings and Precautions (5.2)].
642
Lactic Acidosis/Hepatomegaly: Patients should be informed that some HIV medicines,
643
including RETROVIR, can cause a rare, but serious condition called lactic acidosis with liver
644
enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.3)].
645
HIV-1/HCV Co-Infection: Patients with HIV-1/HCV co-infection should be informed
646
that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
647
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
648
ribavirin [see Warnings and Precautions (5.4)].
649
Redistribution/Accumulation of Body Fat: Patients should be informed that
650
redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
651
and that the cause and long-term health effects of these conditions are not known at this time
652
[see Warnings and Precautions (5.6)].
653
Common Adverse Reactions: Patients should be informed that the most commonly
654
reported adverse reactions in adult patients being treated with RETROVIR were headache,
655
malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in
656
pediatric patients receiving RETROVIR were fever, cough, and digestive disorders. Patients also
657
should be encouraged to contact their physician if they experience muscle weakness, shortness of
658
breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being
659
treated with RETROVIR [see Adverse Reactions (6)].
660
Drug Interactions: Patients should be cautioned about the use of other medications,
661
including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of
662
RETROVIR [see Drug Interactions (7)].
663
Pregnancy: Pregnant women considering the use of RETROVIR during pregnancy for
664
prevention of HIV-1 transmission to their infants should be informed that transmission may still
665
occur in some cases despite therapy. The long-term consequences of in utero and infant exposure
666
to RETROVIR are unknown, including the possible risk of cancer [see Use in Specific
667
Populations (8.1)].
668
HIV-1-infected pregnant women should be informed not to breastfeed to avoid postnatal
669
transmission of HIV to a child who may not yet be infected [see Use in Specific Populations
670
(8.3)].
671
Information About Therapy With RETROVIR: RETROVIR is not a cure for HIV-1
672
infection, and patients may continue to acquire illnesses associated with HIV-1 infection,
673
including opportunistic infections. Therefore, patients should be informed to seek medical care
674
for any significant change in their health status.
675
Patients should be informed of the importance of taking RETROVIR exactly as
676
prescribed. They should be informed not to share medication and not to exceed the
677
recommended dose. Patients should be informed that the long-term effects of RETROVIR are
678
unknown at this time.
679
Patients should be informed that therapy with RETROVIR has not been shown to reduce
680
the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
681
682
RETROVIR, COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of
683
GlaxoSmithKline.
684
685
686
687
GlaxoSmithKline
688
Research Triangle Park, NC 27709
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
689
690
©2009, GlaxoSmithKline. All rights reserved.
691
692
November 2009
693
RTT:xPI
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019910s035lbl.pdf', 'application_number': 19910, 'submission_type': 'SUPPL ', 'submission_number': 35}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19931slr008_Aventis_lbl.pdf', 'application_number': 19931, 'submission_type': 'SUPPL ', 'submission_number': 8}
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S
tructural Formula
ADENOCARD® IV
(adenosine injection)
FOR RAPID BOLUS INTRAVENOUS USE
Description
Adenosine is an endogenous nucleoside occurring in all cells of the body. It is chemically 6
amino-9-β-D-ribofuranosyl-9-H-purine and has the following structural formula:
Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol.
Solubility increases by warming and lowering the pH. Adenosine is not chemically related to
other antiarrhythmic drugs. Adenocard® (adenosine injection) is a sterile, nonpyrogenic solution
for rapid bolus intravenous injection. Each mL contains 3 mg adenosine and 9 mg sodium
chloride in Water for Injection. The pH of the solution is between 4.5 and 7.5.
The Ansyr® plastic syringe is molded from a specially formulated polypropylene. Water
permeates from inside the container at an extremely slow rate which will have an insignificant
effect on solution concentration over the expected shelf life.
Solutions in contact with the plastic container may leach out certain chemical components from
the plastic in very small amounts; however, biological testing was supportive of the safety of the
syringe material.
Clinical Pharmacology
Mechanism of Action
Adenocard (adenosine injection) slows conduction time through the A-V node, can interrupt the
reentry pathways through the A-V node, and can restore normal sinus rhythm in patients with
paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-
Parkinson-White Syndrome.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adenocard is antagonized competitively by methylxanthines such as caffeine and theophylline,
and potentiated by blockers of nucleoside transport such as dipyridamole. Adenocard is not
blocked by atropine.
Hemodynamics
The intravenous bolus dose of 6 or 12 mg Adenocard (adenosine injection) usually has no
systemic hemodynamic effects. When larger doses are given by infusion, adenosine decreases
blood pressure by decreasing peripheral resistance.
Pharmacokinetics
Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake,
primarily by erythrocytes and vascular endothelial cells. This process involves a specific
transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally
symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to
adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine
deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine
deaminase, deamination plays a significant role only when cytosolic adenosine saturates the
phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or
can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate
formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool.
While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than
10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine
deaminase. As Adenocard requires no hepatic or renal function for its activation or inactivation,
hepatic and renal failure would not be expected to alter its effectiveness or tolerability.
Clinical Trial Results
In controlled studies in the United States, bolus doses of 3, 6, 9, and 12 mg were studied. A
cumulative 60% of patients with paroxysmal supraventricular tachycardia had converted to
normal sinus rhythm within one minute after an intravenous bolus dose of 6 mg Adenocard (some
converted on 3 mg and failures were given 6 mg), and a cumulative 92% converted after a bolus
dose of 12 mg. Seven to sixteen percent of patients converted after 1-4 placebo bolus injections.
Similar responses were seen in a variety of patient subsets, including those using or not using
digoxin, those with Wolff-Parkinson-White Syndrome, males, females, blacks, Caucasians, and
Hispanics.
Adenosine is not effective in converting rhythms other than PSVT, such as atrial flutter, atrial
fibrillation, or ventricular tachycardia, to normal sinus rhythm.
Indications and Usage
Intravenous Adenocard (adenosine injection) is indicated for the following.
Conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including that
associated with accessory bypass tracts (Wolff-Parkinson-White Syndrome). When clinically
advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver), should be attempted prior to
Adenocard administration.
It is important to be sure the Adenocard solution actually reaches the systemic circulation (see
DOSAGE AND ADMINISTRATION).
Adenocard does not convert atrial flutter, atrial fibrillation, or ventricular tachycardia to normal
sinus rhythm. In the presence of atrial flutter or atrial fibrillation, a transient modest slowing of
ventricular response may occur immediately following Adenocard administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Contraindications
Intravenous Adenocard (adenosine injection) is contraindicated in:
1. Second- or third-degree A-V block (except in patients with a functioning artificial
pacemaker).
2. Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in
patients with a functioning artificial pacemaker).
3. Known hypersensitivity to adenosine.
Warnings
Heart Block
Adenocard (adenosine injection) exerts its effect by decreasing conduction through the A-V node
and may produce a short lasting first-, second- or third-degree heart block. Appropriate therapy
should be instituted as needed. Patients who develop high-level block on one dose of Adenocard
should not be given additional doses. Because of the very short half-life of adenosine, these
effects are generally self-limiting. Appropriate resuscitative measures should be available.
Transient or prolonged episodes of asystole have been reported with fatal outcomes in some
cases. Rarely, ventricular fibrillation has been reported following Adenocard administration,
including both resuscitated and fatal events. In most instances, these cases were associated with
the concomitant use of digoxin and, less frequently with digoxin and verapamil. Although no
causal relationship or drug-drug interaction has been established, Adenocard should be used with
caution in patients receiving digoxin or digoxin and verapamil in combination.
Arrhythmias at Time of Conversion
At the time of conversion to normal sinus rhythm, a variety of new rhythms may appear on the
electrocardiogram. They generally last only a few seconds without intervention, and may take the
form of premature ventricular contractions, atrial premature contractions, atrial fibrillation, sinus
bradycardia, sinus tachycardia, skipped beats, and varying degrees of A-V nodal block. Such
findings were seen in 55% of patients.
Bronchoconstriction
Adenocard (adenosine injection) is a respiratory stimulant (probably through activation of carotid
body chemoreceptors) and intravenous administration in man has been shown to increase minute
ventilation (Ve) and reduce arterial PCO2 causing respiratory alkalosis.
Adenosine administered by inhalation has been reported to cause bronchoconstriction in
asthmatic patients, presumably due to mast cell degranulation and histamine release. These
effects have not been observed in normal subjects. Adenocard has been administered to a limited
number of patients with asthma and mild to moderate exacerbation of their symptoms has been
reported. Respiratory compromise has occurred during adenosine infusion in patients with
obstructive pulmonary disease. Adenocard should be used with caution in patients with
obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis,
etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma).
Adenocard should be discontinued in any patient who develops severe respiratory difficulties.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Precautions
Drug Interactions
Intravenous Adenocard (adenosine injection) has been effectively administered in the presence of
other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel
blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse
reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation
when combined with Adenocard (see WARNINGS). Because of the potential for additive or
synergistic depressant effects on the SA and AV nodes, however, Adenocard should be used with
caution in the presence of these agents. The use of Adenocard in patients receiving digitalis may
be rarely associated with ventricular fibrillation (see WARNINGS).
The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline.
In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine
may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of
adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to
increase the degree of heart block produced by other agents. As the primary effect of adenosine is
to decrease conduction through the A-V node, higher degrees of heart block may be produced in
the presence of carbamazepine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals have not been performed to evaluate the carcinogenic potential of Adenocard
(adenosine injection). Adenosine was negative for genotoxic potential in the Salmonella (Ames
Test) and Mammalian Microsome Assay.
Adenosine, however, like other nucleosides at millimolar concentrations present for several
doubling times of cells in culture, is known to produce a variety of chromosomal alterations.
Fertility studies in animals have not been conducted with adenosine.
Pregnancy Category C
Animal reproduction studies have not been conducted with adenosine; nor have studies been
performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed
throughout the body, no fetal effects would be anticipated. However, since it is not known
whether Adenocard can cause fetal harm when administered to pregnant women, Adenocard
should be used during pregnancy only if clearly needed.
Pediatric Use
No controlled studies have been conducted in pediatric patients to establish the safety and
efficacy of Adenocard for the conversion of paroxysmal supraventricular tachycardia (PSVT).
However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants,
children and adolescents (see DOSAGE AND ADMINISTRATION).
Geriatric Use
Clinical studies of Adenocard did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between elderly and younger patients. In
general, Adenocard in geriatric patients should be used with caution since this population may
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that
may alter hemodynamic function and produce severe bradycardia or AV block.
Adverse Reactions
The following reactions were reported with intravenous Adenocard (adenosine injection) used in
controlled U.S. clinical trials. The placebo group had a less than 1% rate of all of these reactions.
Cardiovascular
Facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (less than
1%).
Respiratory
Shortness of breath/dyspnea (12%), chest pressure (7%), hyperventilation, head pressure (less
than 1%).
Central Nervous System
Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision,
burning sensation, heaviness in arms, neck and back pain (less than 1%).
Gastrointestinal
Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%).
Post Marketing Experience (see WARNINGS)
The following adverse events have been reported from marketing experience with Adenocard.
Because these events are reported voluntarily from a population of uncertain size, are associated
with concomitant diseases and multiple drug therapies and surgical procedures, it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Decisions to include these events in labeling are typically based on one or more of the following
factors: (1) seriousness of the event, (2) frequency of the reporting, (3) strength of causal
connection to the drug, or a combination of these factors.
Cardiovascular
Prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood
pressure, bradycardia, atrial fibrillation, and Torsade de Pointes
Respiratory
Bronchospasm
Central Nervous System
Seizure activity, including tonic clonic (grand mal) seizures, and loss of consciousness.
Overdosage
The half-life of Adenocard (adenosine injection) is less than 10 seconds. Thus, adverse effects are
generally rapidly self-limiting. Treatment of any prolonged adverse effects should be
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
individualized and be directed toward the specific effect. Methylxanthines, such as caffeine and
theophylline, are competitive antagonists of adenosine.
Dosage and Administration
For rapid bolus intravenous use only.
Adenocard (adenosine injection) should be given as a rapid bolus by the peripheral
intravenous route. To be certain the solution reaches the systemic circulation, it should be
administered either directly into a vein or, if given into an IV line, it should be given as close
to the patient as possible and followed by a rapid saline flush.
Adult Patients
The dose recommendation is based on clinical studies with peripheral venous bolus dosing.
Central venous (CVP or other) administration of Adenocard has not been systematically studied.
The recommended intravenous doses for adults are as follows:
Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1-2 second period).
Repeat administration: If the first dose does not result in elimination of the supraventricular
tachycardia within 1-2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12 mg
dose may be repeated a second time if required.
Pediatric Patients
The dosages used in neonates, infants, children and adolescents were equivalent to those
administered to adults on a weight basis.
Pediatric Patients with a Body Weight < 50 kg:
Initial dose: Give 0.05 to 0.1 mg/kg as a rapid IV bolus given either centrally or peripherally. A
saline flush should follow.
Repeat administration: If conversion of PSVT does not occur within 1-2 minutes, additional
bolus injections of adenosine can be administered at incrementally higher doses, increasing the
amount given by 0.05 to 0.1 mg/kg. Follow each bolus with a saline flush. This process should
continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used.
Pediatric Patients with a Body Weight ≥ 50 kg: Administer the adult dose.
Doses greater than 12 mg are not recommended for adult and pediatric patients.
NOTE: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration.
How Supplied
Adenocard® (adenosine injection) is supplied as a sterile non-pyrogenic solution in normal
saline.
NDC 0469-8234-12 Product Code 823412
6 mg/2 mL (3 mg/mL) in 2 mL (fill volume) Ansyr® plastic disposable syringe, in a package of
ten.
NDC 0469-8234-14 Product Code 823414
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12 mg/4 mL (3 mg/mL) in 4 mL (fill volume) Ansyr® plastic disposable syringe, in a package of
ten.
Store at controlled room temperature 15º-30ºC (59º-86ºF).
DO NOT REFRIGERATE as crystallization may occur. If crystallization has occurred, dissolve
crystals by warming to room temperature. The solution must be clear at the time of use.
Contains no preservatives. Discard unused portion.
May require needle or blunt. To prevent needle-stick injuries, needles should not be recapped,
purposely bent or broken by hand.
Rx Only
REFERENCE
1. Paul T, Pfammatter. J-P. Adenosine: an effective and safe antiarrhythmic drug in pediatrics.
Pediatric Cardiology 1997; 18:118-126
Ansyr® is a registered trademark of Hospira, Inc.
Marketed by:
Astellas Pharma US, Inc.
Deerfield, IL 60015-2548
Manufactured by:
Hospira, Inc.
Lake Forest, IL 60045 USA
09E006-ADC-CPI
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019937s024lbl.pdf', 'application_number': 19937, 'submission_type': 'SUPPL ', 'submission_number': 24}
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1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 2
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 3
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 4
NovoPen
3 Demi Instruction Manual
4
5
Dial-A-Dose Insulin Delivery System
6
7
INTRODUCTION
8
9
10
11
12
NovoPen®3 Demi delivers a minimum dose of 1 unit to a maximum dose of 35
13
units of insulin in half unit steps. A raised circle on the push button makes it easy
14
for you to know your NovoPen 3 Demi from the ordinary NovoPen 3. This booklet
15
includes everything you need to know about using the NovoPen 3 Demi. Please
16
read it carefully before using your NovoPen 3 Demi for the first time.
17
18
The NovoPen 3 Demi is designed for use with:
19
! PenFill® 3 mL cartridges.
20
! NovoFine® disposable needles.
21
NovoFine disposable needles are for single-use only.
22
You will also need alcohol swabs.
23
24
If you have any questions about your NovoPen 3 Demi insulin delivery system,
25
please call Novo Nordisk Pharmaceuticals, Inc. at 1-800-727-6500.
26
27
Please complete and return the NovoPen 3 Demi warranty card.
28
29
30
31
See Important Things to Know and Important Notes on pages 33-35.
32
33
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 5
HOW TO USE THIS BOOKLET
35
36
This booklet gives you step-by-step instructions for using the NovoPen 3
37
Demi.
38
39
Begin by reviewing the drawing layout of the parts of the NovoPen 3 Demi,
40
PenFill 3 mL cartridge, and NovoFine disposable needle. The inside front cover
41
opens out so you have a handy reference while you read the rest of the booklet.
42
43
Most pages contain a drawing on the right with numbered instructions to the left
44
of the drawing.
45
Important additional information is given below the drawing.
46
47
We suggest that you read the text and look at the drawing to make sure that
48
you understand each step thoroughly.
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
3
78
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 6
TABLE OF CONTENTS
79
80
SECTION 1:
81
Preparing the NovoPen 3 Demi…………......................................................5
82
83
SECTION 2:
84
Inserting the PenFill 3 mL Cartridge............................................................. 8
85
86
SECTION 3:
87
Attaching the NovoFine Disposable Needle................................................ 12
88
89
SECTION 4:
90
Doing an Air Shot ........................................................................................ 16
91
92
SECTION 5:
93
Giving the Injection ..................................................................................... 20
94
95
SECTION 6:
96
Removing the NovoFine Disposable Needle................................................ 24
97
98
SECTION 7:
99
Removing the PenFill 3 mL Cartridge......................................................... 26
100
101
FUNCTION CHECK ................................................................................... 28
102
103
STORAGE..................................................................................................
31
104
105
MAINTENANCE........................................................................................
32
106
107
IMPORTANT THINGS TO KNOW...........................................................
33
108
109
IMPORTANT NOTES.................................................................................
34
110
111
WHAT TO DO IF......................................................................................
36
112
113
WARRANTY .............................................................................................
37
114
Corrections on this page =
115
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 7
SECTION 1
Preparing the NovoPen 3 Demi
116
117
Remove the device cap:
118
1. Remove the NovoPen 3 Demi from the case.
119
2. Gently twist the pen cap until the cap separates from the barrel.
120
3. Pull the pen cap straight up to remove it.
121
122
123
124
If you use more than one insulin product (such as Novolin® R, Novolin® N,
125
Novolin® 70/30, or NovoLog®), use a separate insulin delivery device for each
126
product.
127
5
128
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 8
SECTION 1 (cont.)
129
130
Separate the cartridge holder from the barrel:
131
132
4. Unscrew and remove the cartridge holder from the barrel.
133
134
135
136
Make sure the dose indicator window shows zero:
137
138
5. Press the push button all the way in until zero (0) appears in the window.
139
The zero should be lined up with the stripe below the dose indicator
140
window.
141
142
143
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 9
6
144
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 10
145
SECTION 1 (cont.)
146
147
The end of the piston rod should be flat against the end of the reset mechanism
148
prior to inserting each new PenFill 3 mL cartridge. It should not be sticking out.
149
150
If the piston rod is sticking out:
151
152
Turn the end of the reset mechanism in a clockwise direction until it is no longer
153
sticking out. Never push the piston rod back in.
154
155
156
157
158
You should never reset the piston rod until it is time to remove the used PenFill 3
159
mL cartridge and insert a new one.
160
161
If the reset mechanism locks, it is usually due to improper technique. Gently turn
162
the mechanism side to side until it unlocks. Then call our toll free number (1-800-
163
727-6500) so that we may go over your technique with you.
164
165
7
166
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NovoPen 3 Demi Final revision
Page 11
SECTION 2
Inserting the PenFill 3 mL Cartridge
167
168
1. To remove the PenFill cartridge from its wrapper, push the cartridge
169
through the foil side of the packaging. Always make sure that the PenFill
170
cartridge you use contains the correct type of insulin (such as Novolin R,
171
Novolin N, Novolin 70/30, or NovoLog). If you are treated with more than
172
one type of insulin in PenFill cartridges, you should use a separate insulin
173
delivery device for each type of insulin. Before use, check that the PenFill
174
cartridge is full and intact. If not, do not use it.
175
176
2-1
177
1
178
2. In the PenFill Information For The Patient leaflet, you will find instructions
179
on how to prepare the insulin if the PenFill contains a suspension insulin
180
(white and cloudy) such as Novolin N or Novolin 70/30.
181
182
-4
183
Each PenFill 3 mL cartridge contains a total of 300 units of insulin. Make sure
184
you are using the correct type of insulin. On the glass part of the cartridge is the
185
name of the insulin.
186
187
Each PenFill cartridge is for single-person use only. DO NOT share the same
188
cartridge with anyone even if you attach a new disposable needle for each
189
injection. Sharing the cartridge can spread disease.
190
Use only a new PenFill 3 mL cartridge when loading the NovoPen 3 Demi.
191
Never load a partially filled cartridge.
192
Never try to refill a used PenFill 3 mL cartridge.
193
194
8
195
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NovoPen 3 Demi Final revision
Page 12
B
196
9
197
SECTION 2 (cont.)
198
199
Insert the PenFill cartridge:
200
201
2. Hold the cartridge holder so the wider opening is up.
202
3. Drop the PenFill cartridge into the cartridge holder, plastic cap first.
203
204
205
A threaded plastic cap surrounds the end of the PenFill® cartridge, like the cap
206
on a bottle. In the center is the front rubber stopper.
207
208
The rear rubber stopper is at the other end of the PenFill cartridge.
209
210
10
211
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NovoPen 3 Demi Final revision
Page 13
SECTION 2 (cont.)
212
213
Re-attach the cartridge holder:
214
215
4. Screw the barrel into the cartridge holder completely until it is tight.
216
217
218
219
220
221
You can see the cartridge in the insulin scale window. The cartridge holder has a
222
scale with marks showing about how much insulin is left in the PenFill cartridge.
223
224
11
225
2
226
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NovoPen 3 Demi Final revision
Page 14
SECTION 3
Attaching the NovoFine® Disposable Needle
227
228
At the end of the cartridge holder are two inspection windows. You can see the
229
cartridge through these windows.
230
231
If you use a suspension insulin (white and cloudy) such as Novolin® N or
232
Novolin® 70/30, use the windows to check if there is enough insulin left for
233
proper mixing. (see below)
234
235
Check the amount of insulin remaining:
236
! If the rear rubber stopper cannot be seen in the inspection window, you have
237
enough insulin for mixing left in the cartridge.
238
! If the rear rubber stopper can be seen in the inspection window, you do not
239
have enough insulin left in the cartridge and must insert a new PenFill 3 mL
240
cartridge.
241
242
See Section 7 for instructions on removing a PenFill cartridge and Section 2 for
243
inserting a new one.
244
245
At least
246
12
247
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NovoPen 3 Demi Final revision
Page 15
12
248
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NovoPen 3 Demi Final revision
Page 16
SECTION 3 (cont.)
249
250
For users of suspension insulin (white and cloudy) such as Novolin N or
251
Novolin 70/30:
252
253
Always remix the insulin before each injection.
254
To remix the insulin, turn the NovoPen 3 Demi up and down between positions A
255
and B 10 times or until the insulin looks uniformly white and cloud
256
257
258
259
260
13
261
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NovoPen 3 Demi Final revision
Page 17
SECTION 3 (cont.)
262
263
1. Wipe the front rubber stopper with an alcohol swab.
264
1
265
266
267
You must wipe the front rubber stopper with an alcohol swab before each
268
injection, even if you are using the same PenFill cartridge.
269
3-3
270
14
271
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NovoPen 3 Demi Final revision
Page 18
SECTION 3 (cont.)
272
273
2. Remove the protective tab from the NovoFine disposable needle.
274
3. Screw the NovoFine disposable needle firmly onto the PenFill 3 mL
275
cartridge until it is tight.
276
2 33
277
278
279
Never place a NovoFine disposable needle on your NovoPen 3 Demi until you
280
are ready to do an air shot and give an injection.
281
If the NovoFine needle is left on, some liquid may leak out of the PenFill
282
cartridge. This may cause a change in the strength of the suspension insulin
283
such as Novolin N or Novolin 70/30.
284
15
285
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NovoPen 3 Demi Final revision
Page 19
286
SECTION 4
Doing an Air Shot
287
288
The PenFill cartridge may contain an air bubble, and small amounts of air may
289
collect in the needle and PenFill cartridge when you use them. To avoid injecting
290
air and to ensure proper dosing, you must perform an air shot before each
291
injection.
292
293
Before doing the air shot, the dose indicator window must show zero (0).
294
295
If you use a suspension insulin, such as Novolin N or Novolin 70/30 and have
296
used the PenFill cartridge for previous injections, make sure there is enough
297
insulin left in the PenFill cartridge to properly mix the insulin (see page 12). If
298
there is enough insulin left in the PenFill cartridge, see the next page for
299
instructions.
300
301
16
302
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NovoPen 3 Demi Final revision
Page 20
SECTION 4 (cont.)
303
304
Set the NovoPen 3 Demi for the air shot:
305
306
1. Turn the dial-a-dose selector to 2 units. Full units are shown as numbers.
307
Half units are shown as long lines between the numbers.
308
1
309
310
4-1
311
If you dial more than 2 units, DO NOT turn the dial back to zero (0). If you
312
do, the extra insulin will squirt out of the needle. You may complete the air shot
313
with the number of units you have dialed or refer to Section 5 on page 21 for
314
instructions on how to reset the dose to zero.
315
17
316
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NovoPen 3 Demi Final revision
Page 21
SECTION 4 (cont.)
317
318
Uncap the NovoFine needle:
319
320
2. Pull off the outer needle cap and set aside.
321
3. Pull off the inner needle cap and discard.
322
2
323
Do not use the needle if it is bent or damaged.
324
325
326
327
4. Hold the NovoPen 3 Demi with the NovoFine needle pointing up.
328
5. Tap the cartridge holder with your finger a few times to raise any air
329
bubbles that may be present to the top of the cartridge.
330
331
332
18-3
333
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NovoPen 3 Demi Final revision
Page 22
SECTION 4 (cont.)
334
335
Do the air shot:
336
337
6. Press the push button all the way in. A drop of insulin should appear at the
338
needle tip.
339
340
If no insulin appears, repeat the following steps, until a drop of insulin
341
appears:
342
343
a. Make sure the NovoFine needle is securely attached.
344
b. Dial 2 units.
345
c. Tap the cartridge holder with your finger.
346
d. Press the push button all the way in.
347
348
There may still be some small air bubble(s) in the PenFill cartridge after this, but
349
they will not affect your dose and they will not be injected.
350
351
352
353
When you press the push button, the piston rod presses against the rear rubber
354
stopper. This moves the rear rubber stopper and pushes the correct amount of
355
insulin up through the needle.
356
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NovoPen 3 Demi Final revision
Page 23
19
357
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NovoPen 3 Demi Final revision
Page 24
SECTION 5
Giving the Injection
358
359
Be sure to do an air shot before giving each injection (see pages 16-19).
360
Select the dose:
361
362
1. Check that the dial-a-dose selector is set to zero. If not, follow the
363
instructions on the next page. Turn the dial-a-dose selector until you see
364
the correct number of units in the dose indicator window. Full units are
365
shown as numbers. Half units are shown as long lines between the
366
numbers.
367
368
1 DO NOT use the clicking sound as a guide for selecting your dose.
369
370
371
4-4
372
The NovoPen 3 Demi can deliver insulin in half unit steps from a minimum dose
373
of 1 unit to a maximum dose of 35 units.
374
375
If you dial more than your dose, DO NOT turn the dial back to zero (0). If you
376
do, the extra insulin will squirt out of the needle. For instructions on how to reset
377
the dose to zero (0) so you can start again, see the next page.
378
379
380
20
381
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NovoPen 3 Demi Final revision
Page 25
SECTION 5 (cont.)
382
383
If you dial a larger dose than you need, pull the barrel and the cartridge holder
384
apart, as shown in the drawing A. While holding them apart, gently press the
385
push button against a hard surface and release your grip B. Your dose indicator
386
window should be back to zero (0).
387
388
You can now dial the correct number of units.
389
390
391
392
21
393
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NovoPen 3 Demi Final revision
Page 26
SECTION 5 (cont.)
394
395
Giving the injection:
396
397
2. After the air shot is done and you have chosen the correct number of
398
units, insert the NovoFine needle in the correct injection site on your body.
399
(Use the injection technique recommended by your health care
400
professional). If you use a suspension insulin such as Novolin N or
401
Novolin 70/30, mix the insulin (see page 13, Section 3) and make sure the
402
insulin looks uniformly white and cloudy before you inject.
403
404
3. Press the push button as far as it will go to deliver the insulin. Do not
405
force it.
406
407
To ensure that all the insulin is injected, keep the NovoFine needle in the skin for
408
several seconds after the injection with your thumb on the push button. Keep the
409
push button fully depressed until after the NovoFine needle has been withdrawn.
410
411
Important: Never turn the dial-a-dose selector to inject the insulin.
412
413
414
415
When you get near the end of a PenFill cartridge, you may need to give yourself
416
two injections to receive your full dose. Check the dose indicator window after
417
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NovoPen 3 Demi Final revision
Page 27
giving an injection. If zero does not appear in the dose indicator window, you did
418
not receive your full dose. See the next page for instructions on how to get the
419
remaining part of your dose.
420
22
421
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NovoPen 3 Demi Final revision
Page 28
422
SECTION 5 (cont.)
423
424
4. Check the dose indicator window to make sure it shows zero (0). If
425
zero does not appear, you did not receive the full dose.
426
427
If the dose indicator window does not show zero, there were not enough units of
428
insulin in the PenFill cartridge for you to receive the full dose. The dose indicator
429
window shows the number of units that you did not receive.
430
431
For example, if you dial 25 units and there are only 20 units left in the PenFill
432
cartridge, after the injection the number in the dose indicator window will be
433
5 (25-20 = 5). If this happens, proceed with the following steps to get the
434
remaining part of your dose:
435
436
437
a. Note the number of units in the dose indicator window.
438
b. Remove the NovoFine needle (see Section 6).
439
c. Remove the empty PenFill 3 mL cartridge (see Section 7).
440
d. Insert a new PenFill 3 mL cartridge (see Section 2).
441
e. Attach a NovoFine needle (see Section 3).
442
f. Do an air shot (see Section 4).
443
g. Dial the number of units noted in step a.
444
h. Give the injection.
445
446
447
4
448
449
23
450
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NovoPen 3 Demi Final revision
Page 29
SECTION 6 Removing the NovoFine Disposable Needle
451
452
Remove the NovoFine disposable needle:
453
454
1. After the injection, remove the needle without replacing the cap.
455
456
2. Hold the cartridge holder firmly while you unscrew the NovoFine
457
disposable needle.
458
459
3. Place the NovoFine disposable needle in a puncture-resistant disposable
460
container.
461
462
Health care professionals, relatives, and other caregivers should also follow the
463
above instructions to eliminate the risk of unintended needle penetration.
464
465
466
467
The NovoFine disposable needle must be removed immediately after each
468
injection without replacing the cap. If the NovoFine disposable needle is not
469
removed, some liquid may leak out of the PenFill cartridge. This may cause a
470
change in the strength of suspension insulins (white and cloudy) such as Novolin
471
N or Novolin 70/30.
472
473
For information on how to throw away needle containers properly, contact your
474
local trash company.
475
24
476
SECTION 6 (cont.)
477
478
Replace the pen cap:
479
480
4. After you remove the disposable needle, hold the pen cap so that the clip
481
is lined up with the dose indicator window.
482
483
5. Gently slide the pen cap onto the barrel.
484
485
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NovoPen 3 Demi Final revision
Page 30
486
4
487
25
488
489
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NovoPen 3 Demi Final revision
Page 31
490
SECTION 7 Removing the PenFill 3 mL Cartridge
491
492
You will need to remove the PenFill cartridge for the following reasons:
493
494
! When tThe PenFill cartridge is empty.
495
496
! If you use a suspension insulin such as Novolin N or Novolin 70/30:
497
498
When you see the rear rubber stopper in the inspection window, then you
499
do not have enough insulin left in the PenFill cartridge for proper mixing.
500
501
Remove the barrel:
502
503
1. Remove the pen cap.
504
505
2. Hold the NovoPen 3 Demi with the dose indicator window at the top.
506
507
3. Unscrew the barrel from the cartridge holder.
508
509
7-1
510
511
26
512
This label may not be the latest approved by FDA.
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NovoPen 3 Demi Final revision
Page 32
SECTION 7 (cont.)
513
514
Remove the PenFill 3 mL cartridge:
515
516
4. Tip the cartridge holder. The PenFill cartridge will drop out.
517
518
5. Press the push button all the way in until zero (0) appears in the window.
519
520
6. Turn the end of the reset mechanism in a clockwise direction until the
521
piston rod is no longer sticking out (refer to figure 1-4 on page 7).
522
523
7. To insert a new PenFill cartridge, please refer to Section 2.
524
525
526
527
If the reset mechanism locks, it is usually due to improper technique. Gently turn
528
the mechanism side to side until it unlocks and then call our toll free number (1-
529
800-727-6500) so that we may go over your technique with you.
530
5
531
27
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 33
FUNCTION CHECK
533
534
You should regularly check the functioning of your NovoPen 3 Demi, (for
535
example, once a month or before starting a new box of PenFill cartridges). The
536
function check is done by delivering 20 units of insulin into the outer needle cap.
537
You will not be injecting insulin into your body.
538
539
Always check the functioning of the NovoPen 3 Demi if you suspect it has been
540
damaged or if you are uncertain that it is delivering the correct dose.
541
542
Do not use NovoPen 3 Demi unless you are sure that it is working properly.
543
Help? Call 1-800-727-6500
544
To perform the function check:
545
546
1. Attach a NovoFine disposable needle(see pages 12-15).
547
548
2. Do an air shot (see pages 16-19).
549
550
28
551
1
552
This label may not be the latest approved by FDA.
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NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 34
553
FUNCTION CHECK (cont.)
554
555
556
3. Do not replace the inner needle cap. Place the outer needle cap
557
securely over the exposed NovoFine needle.
558
559
560
561
562
Expel 20 units of insulin into the outer needle cap:
563
564
4. Turn the dial-a-dose selector so the dose indicator window shows 20.
565
566
567
This label may not be the latest approved by FDA.
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NovoPen 3 Demi Final revision
Page 35
568
29
569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NovoPen 3 Demi Final revision
Page 36
FUNCTION CHECK (cont.)
570
571
5. Hold the NovoPen 3 Demi so the NovoFine disposable needle is pointing
572
down.
573
574
6. Slowly press the push button as far as it will go.
575
576
7. Check the dose indicator window to see if it shows zero (0). If it does not
577
show zero (0), there is not enough insulin in the cartridge to do a function
578
check. Insert a new PenFill cartridge (see pages 8-11) and repeat the
579
function check. If there is enough insulin in the cartridge but the dose
580
indicator window does not show zero, repeat the FUNCTION CHECK. If
581
you do not see zero after repeating the above steps, do not use your
582
NovoPen 3 Demi. Contact Novo Nordisk Pharmaceuticals, Inc. at our tool
583
free number (1-800-727-6500).
584
585
586
The insulin should fill the bottom part of the outer needle cap. This indicates the
587
device is functioning properly.
588
589
If the insulin does not fill or overfills this part of the cap, review the function
590
check procedure. Then repeat the function check with a new NovoFine
591
disposable needle and outer needle cap.
592
593
If the second function check also shows under- or over-filling, do not use your
594
NovoPen 3 Demi.
595
596
DO NOT try to repair a NovoPen 3 Demi that you think is not working
597
properly.
598
599
See Warranty section for further information.
600
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 37
230
601
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 38
-3
602
STORAGE
603
604
Guidelines for storing the NovoPen 3 Demi and PenFill 3 mL cartridges:
605
606
! PenFill cartridges should be stored in a cool place, such as in a
607
refrigerator, but not in thea freezer.
608
609
! After the first use of PenFill cartridge in the NovoPen 3 Demi, the
610
NovoPen 3 Demi (with the PenFill cartridge inside) can be kept at room
611
temperature below 86°F (30°C) for the amount of time days specified
612
listed in the PenFill Information for the Patient leaflet for the type of insulin
613
you are using.
614
615
! Do not store the NovoPen 3 Demi (with the PenFill cartridge inside) in a
616
refrigerator or areas where there may be extreme temperatures or
617
moisture, such as in your car.
618
619
! The expiration date printed on the cartridge is for unused cartridges
620
under refrigeration. Never use the cartridge after the expiration date
621
on the cartridge or its box.
622
623
624
625
! Store the NovoPen 3 Demi without the NovoFine needle attached and
626
with the pen cap in position.
627
628
! For information on storing PenFill cartridges, see the package leaflet that
629
comes in the PenFill cartridge box.
630
631
632
31
633
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 39
MAINTENANCE
634
635
Guidelines for maintaining the NovoPen 3 Demi.
636
637
Be sure to:
638
639
1. Clean it by wiping with a soft cloth moistened with alcohol.
640
641
2. Protect it from dust, dirt, and moisture when not in its case.
642
643
644
Make certain you:
645
646
1. Do not soak it in alcohol, do not wash it in soap and water, or do not
647
lubricate it, since this may cause damage.
648
649
2. Do not expose it to excessive pressure or blows.
650
651
3. Do not drop it.
652
653
32
654
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 40
IMPORTANT THINGS TO KNOW
655
2
656
! The NovoPen 3 Demi is not recommended for the blind or visually
657
impaired, without the assistance of a sighted individual trained to use it.
658
659
! If you use more than one type of insulin (such as Novolin R, Novolin N, or
660
Novolin 70/30, or NovoLog), use a separate insulin delivery device for
661
each type of insulin.
662
663
! Use only a new PenFill 3 mL cartridge when loading the NovoPen 3 Demi
664
Never load the NovoPen 3 Demi with a partially filled PenFill cartridge.
665
666
! Always keep a spare insulin delivery system available, in case your
667
NovoPen 3 Demi is lost or damaged.
668
669
! Keep the NovoPen 3 Demi, PenFill cartridges, and NovoFine needles out
670
of the reach of children. The American Diabetes Association recommends
671
that insulin should be self-administered. The proper age for initiating this
672
should be assessed by the adult caregiver.
673
674
! Keep the NovoPen 3 Demi away from areas where temperatures may get
675
too hot or too cold such as a car or refrigerator.
676
677
! The NovoPen 3 Demi is designed for use with PenFill 3 mL insulin
678
cartridges and NovoFine single-use disposable needles.
679
680
Novo Nordisk is not responsible for any consequences arising from the use of
681
the NovoPen 3 Demi with products other than PenFill 3 mL insulin cartridges
682
and NovoFine single-use disposable needles.
683
684
33
685
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 41
IMPORTANT NOTES
686
687
The following is a review of some important information about the use and
688
care of your NovoPen 3 Demi.
689
690
691
Before each injection, be certain:
692
693
1. The NovoPen 3 Demi contains the correct insulin cartridge (such as
694
Novolin R, Novolin N, Novolin 70/30, or NovoLog), if you use more than
695
one type of insulin.
696
697
2. The PenFill cartridge contains enough insulin for mixing, if you use a
698
suspension insulin (white and cloudy) such as Novolin N or Novolin
699
70/30.
700
701
3. To do an air shot with the NovoFine needle pointing up before each
702
injection.
703
1
704
2 3
705
Be sure to:
706
707
1. Check the dose indicator window after each injection to make sure you
708
have received your full dose (see page 23, Section 5).
709
710
2. Remove the NovoFine needle immediately after each injection without
711
replacing the cap.
712
713
3. Select your dose only by using the number in the dose indicator window.
714
715
4. Perform the function check regularly or if you think your NovoPen 3 Demi
716
is not working properly.
717
1
718
34
719
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 42
IMPORTANT NOTES (cont.)
720
721
Make certain you:
722
723
1. DO NOT place a NovoFine needle on the NovoPen 3 Demi until you are
724
ready to do an air shot and give an injection or do a function check.
725
Remove the needle immediately after each injection without recapping the
726
needle. If the NovoFine needle is not removed, some liquid may leak out
727
of the PenFill cartridge. This may cause a change in the strength of
728
suspension insulin (white and cloudy) such as Novolin N or Novolin
729
70/30.
730
731
2. DO NOT use the clicking sound to set your insulin dose.
732
733
3. DO NOT try to refill a PenFill cartridge.
734
735
4. DO NOT share the same PenFill cartridge with anyone else even if you
736
attach a new NovoFine needle for each injection. Sharing cartridge can
737
spread disease. Each PenFill cartridge is for single-person use only.
738
739
Blood glucose levels should be tested frequently to monitor your insulin regimen.
740
741
Any change in insulin should be made cautiously and only under medical
742
supervision.
743
Corrections on this
744
35
745
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 43
746
WHAT TO DO IF…
747
748
The dose indicator window does not show zero after the injection:
749
750
1. You did not receive your full dose.
751
1
Follow the steps on page 23 to get the remaining part of your dose.
752
753
2 Your NovoPen 3 Demi is malfunctioning.
754
Do not use your NovoPen 3 Demi. Contact Novo Nordisk
755
Pharmaceuticals, Inc. at our tool free number (1-800-727-6500).
756
757
No insulin appears when you do the air shot:
758
759
1. The piston rod is not far enough down the cartridge holder to reach
760
the rear rubber stopper.
761
Repeat the air shot (see pages 16-19).
762
763
2. The NovoFine needle may not be securely attached.
764
a. Put the plastic outer cap back on the NovoFine needle.
765
b. Turn the plastic outer cap in a clockwise direction to tighten the
766
NovoFine needle.
767
768
3. The NovoFine needle may be blocked.
769
Change the NovoFine needle (see pages 14-15) and do an air shot (see
770
pages 16-19).
771
772
The piston rod is sticking out too far to attach the cartridge holder to the
773
barrel:
774
775
You must screw the piston rod back into the barrel (see page 7). Never
776
try to push it in or you can damage the mechanism.
777
1
778
The push button will not return to zero or the piston rod will not turn back
779
into the reset mechanism:
780
781
The return mechanism may be locked. This is usually due to improper
782
technique. Gently turn the mechanism side to side until it unlocks and then
783
call our toll free number (1-800-727-6500) so that we may review go over
784
your technique with you.
785
786
36
787
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 44
WARRANTY
788
789
Should your NovoPen® 3 Demi device be defective in materials or
790
workmanship within two (2) years of purchase, Novo Nordisk
791
Pharmaceuticals, Inc. will replace it at no charge if you mail the defective
792
unit along with a description of the problem and the sales receipt or other
793
proof of purchase to:
794
795
Novo Nordisk Pharmaceuticals, Inc.
796
Product Safety
797
100 College Road West
798
Princeton, NJ 08540
799
800
Protected by U.S. Patent Nos. 5,693,027; 5,626,566; 6,126,646 and Des.
801
347,894 (cartridge) restricted to use with Novo Nordisk insulin cartridges and
802
Novo Nordisk pen needles.
803
804
No other warranty is made with respect to NovoPen® 3 Demi. This warranty will
805
be invalid and Novo Nordisk A/S, Novo Nordisk Pharmaceuticals, Inc., Bristol-
806
Myers Squibb Co., Nipro Medical Industries Ltd., and Bang & Olufsen A/S cannot
807
be held responsible in the case of defects or damages arising from:
808
809
! The use of the NovoPen® 3 Demi with products other than PenFill 3 mL
810
cartridges and NovoFine single-use disposable needles.
811
812
! The use of the NovoPen® 3 Demi not in accordance with the instructions
813
in this booklet.
814
815
! Physical damage to the NovoPen® 3 Demi caused by neglect, misuse,
816
unauthorized repair, accident, or other breakage.
817
37
818
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen 3 Demi Final revision
Page 45
For assistance or further information, write to:
819
820
Novo Nordisk Pharmaceuticals, Inc.
821
Customer Relations
822
100 College Road West
823
Princeton, NJ 08540
824
825
Or call: 1-800-727-6500
826
827
828
Novo Nordisk®, NovoPen®, Novolin®, NovoLog®, PenFill® and NovoFine® are
829
registered trademarks of Novo Nordisk A/S
830
831
© 2002 Novo Nordisk A/S
832
833
Novo Nordisk Pharmaceuticals, Inc.
834
Princeton, NJ 08540
835
836
http://www.novonordisk-us.com
837
838
8-4241-31-002-1
839
840
Corrections on this page =
841
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
4/15/02 10:14:06 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:19.870131
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19938s33lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 33}
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NDA 19-938/S-048
Page 1
Novolin® R
Regular,
Human Insulin Injection
(recombinant DNA origin) USP
100 units/mL
DESCRIPTION
Novolin® R Regular, Human Insulin Injection (rDNA origin) USP is a polypeptide hormone
structurally identical to natural human insulin and is produced by rDNA technology, utilizing
Saccharomyces cerevisiae (bakers’ yeast) as the production organism. Human insulin has the
empirical formula C257H383N65O77S6 and a molecular weight of 5808 Da.
Figure 1. Structural formula of human insulin
Novolin R is a sterile, clear, aqueous, and colorless solution, that contains human insulin (rDNA
origin) 100 units/mL, glycerin 16 mg/ml, metacresol 3 mg/mL and zinc chloride approximately 7
µg/mL. The pH is adjusted to 7.4. Hydrochloric acid 2N and/or sodium hydroxide 2N may be
added to adjust pH.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-048
Page 2
CLINICAL PHARMACOLOGY
Insulin is a polypeptide hormone that controls the storage and metabolism of carbohydrates,
proteins, and fats. This activity occurs primarily in the liver, in muscle, and in adipose tissues
after binding of the insulin molecules to receptor sites on cellular plasma membranes.
Insulin promotes uptake of carbohydrates, proteins, and fats in most tissues. Also, insulin
influences carbohydrate, protein, and fat metabolism by stimulating protein and free fatty acid
synthesis, and by inhibiting release of free fatty acid from adipose cells. Insulin increases active
glucose transport through muscle and adipose cellular membranes, and promotes conversion of
intracellular glucose and free fatty acid to the appropriate storage forms (glycogen and
triglyceride, respectively). Although the liver does not require active glucose transport, insulin
increases hepatic glucose conversion to glycogen and suppresses hepatic glucose output. Even
though the actions of exogenous insulin are identical to those of endogenous insulin, the ability
to negatively affect hepatic glucose output differs on a unit per unit basis because a smaller
quantity of an exogenous insulin dose reaches the portal vein.
Administered insulin, including Novolin R, substitutes for inadequate endogenous insulin
secretion and partially corrects the disordered metabolism and inappropriate hyperglycemia of
diabetes mellitus, which are caused by either a deficiency or a reduction in the biologic
effectiveness of insulin. When administered in appropriate doses at prescribed intervals to
patients with diabetes mellitus, Novolin R temporarily restores their ability to metabolize
carbohydrates, proteins and fats.
Novolin R is a sterile, aqueous, and colorless solution of human insulin with a short duration of
action. The pharmacologic effect of Novolin R begins approximately one-half (½) hour after
subcutaneous administration. The effect is maximal between 2½ and 5 hours and terminates
after approximately 8 hours. The onset of action of intravenous insulin is more rapid.
INDICATIONS AND USAGE
Novolin R is indicated for subcutaneous administration for the treatment of patients with
diabetes mellitus, for the control of hyperglycemia. Treatment with Novolin R is as an adjunct to
diet and exercise for lowering blood glucose in patients with Type 1 diabetes or in patients with
Type 2 diabetes for whom oral antidiabetic therapy is inadequate.
Novolin R may be administered intravenously under proper medical supervision in a clinical
setting for glycemic control. (See DOSAGE AND ADMINISTRATION and
RECOMMENDED STORAGE.)
CONTRAINDICATIONS
Insulin is contraindicated during episodes of hypoglycemia and in patients hypersensitive to
Novolin R or one of its excipients.
WARNING
Any change of insulin dose should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, etc.), species
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-048
Page 3
(animal, human), or method of manufacture (rDNA versus animal-source insulin) may
result in the need for a change in dosage.
Special care should be taken when the transfer is from a standard beef or mixed species
insulin to a purified pork or human insulin. If a dosage adjustment is needed, it will
usually become apparent either in the first few days or over a period of several weeks. Any
change in treatment should be carefully monitored.
PRECAUTIONS
General
Hypoglycemia, hypokalemia, lipodystrophy and hypersensitivity are among the potential clinical
adverse effects associated with the use of all insulins.
As with all insulin preparations, the time course of Novolin R action may vary in different
individuals or at different times in the same individual and is dependent on dose, site of injection,
blood supply, temperature, and physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity
or their usual meal plan. Insulin requirements may be altered during illness, emotional
disturbances, or other stresses.
Novolin R should only be used if it is clear and colorless. Due to the risk of precipitation in
some pump catheters, Novolin R is not recommended for use in insulin pumps.
Hypoglycemia and hypokalemia - As with all insulin preparations, hypoglycemic and
hypokalemic reactions may be associated with the administration of Novolin R, particularly via
the IV route. Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in
persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as long
duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or
intensified diabetes control (see PRECAUTIONS, Drug Interactions). Such situations may result
in severe hypoglycemia (and, possibly, loss of consciousness) prior to patients’ awareness of
hypoglycemia. Severe hypoglycemia can result in temporary or permanent impairment of brain
function and death. Insulin stimulates potassium movement into the cells, possibly leading to
hypokalemia that left untreated may cause respiratory paralysis, ventricular arrhythmia, and
death. Since intravenously administered insulin has a rapid onset of action, increased attention to
hypoglycemia and hypokalemia is necessary. Therefore, glucose and potassium levels must be
monitored closely when NovoLog or any other insulin is administered intravenously.
In certain cases, the nature and intensity of the warning symptoms of hypoglycemia may change.
A few patients have reported that after being transferred to human insulin, the early warning
symptoms for hypoglycemia had been less pronounced than they were with animal-source
insulin.
Hyperglycemia and ketosis – Hyperglycemia, diabetic ketoacidosis, or diabetic coma may
develop if the patient takes less Novolin R than needed to control blood glucose levels. This
could be due to insulin demand during illness or infection, neglect of diet, omission or improper
administration of prescribed insulin doses. A developing ketoacidosis will be revealed by urine
tests which show large amounts of sugar and acetone. The symptoms of polydipsia, polyurea,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-048
Page 4
loss of appetite, fatigue, dry skin and deep and rapid breathing come on gradually, usually over a
period of some hours or days. Severe sustained hyperglycemia may result in diabetic coma or
death.
Renal Impairment - As with other insulins, the dose requirements for Novolin R may be reduced
in patients with renal impairment.
Hepatic Impairment - As with other insulins, the dose requirements for Novolin R may be
reduced in patients with hepatic impairment.
Allergy - Local Allergy - As with other insulin therapy, patients may experience redness,
swelling, or itching at the site of injection. These minor reactions usually resolve in a few days
to a few weeks, but in some occasions, may require discontinuation of Novolin R. In some
instances, these reactions may be related to factors other than insulin, such as irritants in a skin
cleansing agent or poor injection technique.
Systemic Allergy - Less common, but potentially more serious, is generalized allergy to insulin,
which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing,
reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy,
including anaphylactic reaction, may be life threatening.
Localized reactions and generalized myalgias have been reported with the use of cresol as an
injectable excipient.
Usage in Pregnancy
It is particularly important for patients to maintain good control of diabetes during pregnancy and
special attention must be paid to diet, exercise and insulin regimens. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant.
Information for Patients
Patients should be informed about potential risks and advantages of Novolin R therapy including
the possible side effects. Patients should also be offered continued education and advice on
insulin therapies, injection technique, life-style management, regular glucose monitoring,
periodic glycosylated hemoglobin testing, recognition and management of hypo- and
hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose,
instruction in the use of injection devices, and proper storage of insulin. Patients should be
informed that frequent, patient performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia. Female patients should be
advised to tell their physician if they intend to become, or if they become pregnant.
Laboratory Tests
As with all insulin therapy, the therapeutic response to Novolin R should be monitored by
periodic blood glucose tests. Periodic measurement of glycosylated hemoglobin is
recommended for the monitoring of long-term glycemic control. Urine ketones should be
monitored frequently.
When Novolin R is administered intravenously, glucose and potassium levels must be closely
monitored to avoid potentially fatal hypoglycemia and hypokalemia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-048
Page 5
Drug Interactions
A number of substances affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
• The following are examples of substances that may reduce insulin requirement: oral
hypoglycemic agents (OHA), octreotide, monoamine oxidase inhibitors (MAOI), non-
selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates,
alcohol, sulphonamide antibiotics, anabolic steroids, quinine, quinidine and alpha-adrenergic
blocking agents.
• The following are examples of substances that may increase insulin requirement: oral
contraceptives, thiazides, glucocorticoids, thryroid hormones and sympathomimetics, growth
hormone, diazoxide, asparaginase and nicotinic acid.
• Beta-blocking agents may mask the symptoms of hypoglycemia and delay recovery from
hypoglycemia.
• Alcohol may intensify and prolong the hypoglycemic effect of insulin.
Mixing of Insulins
• Novolin R should only be mixed as directed by the physician.
• Novolin R is a short-acting insulin and is often used in combination with intermediate- or
long-acting insulins.
• The order of mixing and brand or model of syringe should be specified by the physician. A
U-100 insulin syringe should always be used. Failure to use the correct syringe can lead to
dosage errors.
• In general, when a longer-acting insulin (e.g. NPH insulin isophane suspensions) is mixed
with short-acting soluble insulin (e.g., regular), the short-acting insulin should be drawn into
the syringe first.
ADVERSE REACTIONS
Adverse events commonly associated with human insulin therapy include the following:
Body as Whole - Allergic reactions (see PRECAUTIONS, Allergy).
Skin and Appendages - Injection site reaction, lipodystrophy, pruritus, rash (see
PRECAUTIONS, Allergy).
Other – Hypoglycemia, Hyperglycemia and ketosis (see PRECAUTIONS).
OVERDOSAGE
Excess insulin may cause hypoglycemia and hypokalemia, particularly after IV administration.
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy
expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose.
Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes
with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous
glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation
may be necessary because hypoglycemia may recur after apparent clinical recovery.
Hypokalemia must be corrected appropriately.
DOSAGE AND ADMINISTRATION
Novolin R, when used alone subcutaneously, is usually given three or more times daily before
meals. The dosage and timing of Novolin R should be individualized and determined, base on
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-048
Page 6
the physician’s advice, in accordance with the needs of the patient. Novolin R may also be used
in combination with oral antidiabetic agents or longer-acting insulin products to suit the needs of
the individual patients. The injection of Novolin R should be followed by a meal within
approximately 30 minutes of administration.
The average range of total daily insulin requirement for maintenance therapy in insulin-treated
patients lies between 0.5 and 1.0 IU/kg. However, in pre-pubertal children it usually varies from
0.7 to 1.0 IU/kg, but can be much lower during the period of partial remission. In severe insulin
resistance, e.g. during puberty or due to obesity, the daily insulin requirement may be
substantially higher. Initial dosages for Type 2 diabetes patients are often lower, e.g. 0.2 to 0.4
IU/kg/day.
Novolin R should be administered by subcutaneous injection in the abdominal wall, the thigh,
the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall ensures a
faster absorption than from other injection sites. Injection into a lifted skin fold minimizes the
risk of intramuscular injection. Injection sites should be rotated within the same region. As with
all insulins, the duration of action will vary according to the dose, injection site, blood flow,
temperature, and level of physical activity.
Intramuscular and intravenous administrations of Novolin R are possible under medical
supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia
and hypokalemia.
For intravenous use, Novolin R should be used at concentrations from 0.05 U/mL to 1.0 U/mL in
infusion systems with the infusion fluids 0.9% sodium chloride, 5% dextrose, or 10% dextrose
with 40 mmol/l potassium chloride using polypropylene infusion bags.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Never use Novolin R if it has
become viscous (thickened) or cloudy; use it only if it is clear and colorless. Novolin R should
not be used after the printed expiration date.
RECOMMENDED STORAGE
Novolin R vials, Novolin® R PenFill® cartridges, and Novolin® R InnoLet® prefilled insulin
syringes should be stored in a cold (36° - 46°F [2° - 8°C]) place, preferably in a refrigerator, but
not in the freezer. Do not freeze. Keep Novolin R vials, Novolin R PenFill cartridges and
Novolin R InnoLet in their cartons so that they will stay clean and protected from light. They
should not be exposed to heat or sunlight. A Novolin R vial in use can be kept unrefrigerated as
long as it is kept as cool as possible and away from heat or sunlight. A Novolin R PenFill
cartridge and Novolin R InnoLet in use should not be refrigerated but should be kept as cool as
possible (below 86°F [30°C]) and away from direct heat and light. Unrefrigerated Novolin R
PenFill cartridges and Novolin R InnoLet must be discarded 28 days after the first use, even if
they still contain Novolin R insulin.
Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION are stable at
room temperature for 24 hours. A certain amount of insulin will be initially adsorbed to the
material of the infusion bag.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-938/S-048
Page 7
Never use insulin after the expiration date which is printed on the label and carton.
HOW SUPPLIED
Novolin R, Regular, Human Insulin Injection (rDNA origin) USP, 100 units/mL, is supplied as
follows:
10 mL vial
NDC 0169-1833-11
3 mL PenFill cartridges*
NDC 0169-3473-18
3 mL Novolin R InnoLet
NDC 0169-2313-21
*Novolin R PenFill 3 mL cartridges are designed for use with Novo Nordisk 3 mL PenFill
cartridge compatible insulin delivery devices, the NovoPen® 3 PenMate® and with NovoFine®
disposable needles.
Date of issue:
8-XXXX-XX-XXX-X
For information contact:
Novo Nordisk Inc., Princeton, NJ 08540
1-800-727-6500
www.novonordisk-us.com
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
Novo Nordisk®, Lente®, Novolin®, PenFill®, InnoLet®, NovoPen®, PenMate® and NovoFine®
are trademarks owned by Novo Nordisk A/S.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019938s048lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 48}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Novolin
R safely and effectively. See full prescribing information for Novolin R.
Novolin® R (Regular, Human Insulin [rDNA origin] USP) solution for
subcutaneous or intravenous use
Initial U.S. Approval: 1991
--------------------RECENT MAJOR CHANGES-------------------
Warnings and Precautions (5.9) 3/2013
----------------------------INDICATIONS AND USAGE---------------------------
Novolin R is a short-acting recombinant human insulin indicated to improve
glycemic control in adults and children with diabetes mellitus (1).
----------------------DOSAGE AND ADMINISTRATION-----------------------
The dosage and timing of Novolin R must be individualized (2.1).
Subcutaneous injection: Administer approximately 30 minutes prior to
the start of a meal (2.2).
Intravenous use: Use at concentrations from 0.05 to 1.0 Unit/mL in
infusion systems using polypropylene infusion bags. Novolin R is stable
in 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L
potassium chloride (2.3).
Use in pumps: Not recommended due to risk of precipitation (2.4).
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Novolin R, Regular, Human Insulin Injection (rDNA origin) USP, 100
units/mL (U-100), is supplied in 10 mL vials (3).
-------------------------------CONTRAINDICATIONS------------------------------
Do not use during episodes of hypoglycemia (4).
Do not use in patients with hypersensitivity to Novolin R or one of its
excipients (4).
-----------------------WARNINGS AND PRECAUTIONS------------------------
Hypoglycemia: Most common adverse reaction of insulin therapy and
may be life-threatening. Closely monitor blood glucose. Changes in
insulin or dosage should be made cautiously and only under medical
supervision (5.2).
Hypokalemia: Particularly when insulin is given intravenously or in
settings of poor glycemic control. Use caution in patients predisposed to
hypokalemia (5.3).
Renal or hepatic impairment: As with other insulins, the dose
requirements for Novolin R may be reduced (5.5).
Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, may occur (5.6).
Mixing: Do not mix Novolin R with any insulin for intravenous use. Do
not mix with insulins other than NPH insulin for subcutaneous use (5.7).
Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and
insulin, including Novolin R (5.9).
------------------------------ADVERSE REACTIONS-------------------------------
Adverse reactions observed with Novolin R include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, weight gain and edema (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Certain medications affect glucose metabolism and may require insulin
dose adjustment and close monitoring (7).
The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic medications (e.g., beta-blockers, clonidine, guanethidine,
and reserpine) (7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 3/2013
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Intravenous Use
2.4 Use in Insulin Pumps
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar
Hyperglycemic Non-Ketotic Syndrome
5.5 Renal or Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Mixing of Insulins
5.8 Antibody Production
5.9 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Type 1 diabetes mellitus (adults)
14.2 Type 2 diabetes mellitus (adults)
14.3 Type 1 diabetes mellitus (children and adolescents)
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for All Patients
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3273161
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
Novolin R is indicated to improve glycemic control in adults and children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
The dosage and timing of Novolin R must be individualized. Blood glucose monitoring is
essential for all patients receiving insulin therapy.
Total daily insulin requirements vary and are usually between 0.5 and 1.0 units/kg/day. Insulin
requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or
coadministered medications.
2.2
Subcutaneous Injection
Novolin R should generally be injected approximately 30 minutes prior to the start of a meal.
Novolin R given by subcutaneous injection should generally be used in regimens that include an
intermediate or long-acting insulin [see How Supplied/Storage and Handling (16.1, 16.2)].
Novolin R should be administered by subcutaneous injection in the abdominal region, buttocks,
thigh, or the upper arm. Subcutaneous injection into the abdominal wall is generally associated with
faster absorption than other injection sites. Injection sites should be rotated within the same region to
reduce the risk of lipodystrophy. Injection into a lifted skin fold minimizes the risk of intramuscular
injection.
2.3
Intravenous Use
Novolin R can be administered intravenously under medical supervision for glycemic control,
with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5.2, 5.3), How Supplied/Storage and Handling (16.1,
16.2)].
Intravenous administration of insulin is commonly used in the treatment of diabetic ketoacidosis,
peri-operative management of diabetes, and maintenance of glycemic control during labor in pregnant
diabetic women. For intravenous use, Novolin R should be used at concentrations from 0.05 units/mL to
1.0 unit/mL in infusion systems using polypropylene infusion bags. Novolin R can be used with the
following infusion fluids: 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L
potassium chloride.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Never use Novolin R if it has become
viscous or cloudy; use Novolin R only if it is clear and colorless. Vials should not be used if leakage is
observed. Novolin R should not be used after the printed expiration date.
The onset of action of Novolin R, when administered intravenously, is more rapid in comparison
to subcutaneous administration.
Reference ID: 3273161
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2.4
Use in Insulin Pumps
Use of Novolin R in insulin pumps is not recommended because of the risk of precipitation.
3
DOSAGE FORMS AND STRENGTHS
Novolin R is available in 10 mL vials. The concentration of Novolin R is 100 USP units of human
insulin (rDNA origin)/mL.
4
CONTRAINDICATIONS
Novolin R is contraindicated:
During episodes of hypoglycemia
In patients with hypersensitivity to Novolin R or one of its excipients
5
WARNINGS AND PRECAUTIONS
5.1
Administration
Subcutaneous injection of Novolin R should be followed by a meal. Patients should wait
approximately 30 minutes after injection before starting the meal [see Dosage and Administration (2.2)].
Any change of insulin dose should be made cautiously and only under medical supervision.
Changing from one insulin product to another or changing the insulin strength may result in the need for
a change in dosage. As with all insulin preparations, the time course of Novolin R action may vary in
different individuals or at different times in the same individual and is dependent on many conditions,
including dosage, the site of injection, local blood supply, temperature, and physical activity. Patients
who change their level of physical activity or meal plan may require adjustment of insulin dosages.
Insulin requirements may be altered during illness, emotional disturbances, or other stresses.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse reaction of all insulin therapies, including Novolin
R. Severe hypoglycemia may lead to unconsciousness, convulsions, temporary or permanent
impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person,
parenteral glucose infusion, and glucagon administration has been observed in clinical trials with
nsulin, including trials with Novolin R.
i
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations [see Clinical Pharmacology (12.2, 12.3)]. Other factors such as changes in food intake
(e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also
alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all insulins, use caution in patients
with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., patients
who are fasting or have erratic food intake, pediatric patients, and the elderly). The patient’s ability to
concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations
where these abilities are especially important, such as driving or operating other machinery.
Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in
patients with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may
be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic
neuropathy, use of medications such as beta-blockers, or intensified glycemic control [see Drug
Interactions (7)]. These situations may result in severe hypoglycemia (and, possibly, loss of
consciousness) prior to the patient’s awareness of hypoglycemia. Intravenously administered insulin has
Reference ID: 3273161
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a more rapid onset of action than subcutaneously administered insulin, requiring more close monitoring
for hypoglycemia.
5.3
Hypokalemia
All insulins, including Novolin R, cause a shift in potassium from the extracellular to
intracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratory
paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia
(e.g., patients using potassium-lowering medications and patients taking medications sensitive to serum
potassium concentrations). Monitor glucose and potassium frequently when Novolin R is administered
intravenously.
5.4
Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Non-Ketotic
Syndrome
Hyperglycemia, diabetic ketoacidosis, or hyperosmolar hyperglycemic non-ketotic syndrome
may develop in patients who take less insulin than needed to control blood glucose. These conditions
can be precipitated by illness, infection, dietary indiscretion, or omission or improper administration of
the prescribed insulin dose.
5.5
Renal or Hepatic Impairment
As with other insulins, the dose requirements for Novolin R may be reduced in patients with
renal or hepatic impairment.
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulins, patients may experience redness, swelling, or itching at
the site of injection of Novolin R. These reactions usually resolve in a few days to a few weeks, but in
some occasions, may require discontinuation of Novolin R. In some instances, these reactions may be
related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection
technique. Localized reactions and generalized myalgias have been reported with the use of meta-
cresol, which is an excipient in Novolin R.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis may
occur with any insulin, including Novolin R. Generalized allergy to insulin may manifest as a whole
body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
5.7
Mixing of Insulins
If Novolin R is mixed with NPH human insulin, Novolin R should be drawn into the syringe first
and the mixture should be injected immediately after mixing. Insulin mixtures should not be
administered intravenously.
5.8
Antibody Production
Increases in titers of anti-insulin antibodies that react with human insulin have been observed in
patients treated with Novolin R. Data from a 12-month controlled trial in patients with type 1 diabetes
suggest that the increase in these antibodies is transient. The clinical significance of these antibodies is
not known but does not appear to cause deterioration in glycemic control or necessitate increases in
insulin dose.
Reference ID: 3273161
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5.9 Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-
gamma agonists, can cause dose-related fluid retention, particularly when used in combination with
insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including
NOVOLIN R, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure.
If heart failure develops, it should be managed according to current standards of care, and
discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
Novolin R [see Warnings and Precautions (5.2)].
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a transitory,
reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful
peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of
diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including Novolin R, can cause lipodystrophy at the site of repeated
insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and
lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection
sites within the same region to reduce the risk of lipodystrophy.
Weight gain
Weight gain can occur with insulin therapies, including Novolin R, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria.
Peripheral edema
Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is
improved by intensified insulin therapy. These symptoms are usually transitory.
Allergic reactions
As with other insulins, Novolin R can cause injection site reactions. Severe, life-threatening,
generalized allergy, including anaphylaxis may occur with any insulin, including Novolin R [see
Warnings and Precautions (5.6)].
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates
reported in one clinical trial may not be easily compared to those rates reported in another clinical trial,
and may not reflect the rates actually observed in clinical practice.
Adults with type 1 or type 2 diabetes
Reference ID: 3273161
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The incidence of adverse reactions during clinical trials comparing Novolin R and insulin aspart
in adults with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Adults with Type 1 Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an
incidence ≥ 5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 286
Insulin aspart + NPH
N=596
%
%
Hypoglycemia*
72
75
* Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms.
Table 2: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Adults with Type 2 Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an
incidence ≥ 5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 91
Insulin aspart + NPH
N= 91
(%)
(%)
Hypoglycemia*
36
27
*Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms.
Children and adolescents with type 1 diabetes
The incidence of adverse reactions during a 24-week clinical trial comparing Novolin R and
insulin aspart in children and adolescents with type 1 diabetes mellitus are listed in the table below.
Table 3: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Children and Adolescents with Type 1 Diabetes Mellitus Also Treated with NPH Insulin (adverse
reactions with an incidence ≥5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 96
Insulin aspart + NPH
N= 187
(%)
(%)
Hypoglycemia*
85
79
Injection site hypertrophy
8
8
*Hypoglycemia was defined as an episode of blood glucose concentration <50 mg/dL, with or without symptoms.
Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including Novolin R [See Warnings and Precautions (5.3)]. Tables 4 and 5 summarize the incidence of
severe hypoglycemia in the Novolin R clinical trials. Severe hypoglycemia was defined as
hypoglycemia associated with central nervous system symptoms and requiring intervention of another
person or hospitalization. The rates of severe hypoglycemia in the Novolin R clinical trials (see Section
14 for a description of the study designs) were comparable for all treatment regimens (see Tables 4 and
5).
Table 4: Severe Hypoglycemia in Patients with Type 1 Diabetes
Reference ID: 3273161
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Type 1 Diabetes
Adults
24 weeks in combination
with NPH insulin
Type 1 Diabetes
Children and Adolescents
(age 6-18)
24 weeks in combination
with NPH insulin
Type 1 Diabetes
Children
(age 2-6)
24 weeks in combination
with NPH insulin
Novolin R
Insulin
aspart
Novolin R
Insulin
aspart
Novolin R
Insulin
aspart
Percent of patients
(n/total N)
19
(55/286)
18
(105/596)
9
(9/96)
6
(11/187)
12
(3/25)
8
(2/26)
Event/patient/
year
1.1
0.9
0.3
0.2
0.5
0.3
Table 5: Severe Hypoglycemia in Patients with Type 2 Diabetes
Type 2 Diabetes
Adults
24 weeks in combination with
NPH insulin
Novolin R
Insulin aspart
Percent of patients
(n/total N)
5
(5/91)
10
(9/91)
Event/patient/
year
0.2
0.3
7
DRUG INTERACTIONS
A number of medications affect glucose metabolism that may require insulin dose adjustment
and particularly close monitoring for hypoglycemia or worsening glycemic control.
The following are examples of medications that may increase the blood glucose-lowering effect
of insulin and increase susceptibility to hypoglycemia: oral antidiabetic medications, pramlintide
acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine,
monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analogs (e.g.,
octreotide), and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood glucose-lowering effect of
insulin, leading to worsening of glycemic control: corticosteroids, niacin, danazol, diuretics,
sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine
derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
and atypical antipsychotics.
Beta-blockers, clonidine, and lithium salts may either potentiate or weaken the blood glucose-
lowering effect of insulin.
Alcohol can increase susceptibility to hypoglycemia.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
medications such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
Reference ID: 3273161
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8.1
Pregnancy
Pregnancy Category B: All pregnancies have a background risk of birth defects, loss, or other
adverse outcome regardless of drug exposure. This background risk is increased in pregnancies
complicated by hyperglycemia and may be decreased with good glycemic control. It is essential for
patients with diabetes or a history of gestational diabetes to maintain good glycemic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful
monitoring of glucose control is important during pregnancy in patients with diabetes. Therefore,
women should be advised to tell their healthcare provider if they intend to become, or if they become,
pregnant while taking Novolin R.
No reproductive toxicity studies have been performed with Novolin R.
8.3
Nursing Mothers
It is unknown whether Novolin R is excreted in breast milk. Small amounts of human insulin are
secreted into breast milk, the significance of which is not known. Use of Novolin R is compatible with
breastfeeding, but insulin doses may need to be adjusted because lactation can reduce insulin
requirements.
8.4
Pediatric Use
The safety and effectiveness of subcutaneous injections of Novolin R have been established in
pediatric patients (ages 2 to18 years) with type 1 diabetes [see Clinical Studies (14.3)]. Novolin R has
not been studied in pediatric patients younger than 2 years of age. Novolin R has not been studied in
pediatric patients with type 2 diabetes.
In general, pediatric patients with type 1 diabetes are more susceptible to hypoglycemia than
adult patients with type 1 diabetes. As in adults, the dosage of Novolin R must be individualized in
pediatric patients based on metabolic needs and frequent monitoring of blood glucose [see Dosage and
Administration (2.1) and Warnings and Precautions (5.2)].
8.5
Geriatric Use
In 3 controlled clinical trials 18 of 1285 patients (1.4%) with type 1 diabetes treated with
Novolin R and insulin aspart were ≥65 years of age. In 4 controlled clinical trials 151 of 635 patients
(24%) with type 2 diabetes were ≥65 years of age. Therefore, conclusions are limited regarding the
efficacy and safety of Novolin R in patients ≥65 years of age, particularly in patients with type 1
diabetes. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on Novolin R have not
been performed.
Use caution in patients with advanced age, due to the potential for decreased renal function in
this population [see Warnings and Precautions (5.2 and 5.5)].
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose.
Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with
coma, seizure, or neurologic impairment can be treated with intramuscular or subcutaneous glucagon or
intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
Reference ID: 3273161
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hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.
[see Warnings and Precautions (5.2, 5.3)]
11
DESCRIPTION
Novolin R (Regular Human Insulin Injection [Recombinant DNA origin] United States
Pharmacopeia) is a polypeptide hormone structurally identical to native human insulin and is produced
by recombinant DNA technology, utilizing Saccharomyces cerevisiae (baker’s yeast) as the production
organism. Novolin R has the empirical formula C257H383N65O77S6 and a molecular weight of 5808.
Figure 1: Structural formula of Novolin R
Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA
origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL
and water for injection. The pH is adjusted to 7.4. Hydrochloric acid 2N or sodium hydroxide 2N may
be added to adjust pH. Novolin R vials are latex-free.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of Novolin R is the regulation of glucose metabolism. Insulins, including
Novolin R, bind to insulin receptors on muscle and adipocytes and lower blood glucose by facilitating
the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.
12.2
Pharmacodynamics
Novolin R is a short-acting insulin. When injected subcutaneously, the glucose-lowering effect
of Novolin R begins approximately 30 minutes post-dose, is maximal between 1.5 and 3.5 hours post-
dose and terminates approximately 8 hours post-dose. The onset of action of Novolin R, when
administered intravenously, is more rapid in comparison to the subcutaneous administration. When
Reference ID: 3273161
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injected subcutaneously, Novolin R has a slower onset of action and longer duration of action compared
to the rapid-acting insulin analogs.
12.3
Pharmacokinetics
After single subcutaneous administration of 0.1 unit/kg of Novolin R to healthy subjects, peak
insulin concentrations occurred between 1.5 to 2.5 hours post-dose. On average, insulin concentrations
returned to baseline at around 5 hours post-dose.
The effects of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, and
smoking, on the pharmacodynamics and pharmacokinetics of Novolin R have not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
carcinogenic potential of Novolin R.
Novolin R is not mutagenic in the following in vitro tests: The chromosomal aberration assay in
human lymphocytes, the micronucleus assay in mouse polychromatic erythrocytes, and the mutation
frequency assay in Chinese hamster cells.
Standard reproduction and teratology studies in animals, including fertility assessments have not
been conducted with Novolin R.
14
CLINICAL STUDIES
Please see Section 12 CLINICAL PHARMACOLOGY for information on the pharmacokinetics
and pharmacodynamics of Novolin R.
14.1 Type 1 diabetes mellitus (adults)
Two six-month, open-label, active-controlled studies were conducted to compare the safety and
efficacy of Novolin R and insulin aspart in adults with type 1 diabetes. Insulin aspart was administered
by subcutaneous injection immediately prior to meals and Novolin R was administered by subcutaneous
injection 30 minutes before meals. Both treatment groups also received subcutaneous injections of NPH
insulin in either single or divided daily doses. Because the two study designs and results were similar,
data are shown for only one study (see Table 6)
Table 6: Subcutaneous Novolin R Administration in Type 1 Diabetes (24 weeks; N=882)
Novolin R + NPH
N=286
Insulin aspart + NPH
N=596
Baseline HbA1c (%)*
8.0 ± 1.2
7.9 ±1.1
Change from Baseline HbA1c (%)*
0.0 ± 0.8
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group
0.2 [0.1; 0.3]
Baseline, total insulin dose (units/kg/day)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study, total insulin dose (units/kg/day)*
0.7 ± 0.2
0.7 ± 0.2
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.9 ± 13.1
0.9 ± 2.9
75.3 ± 14.5
0.5 ± 3.3
*Values are Mean ± SD
Reference ID: 3273161
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14.2 Type 2 diabetes mellitus (adults)
A six-month, open-label, active-controlled study was conducted to compare the safety and
efficacy of Novolin R and insulin aspart in adults with type 2 diabetes (Table 7). Insulin aspart was
administered by subcutaneous injection immediately prior to meals and Novolin R was administered by
subcutaneous injection 30 minutes before meals. Both treatment groups also received subcutaneous
injections of NPH insulin in either single or divided daily doses.
Table 7: Subcutaneous Novolin R Administration in Type 2 Diabetes (24 weeks; N=182)
Novolin R + NPH
N = 91
Insulin aspart + NPH
N = 91
Baseline HbA1c (%)*
7.8 ± 1.1
8.1 ± 1.2
Change from Baseline HbA1c (%)*
-0.1 ± 0.8
-0.3 ± 1.0
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group
0.1 [-0.1; 0.4]
Baseline, total insulin dose (units/kg/day)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study, total insulin dose (units/kg/day)*
0.7 ± 0.3
0.7 ± 0.3
Baseline body weight (kg)*
Weight Change from baseline (kg)*
85.8 ± 14.8
0.4 ± 3.1
88.4 ± 13.3
1.2 ± 3.0
*Values are Mean ± SD
14.3 Type 1 diabetes mellitus (children and adolescents)
A six-month, open-label, active-controlled study was conducted to compare the safety and
efficacy of Novolin R and insulin aspart in children and adolescents aged 6-18 years with type 1
diabetes (Table 8). Insulin aspart was administered by subcutaneous injection immediately prior to
meals and Novolin R was administered by subcutaneous injection 30 minutes before meals. Both
treatment groups also received subcutaneous injections of NPH insulin.
Table 8: Subcutaneous Novolin R Administration in Children and Adolescents with Type 1
Diabetes (24 weeks; N=283)
Novolin R + NPH
N=96
Insulin aspart + NPH
N=187
Baseline HbA1c (%)*
8.3 1.3
8.3 1.2
Change from Baseline HbA1c (%)*
0.1 1.1
0.1 1.0
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group #
0.2 [-0.1; 0.5]
Baseline, total insulin dose (units/kg/day)*
1.0 0.4
1.0 0.3
End-of-Study, total insulin dose (units/kg/day)*
1.2 0.4
1.2 0.4
Diabetic ketoacidosis n (%)
2 (2%)
10 (5%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
48.7 15.8
2.4 2.6
50.6 19.6
2.7 3.5
* Values are Mean ± SD
# The treatment difference and corresponding 95% confidence interval is based on the Analysis of Covariance Model
Novolin R and insulin aspart have also been compared in an open-label, randomized, crossover
trial in 26 children with type 1 diabetes aged 2-6 years. Patients received each treatment for 12 weeks.
Insulin aspart was administered by subcutaneous injection immediately prior to meals and Novolin R
was administered by subcutaneous injection 30 minutes before meals. Both treatment groups also
received subcutaneous injections of NPH insulin. In this study, the mean baseline HbA1c was 7.8%.
The estimated HbA1c at end of treatment was 7.6% with Novolin R and 7.7% with insulin aspart.
Reference ID: 3273161
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16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
Novolin R is available in 10 mL vials (NDC 0169-1833-11 and ReliOn® brand NDC 0169-1833-
02). The concentration of Novolin R is 100 USP units of human insulin (rDNA origin)/mL. One vial is
provided in each sale pack.
16.2
Recommended Storage
Unopened Novolin R vials should be stored in the refrigerator (36° - 46°F [2° - 8°C]). If carried
as a spare or if refrigeration is not possible, unopened Novolin R vials can be kept at room temperature
provided they are kept as cool as possible (not above 77oF [25oC]). If kept at room temperature, Novolin
R vials must be discarded after 42 days even if they are unopened.
Do not freeze and do not use Novolin R if it has been frozen. In addition, unopened Novolin
R vials should be kept in their cartons so that they will stay clean and protected from light. They should
not be exposed to heat or light.
An opened (In use) Novolin R vial can be kept at room temperature provided it is kept as cool as
possible (not above 77oF [25oC]) and away from heat or light. Do not refrigerate after first use.
Unopened and opened (In use) Novolin R vials must be discarded 42 days after they are first
kept out of the refrigerator, even if they still contain Novolin R insulin.
Table 9: Storage Conditions for Novolin R vials
Unopened
(Refrigerated)
Unopened
(Room Temperature up to 77oF [25oC] )
Opened (In use)
(Room Temperature up to 77oF [25oC])
Until expiration date
42 days*
42 days*
* The total time allowed at room temperature (up to 25oC) is 42 days regardless of whether the product is unopened or
opened (In use)
Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION (2.3) are stable at
room temperature for 24 hours. A certain amount of insulin will be initially adsorbed to the material of
the infusion bag.
Always remove the needle after each injection. Always use a new disposable syringe and needle
for each injection to prevent contamination.
Never use insulin after the expiry date which is printed on the label and carton.
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1
Instructions for All Patients
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes mellitus
and has been associated with a reduction in some diabetic complications. Patients should be informed
about potential risks and benefits of Novolin R therapy including possible adverse reactions. Patients
should also be offered continued education and advice on insulin therapies, injection technique, life-
style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition
and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin
therapy, timing of dose, instruction in the use of injection devices, and proper storage of insulin. Patients
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
should be informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery. Patients who have frequent hypoglycemia or reduced or absent warning
signs of hypoglycemia should be advised to use caution when driving or operating machinery. Female
patients should be advised to tell their physician if they intend to become, or if they become pregnant.
Patients should be instructed to always carefully check that they are administering the correct
insulin to avoid medication errors between Novolin R and other insulins. Patients should check the label
for the drug name Novolin R, the enlarged R letter, and the blue horizontal bar. If a prescription for
Novolin R is needed, it should be written clearly to avoid confusion with other insulin products.
Novolin® is a registered trademark of Novo Nordisk A/S.
ReliOn® is a registered trademark of Wal-Mart Stores, Inc. and is used under license by Novo Nordisk
Inc.
© 2002-201x Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
ReliOn® brand manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For Wal-Mart Stores Inc.
For information about Novolin R contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
www.novonordisk-us.com
1-800-727-6500
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
NOVOLIN
®
R (NO-voe-lin)
(Regular, Human Insulin Injection [recombinant DNA origin] USP)
solution for subcutaneous injection
Read the Patient Information leaflet that comes with Novolin® R before you
start taking it and each time you get a refill. There may be new information.
This leaflet does not take the place of talking with your healthcare provider
about your diabetes or your treatment. Make sure you know how to manage
your diabetes. Ask your healthcare provider if you have any questions about
managing your diabetes.
What is Novolin® R?
Novolin® R is a man-made insulin (recombinant DNA origin) that is used to
control high blood sugar in adults and children with diabetes mellitus.
Who should not use Novolin® R?
Do not take Novolin® R if:
•
Your blood sugar is too low (hypoglycemia). After treating your low
blood sugar, follow your healthcare provider’s instructions on the use of
Novolin® R.
•
You are allergic to any of the ingredients in Novolin® R. See the end of
this leaflet for a complete list of ingredients in Novolin® R. Check with
your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking Novolin®
R?
Before you take Novolin® R, tell your healthcare providers if you:
have liver or kidney problems.
take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
have heart failure or other heart problems. If you have heart
failure, it may get worse while you take TZDs with Novolin® R.
have any other medical conditions. Medical conditions can affect
your insulin needs and your dose of Novolin® R.
•
are pregnant or plan to become pregnant. Talk to your healthcare
provider if you are pregnant or plan to become pregnant. You and your
healthcare provider should talk about the best way to manage your
diabetes while you are pregnant.
•
are breast-feeding or plan to breast-feed. It is not known if
Novolin® R passes into breast milk. You and your healthcare provider
should decide if you will take Novolin® R while you breast-feed.
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all of the medicines you take,
including prescription and nonprescription medicines, vitamins and herbal
supplements. Novolin® R may affect the way other medicines work, and other
medicines may affect how Novolin® R works.
Know the medicines you take. Keep a list of your medicines with you to
show all your healthcare providers and pharmacist when you get a new
medicine.
How should I take Novolin® R?
•
Novolin® R comes in 10 mL vials for use with a syringe.
•
Take Novolin® R exactly as prescribed.
•
Your healthcare provider will tell you how much Novolin® R to take and
when to take it.
•
Do not make any changes to your dose or type of insulin unless you are
told to do so by your healthcare provider.
•
The effects of Novolin® R usually start working within about 30 minutes
after your injection and usually lasts for up to 8 hours.
•
While using Novolin® R your healthcare provider may change
your total dose of insulin, your dose of Novolin® R, your dose of longer-
acting insulin, or the number of injections of insulin you use.
•
Do not mix Novolin® R with any insulins other than NPH in the same
syringe.
•
Inject Novolin® R under your skin (subcutaneously) of your
abdomen (stomach area), upper arms, buttocks or upper legs.
Novolin® R may affect your blood sugar levels faster if you inject it into
the skin of your abdomen (stomach area). Never inject Novolin® R
into a vein or into a muscle.
•
Do not use Novolin® R in an insulin pump.
•
Change (rotate) your injection site within the chosen area (for
example, stomach or upper arm) with each dose. Do not inject
into the same spot for each injection.
•
Read the instructions for use that comes with your Novolin® R.
Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject Novolin® R before
you start taking it.
•
If you take too much Novolin® R, your blood sugar may fall too
low (hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away (fruit
juice, sugar candies, or glucose tablets). It is important to treat low
blood sugar (hypoglycemia) right away because it could get worse and
could lead to passing out (loss of consciousness), seizures and death.
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
If you forget to take your dose of Novolin® R, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like loss
of consciousness (passing out), coma or even death. Follow your
healthcare provider’s instructions for treating high blood sugar. Know
your symptoms of high blood sugar which may include:
•
increased thirst
•
frequent urination and
dehydration
• confusion or drowsiness
•
loss of appetite
fruity smell on breath
•
high amounts of sugar and
ketones in your urine
•
nausea, vomiting (throwing
up) or stomach pain
• a hard time breathing
•
Do not share needles or syringes with others. You may give an
infection to them or get an infection from them.
•
Check your blood sugar levels. Ask your healthcare provider what
your blood sugars should be and how often you should check your
blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
•
illness
•
stress
•
other medicines you take
•
change in diet
change in physical activity or
exercise
•
surgery
See the end of this patient information for instructions about preparing and
giving the injection.
What should I avoid while taking Novolin® R?
•
Drinking alcohol. Alcohol may affect your blood sugar when you take
Novolin® R. This could lead to blood sugar that is too low
(hypoglycemia).
Driving and operating machinery. You may have trouble paying
attention or reacting if you have low blood sugar (hypoglycemia). Be
careful when you drive a car or operate machinery. Ask your
healthcare provider if it is alright for you to drive if you often have:
low blood sugar
decreased or no warning signs of low blood sugar
What are the possible side effects of Novolin® R?
Novolin® R may cause serious side effects, including:
• Low blood sugar (hypoglycemia).
The general symptoms of low blood sugar (hypoglycemia) may be one or
more of the following:
sweating
dizziness or lightheadedness
shakiness
hunger
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
fast heart beat
tingling in your hands, feet,
lips or tongue
trouble concentrating or
confusion
blurred vision
slurred speech
anxiety, irritability or mood
changes
headache
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, temporary or permanent brain problems or death.
Talk to your healthcare provider about how to tell if you have low blood
sugar and what to do if this happens while taking Novolin® R. Know your
symptoms of low blood sugar. Follow your healthcare provider’s instructions
for treating low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for you.
Your dose of Novolin® R may need to be changed.
Low blood potassium (hypokalemia). A decrease of potassium in
your blood can cause breathing problems, a change in your heartbeat
and death.
Serious allergic reaction (whole body reaction). You can have a
serious allergic reaction that may be life-threatening. Get
medical help right away if you have any of these symptoms of an
allergic reaction:
•
a rash over your body
•
have trouble breathing
•
a fast heartbeat
•
sweating
•
feel faint
•
Swelling of your hands and feet.
•
Heart Failure. Taking certain diabetes pills called thiazolidinediones or
“TZDs” with Novolin® R may cause heart failure in some people. This
can happen even if you have never had heart failure or heart problems
before. If you already have heart failure it may get worse while you
take TZDs with Novolin® R . Your healthcare provider should monitor
you closely while you are taking TZDs with Novolin® R. Tell your
healthcare provider if you have any new or worse symptoms of heart
failure including:
•
shortness of breath
•
swelling of your ankles or feet
•
sudden weight gain
Treatment with TZDs and Novolin® R may need to be adjusted or
stopped by your healthcare provider if you have new or worse heart
failure.
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other side effects of Novolin® R may include:
•
Reactions at the injection site (local allergic reaction). You may
get redness, swelling, and itching at the injection site. If you keep
having skin reactions, or they are serious, talk to your healthcare
provider. You may need to stop using Novolin® R and use a different
insulin. Do not inject insulin into skin that is red, swollen, or itchy.
•
Changes at the injection site (lipodystrophy). The fatty tissue
under the skin may shrink (lipoatrophy) or thicken (lipohypertrophy) at
the injection site. Change (rotate) the site where you inject your insulin
to help reduce the chance of developing these skin changes. Do not
inject insulin into this type of skin.
•
Weight gain.
•
Swelling of your arms and legs.
Tell your healthcare provider if you have any side effect that bothers you or
that does not go away.
These are not all of the possible side effects from Novolin® R. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store Novolin® R?
Unopened Novolin® R:
•
Unopened Novolin® R should be kept in the refrigerator
between 36°F to 46°F (2° to 8°C). Unopened vials can be used
until the expiration date on the Novolin® R label, if the medicine has
been stored in a refrigerator.
•
If refrigeration is not possible or if you want to carry a spare Novolin®
R vial you can keep the unopened vial at room temperature for up to
42 days, as long as it is kept at or below 77°F (25°C). Throw away the
vial 42 days after it is first kept out of the refrigerator, even if the vial
is unopened.
•
Do not freeze. Do not use Novolin® R if it has been frozen.
•
Keep unopened Novolin® R in the carton to protect it from light.
Novolin® R in use:
Keep at room temperature below 77°F (25°C).
•
Keep vials away from heat or light.
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Do not refrigerate an opened vial.
•
Throw away the vial 42 days after it is first kept out of the refrigerator,
even if there is insulin left in the vial.
Never use insulin after the expiration date which is printed on the
label and carton.
General information about Novolin® R
Medicines are sometimes prescribed for conditions that are not mentioned in
the patient leaflet. Do not use Novolin® R for a condition for which it was not
prescribed. Do not give Novolin® R to other people, even if they have the
same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin® R. If
you would like more information about Novolin® R or diabetes, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for
information about Novolin® R that is written for healthcare professionals.
For more information about Novolin® R, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in Novolin® R?
Active ingredient: Regular Human Insulin Injection (recombinant DNA
origin) USP.
Inactive ingredients: glycerol, metacresol, zinc chloride, water for
injection. hydrochloric acid and sodium hydroxide may be added.
All Novolin® R vials are latex-free.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Date of issue: xx/201x
Novolin® is a registered trademark of Novo Nordisk A/S.
© 2002-201X Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin® R contact:
Novo Nordisk Inc.
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® R 10 mL vial (100 Units/mL, U-100)
Please read the following Instructions for Use carefully before using your
Novolin® R 10 mL vial and each time you get a refill. You should read the
instructions in this manual even if you have used an insulin 10 mL vial before.
There may be new information.
Before starting, gather all of the supplies that you will need to use for
preparing and giving your insulin injection.
Never re-use syringes and needles.
How should I use the Novolin R vial?
1. Check to make sure that you have the correct type of
insulin. This is especially important if you use different
types of insulin.
2. Look at the vial and the insulin. The insulin should be
clear and colorless. The tamper-resistant cap should be
in place before the first use. If the cap had been
removed before your first use of the vial, or if the insulin
is cloudy, colored, or contains any particles, do not use it
and call Novo Nordisk at 1-800-727-6500.
3. Wash your hands with soap and water. Clean your
injection site with an alcohol swab and let the injection
site dry before you inject. Talk with your healthcare
provider about how to rotate injection sites and how to
give an injection.
4. If you are using a new vial, pull off the tamper-resistant
cap.
Wipe the rubber stopper with an alcohol swab.
Reference ID: 3091443
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Do not roll or shake the vial. Shaking right before the
dose is drawn into the syringe may cause bubbles or
foam. This can cause you to draw up the wrong dose of
insulin.
6. Pull back the plunger on the syringe until the black tip
reaches the marking for the number of units you will
inject.
7. Push the needle through the rubber stopper of the vial.
8. Push the plunger all the way in to force air into the vial.
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose.
Reference ID: 3091443
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10. If there are any air bubbles, tap the syringe gently with
your finger to raise the air bubbles to the top. Then
slowly push the plunger to the marking for your correct
dose. This process should move any air bubbles present
in the syringe back into the vial.
11. Check to make sure you have the right dose of Novolin R
in the syringe.
12. Pull the syringe out of the vial’s rubber stopper.
13. Your healthcare provider should tell you if you need to
pinch the skin before and while inserting the
needle. This can vary from patient to patient so it is
important to ask your healthcare provider if you did
not receive instructions on pinching the skin. Insert the
needle into the skin. Press the plunger of the syringe to
inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a
drop of Novolin R at the needle tip. This is normal and
has no effect on the dose you just received. If you see
blood after you take the needle out of your skin, press
the injection site lightly with a piece of gauze or an
alcohol wipe. Do not rub the area.
14. After your injection, do not recap the needle. Place used
syringes, needles and used insulin vials in a disposable
puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a
detergent bottle or coffee can.
15. Ask your healthcare provider about the right way to
throw away used syringes and needles. There may be
state or local laws about the right way to throw away
used syringes and needles. Do not throw away used
needles and syringes in household trash or recycle.
How should I mix Novolin R with NPH insulin?
Different insulins should be mixed only under instruction from a
healthcare provider. Do not mix Novolin R with any other
type of insulin except NPH insulin. Novolin R should be
mixed with NPH insulin right before use. When you are mixing
Reference ID: 3091443
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin R insulin with NPH insulin, always draw the Novolin R
(clear) insulin into the syringe first.
1. Add together the total number of units of NPH and
Novolin R that you need to inject. Your total dose of
medicine to inject will be the amount of NPH and Novolin
R in the syringe after drawing up both insulins. For
example, if you need 5 units of NPH and 2 units of
Novolin R, the total dose of insulin in the syringe would
be 7 units.
Preparing your NPH and Novolin R insulins for
injection:
2. Roll the NPH vial between your hands until all of the liquid
in the vial is cloudy.
3. Pull the plunger of the syringe down so that the dark end
is lined up to the number of units needed for your NPH
insulin. This will draw into the syringe the same amount
of air as the NPH dose needed.
4. Put the needle through the rubber stopper of the cloudy
NPH insulin bottle. After you inject the air into the NPH
vial, remove the needle from the vial but do not withdraw
any of the NPH insulin. Putting air in the bottle makes it
easier to draw the insulin out of the bottle.
5. Pull the plunger of the syringe down to the number of
units needed for your Novolin R insulin. After you draw
the air into the syringe, inject the air into the Novolin R
vial.
Drawing up and mixing your NPH and Novolin R
insulins for injection:
6. With the needle in place, turn the clear insulin vial of
Novolin R upside down and slowly pull the plunger back to
a few units beyond the right dose of Novolin R. The tip of
the needle must be in the Novolin R liquid to get the full
dose and not an air dose.
7. Check the syringe for air bubbles. If you see air bubbles,
tap the syringe gently with your finger to raise the air
bubbles to the top. Then slowly push the plunger to the
marking for your correct dose. This process should move
any air bubbles in the syringe back into the vial.
Reference ID: 3091443
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8. After withdrawing the needle from the Novolin R vial,
insert the needle into the NPH vial.
9. Turn the NPH vial upside down with the syringe and
needle still in the vial. Slowly pull the plunger back to
withdraw your NPH dose.
Remember the total dose of medicine in the syringe
should be your total dose of NPH and Novolin R
insulins. (See Step 1 under “How should I mix Novolin
R with NPH insulin?”)
10. Inject your insulin right away otherwise it might not
work properly.
This Patient Instructions for Use has been approved by the Food
and Drug Administration.
Date of Issue: 02/2012
Novolin® is a trademark of Novo Nordisk A/S.
© 2002-2012 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin R contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3091443
Reference ID: 3273161
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
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_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Novolin
R safely and effectively. See full prescribing information for Novolin R.
Novolin® R (Regular, Human Insulin [rDNA origin] USP) solution for
subcutaneous or intravenous use
Initial U.S. Approval: 1991
----------------------------INDICATIONS AND USAGE---------------------------
Novolin R is a short-acting recombinant human insulin indicated to improve
glycemic control in adults and children with diabetes mellitus (1).
----------------------DOSAGE AND ADMINISTRATION----------------------
The dosage and timing of Novolin R must be individualized (2.1).
Subcutaneous injection: Administer approximately 30 minutes prior to
the start of a meal (2.2).
Intravenous use: Use at concentrations from 0.05 to 1.0 Unit/mL in
infusion systems using polypropylene infusion bags. Novolin R is stable
in 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L
potassium chloride (2.3).
Use in pumps: Not recommended due to risk of precipitation (2.4).
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Novolin R, Regular, Human Insulin Injection (rDNA origin) USP, 100
units/mL (U-100), is supplied in 10 mL vials (3).
-------------------------------CONTRAINDICATIONS-----------------------------
Do not use during episodes of hypoglycemia (4).
Do not use in patients with hypersensitivity to Novolin R or one of its
excipients (4).
-----------------------WARNINGS AND PRECAUTIONS-----------------------
Hypoglycemia: Most common adverse reaction of insulin therapy and
may be life-threatening. Closely monitor blood glucose. Changes in
insulin or dosage should be made cautiously and only under medical
supervision (5.2).
Hypokalemia: Particularly when insulin is given intravenously or in
settings of poor glycemic control. Use caution in patients predisposed to
hypokalemia (5.3).
Renal or hepatic impairment: As with other insulins, the dose
requirements for Novolin R may be reduced (5.5).
Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, may occur (5.6).
Mixing: Do not mix Novolin R with any insulin for intravenous use. Do
not mix with insulins other than NPH insulin for subcutaneous use (5.7).
------------------------------ADVERSE REACTIONS------------------------------
Adverse reactions observed with Novolin R include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, weight gain and edema (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
Certain medications affect glucose metabolism and may require insulin
dose adjustment and close monitoring (7).
The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic medications (e.g., beta-blockers, clonidine, guanethidine,
and reserpine) (7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 2/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Intravenous Use
2.4 Use in Insulin Pumps
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar
Hyperglycemic Non-Ketotic Syndrome
5.5 Renal or Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Mixing of Insulins
5.8 Antibody Production
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Type 1 diabetes mellitus (adults)
14.2 Type 2 diabetes mellitus (adults)
14.3 Type 1 diabetes mellitus (children and adolescents)
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for All Patients
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3257364
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
Novolin R is indicated to improve glycemic control in adults and children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
The dosage and timing of Novolin R must be individualized. Blood glucose monitoring is
essential for all patients receiving insulin therapy.
Total daily insulin requirements vary and are usually between 0.5 and 1.0 units/kg/day. Insulin
requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or
coadministered medications.
2.2
Subcutaneous Injection
Novolin R should generally be injected approximately 30 minutes prior to the start of a meal.
Novolin R given by subcutaneous injection should generally be used in regimens that include an
intermediate or long-acting insulin [see How Supplied/Storage and Handling (16.1, 16.2)].
Novolin R should be administered by subcutaneous injection in the abdominal region, buttocks,
thigh, or the upper arm. Subcutaneous injection into the abdominal wall is generally associated with
faster absorption than other injection sites. Injection sites should be rotated within the same region to
reduce the risk of lipodystrophy. Injection into a lifted skin fold minimizes the risk of intramuscular
injection.
2.3
Intravenous Use
Novolin R can be administered intravenously under medical supervision for glycemic control,
with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5.2, 5.3), How Supplied/Storage and Handling (16.1,
16.2)].
Intravenous administration of insulin is commonly used in the treatment of diabetic ketoacidosis,
peri-operative management of diabetes, and maintenance of glycemic control during labor in pregnant
diabetic women. For intravenous use, Novolin R should be used at concentrations from 0.05 units/mL to
1.0 unit/mL in infusion systems using polypropylene infusion bags. Novolin R can be used with the
following infusion fluids: 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L
potassium chloride.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Never use Novolin R if it has become
viscous or cloudy; use Novolin R only if it is clear and colorless. Vials should not be used if leakage is
observed. Novolin R should not be used after the printed expiration date.
The onset of action of Novolin R, when administered intravenously, is more rapid in comparison
to subcutaneous administration.
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2.4
Use in Insulin Pumps
Use of Novolin R in insulin pumps is not recommended because of the risk of precipitation.
3
DOSAGE FORMS AND STRENGTHS
Novolin R is available in 10 mL vials. The concentration of Novolin R is 100 USP units of human
insulin (rDNA origin)/mL.
4
CONTRAINDICATIONS
Novolin R is contraindicated:
During episodes of hypoglycemia
In patients with hypersensitivity to Novolin R or one of its excipients
5
WARNINGS AND PRECAUTIONS
5.1
Administration
Subcutaneous injection of Novolin R should be followed by a meal. Patients should wait
approximately 30 minutes after injection before starting the meal [see Dosage and Administration (2.2)].
Any change of insulin dose should be made cautiously and only under medical supervision.
Changing from one insulin product to another or changing the insulin strength may result in the need for
a change in dosage. As with all insulin preparations, the time course of Novolin R action may vary in
different individuals or at different times in the same individual and is dependent on many conditions,
including dosage, the site of injection, local blood supply, temperature, and physical activity. Patients
who change their level of physical activity or meal plan may require adjustment of insulin dosages.
Insulin requirements may be altered during illness, emotional disturbances, or other stresses.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse reaction of all insulin therapies, including Novolin
R. Severe hypoglycemia may lead to unconsciousness, convulsions, temporary or permanent
impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person,
parenteral glucose infusion, and glucagon administration has been observed in clinical trials with
insulin, including trials with Novolin R.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations [see Clinical Pharmacology (12.2, 12.3)]. Other factors such as changes in food intake
(e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also
alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all insulins, use caution in patients
with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., patients
who are fasting or have erratic food intake, pediatric patients, and the elderly). The patient’s ability to
concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations
where these abilities are especially important, such as driving or operating other machinery.
Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in
patients with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may
be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic
neuropathy, use of medications such as beta-blockers, or intensified glycemic control [see Drug
Interactions (7)]. These situations may result in severe hypoglycemia (and, possibly, loss of
consciousness) prior to the patient’s awareness of hypoglycemia. Intravenously administered insulin has
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a more rapid onset of action than subcutaneously administered insulin, requiring more close monitoring
for hypoglycemia.
5.3
Hypokalemia
All insulins, including Novolin R, cause a shift in potassium from the extracellular to
intracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratory
paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia
(e.g., patients using potassium-lowering medications and patients taking medications sensitive to serum
potassium concentrations). Monitor glucose and potassium frequently when Novolin R is administered
intravenously.
5.4
Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Non-Ketotic
Syndrome
Hyperglycemia, diabetic ketoacidosis, or hyperosmolar hyperglycemic non-ketotic syndrome
may develop in patients who take less insulin than needed to control blood glucose. These conditions
can be precipitated by illness, infection, dietary indiscretion, or omission or improper administration of
the prescribed insulin dose.
5.5
Renal or Hepatic Impairment
As with other insulins, the dose requirements for Novolin R may be reduced in patients with
renal or hepatic impairment.
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulins, patients may experience redness, swelling, or itching at
the site of injection of Novolin R. These reactions usually resolve in a few days to a few weeks, but in
some occasions, may require discontinuation of Novolin R. In some instances, these reactions may be
related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection
technique. Localized reactions and generalized myalgias have been reported with the use of meta
cresol, which is an excipient in Novolin R.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis may
occur with any insulin, including Novolin R. Generalized allergy to insulin may manifest as a whole
body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
5.7
Mixing of Insulins
If Novolin R is mixed with NPH human insulin, Novolin R should be drawn into the syringe first
and the mixture should be injected immediately after mixing. Insulin mixtures should not be
administered intravenously.
5.8
Antibody Production
Increases in titers of anti-insulin antibodies that react with human insulin have been observed in
patients treated with Novolin R. Data from a 12-month controlled trial in patients with type 1 diabetes
suggest that the increase in these antibodies is transient. The clinical significance of these antibodies is
not known but does not appear to cause deterioration in glycemic control or necessitate increases in
insulin dose.
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6
ADVERSE REACTIONS
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
Novolin R [see Warnings and Precautions (5.2)].
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a transitory,
reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful
peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of
diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including Novolin R, can cause lipodystrophy at the site of repeated
insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and
lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection
sites within the same region to reduce the risk of lipodystrophy.
Weight gain
Weight gain can occur with insulin therapies, including Novolin R, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria.
Peripheral edema
Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is
improved by intensified insulin therapy. These symptoms are usually transitory.
Allergic reactions
As with other insulins, Novolin R can cause injection site reactions. Severe, life-threatening,
generalized allergy, including anaphylaxis may occur with any insulin, including Novolin R [see
Warnings and Precautions (5.6)].
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates
reported in one clinical trial may not be easily compared to those rates reported in another clinical trial,
and may not reflect the rates actually observed in clinical practice.
Adults with type 1 or type 2 diabetes
The incidence of adverse reactions during clinical trials comparing Novolin R and insulin aspart
in adults with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Adults with Type 1 Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an
incidence ≥ 5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 286
Insulin aspart + NPH
N=596
%
%
Hypoglycemia*
72
75
* Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms.
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Table 2: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Adults with Type 2 Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an
incidence ≥ 5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 91
Insulin aspart + NPH
N= 91
(%)
(%)
Hypoglycemia*
36
27
*Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms.
Children and adolescents with type 1 diabetes
The incidence of adverse reactions during a 24-week clinical trial comparing Novolin R and
insulin aspart in children and adolescents with type 1 diabetes mellitus are listed in the table below.
Table 3: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Children and Adolescents with Type 1 Diabetes Mellitus Also Treated with NPH Insulin (adverse
reactions with an incidence ≥5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 96
Insulin aspart + NPH
N= 187
(%)
(%)
Hypoglycemia*
85
79
Injection site hypertrophy
8
8
*Hypoglycemia was defined as an episode of blood glucose concentration <50 mg/dL, with or without symptoms.
Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including Novolin R [See Warnings and Precautions (5.3)]. Tables 4 and 5 summarize the incidence of
severe hypoglycemia in the Novolin R clinical trials. Severe hypoglycemia was defined as
hypoglycemia associated with central nervous system symptoms and requiring intervention of another
person or hospitalization. The rates of severe hypoglycemia in the Novolin R clinical trials (see Section
14 for a description of the study designs) were comparable for all treatment regimens (see Tables 4 and
5).
Table 4: Severe Hypoglycemia in Patients with Type 1 Diabetes
Type 1 Diabetes
Adults
24 weeks in combination
with NPH insulin
Type 1 Diabetes
Children and Adolescents
(age 6-18)
24 weeks in combination
with NPH insulin
Type 1 Diabetes
Children
(age 2-6)
24 weeks in combination
with NPH insulin
Novolin R
Insulin
Novolin R
Insulin
Novolin R
Insulin
aspart
aspart
aspart
Percent of patients
(n/total N)
19
(55/286)
18
(105/596)
9
(9/96)
6
(11/187)
12
(3/25)
8
(2/26)
Event/patient/
year
1.1
0.9
0.3
0.2
0.5
0.3
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Table 5: Severe Hypoglycemia in Patients with Type 2 Diabetes
Type 2 Diabetes
Adults
24 weeks in combination with
NPH insulin
Novolin R
Insulin aspart
Percent of patients
(n/total N)
5
(5/91)
10
(9/91)
Event/patient/
year
0.2
0.3
7
DRUG INTERACTIONS
A number of medications affect glucose metabolism that may require insulin dose adjustment
and particularly close monitoring for hypoglycemia or worsening glycemic control.
The following are examples of medications that may increase the blood glucose-lowering effect
of insulin and increase susceptibility to hypoglycemia: oral antidiabetic medications, pramlintide
acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine,
monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analogs (e.g.,
octreotide), and sulfonamide antibiotics.
The following are examples of medications that may reduce the blood glucose-lowering effect of
insulin, leading to worsening of glycemic control: corticosteroids, niacin, danazol, diuretics,
sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine
derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
and atypical antipsychotics.
Beta-blockers, clonidine, and lithium salts may either potentiate or weaken the blood glucose-
lowering effect of insulin.
Alcohol can increase susceptibility to hypoglycemia.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
medications such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B: All pregnancies have a background risk of birth defects, loss, or other
adverse outcome regardless of drug exposure. This background risk is increased in pregnancies
complicated by hyperglycemia and may be decreased with good glycemic control. It is essential for
patients with diabetes or a history of gestational diabetes to maintain good glycemic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful
monitoring of glucose control is important during pregnancy in patients with diabetes. Therefore,
women should be advised to tell their healthcare provider if they intend to become, or if they become,
pregnant while taking Novolin R.
No reproductive toxicity studies have been performed with Novolin R.
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8.3
Nursing Mothers
It is unknown whether Novolin R is excreted in breast milk. Small amounts of human insulin are
secreted into breast milk, the significance of which is not known. Use of Novolin R is compatible with
breastfeeding, but insulin doses may need to be adjusted because lactation can reduce insulin
requirements.
8.4
Pediatric Use
The safety and effectiveness of subcutaneous injections of Novolin R have been established in
pediatric patients (ages 2 to18 years) with type 1 diabetes [see Clinical Studies (14.3)]. Novolin R has
not been studied in pediatric patients younger than 2 years of age. Novolin R has not been studied in
pediatric patients with type 2 diabetes.
In general, pediatric patients with type 1 diabetes are more susceptible to hypoglycemia than
adult patients with type 1 diabetes. As in adults, the dosage of Novolin R must be individualized in
pediatric patients based on metabolic needs and frequent monitoring of blood glucose [see Dosage and
Administration (2.1) and Warnings and Precautions (5.2)].
8.5
Geriatric Use
In 3 controlled clinical trials 18 of 1285 patients (1.4%) with type 1 diabetes treated with
Novolin R and insulin aspart were ≥65 years of age. In 4 controlled clinical trials 151 of 635 patients
(24%) with type 2 diabetes were ≥65 years of age. Therefore, conclusions are limited regarding the
efficacy and safety of Novolin R in patients ≥65 years of age, particularly in patients with type 1
diabetes. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on Novolin R have not
been performed.
Use caution in patients with advanced age, due to the potential for decreased renal function in
this population [see Warnings and Precautions (5.2 and 5.5)].
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose.
Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with
coma, seizure, or neurologic impairment can be treated with intramuscular or subcutaneous glucagon or
intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.
[see Warnings and Precautions (5.2, 5.3)]
11
DESCRIPTION
Novolin R (Regular Human Insulin Injection [Recombinant DNA origin] United States
Pharmacopeia) is a polypeptide hormone structurally identical to native human insulin and is produced
by recombinant DNA technology, utilizing Saccharomyces cerevisiae (baker’s yeast) as the production
organism. Novolin R has the empirical formula C257H383N65O77S6 and a molecular weight of 5808.
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structural formula
Figure 1: Structural formula of Novolin R
Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA
origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL
and water for injection. The pH is adjusted to 7.4. Hydrochloric acid 2N or sodium hydroxide 2N may
be added to adjust pH. Novolin R vials are latex-free.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of Novolin R is the regulation of glucose metabolism. Insulins, including
Novolin R, bind to insulin receptors on muscle and adipocytes and lower blood glucose by facilitating
the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.
12.2
Pharmacodynamics
Novolin R is a short-acting insulin. When injected subcutaneously, the glucose-lowering effect
of Novolin R begins approximately 30 minutes post-dose, is maximal between 1.5 and 3.5 hours post-
dose and terminates approximately 8 hours post-dose. The onset of action of Novolin R, when
administered intravenously, is more rapid in comparison to the subcutaneous administration. When
injected subcutaneously, Novolin R has a slower onset of action and longer duration of action compared
to the rapid-acting insulin analogs.
12.3
Pharmacokinetics
After single subcutaneous administration of 0.1 unit/kg of Novolin R to healthy subjects, peak
insulin concentrations occurred between 1.5 to 2.5 hours post-dose. On average, insulin concentrations
returned to baseline at around 5 hours post-dose.
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The effects of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, and
smoking, on the pharmacodynamics and pharmacokinetics of Novolin R have not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
carcinogenic potential of Novolin R.
Novolin R is not mutagenic in the following in vitro tests: The chromosomal aberration assay in
human lymphocytes, the micronucleus assay in mouse polychromatic erythrocytes, and the mutation
frequency assay in Chinese hamster cells.
Standard reproduction and teratology studies in animals, including fertility assessments have not
been conducted with Novolin R.
14
CLINICAL STUDIES
Please see Section 12 CLINICAL PHARMACOLOGY for information on the pharmacokinetics
and pharmacodynamics of Novolin R.
14.1
Type 1 diabetes mellitus (adults)
Two six-month, open-label, active-controlled studies were conducted to compare the safety and
efficacy of Novolin R and insulin aspart in adults with type 1 diabetes. Insulin aspart was administered
by subcutaneous injection immediately prior to meals and Novolin R was administered by subcutaneous
injection 30 minutes before meals. Both treatment groups also received subcutaneous injections of NPH
insulin in either single or divided daily doses. Because the two study designs and results were similar,
data are shown for only one study (see Table 6)
Table 6: Subcutaneous Novolin R Administration in Type 1 Diabetes (24 weeks; N=882)
Novolin R + NPH
N=286
Insulin aspart + NPH
N=596
Baseline HbA1c (%)*
8.0 ± 1.2
7.9 ±1.1
Change from Baseline HbA1c (%)*
0.0 ± 0.8
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group
0.2 [0.1; 0.3]
Baseline, total insulin dose (units/kg/day)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study, total insulin dose (units/kg/day)*
0.7 ± 0.2
0.7 ± 0.2
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.9 ± 13.1
0.9 ± 2.9
75.3 ± 14.5
0.5 ± 3.3
*Values are Mean ± SD
14.2
Type 2 diabetes mellitus (adults)
A six-month, open-label, active-controlled study was conducted to compare the safety and
efficacy of Novolin R and insulin aspart in adults with type 2 diabetes (Table 7). Insulin aspart was
administered by subcutaneous injection immediately prior to meals and Novolin R was administered by
subcutaneous injection 30 minutes before meals. Both treatment groups also received subcutaneous
injections of NPH insulin in either single or divided daily doses.
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Table 7: Subcutaneous Novolin R Administration in Type 2 Diabetes (24 weeks; N=182)
Novolin R + NPH
N = 91
Insulin aspart + NPH
N = 91
Baseline HbA1c (%)*
7.8 ± 1.1
8.1 ± 1.2
Change from Baseline HbA1c (%)*
-0.1 ± 0.8
-0.3 ± 1.0
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group
0.1 [-0.1; 0.4]
Baseline, total insulin dose (units/kg/day)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study, total insulin dose (units/kg/day)*
0.7 ± 0.3
0.7 ± 0.3
Baseline body weight (kg)*
Weight Change from baseline (kg)*
85.8 ± 14.8
0.4 ± 3.1
88.4 ± 13.3
1.2 ± 3.0
*Values are Mean ± SD
14.3
Type 1 diabetes mellitus (children and adolescents)
A six-month, open-label, active-controlled study was conducted to compare the safety and
efficacy of Novolin R and insulin aspart in children and adolescents aged 6-18 years with type 1
diabetes (Table 8). Insulin aspart was administered by subcutaneous injection immediately prior to
meals and Novolin R was administered by subcutaneous injection 30 minutes before meals. Both
treatment groups also received subcutaneous injections of NPH insulin.
Table 8: Subcutaneous Novolin R Administration in Children and Adolescents with Type 1
Diabetes (24 weeks; N=283)
Novolin R + NPH
N=96
Insulin aspart + NPH
N=187
Baseline HbA1c (%)*
8.3 1.3
8.3 1.2
Change from Baseline HbA1c (%)*
0.1 1.1
0.1 1.0
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group #
0.2 [-0.1; 0.5]
Baseline, total insulin dose (units/kg/day)*
1.0 0.4
1.0 0.3
End-of-Study, total insulin dose (units/kg/day)*
1.2 0.4
1.2 0.4
Diabetic ketoacidosis n (%)
2 (2%)
10 (5%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
48.7 15.8
2.4 2.6
50.6 19.6
2.7 3.5
* Values are Mean ± SD
# The treatment difference and corresponding 95% confidence interval is based on the Analysis of Covariance Model
Novolin R and insulin aspart have also been compared in an open-label, randomized, crossover
trial in 26 children with type 1 diabetes aged 2-6 years. Patients received each treatment for 12 weeks.
Insulin aspart was administered by subcutaneous injection immediately prior to meals and Novolin R
was administered by subcutaneous injection 30 minutes before meals. Both treatment groups also
received subcutaneous injections of NPH insulin. In this study, the mean baseline HbA1c was 7.8%.
The estimated HbA1c at end of treatment was 7.6% with Novolin R and 7.7% with insulin aspart.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
Novolin R is available in 10 mL vials (NDC 0169-1833-11 and ReliOn® brand NDC 0169-1833
02). The concentration of Novolin R is 100 USP units of human insulin (rDNA origin)/mL. One vial is
provided in each sale pack.
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16.2
Recommended Storage
Unopened Novolin R vials should be stored in the refrigerator (36° - 46°F [2° - 8°C]). If carried
as a spare or if refrigeration is not possible, unopened Novolin R vials can be kept at room temperature
provided they are kept as cool as possible (not above 77oF [25oC]). If kept at room temperature, Novolin
R vials must be discarded after 42 days even if they are unopened.
Do not freeze and do not use Novolin R if it has been frozen. In addition, unopened Novolin
R vials should be kept in their cartons so that they will stay clean and protected from light. They should
not be exposed to heat or light.
An opened (In use) Novolin R vial can be kept at room temperature provided it is kept as cool as
possible (not above 77oF [25oC]) and away from heat or light. Do not refrigerate after first use.
Unopened and opened (In use) Novolin R vials must be discarded 42 days after they are first
kept out of the refrigerator, even if they still contain Novolin R insulin.
Table 9: Storage Conditions for Novolin R vials
Unopened
(Refrigerated)
Unopened
(Room Temperature up to 77oF [25oC] )
Opened (In use)
(Room Temperature up to 77oF [25oC])
Until expiration date
42 days*
42 days*
* The total time allowed at room temperature (up to 25oC) is 42 days regardless of whether the product is unopened or
opened (In use)
Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION (2.3) are stable at
room temperature for 24 hours. A certain amount of insulin will be initially adsorbed to the material of
the infusion bag.
Always remove the needle after each injection. Always use a new disposable syringe and needle
for each injection to prevent contamination.
Never use insulin after the expiry date which is printed on the label and carton.
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1
Instructions for All Patients
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes mellitus
and has been associated with a reduction in some diabetic complications. Patients should be informed
about potential risks and benefits of Novolin R therapy including possible adverse reactions. Patients
should also be offered continued education and advice on insulin therapies, injection technique, life
style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition
and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin
therapy, timing of dose, instruction in the use of injection devices, and proper storage of insulin. Patients
should be informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery. Patients who have frequent hypoglycemia or reduced or absent warning
signs of hypoglycemia should be advised to use caution when driving or operating machinery. Female
patients should be advised to tell their physician if they intend to become, or if they become pregnant.
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be instructed to always carefully check that they are administering the correct
insulin to avoid medication errors between Novolin R and other insulins. Patients should check the label
for the drug name Novolin R, the enlarged R letter, and the blue horizontal bar. If a prescription for
Novolin R is needed, it should be written clearly to avoid confusion with other insulin products.
Novolin® is a registered trademark of Novo Nordisk A/S.
ReliOn® is a registered trademark of Wal-Mart Stores, Inc. and is used under license by Novo Nordisk
Inc.
© 2002-2012 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
ReliOn® brand manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For Wal-Mart Stores Inc.
For information about Novolin R contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
www.novonordisk-us.com
1-800-727-6500
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
®
NOVOLIN R (NO-voe-lin)
(Regular, Human Insulin Injection [recombinant DNA origin] USP)
solution for subcutaneous injection
Read the Patient Information leaflet that comes with Novolin R before you start
taking it and each time you get a refill. There may be new information. This
leaflet does not take the place of talking with your healthcare provider about
your diabetes or your treatment. Make sure you know how to manage your
diabetes. Ask your healthcare provider if you have any questions about
managing your diabetes.
What is Novolin R?
Novolin R is a man-made insulin (recombinant DNA origin) that is used to
control high blood sugar in adults and children with diabetes mellitus.
Who should not use Novolin R?
Do not take Novolin R if:
•
Your blood sugar is too low (hypoglycemia). After treating your low
blood sugar, follow your healthcare provider’s instructions on the use of
Novolin R.
•
You are allergic to any of the ingredients in Novolin R. See the end of
this leaflet for a complete list of ingredients in Novolin R. Check with
your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking Novolin R?
Before you take Novolin R, tell your healthcare providers if you:
•
have liver or kidney problems.
•
have any other medical conditions. Medical conditions can affect
your insulin needs and your dose of Novolin R.
•
are pregnant or plan to become pregnant. Talk to your healthcare
provider if you are pregnant or plan to become pregnant. You and your
healthcare provider should talk about the best way to manage your
diabetes while you are pregnant.
•
are breast-feeding or plan to breast-feed. It is not known if Novolin
R passes into breast milk. You and your healthcare provider should
decide if you will take Novolin R while you breast-feed.
Tell your healthcare provider about all of the medicines you take,
including prescription and nonprescription medicines, vitamins and herbal
supplements. Novolin R may affect the way other medicines work, and other
medicines may affect how Novolin R works.
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Know the medicines you take. Keep a list of your medicines with you to
show all your healthcare providers and pharmacist when you get a new
medicine.
How should I take Novolin R?
•
Novolin R comes in 10 mL vials for use with a syringe.
•
Take Novolin R exactly as prescribed.
•
Your healthcare provider will tell you how much Novolin R to take and
when to take it.
•
Do not make any changes to your dose or type of insulin unless you are
told to do so by your healthcare provider.
•
The effects of Novolin R usually start working within about 30 minutes
after your injection and usually lasts for up to 8 hours.
•
While using Novolin R your healthcare provider may change your
total dose of insulin, your dose of Novolin R, your dose of longer-acting
insulin, or the number of injections of insulin you use.
•
Do not mix Novolin R with any insulins other than NPH in the same
syringe.
•
Inject Novolin R under your skin (subcutaneously) of your
abdomen (stomach area), upper arms, buttocks or upper legs.
Novolin R may affect your blood sugar levels faster if you inject it into
the skin of your abdomen (stomach area). Never inject Novolin R into
a vein or into a muscle.
•
Do not use Novolin R in an insulin pump.
•
Change (rotate) your injection site within the chosen area (for
example, stomach or upper arm) with each dose. Do not inject
into the same spot for each injection.
•
Read the instructions for use that comes with your Novolin R.
Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject Novolin R before you
start taking it.
•
If you take too much Novolin R, your blood sugar may fall too
low (hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away (fruit
juice, sugar candies, or glucose tablets). It is important to treat low
blood sugar (hypoglycemia) right away because it could get worse and
could lead to passing out (loss of consciousness), seizures and death.
•
If you forget to take your dose of Novolin R, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like loss
of consciousness (passing out), coma or even death. Follow your
healthcare provider’s instructions for treating high blood sugar. Know
your symptoms of high blood sugar which may include:
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• increased thirst
• high amounts of sugar and
• frequent urination and
ketones in your urine
dehydration
• nausea, vomiting (throwing
• confusion or drowsiness
up) or stomach pain
• loss of appetite
• a hard time breathing
• fruity smell on breath
•
Do not share needles or syringes with others. You may give an
infection to them or get an infection from them.
•
Check your blood sugar levels. Ask your healthcare provider what
your blood sugars should be and how often you should check your
blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
•
illness
•
change in diet
•
stress
•
change in physical activity or
•
other medicines you take
exercise
•
surgery
See the end of this patient information for instructions about preparing and
giving the injection.
What should I avoid while taking Novolin R?
•
Drinking alcohol. Alcohol may affect your blood sugar when you take
Novolin R. This could lead to blood sugar that is too low
(hypoglycemia).
•
Driving and operating machinery. You may have trouble paying
attention or reacting if you have low blood sugar (hypoglycemia). Be
careful when you drive a car or operate machinery. Ask your
healthcare provider if it is alright for you to drive if you often have:
• low blood sugar
• decreased or no warning signs of low blood sugar
What are the possible side effects of Novolin R?
Novolin R may cause serious side effects, including:
• Low blood sugar (hypoglycemia).
The general symptoms of low blood sugar (hypoglycemia) may be one or
more of the following:
• sweating
•
tingling in your hands, feet,
• dizziness or lightheadedness
lips or tongue
• shakiness
•
trouble concentrating or
• hunger
confusion
• fast heart beat
•
blurred vision
• slurred speech
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• anxiety, irritability or mood
•
headache
changes
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, temporary or permanent brain problems or death.
Talk to your healthcare provider about how to tell if you have low blood
sugar and what to do if this happens while taking Novolin R. Know your
symptoms of low blood sugar. Follow your healthcare provider’s instructions
for treating low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for you.
Your dose of Novolin R may need to be changed.
• Low blood potassium (hypokalemia). A decrease of potassium in
your blood can cause breathing problems, a change in your heartbeat
and death.
• Serious allergic reaction (whole body reaction). You can have a
serious allergic reaction that may be life-threatening. Get
medical help right away if you have any of these symptoms of an
allergic reaction:
• a rash over your body
• have trouble breathing
• a fast heartbeat
• sweating
• feel faint
Other side effects of Novolin R may include:
• Reactions at the injection site (local allergic reaction). You may
get redness, swelling, and itching at the injection site. If you keep
having skin reactions, or they are serious, talk to your healthcare
provider. You may need to stop using Novolin R and use a different
insulin. Do not inject insulin into skin that is red, swollen, or itchy.
• Changes at the injection site (lipodystrophy). The fatty tissue
under the skin may shrink (lipoatrophy) or thicken (lipohypertrophy) at
the injection site. Change (rotate) the site where you inject your insulin
to help reduce the chance of developing these skin changes. Do not
inject insulin into this type of skin.
• Weight gain.
• Swelling of your arms and legs.
Tell your healthcare provider if you have any side effect that bothers you or
that does not go away.
These are not all of the possible side effects from Novolin R. Ask your
healthcare provider or pharmacist for more information.
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store Novolin R?
Unopened Novolin R:
•
Unopened Novolin R should be kept in the refrigerator between
36°F to 46°F (2° to 8°C). Unopened vials can be used until the
expiration date on the Novolin R label, if the medicine has been stored
in a refrigerator.
•
If refrigeration is not possible or if you want to carry a spare Novolin R
vial you can keep the unopened vial at room temperature for up to 42
days, as long as it is kept at or below 77°F (25°C). Throw away the
vial 42 days after it is first kept out of the refrigerator, even if the vial
is unopened.
•
Do not freeze. Do not use Novolin R if it has been frozen.
•
Keep unopened Novolin R in the carton to protect it from light.
Novolin R in use:
•
Keep at room temperature below 77°F (25°C).
•
Keep vials away from heat or light.
•
Do not refrigerate an opened vial.
•
Throw away the vial 42 days after it is first kept out of the refrigerator,
even if there is insulin left in the vial.
Never use insulin after the expiration date which is printed on the
label and carton.
General information about Novolin R
Medicines are sometimes prescribed for conditions that are not mentioned in
the patient leaflet. Do not use Novolin R for a condition for which it was not
prescribed. Do not give Novolin R to other people, even if they have the
same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin R. If
you would like more information about Novolin R or diabetes, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for
information about Novolin R that is written for healthcare professionals.
For more information about Novolin R, call 1-800-727-6500 or go to
www.novonordisk-us.com.
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What are the ingredients in Novolin R?
Active ingredient: Regular Human Insulin Injection (recombinant DNA
origin) USP.
Inactive ingredients: glycerol, metacresol, zinc chloride, water for
injection. hydrochloric acid and sodium hydroxide may be added.
All Novolin R vials are latex-free.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Date of issue: 02/2012
Novolin® is a trademark of Novo Nordisk A/S.
© 2002-2012 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin R contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Instructions for Use
Novolin® R 10 mL vial (100 Units/mL, U-100)
Please read the following Instructions for Use carefully before using your
Novolin® R 10 mL vial and each time you get a refill. You should read the
instructions in this manual even if you have used an insulin 10 mL vial before.
There may be new information.
Before starting, gather all of the supplies that you will need to use for
preparing and giving your insulin injection.
Never re-use syringes and needles.
How should I use the Novolin R vial?
1. Check to make sure that you have the correct type of
insulin. This is especially important if you use different
types of insulin.
2. Look at the vial and the insulin. The insulin should be
clear and colorless. The tamper-resistant cap should be
in place before the first use. If the cap had been
removed before your first use of the vial, or if the insulin
is cloudy, colored, or contains any particles, do not use it
and call Novo Nordisk at 1-800-727-6500.
3. Wash your hands with soap and water. Clean your
injection site with an alcohol swab and let the injection
site dry before you inject. Talk with your healthcare
provider about how to rotate injection sites and how to
give an injection.
4. If you are using a new vial, pull off the tamper-resistant
cap. usage illustration
Wipe the rubber stopper with an alcohol swab.
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Do not roll or shake the vial. Shaking right before the
dose is drawn into the syringe may cause bubbles or
foam. This can cause you to draw up the wrong dose of
insulin.
6. Pull back the plunger on the syringe until the black tip
reaches the marking for the number of units you will
inject.
7. Push the needle through the rubber stopper of the vial.
8. Push the plunger all the way in to force air into the vial.
9. Turn the vial and syringe upside down and slowly pull the
plunger back to a few units beyond the correct dose. usage illustrationusage illustrationusage illustrationusage illustration
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10. If there are any air bubbles, tap the syringe gently with
your finger to raise the air bubbles to the top. Then
slowly push the plunger to the marking for your correct
dose. This process should move any air bubbles present
in the syringe back into the vial. usage illustration
11. Check to make sure you have the right dose of Novolin R
in the syringe.
12. Pull the syringe out of the vial’s rubber stopper.
13. Your healthcare provider should tell you if you need to
pinch the skin before and while inserting the
needle. This can vary from patient to patient so it is
important to ask your healthcare provider if you did
not receive instructions on pinching the skin. Insert the
needle into the skin. Press the plunger of the syringe to
inject the insulin. When you are finished injecting the
insulin, pull the needle out of your skin. You may see a
drop of Novolin R at the needle tip. This is normal and
has no effect on the dose you just received. If you see
blood after you take the needle out of your skin, press
the injection site lightly with a piece of gauze or an
alcohol wipe. Do not rub the area.
14. After your injection, do not recap the needle. Place used
syringes, needles and used insulin vials in a disposable
puncture-resistant sharps container, or some type of hard
plastic or metal container with a screw on cap such as a
detergent bottle or coffee can.
15. Ask your healthcare provider about the right way to
throw away used syringes and needles. There may be
state or local laws about the right way to throw away
used syringes and needles. Do not throw away used
needles and syringes in household trash or recycle.
How should I mix Novolin R with NPH insulin?
Different insulins should be mixed only under instruction from a
healthcare provider. Do not mix Novolin R with any other
type of insulin except NPH insulin. Novolin R should be
mixed with NPH insulin right before use. When you are mixing usage illustration
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Novolin R insulin with NPH insulin, always draw the Novolin R
(clear) insulin into the syringe first.
1. Add together the total number of units of NPH and
Novolin R that you need to inject. Your total dose of
medicine to inject will be the amount of NPH and Novolin
R in the syringe after drawing up both insulins. For
example, if you need 5 units of NPH and 2 units of
Novolin R, the total dose of insulin in the syringe would
be 7 units.
Preparing your NPH and Novolin R insulins for
injection:
2. Roll the NPH vial between your hands until all of the liquid
in the vial is cloudy.
3. Pull the plunger of the syringe down so that the dark end
is lined up to the number of units needed for your NPH
insulin. This will draw into the syringe the same amount
of air as the NPH dose needed.
4. Put the needle through the rubber stopper of the cloudy
NPH insulin bottle. After you inject the air into the NPH
vial, remove the needle from the vial but do not withdraw
any of the NPH insulin. Putting air in the bottle makes it
easier to draw the insulin out of the bottle.
5. Pull the plunger of the syringe down to the number of
units needed for your Novolin R insulin. After you draw
the air into the syringe, inject the air into the Novolin R
vial.
Drawing up and mixing your NPH and Novolin R
insulins for injection:
6. With the needle in place, turn the clear insulin vial of
Novolin R upside down and slowly pull the plunger back to
a few units beyond the right dose of Novolin R. The tip of
the needle must be in the Novolin R liquid to get the full
dose and not an air dose.
7. Check the syringe for air bubbles. If you see air bubbles,
tap the syringe gently with your finger to raise the air
bubbles to the top. Then slowly push the plunger to the
marking for your correct dose. This process should move
any air bubbles in the syringe back into the vial.
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8. After withdrawing the needle from the Novolin R vial,
insert the needle into the NPH vial.
9. Turn the NPH vial upside down with the syringe and
needle still in the vial. Slowly pull the plunger back to
withdraw your NPH dose.
Remember the total dose of medicine in the syringe
should be your total dose of NPH and Novolin R
insulins. (See Step 1 under “How should I mix Novolin
R with NPH insulin?”)
10. Inject your insulin right away otherwise it might not
work properly.
This Patient Instructions for Use has been approved by the Food
and Drug Administration.
Date of Issue: 02/2012
Novolin® is a trademark of Novo Nordisk A/S.
© 2002-2012 Novo Nordisk Inc.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin R contact:
Novo Nordisk Inc.
100 College Road West
Princeton, New Jersey 08540
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3091443
Reference ID: 3257364
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:46:20.425616
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019938s072lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 72}
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_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Novolin
R safely and effectively. See full prescribing information for Novolin R.
Novolin® R (Regular, Human Insulin [rDNA origin] USP) solution for
subcutaneous or intravenous use
Initial U.S. Approval: 1991
----------------------------INDICATIONS AND USAGE---------------------------
Novolin R is a short-acting recombinant human insulin indicated to improve
glycemic control in adults and children with diabetes mellitus (1).
----------------------DOSAGE AND ADMINISTRATION----------------------
•
The dosage and timing of Novolin R must be individualized (2.1).
•
Subcutaneous injection: Administer approximately 30 minutes prior to
the start of a meal (2.2).
•
Intravenous use: Use at concentrations from 0.05 to 1.0 Unit/mL in
infusion systems using polypropylene infusion bags. Novolin R is stable
in 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L
potassium chloride (2.3).
•
Use in pumps: Not recommended due to risk of precipitation (2.4).
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Novolin R, Regular, Human Insulin Injection (rDNA origin) USP, 100
units/mL (U-100), is supplied in 10 mL vials (3).
-------------------------------CONTRAINDICATIONS-----------------------------
•
Do not use during episodes of hypoglycemia (4).
•
Do not use in patients with hypersensitivity to Novolin R or one of its
excipients (4).
-----------------------WARNINGS AND PRECAUTIONS-----------------------
•
Hypoglycemia: Most common adverse reaction of insulin therapy and
may be life-threatening. Closely monitor blood glucose. Changes in
insulin or dosage should be made cautiously and only under medical
supervision (5.2).
•
Hypokalemia: Particularly when insulin is given intravenously or in
settings of poor glycemic control. Use caution in patients predisposed to
hypokalemia (5.3).
•
Renal or hepatic impairment: As with other insulins, the dose
requirements for Novolin R may be reduced (5.5).
•
Allergic reactions: Severe, life-threatening, generalized allergy,
including anaphylaxis, may occur (5.6).
•
Mixing: Do not mix Novolin R with any insulin for intravenous use. Do
not mix with insulins other than NPH insulin for subcutaneous use (5.7).
•
Fluid retention and heart failure can occur with concomitant use of
thiazolidinediones (TZDs), which are PPAR-gamma agonists, and
insulin, including Novolin R (5.9).
------------------------------ADVERSE REACTIONS------------------------------
Adverse reactions observed with Novolin R include hypoglycemia, allergic
reactions, injection site reactions, lipodystrophy, weight gain and edema (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
•
Certain medications affect glucose metabolism and may require insulin
dose adjustment and close monitoring (7).
•
The signs of hypoglycemia may be reduced or absent in patients taking
anti-adrenergic medications (e.g., beta-blockers, clonidine, guanethidine,
and reserpine) (7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: 01/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Treatment of Diabetes Mellitus
2
DOSAGE AND ADMINISTRATION
2.1 Dosing
2.2 Subcutaneous Injection
2.3 Intravenous Use
2.4 Use in Insulin Pumps
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Administration
5.2 Hypoglycemia
5.3 Hypokalemia
5.4 Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar
Hyperglycemic Non-Ketotic Syndrome
5.5 Renal or Hepatic Impairment
5.6 Hypersensitivity and Allergic Reactions
5.7 Mixing of Insulins
5.8 Antibody Production
5.9 Fluid retention and heart failure with concomitant use of PPAR-
gamma agonists
6
ADVERSE REACTIONS
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Type 1 diabetes mellitus (adults)
14.2 Type 2 diabetes mellitus (adults)
14.3 Type 1 diabetes mellitus (children and adolescents)
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for All Patients
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Treatment of Diabetes Mellitus
Novolin R is indicated to improve glycemic control in adults and children with diabetes mellitus.
2
DOSAGE AND ADMINISTRATION
2.1
Dosing
The dosage and timing of Novolin R must be individualized. Blood glucose monitoring is
essential for all patients receiving insulin therapy.
Total daily insulin requirements vary and are usually between 0.5 and 1.0 units/kg/day. Insulin
requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or
coadministered medications.
2.2
Subcutaneous Injection
Novolin R should generally be injected approximately 30 minutes prior to the start of a meal.
Novolin R given by subcutaneous injection should generally be used in regimens that include an
intermediate or long-acting insulin [see How Supplied/Storage and Handling (16.1, 16.2)].
Novolin R should be administered by subcutaneous injection in the abdominal region, buttocks,
thigh, or the upper arm. Subcutaneous injection into the abdominal wall is generally associated with
faster absorption than other injection sites. Injection sites should be rotated within the same region to
reduce the risk of lipodystrophy. Injection into a lifted skin fold minimizes the risk of intramuscular
injection.
2.3
Intravenous Use
Novolin R can be administered intravenously under medical supervision for glycemic control,
with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia and
hypokalemia [see Warnings and Precautions (5.2, 5.3), How Supplied/Storage and Handling (16.1,
16.2)].
Intravenous administration of insulin is commonly used in the treatment of diabetic ketoacidosis,
peri-operative management of diabetes, and maintenance of glycemic control during labor in pregnant
diabetic women. For intravenous use, Novolin R should be used at concentrations from 0.05 units/mL to
1.0 unit/mL in infusion systems using polypropylene infusion bags. Novolin R can be used with the
following infusion fluids: 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L
potassium chloride.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit. Never use Novolin R if it has become
viscous or cloudy; use Novolin R only if it is clear and colorless. Vials should not be used if leakage is
observed. Novolin R should not be used after the printed expiration date.
The onset of action of Novolin R, when administered intravenously, is more rapid in comparison
to subcutaneous administration.
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.4
Use in Insulin Pumps
Use of Novolin R in insulin pumps is not recommended because of the risk of precipitation.
3
DOSAGE FORMS AND STRENGTHS
• Novolin R is available in 10 mL vials. The concentration of Novolin R is 100 USP units of human
insulin (rDNA origin)/mL.
4
CONTRAINDICATIONS
Novolin R is contraindicated:
• During episodes of hypoglycemia
• In patients with hypersensitivity to Novolin R or one of its excipients
5
WARNINGS AND PRECAUTIONS
5.1
Administration
Subcutaneous injection of Novolin R should be followed by a meal. Patients should wait
approximately 30 minutes after injection before starting the meal [see Dosage and Administration (2.2)].
Any change of insulin dose should be made cautiously and only under medical supervision.
Changing from one insulin product to another or changing the insulin strength may result in the need for
a change in dosage. As with all insulin preparations, the time course of Novolin R action may vary in
different individuals or at different times in the same individual and is dependent on many conditions,
including dosage, the site of injection, local blood supply, temperature, and physical activity. Patients
who change their level of physical activity or meal plan may require adjustment of insulin dosages.
Insulin requirements may be altered during illness, emotional disturbances, or other stresses.
5.2
Hypoglycemia
Hypoglycemia is the most common adverse reaction of all insulin therapies, including Novolin
R. Severe hypoglycemia may lead to unconsciousness, convulsions, temporary or permanent
impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person,
parenteral glucose infusion, and glucagon administration has been observed in clinical trials with
insulin, including trials with Novolin R.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations [see Clinical Pharmacology (12.2, 12.3)]. Other factors such as changes in food intake
(e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also
alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all insulins, use caution in patients
with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., patients
who are fasting or have erratic food intake, pediatric patients, and the elderly). The patient’s ability to
concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations
where these abilities are especially important, such as driving or operating other machinery.
Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in
patients with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may
be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic
neuropathy, use of medications such as beta-blockers, or intensified glycemic control [see Drug
Interactions (7)]. These situations may result in severe hypoglycemia (and, possibly, loss of
consciousness) prior to the patient’s awareness of hypoglycemia. Intravenously administered insulin has
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
a more rapid onset of action than subcutaneously administered insulin, requiring more close monitoring
for hypoglycemia.
5.3
Hypokalemia
All insulins, including Novolin R, cause a shift in potassium from the extracellular to
intracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratory
paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia
(e.g., patients using potassium-lowering medications and patients taking medications sensitive to serum
potassium concentrations). Monitor glucose and potassium frequently when Novolin R is administered
intravenously.
5.4
Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Non-Ketotic
Syndrome
Hyperglycemia, diabetic ketoacidosis, or hyperosmolar hyperglycemic non-ketotic syndrome
may develop in patients who take less insulin than needed to control blood glucose. These conditions
can be precipitated by illness, infection, dietary indiscretion, or omission or improper administration of
the prescribed insulin dose.
5.5
Renal or Hepatic Impairment
As with other insulins, the dose requirements for Novolin R may be reduced in patients with
renal or hepatic impairment.
5.6
Hypersensitivity and Allergic Reactions
Local Reactions - As with other insulins, patients may experience redness, swelling, or itching at
the site of injection of Novolin R. These reactions usually resolve in a few days to a few weeks, but in
some occasions, may require discontinuation of Novolin R. In some instances, these reactions may be
related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection
technique. Localized reactions and generalized myalgias have been reported with the use of meta
cresol, which is an excipient in Novolin R.
Systemic Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis may
occur with any insulin, including Novolin R. Generalized allergy to insulin may manifest as a whole
body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
5.7
Mixing of Insulins
If Novolin R is mixed with NPH human insulin, Novolin R should be drawn into the syringe first
and the mixture should be injected immediately after mixing. Insulin mixtures should not be
administered intravenously.
5.8
Antibody Production
Increases in titers of anti-insulin antibodies that react with human insulin have been observed in
patients treated with Novolin R. Data from a 12-month controlled trial in patients with type 1 diabetes
suggest that the increase in these antibodies is transient. The clinical significance of these antibodies is
not known but does not appear to cause deterioration in glycemic control or necessitate increases in
insulin dose.
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.9
Fluid retention and heart failure with concomitant use of PPAR-gamma agonists
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)
gamma agonists, can cause dose-related fluid retention, particularly when used in combination with
insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including
NOVOLIN R, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure.
If heart failure develops, it should be managed according to current standards of care, and
discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6
ADVERSE REACTIONS
•
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including
Novolin R [see Warnings and Precautions (5.2)].
•
Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with a transitory,
reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful
peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of
diabetic retinopathy and neuropathy.
•
Lipodystrophy
Long-term use of insulin, including Novolin R, can cause lipodystrophy at the site of repeated
insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and
lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection
sites within the same region to reduce the risk of lipodystrophy.
•
Weight gain
Weight gain can occur with insulin therapies, including Novolin R, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria.
•
Peripheral edema
Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is
improved by intensified insulin therapy. These symptoms are usually transitory.
•
Allergic reactions
As with other insulins, Novolin R can cause injection site reactions. Severe, life-threatening,
generalized allergy, including anaphylaxis may occur with any insulin, including Novolin R [see
Warnings and Precautions (5.6)].
Clinical Trial Experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates
reported in one clinical trial may not be easily compared to those rates reported in another clinical trial,
and may not reflect the rates actually observed in clinical practice.
Adults with type 1 or type 2 diabetes
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The incidence of adverse reactions during clinical trials comparing Novolin R and insulin aspart
in adults with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Adults with Type 1 Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an
incidence ≥ 5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 286
Insulin aspart + NPH
N=596
%
%
Hypoglycemia*
72
75
* Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms.
Table 2: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Adults with Type 2 Diabetes Mellitus Also Treated with NPH Insulin (adverse reactions with an
incidence ≥ 5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 91
Insulin aspart + NPH
N= 91
(%)
(%)
Hypoglycemia*
36
27
*Hypoglycemia was defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms.
Children and adolescents with type 1 diabetes
The incidence of adverse reactions during a 24-week clinical trial comparing Novolin R and
insulin aspart in children and adolescents with type 1 diabetes mellitus are listed in the table below.
Table 3: Adverse Reactions in a 24-Week Trial Comparing Novolin R and Insulin Aspart in
Children and Adolescents with Type 1 Diabetes Mellitus Also Treated with NPH Insulin (adverse
reactions with an incidence ≥5% in the Novolin R treatment group are listed)
Novolin R + NPH
N= 96
Insulin aspart + NPH
N= 187
(%)
(%)
Hypoglycemia*
85
79
Injection site hypertrophy
8
8
*Hypoglycemia was defined as an episode of blood glucose concentration <50 mg/dL, with or without symptoms.
Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including Novolin R [See Warnings and Precautions (5.3)]. Tables 4 and 5 summarize the incidence of
severe hypoglycemia in the Novolin R clinical trials. Severe hypoglycemia was defined as
hypoglycemia associated with central nervous system symptoms and requiring intervention of another
person or hospitalization. The rates of severe hypoglycemia in the Novolin R clinical trials (see Section
14 for a description of the study designs) were comparable for all treatment regimens (see Tables 4 and
5).
Table 4: Severe Hypoglycemia in Patients with Type 1 Diabetes
Reference ID: 3870090
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Type 1 Diabetes
Adults
24 weeks in combination
with NPH insulin
Type 1 Diabetes
Children and Adolescents
(age 6-18)
24 weeks in combination
with NPH insulin
Type 1 Diabetes
Children
(age 2-6)
24 weeks in combination
with NPH insulin
Novolin R
Insulin
Novolin R
Insulin
Novolin R
Insulin
aspart
aspart
aspart
Percent of patients
(n/total N)
19
(55/286)
18
(105/596)
9
(9/96)
6
(11/187)
12
(3/25)
8
(2/26)
Event/patient/
year
1.1
0.9
0.3
0.2
0.5
0.3
Table 5: Severe Hypoglycemia in Patients with Type 2 Diabetes
Type 2 Diabetes
Adults
24 weeks in combination with
NPH insulin
Novolin R
Insulin aspart
Percent of patients
(n/total N)
5
(5/91)
10
(9/91)
Event/patient/
year
0.2
0.3
7
DRUG INTERACTIONS
A number of medications affect glucose metabolism that may require insulin dose adjustment
and particularly close monitoring for hypoglycemia or worsening glycemic control.
• The following are examples of medications that may increase the blood glucose-lowering effect
of insulin and increase susceptibility to hypoglycemia: oral antidiabetic medications, pramlintide
acetate, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine,
monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analogs (e.g.,
octreotide), and sulfonamide antibiotics.
• The following are examples of medications that may reduce the blood glucose-lowering effect of
insulin, leading to worsening of glycemic control: corticosteroids, niacin, danazol, diuretics,
sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine
derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives),
and atypical antipsychotics.
• Beta-blockers, clonidine, and lithium salts may either potentiate or weaken the blood glucose-
lowering effect of insulin.
• Alcohol can increase susceptibility to hypoglycemia.
• Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
• The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic
medications such as beta-blockers, clonidine, guanethidine, and reserpine.
8
USE IN SPECIFIC POPULATIONS
Reference ID: 3870090
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8.1
Pregnancy
Pregnancy Category B: All pregnancies have a background risk of birth defects, loss, or other
adverse outcome regardless of drug exposure. This background risk is increased in pregnancies
complicated by hyperglycemia and may be decreased with good glycemic control. It is essential for
patients with diabetes or a history of gestational diabetes to maintain good glycemic control before
conception and throughout pregnancy. Insulin requirements may decrease during the first trimester,
generally increase during the second and third trimesters, and rapidly decline after delivery. Careful
monitoring of glucose control is important during pregnancy in patients with diabetes. Therefore,
women should be advised to tell their healthcare provider if they intend to become, or if they become,
pregnant while taking Novolin R.
No reproductive toxicity studies have been performed with Novolin R.
8.3
Nursing Mothers
It is unknown whether Novolin R is excreted in breast milk. Small amounts of human insulin are
secreted into breast milk, the significance of which is not known. Use of Novolin R is compatible with
breastfeeding, but insulin doses may need to be adjusted because lactation can reduce insulin
requirements.
8.4
Pediatric Use
The safety and effectiveness of subcutaneous injections of Novolin R have been established in
pediatric patients (ages 2 to18 years) with type 1 diabetes [see Clinical Studies (14.3)]. Novolin R has
not been studied in pediatric patients younger than 2 years of age. Novolin R has not been studied in
pediatric patients with type 2 diabetes.
In general, pediatric patients with type 1 diabetes are more susceptible to hypoglycemia than
adult patients with type 1 diabetes. As in adults, the dosage of Novolin R must be individualized in
pediatric patients based on metabolic needs and frequent monitoring of blood glucose [see Dosage and
Administration (2.1) and Warnings and Precautions (5.2)].
8.5
Geriatric Use
In 3 controlled clinical trials 18 of 1285 patients (1.4%) with type 1 diabetes treated with
Novolin R and insulin aspart were ≥65 years of age. In 4 controlled clinical trials 151 of 635 patients
(24%) with type 2 diabetes were ≥65 years of age. Therefore, conclusions are limited regarding the
efficacy and safety of Novolin R in patients ≥65 years of age, particularly in patients with type 1
diabetes. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on Novolin R have not
been performed.
Use caution in patients with advanced age, due to the potential for decreased renal function in
this population [see Warnings and Precautions (5.2 and 5.5)].
10
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and, particularly when given
intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose.
Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with
coma, seizure, or neurologic impairment can be treated with intramuscular or subcutaneous glucagon or
intravenous glucose. Sustained carbohydrate intake and observation may be necessary because
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.
[see Warnings and Precautions (5.2, 5.3)]
11
DESCRIPTION
Novolin R (Regular Human Insulin Injection [Recombinant DNA origin] United States
Pharmacopeia) is a polypeptide hormone structurally identical to native human insulin and is produced
by recombinant DNA technology, utilizing Saccharomyces cerevisiae (baker’s yeast) as the production
organism. Novolin R has the empirical formula C257H383N65O77S6 and a molecular weight of 5808. structural formula
Figure 1: Structural formula of Novolin R
Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA
origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL
and water for injection. The pH is adjusted to 7.4. Hydrochloric acid 2N or sodium hydroxide 2N may
be added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The primary activity of Novolin R is the regulation of glucose metabolism. Insulins, including
Novolin R, bind to insulin receptors on muscle and adipocytes and lower blood glucose by facilitating
the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.
12.2
Pharmacodynamics
Novolin R is a short-acting insulin. When injected subcutaneously, the glucose-lowering effect
of Novolin R begins approximately 30 minutes post-dose, is maximal between 1.5 and 3.5 hours post-
dose and terminates approximately 8 hours post-dose. The onset of action of Novolin R, when
administered intravenously, is more rapid in comparison to the subcutaneous administration. When
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
injected subcutaneously, Novolin R has a slower onset of action and longer duration of action compared
to the rapid-acting insulin analogs.
12.3
Pharmacokinetics
After single subcutaneous administration of 0.1 unit/kg of Novolin R to healthy subjects, peak
insulin concentrations occurred between 1.5 to 2.5 hours post-dose. On average, insulin concentrations
returned to baseline at around 5 hours post-dose.
The effects of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, and
smoking, on the pharmacodynamics and pharmacokinetics of Novolin R have not been studied.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
carcinogenic potential of Novolin R.
Novolin R is not mutagenic in the following in vitro tests: The chromosomal aberration assay in
human lymphocytes, the micronucleus assay in mouse polychromatic erythrocytes, and the mutation
frequency assay in Chinese hamster cells.
Standard reproduction and teratology studies in animals, including fertility assessments have not
been conducted with Novolin R.
14
CLINICAL STUDIES
Please see Section 12 CLINICAL PHARMACOLOGY for information on the pharmacokinetics
and pharmacodynamics of Novolin R.
14.1
Type 1 diabetes mellitus (adults)
Two six-month, open-label, active-controlled studies were conducted to compare the safety and
efficacy of Novolin R and insulin aspart in adults with type 1 diabetes. Insulin aspart was administered
by subcutaneous injection immediately prior to meals and Novolin R was administered by subcutaneous
injection 30 minutes before meals. Both treatment groups also received subcutaneous injections of NPH
insulin in either single or divided daily doses. Because the two study designs and results were similar,
data are shown for only one study (see Table 6)
Table 6: Subcutaneous Novolin R Administration in Type 1 Diabetes (24 weeks; N=882)
Novolin R + NPH
N=286
Insulin aspart + NPH
N=596
Baseline HbA1c (%)*
8.0 ± 1.2
7.9 ±1.1
Change from Baseline HbA1c (%)*
0.0 ± 0.8
-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group
0.2 [0.1; 0.3]
Baseline, total insulin dose (units/kg/day)*
0.7 ± 0.2
0.7 ± 0.2
End-of-Study, total insulin dose (units/kg/day)*
0.7 ± 0.2
0.7 ± 0.2
Baseline body weight (kg)*
Weight Change from baseline (kg)*
75.9 ± 13.1
0.9 ± 2.9
75.3 ± 14.5
0.5 ± 3.3
*Values are Mean ± SD
Reference ID: 3870090
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14.2
Type 2 diabetes mellitus (adults)
A six-month, open-label, active-controlled study was conducted to compare the safety and
efficacy of Novolin R and insulin aspart in adults with type 2 diabetes (Table 7). Insulin aspart was
administered by subcutaneous injection immediately prior to meals and Novolin R was administered by
subcutaneous injection 30 minutes before meals. Both treatment groups also received subcutaneous
injections of NPH insulin in either single or divided daily doses.
Table 7: Subcutaneous Novolin R Administration in Type 2 Diabetes (24 weeks; N=182)
Novolin R + NPH
N = 91
Insulin aspart + NPH
N = 91
Baseline HbA1c (%)*
7.8 ± 1.1
8.1 ± 1.2
Change from Baseline HbA1c (%)*
-0.1 ± 0.8
-0.3 ± 1.0
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group
0.1 [-0.1; 0.4]
Baseline, total insulin dose (units/kg/day)*
0.6 ± 0.3
0.6 ± 0.3
End-of-Study, total insulin dose (units/kg/day)*
0.7 ± 0.3
0.7 ± 0.3
Baseline body weight (kg)*
Weight Change from baseline (kg)*
85.8 ± 14.8
0.4 ± 3.1
88.4 ± 13.3
1.2 ± 3.0
*Values are Mean ± SD
14.3
Type 1 diabetes mellitus (children and adolescents)
A six-month, open-label, active-controlled study was conducted to compare the safety and
efficacy of Novolin R and insulin aspart in children and adolescents aged 6-18 years with type 1
diabetes (Table 8). Insulin aspart was administered by subcutaneous injection immediately prior to
meals and Novolin R was administered by subcutaneous injection 30 minutes before meals. Both
treatment groups also received subcutaneous injections of NPH insulin.
Table 8: Subcutaneous Novolin R Administration in Children and Adolescents with Type 1
Diabetes (24 weeks; N=283)
Novolin R + NPH
N=96
Insulin aspart + NPH
N=187
Baseline HbA1c (%)*
8.3 ± 1.3
8.3 ± 1.2
Change from Baseline HbA1c (%)*
0.1 ± 1.1
0.1 ± 1.0
Treatment Difference in HbA1c, Mean (95% confidence interval)
Novolin R – insulin aspart group #
0.2 [-0.1; 0.5]
Baseline, total insulin dose (units/kg/day)*
1.0 ± 0.4
1.0 ± 0.3
End-of-Study, total insulin dose (units/kg/day)*
1.2 ± 0.4
1.2 ± 0.4
Diabetic ketoacidosis n (%)
2 (2%)
10 (5%)
Baseline body weight (kg)*
Weight Change from baseline (kg)*
48.7 ± 15.8
2.4 ± 2.6
50.6 ± 19.6
2.7 ± 3.5
* Values are Mean ± SD
# The treatment difference and corresponding 95% confidence interval is based on the Analysis of Covariance Model
Novolin R and insulin aspart have also been compared in an open-label, randomized, crossover
trial in 26 children with type 1 diabetes aged 2-6 years. Patients received each treatment for 12 weeks.
Insulin aspart was administered by subcutaneous injection immediately prior to meals and Novolin R
was administered by subcutaneous injection 30 minutes before meals. Both treatment groups also
received subcutaneous injections of NPH insulin. In this study, the mean baseline HbA1c was 7.8%.
The estimated HbA1c at end of treatment was 7.6% with Novolin R and 7.7% with insulin aspart.
Reference ID: 3870090
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
Novolin R is available in 10 mL vials (NDC 0169-1833-11 and ReliOn® brand NDC 0169-1833
02). The concentration of Novolin R is 100 USP units of human insulin (rDNA origin)/mL. One vial is
provided in each sale pack.
16.2
Recommended Storage
Unopened Novolin R vials should be stored in the refrigerator (36° - 46°F [2° - 8°C]). If carried
as a spare or if refrigeration is not possible, unopened Novolin R vials can be kept at room temperature
provided they are kept as cool as possible (not above 77°F [25°C]). If kept at room temperature, Novolin
R vials must be discarded after 42 days even if they are unopened.
Do not freeze and do not use Novolin R if it has been frozen. In addition, unopened Novolin
R vials should be kept in their cartons so that they will stay clean and protected from light. They should
not be exposed to heat or light.
An opened (In use) Novolin R vial can be kept at room temperature provided it is kept as cool as
possible (below 77°F [25°C]) and away from heat or light. Do not refrigerate after first use.
Unopened and opened (In use) Novolin R vials must be discarded 42 days after they are first
kept out of the refrigerator, even if they still contain Novolin R insulin.
Table 9: Storage Conditions for Novolin R vials
Unopened
(Refrigerated)
Unopened
(Room Temperature up to 77°F [25°C])
Opened (In use)
(Room Temperature below 77°F
[25°C])
Until expiration date
42 days*
42 days*
* The total time allowed at room temperature (up to 25°C) is 42 days regardless of whether the product is unopened or
opened (In use)
Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION (2.3) are stable at
room temperature for 24 hours. A certain amount of insulin will be initially adsorbed to the material of
the infusion bag.
Always remove the needle after each injection. Always use a new disposable syringe and needle
for each injection to prevent contamination.
Never use insulin after the expiry date which is printed on the label and carton.
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information and Instructions for Use)
17.1
Instructions for All Patients
Maintenance of normal or near-normal glucose control is a treatment goal in diabetes mellitus
and has been associated with a reduction in some diabetic complications. Patients should be informed
about potential risks and benefits of Novolin R therapy including possible adverse reactions. Patients
should also be offered continued education and advice on insulin therapies, injection technique, life
style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition
and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin
Reference ID: 3870090
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therapy, timing of dose, instruction in the use of injection devices, and proper storage of insulin. Patients
should be informed that frequent, patient-performed blood glucose measurements are needed to achieve
optimal glycemic control and avoid both hyper- and hypoglycemia.
The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This
may present a risk in situations where these abilities are especially important, such as driving or
operating other machinery. Patients who have frequent hypoglycemia or reduced or absent warning
signs of hypoglycemia should be advised to use caution when driving or operating machinery. Female
patients should be advised to tell their physician if they intend to become, or if they become pregnant.
Patients should be instructed to always carefully check that they are administering the correct
insulin to avoid medication errors between Novolin R and other insulins. Patients should check the label
for the drug name Novolin R, the enlarged R letter, and the blue horizontal bar. If a prescription for
Novolin R is needed, it should be written clearly to avoid confusion with other insulin products.
Novolin® is a registered trademark of Novo Nordisk A/S.
ReliOn® is a registered trademark of Wal-Mart Stores, Inc. and is used under license by Novo Nordisk
Inc.
© 2002-20XX Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
ReliOn® brand manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For Wal-Mart Stores Inc.
For information about Novolin R contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
www.novonordisk-us.com
1-800-727-6500
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
®
NOVOLIN R (NO-voe-lin)
(Regular, Human Insulin Injection [recombinant DNA origin] USP)
solution for subcutaneous injection
Read the Patient Information leaflet that comes with Novolin® R before you
start taking it and each time you get a refill. There may be new information.
This leaflet does not take the place of talking with your healthcare provider
about your diabetes or your treatment. Make sure you know how to manage
your diabetes. Ask your healthcare provider if you have any questions about
managing your diabetes.
What is Novolin® R?
Novolin® R is a man-made insulin (recombinant DNA origin) that is used to
control high blood sugar in adults and children with diabetes mellitus.
Who should not use Novolin® R?
Do not take Novolin® R if:
•
Your blood sugar is too low (hypoglycemia). After treating your low
blood sugar, follow your healthcare provider’s instructions on the use of
Novolin® R.
•
You are allergic to any of the ingredients in Novolin® R. See the end of
this leaflet for a complete list of ingredients in Novolin® R. Check with
your healthcare provider if you are not sure.
What should I tell my healthcare provider before taking Novolin®
R?
Before you take Novolin® R, tell your healthcare providers if you:
•
have liver or kidney problems.
•
take any other medicines, especially ones commonly called TZDs
(thiazolidinediones).
•
have heart failure or other heart problems. If you have heart
failure, it may get worse while you take TZDs with Novolin® R.
•
have any other medical conditions. Medical conditions can affect
your insulin needs and your dose of Novolin® R.
•
are pregnant or plan to become pregnant. Talk to your healthcare
provider if you are pregnant or plan to become pregnant. You and your
healthcare provider should talk about the best way to manage your
diabetes while you are pregnant.
•
are breast-feeding or plan to breast-feed. It is not known if
Novolin® R passes into breast milk. You and your healthcare provider
should decide if you will take Novolin® R while you breast-feed.
Reference ID: 3870090
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all of the medicines you take,
including prescription and nonprescription medicines, vitamins and herbal
supplements. Novolin® R may affect the way other medicines work, and other
medicines may affect how Novolin® R works.
Know the medicines you take. Keep a list of your medicines with you to
show all your healthcare providers and pharmacist when you get a new
medicine.
How should I take Novolin® R?
•
Novolin® R comes in 10 mL vials for use with a syringe.
•
Take Novolin® R exactly as prescribed.
•
Your healthcare provider will tell you how much Novolin® R to take and
when to take it.
•
Do not make any changes to your dose or type of insulin unless you are
told to do so by your healthcare provider.
•
The effects of Novolin® R usually start working within about 30 minutes
after your injection and usually lasts for up to 8 hours.
•
While using Novolin® R your healthcare provider may change
your total dose of insulin, your dose of Novolin® R, your dose of longer-
acting insulin, or the number of injections of insulin you use.
•
Do not mix Novolin® R with any insulins other than NPH in the same
syringe.
•
Inject Novolin® R under your skin (subcutaneously) of your
abdomen (stomach area), upper arms, buttocks or upper legs.
Novolin® R may affect your blood sugar levels faster if you inject it into
the skin of your abdomen (stomach area). Never inject Novolin® R
into a vein or into a muscle.
•
Do not use Novolin® R in an insulin pump.
•
Change (rotate) your injection site within the chosen area (for
example, stomach or upper arm) with each dose. Do not inject
into the same spot for each injection.
•
Read the instructions for use that comes with your Novolin® R.
Talk to your healthcare provider if you have any questions. Your
healthcare provider should show you how to inject Novolin® R before
you start taking it.
•
If you take too much Novolin® R, your blood sugar may fall too
low (hypoglycemia). You can treat mild low blood sugar
(hypoglycemia) by drinking or eating something sugary right away (fruit
juice, sugar candies, or glucose tablets). It is important to treat low
blood sugar (hypoglycemia) right away because it could get worse and
could lead to passing out (loss of consciousness), seizures and death.
Reference ID: 3870090
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For current labeling information, please visit https://www.fda.gov/drugsatfda
•
If you forget to take your dose of Novolin® R, your blood sugar
may go too high (hyperglycemia). If high blood sugar
(hyperglycemia) is not treated it can lead to serious problems, like loss
of consciousness (passing out), coma or even death. Follow your
healthcare provider’s instructions for treating high blood sugar. Know
your symptoms of high blood sugar which may include:
• increased thirst
• high amounts of sugar and
• frequent urination and
ketones in your urine
dehydration
• nausea, vomiting (throwing
• confusion or drowsiness
up) or stomach pain
• loss of appetite
• a hard time breathing
• fruity smell on breath
•
Do not share needles or syringes with others. You may give an
infection to them or get an infection from them.
•
Check your blood sugar levels. Ask your healthcare provider what
your blood sugars should be and how often you should check your
blood sugar levels for hypoglycemia (too low blood sugar) and
hyperglycemia (too high blood sugar).
Your insulin dosage may need to change because of:
•
illness
•
change in diet
•
stress
•
change in physical activity or
•
other medicines you take
exercise
•
surgery
See the end of this patient information for instructions about preparing and
giving the injection.
What should I avoid while taking Novolin® R?
•
Drinking alcohol. Alcohol may affect your blood sugar when you take
Novolin® R. This could lead to blood sugar that is too low
(hypoglycemia).
•
Driving and operating machinery. You may have trouble paying
attention or reacting if you have low blood sugar (hypoglycemia). Be
careful when you drive a car or operate machinery. Ask your
healthcare provider if it is alright for you to drive if you often have:
• low blood sugar
• decreased or no warning signs of low blood sugar
What are the possible side effects of Novolin® R?
Novolin® R may cause serious side effects, including:
• Low blood sugar (hypoglycemia).
The general symptoms of low blood sugar (hypoglycemia) may be one or
more of the following:
• sweating
•
shakiness
• dizziness or lightheadedness
•
hunger
Reference ID: 3870090
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• fast heart beat
•
blurred vision
• tingling in your hands, feet,
•
slurred speech
lips or tongue
•
anxiety, irritability or mood
• trouble concentrating or
changes
confusion
•
headache
Very low blood sugar (hypoglycemia) can cause loss of consciousness
(passing out), seizures, temporary or permanent brain problems or death.
Talk to your healthcare provider about how to tell if you have low blood
sugar and what to do if this happens while taking Novolin® R. Know your
symptoms of low blood sugar. Follow your healthcare provider’s instructions
for treating low blood sugar.
Talk to your healthcare provider if low blood sugar is a problem for you.
Your dose of Novolin® R may need to be changed.
• Low blood potassium (hypokalemia). A decrease of potassium in
your blood can cause breathing problems, a change in your heartbeat
and death.
• Serious allergic reaction (whole body reaction). You can have a
serious allergic reaction that may be life-threatening. Get
medical help right away if you have any of these symptoms of an
allergic reaction:
• a rash over your body
• have trouble breathing
• a fast heartbeat
• sweating
• feel faint
• Swelling of your hands and feet.
• Heart Failure. Taking certain diabetes pills called thiazolidinediones or
“TZDs” with Novolin® R may cause heart failure in some people. This
can happen even if you have never had heart failure or heart problems
before. If you already have heart failure it may get worse while you
take TZDs with Novolin® R. Your healthcare provider should monitor
you closely while you are taking TZDs with Novolin® R. Tell your
healthcare provider if you have any new or worse symptoms of heart
failure including:
• shortness of breath
• swelling of your ankles or feet
• sudden weight gain
Treatment with TZDs and Novolin® R may need to be adjusted or
stopped by your healthcare provider if you have new or worse heart
failure.
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other side effects of Novolin® R may include:
• Reactions at the injection site (local allergic reaction). You may
get redness, swelling, and itching at the injection site. If you keep
having skin reactions, or they are serious, talk to your healthcare
provider. You may need to stop using Novolin® R and use a different
insulin. Do not inject insulin into skin that is red, swollen, or itchy.
• Changes at the injection site (lipodystrophy). The fatty tissue
under the skin may shrink (lipoatrophy) or thicken (lipohypertrophy) at
the injection site. Change (rotate) the site where you inject your insulin
to help reduce the chance of developing these skin changes. Do not
inject insulin into this type of skin.
• Weight gain.
• Swelling of your arms and legs.
Tell your healthcare provider if you have any side effect that bothers you or
that does not go away.
These are not all of the possible side effects from Novolin® R. Ask your
healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store Novolin® R?
Unopened Novolin® R:
•
Unopened Novolin® R should be kept in the refrigerator
between 36°F to 46°F (2° to 8°C). Unopened vials can be used
until the expiration date on the Novolin® R label, if the medicine has
been stored in a refrigerator.
•
If refrigeration is not possible or if you want to carry a spare Novolin®
R vial you can keep the unopened vial at room temperature for up to
42 days, as long as it is kept at or below 77°F (25°C). Throw away the
vial 42 days after it is first kept out of the refrigerator, even if the vial
is unopened.
•
Do not freeze. Do not use Novolin® R if it has been frozen.
•
Keep unopened Novolin® R in the carton to protect it from light.
Novolin® R in use:
•
Keep at room temperature below 77°F (25°C).
•
Keep vials away from heat or light.
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Do not refrigerate an opened vial.
•
Throw away the vial 42 days after it is first kept out of the refrigerator,
even if there is insulin left in the vial.
Never use insulin after the expiration date which is printed on the
label and carton.
General information about Novolin® R
Medicines are sometimes prescribed for conditions that are not mentioned in
the patient leaflet. Do not use Novolin® R for a condition for which it was not
prescribed. Do not give Novolin® R to other people, even if they have the
same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Novolin® R. If
you would like more information about Novolin® R or diabetes, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for
information about Novolin® R that is written for healthcare professionals.
For more information about Novolin® R, call 1-800-727-6500 or go to
www.novonordisk-us.com.
What are the ingredients in Novolin® R?
Active ingredient: Regular Human Insulin Injection (recombinant DNA
origin) USP.
Inactive ingredients: glycerol, metacresol, zinc chloride, water for
injection, hydrochloric acid and sodium hydroxide may be added.
This Patient Information has been approved by the U.S. Food and Drug
Administration.
Date of issue: XX/20XX
Novolin® is a registered trademark of Novo Nordisk A/S.
© 2002-20XX Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about Novolin® R contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1-800-727-6500
www.novonordisk-us.com
Reference ID: 3870090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:20.739767
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019938s074lbl.pdf', 'application_number': 19938, 'submission_type': 'SUPPL ', 'submission_number': 74}
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12,081
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NDA 19-941/S-018
Page 3
DESCRIPTION
EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is an emulsion in which the oil phase is a eutectic
mixture of lidocaine and prilocaine in a ratio of 1:1 by weight. This eutectic mixture has a melting
point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as
crystals. It is packaged in 5 gram and 30 gram tubes.
Lidocaine is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl), has an
octanol: water partition ratio of 43 at pH 7.4, and has the following structure:
Prilocaine is chemically designated as propanamide, N-(2-methylphenyl)-2-(propylamino), has an
octanol: water partition ratio of 25 at pH 7.4, and has the following structure:
Each gram of EMLA Cream contains lidocaine 25 mg, prilocaine 25 mg, polyoxyethylene fatty acid
esters (as emulsifiers), carboxypolymethylene (as a thickening agent), sodium hydroxide to adjust to a
pH approximating 9, and purified water to 1 gram. EMLA Cream contains no preservative, however it
passes the USP antimicrobial effectiveness test due to the pH. The specific gravity of EMLA Cream is
1.00.
CLINICAL PHARMACOLOGY
Mechanism of Action:
EMLA Cream (lidocaine 2.5% and prilocaine 2.5%), applied to intact skin under occlusive dressing,
provides dermal analgesia by the release of lidocaine and prilocaine from the cream into the epidermal
and dermal layers of the skin and by the accumulation of lidocaine and prilocaine in the vicinity of
dermal pain receptors and nerve endings. Lidocaine and prilocaine are amide-type local anesthetic
agents. Both lidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes
required for the initiation and conduction of impulses, thereby effecting local anesthetic action.
The onset, depth and duration of dermal analgesia on intact skin provided by EMLA Cream depend
primarily on the duration of application. To provide sufficient analgesia for clinical procedures such as
intravenous catheter placement and venipuncture, EMLA Cream should be applied under an occlusive
dressing for at least 1 hour. To provide dermal analgesia for clinical procedures such as split skin graft
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 4
harvesting, EMLA Cream should be applied under occlusive dressing for at least 2 hours. Satisfactory
dermal analgesia is achieved 1 hour after application, reaches maximum at 2 to 3 hours, and persists
for 1 to 2 hours after removal. Absorption from the genital mucosa is more rapid and onset time is
shorter (5 to 10 minutes) than after application to intact skin. After a 5 to 10 minute application of
EMLA Cream to female genital mucosa, the average duration of effective analgesia to an argon laser
stimulus (which produced a sharp, pricking pain) was 15 to 20 minutes (individual variations in the
range of 5 to 45 minutes).
Dermal application of EMLA Cream may cause a transient, local blanching followed by a transient,
local redness or erythema.
Pharmacokinetics:
EMLA Cream is a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% formulated as an oil in
water emulsion. In this eutectic mixture, both anesthetics are liquid at room temperature (see
DESCRIPTION) and the penetration and subsequent systemic absorption of both prilocaine and
lidocaine are enhanced over that which would be seen if each component in crystalline form was
applied separately as a 2.5% topical cream.
Absorption: The amount of lidocaine and prilocaine systemically absorbed from EMLA Cream is
directly related to both the duration of application and to the area over which it is applied. In two
pharmacokinetic studies, 60 g of EMLA Cream (1.5 g lidocaine and 1.5 g prilocaine) was applied to
400 cm2 of intact skin on the lateral thigh and then covered by an occlusive dressing. The subjects
were then randomized such that one-half of the subjects had the occlusive dressing and residual cream
removed after 3 hours, while the remainder left the dressing in place for 24 hours. The results from
these studies are summarized below.
TABLE 1
Absorption of Lidocaine and Prilocaine from EMLA Cream: Normal Volunteers (N=16)
EMLA
Cream
(g)
Area
(cm2)
Time
on
(hrs)
Drug
Content
(mg)
Absorbed
(mg)
Cmax
(µg/mL)
Tmax
(hr)
60
400
3
lidocaine
1500
54
0.12
4
prilocaine
1500
92
0.07
4
60
400
24*
lidocaine
1500
243
0.28
10
prilocaine
1500
503
0.14
10
* Maximum recommended duration of exposure is 4 hours.
When 60 g of EMLA Cream was applied over 400 cm2 for 24 hours, peak blood levels of lidocaine are
approximately 1/20 the systemic toxic level. Likewise, the maximum prilocaine level is about 1/36 the
toxic level. In a pharmacokinetic study, EMLA Cream was applied to penile skin in 20 adult male
patients in doses ranging from 0.5 g to 3.3 g for 15 minutes. Plasma concentrations of lidocaine and
prilocaine following EMLA Cream application in this study were consistently low (2.5-16 ng/mL for
lidocaine and 2.5-7 ng/mL for prilocaine). The application of EMLA Cream to broken or inflamed
skin, or to 2,000 cm2 or more of skin where more of both anesthetics are absorbed, could result in
higher plasma levels that could, in susceptible individuals, produce a systemic pharmacologic
response.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 5
The absorption of EMLA Cream applied to genital mucous membranes was studied in two open-label
clinical trials. Twenty-nine patients received 10 g of EMLA Cream applied for 10 to 60 minutes in the
vaginal fornices. Plasma concentrations of lidocaine and prilocaine following EMLA Cream
application in these studies ranged from 148 to 641 ng/mL for lidocaine and 40 to 346 ng/mL for
prilocaine and time to reach maximum concentration (tmax) ranged from 21 to 125 minutes for
lidocaine and from 21 to 95 minutes for prilocaine. These levels are well below the concentrations
anticipated to give rise to systemic toxicity (approximately 5000 ng/mL for lidocaine and prilocaine).
Distribution: When each drug is administered intravenously, the steady-state volume of distribution is
1.1 to 2.1 L/kg (mean 1.5, ±0.3 SD, n=13) for lidocaine and is 0.7 to 4.4 L/kg (mean 2.6, ± 1.3 SD,
n=13) for prilocaine. The larger distribution volume for prilocaine produces the lower plasma
concentrations of prilocaine observed when equal amounts of prilocaine and lidocaine are
administered. At concentrations produced by application of EMLA Cream, lidocaine is approximately
70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma
concentrations (1 to 4 µg/mL of free base) the plasma protein binding of lidocaine is concentration
dependent. Prilocaine is 55% bound to plasma proteins. Both lidocaine and prilocaine cross the
placental and blood brain barrier, presumably by passive diffusion.
Metabolism: It is not known if lidocaine or prilocaine are metabolized in the skin. Lidocaine is
metabolized rapidly by the liver to a number of metabolites including monoethylglycinexylidide
(MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less
potent than that of lidocaine. The metabolite, 2,6-xylidine, has unknown pharmacologic activity.
Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36%
and from 5 to 11% of lidocaine concentrations, respectively. Prilocaine is metabolized in both the liver
and kidneys by amidases to various metabolites including ortho-toluidine and N-n-propylalanine. It is
not metabolized by plasma esterases. The ortho-toluidine metabolite has been shown to be
carcinogenic in several animal models (see Carcinogenesis subsection of PRECAUTIONS). In
addition, ortho-toluidine can produce methemoglobinemia following systemic doses of prilocaine
approximating 8 mg/kg (see ADVERSE REACTIONS). Very young patients, patients with glucose-6-
phosphate dehydrogenase deficiencies and patients taking oxidizing drugs such as antimalarials and
sulfonamides are more susceptible to methemoglobinemia (see Methemoglobinemia subsection of
PRECAUTIONS).
Elimination: The terminal elimination half-life of lidocaine from the plasma following IV
administration is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). More than 98% of an
absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. The systemic
clearance is 10 to 20 mL/min/kg (mean 13, ±3 SD, n=13). The elimination half-life of prilocaine is
approximately 10 to 150 minutes (mean 70, ±48 SD, n=13). The systemic clearance is 18 to 64
mL/min/kg (mean 38, ±15 SD, n=13). During intravenous studies, the elimination half-life of
lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients
(1.5 hours). No studies are available on the intravenous pharmacokinetics of prilocaine in elderly
patients.
Pediatrics: Some pharmacokinetic (PK) data are available in infants (1 month to <2 years old) and
children (2 to <12 years old). One PK study was conducted in 9 full-term neonates (mean age: 7 days
and mean gestational age: 38.8 weeks). The study results show that neonates had comparable plasma
lidocaine and prilocaine concentrations and blood methemoglobin concentrations as those found in
previous pediatric PK studies and clinical trials. There was a tendency towards an increase in
This label may not be the latest approved by FDA.
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NDA 19-941/S-018
Page 6
methemoglobin formation. However, due to assay limitations and very little amount of blood that
could be collected from neonates, large variations in the above reported concentrations were found.
Special Populations: No specific PK studies were conducted. The half-life may be increased in
cardiac or hepatic dysfunction. Prilocaine’s half-life also may be increased in hepatic or renal
dysfunction since both of these organs are involved in prilocaine metabolism.
Clinical Studies
EMLA Cream application in adults prior to IV cannulation or venipuncture was studied in 200 patients
in four clinical studies in Europe. Application for at least 1 hour provided significantly more dermal
analgesia than placebo cream or ethyl chloride. EMLA Cream was comparable to subcutaneous
lidocaine, but was less efficacious than intradermal lidocaine. Most patients found EMLA Cream
treatment preferable to lidocaine infiltration or ethyl chloride spray.
EMLA Cream was compared with 0.5% lidocaine infiltration prior to skin graft harvesting in one open
label study in 80 adult patients in England. Application of EMLA Cream for 2 to 5 hours provided
dermal analgesia comparable to lidocaine infiltration.
EMLA Cream application in children was studied in seven non-US studies (320 patients) and one US
study (100 patients). In controlled studies, application of EMLA Cream for at least 1 hour with or
without presurgical medication prior to needle insertion provided significantly more pain reduction
than placebo. In children under the age of seven years, EMLA Cream was less effective than in older
children or adults.
EMLA Cream was compared with placebo in the laser treatment of facial port-wine stains in 72
pediatric patients (ages 5–16). EMLA Cream was effective in providing pain relief during laser
treatment.
EMLA Cream alone was compared with EMLA Cream followed by lidocaine infiltration and lidocaine
infiltration alone prior to cryotherapy for the removal of male genital warts. The data from 121 patients
demonstrated that EMLA Cream was not effective as a sole anesthetic agent in managing the pain from
the surgical procedure. The administration of EMLA Cream prior to lidocaine infiltration provided
significant relief of discomfort associated with local anesthetic infiltration and thus was effective in the
overall reduction of pain from the procedure only when used in conjunction with local anesthetic
infiltration of lidocaine.
EMLA Cream was studied in 105 full term neonates (gestational age: 37 weeks) for blood drawing and
circumcision procedures. When considering the use of EMLA Cream in neonates, the primary
concerns are the systemic absorption of the active ingredients and the subsequent formation of
methemoglobin. In clinical studies performed in neonates, the plasma levels of lidocaine, prilocaine,
and methemoglobin were not reported in a range expected to cause clinical symptoms.
Local dermal effects associated with EMLA Cream application in these studies on intact skin included
paleness, redness and edema and were transient in nature (see ADVERSE REACTIONS).
The application of EMLA Cream on genital mucous membranes for minor, superficial surgical
procedures (eg, removal of condylomata acuminata) was studied in 80 patients in a placebo-controlled
clinical trial (60 patients received EMLA Cream and 20 patients received placebo). EMLA Cream (5
to 10 g) applied between 1 and 75 minutes before surgery, with a median time of 15 minutes, provided
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NDA 19-941/S-018
Page 7
effective local anesthesia for minor superficial surgical procedures. The greatest extent of analgesia,
as measured by VAS scores, was attained after 5 to 15 minutes’ application. The application of EMLA
Cream to genital mucous membranes as pretreatment for local anesthetic infiltration was studied in a
double-blind, placebo-controlled study in 44 female patients (21 patients received EMLA Cream and
23 patients received placebo) scheduled for infiltration prior to a surgical procedure of the external vulva
or genital mucosa. EMLA Cream applied to the genital mucous membranes for 5 to 10 minutes resulted
in adequate topical anesthesia for local anesthetic injection.
Individualization of Dose: The dose of EMLA Cream that provides effective analgesia depends on
the duration of the application over the treated area.
All pharmacokinetic and clinical studies employed a thick layer of EMLA Cream (1–2 g/10 cm2). The
duration of application prior to venipuncture was 1 hour. The duration of application prior to taking
split thickness skin grafts was 2 hours. A thinner application has not been studied and may result in
less complete analgesia or a shorter duration of adequate analgesia.
The systemic absorption of lidocaine and prilocaine is a side effect of the desired local effect. The
amount of drug absorbed depends on surface area and duration of application. The systemic blood
levels depend on the amount absorbed and patient size (weight) and the rate of systemic drug
elimination. Long duration of application, large treatment area, small patients, or impaired elimination
may result in high blood levels. The systemic blood levels are typically a small fraction (1/20 to 1/36)
of the blood levels that produce toxicity. Table 2 below gives maximum recommended doses,
application areas, and application times for infants and children.
TABLE 2
EMLA CREAM MAXIMUM RECOMMENDED DOSE, APPLICATION AREA, AND APPLICATION TIME BY
AGE AND WEIGHT*
For Infants and Children Based on Application to Intact Skin
Age and Body Weight
Requirements
Maximum
Total
Dose of
EMLA
Cream
Maximum
Application
Area**
Maximum
Application
Time
0 up to 3 months or < 5 kg
1 g
10 cm2
1 hour
3 up to 12 months and > 5 kg
2 g
20 cm2
4 hours
1 to 6 years and > 10 kg
10 g
100 cm2
4 hours
7 to 12 years and > 20 kg
20 g
200 cm2
4 hours
Please note: If a patient greater than 3 months old does not meet the minimum weight requirement, the maximum total dose of EMLA Cream should be
restricted to that which corresponds to the patient’s weight.
* These are broad guidelines for avoiding systemic toxicity in applying EMLA Cream to patients with normal intact skin and with normal renal and
hepatic function.
** For more individualized calculation of how much lidocaine and prilocaine may be absorbed, physicians can use the following estimates of lidocaine
and prilocaine absorption for children and adults:
The estimated mean (±SD) absorption of lidocaine is 0.045 (±0.016) mg/cm2/hr.
The estimated mean (±SD) absorption of prilocaine is 0.077 (±0.036) mg/cm2/hr.
An I.V. antiarrhythmic dose of lidocaine is 1 mg/kg (70 mg/70 kg) and gives a blood level of about 1
µg/mL. Toxicity would be expected at blood levels above 5 µg/mL. Smaller areas of treatment are
recommended in a debilitated patient, a small child or a patient with impaired elimination. Decreasing
the duration of application is likely to decrease the analgesic effect.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 8
INDICATIONS AND USAGE
EMLA Cream (a eutectic mixture of lidocaine 2.5% and prilocaine 2.5%) is indicated as a topical
anesthetic for use on:
- normal intact skin for local analgesia.
- genital mucous membranes for superficial minor surgery and as pretreatment for infiltration
anesthesia.
EMLA Cream is not recommended in any clinical situation when penetration or migration beyond the
tympanic membrane into the middle ear is possible because of the ototoxic effects observed in animal
studies (see WARNINGS).
CONTRAINDICATIONS
EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is contraindicated in patients with a known history
of sensitivity to local anesthetics of the amide type or to any other component of the product.
WARNINGS
Application of EMLA Cream to larger areas or for longer times than those recommended could result
in sufficient absorption of lidocaine and prilocaine resulting in serious adverse effects (see
Individualization of Dose).
Patients treated with class III anti-arrhythmic drugs (eg, amiodarone, bretylium, sotalol, dofetilide)
should be under close surveillance and ECG monitoring considered, because cardiac effects may be
additive.
Studies in laboratory animals (guinea pigs) have shown that EMLA Cream has an ototoxic effect when
instilled into the middle ear. In these same studies, animals exposed to EMLA Cream only in the
external auditory canal, showed no abnormality. EMLA Cream should not be used in any clinical
situation when its penetration or migration beyond the tympanic membrane into the middle ear is
possible.
Methemoglobinemia: EMLA Cream should not be used in those rare patients with congenital or
idiopathic methemoglobinemia and in infants under the age of twelve months who are receiving
treatment with methemoglobin-inducing agents.
Very young patients or patients with glucose-6-phosphate dehydrogenase deficiencies are more
susceptible to methemoglobinemia.
Patients taking drugs associated with drug-induced methemoglobinemia such as sulfonamides,
acetaminophen, acetanilid, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and
nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic acid, phenacetin,
phenobarbital, phenytoin, primaquine, quinine, are also at greater risk for developing
methemoglobinemia.
There have been reports of significant methemoglobinemia (20-30%) in infants and children following
excessive applications of EMLA Cream. These cases involved the use of large doses, larger than
recommended areas of application, or infants under the age of 3 months who did not have fully mature
enzyme systems. In addition, a few of these cases involved the concomitant administration of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 9
methemoglobin-inducing agents. Most patients recovered spontaneously after removal of the cream.
Treatment with IV methylene blue may be effective if required.
Physicians are cautioned to make sure that parents or other caregivers understand the need for careful
application of EMLA Cream, to ensure that the doses and areas of application recommended in Table 2
are not exceeded (especially in children under the age of 3 months) and to limit the period of
application to the minimum required to achieve the desired anesthesia.
Neonates and infants up to 3 months of age should be monitored for Met-Hb levels before, during, and
after the application of EMLA Cream, provided the test results can be obtained quickly.
PRECAUTIONS
General:
Repeated doses of EMLA Cream may increase blood levels of lidocaine and prilocaine. EMLA Cream
should be used with caution in patients who may be more sensitive to the systemic effects of lidocaine
and prilocaine including acutely ill, debilitated, or elderly patients.
EMLA Cream should not be applied to open wounds.
Care should be taken not to allow EMLA Cream to come in contact with the eye because animal
studies have demonstrated severe eye irritation. Also the loss of protective reflexes can permit corneal
irritation and potential abrasion. Absorption of EMLA Cream in conjunctival tissues has not been
determined. If eye contact occurs, immediately wash out the eye with water or saline and protect the
eye until sensation returns.
Patients allergic to paraaminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not
shown cross sensitivity to lidocaine and/or prilocaine; however, EMLA Cream should be used with
caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain.
Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally,
are at greater risk of developing toxic plasma concentrations of lidocaine and prilocaine.
Lidocaine and prilocaine have been shown to inhibit viral and bacterial growth. The effect of EMLA
Cream on intradermal injections of live vaccines has not been determined.
Information for Patients: When EMLA Cream is used, the patient should be aware that the
production of dermal analgesia may be accompanied by the block of all sensations in the treated skin.
For this reason, the patient should avoid inadvertent trauma to the treated area by scratching, rubbing,
or exposure to extreme hot or cold temperatures until complete sensation has returned.
EMLA Cream should not be applied near the eyes or on open wounds.
Drug Interactions: EMLA Cream should be used with caution in patients receiving Class I
antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and
potentially synergistic.
Prilocaine may contribute to the formation of methemoglobin in patients treated with other
drugs known to cause this condition (see Methemoglobinemia subsection of WARNINGS).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 10
Specific interaction studies with lidocaine/prilocaine and class III anti-arrhythmic drugs (eg,
amiodarone, bretylium, sotalol, dofetilide) have not been performed, but caution is advised (see
WARNINGS).
Should EMLA Cream be used concomitantly with other products containing lidocaine and/or
prilocaine, cumulative doses from all formulations must be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Long-term studies in animals designed to evaluate the carcinogenic potential of
lidocaine and prilocaine have not been conducted.
Metabolites of prilocaine have been shown to be carcinogenic in laboratory animals. In the animal
studies reported below, doses or blood levels are compared with the Single Dermal Administration
(SDA) of 60 g of EMLA Cream to 400 cm2 for 3 hours to a small person (50 kg). The typical
application of EMLA Cream for one or two treatments for venipuncture sites (2.5 or 5 g) would be
1/24 or 1/12 of that dose in an adult or about the same mg/kg dose in an infant.
Chronic oral toxicity studies of ortho-toluidine, a metabolite of prilocaine, in mice (450 to 7200
mg/m2; 60 to 960 times SDA) and rats (900 to 4,800 mg/m2; 60 to 320 times SDA) have shown that
ortho-toluidine is a carcinogen in both species. The tumors included hepatocarcinomas/adenomas in
female mice, multiple occurrences of hemangiosarcomas/hemangiomas in both sexes of mice,
sarcomas of multiple organs, transitional-cell carcinomas/papillomas of urinary bladder in both sexes
of rats, subcutaneous fibromas/fibrosarcomas and mesotheliomas in male rats, and mammary gland
fibroadenomas/adenomas in female rats. The lowest dose tested (450 mg/m2 in mice, 900 mg/m2 in
rats, 60 times SDA) was carcinogenic in both species. Thus the no-effect dose must be less than 60
times SDA. The animal studies were conducted at 150 to 2,400 mg/kg in mice and at 150 to 800 mg/kg
in rats. The dosages have been converted to mg/m2 for the SDA calculations above.
Mutagenesis: The mutagenic potential of lidocaine HCl has been tested in a bacterial reverse (Ames)
assay in Salmonella, an in vitro chromosomal aberration assay using human lymphocytes and in an in
vivo micronucleus test in mice. There was no indication of mutagenicity or structural damage to
chromosomes in these tests.
Ortho-toluidine, a metabolite of prilocaine, at a concentration of 0.5 µg/mL was genotoxic in
Escherichia coli DNA repair and phage-induction assays. Urine concentrates from rats treated with
ortho-toluidine (300 mg/kg orally; 300 times SDA) were mutagenic when examined in Salmonella
typhimurium in the presence of metabolic activation. Several other tests on ortho-toluidine, including
reverse mutations in five different Salmonella typhimurium strains in the presence or absence of
metabolic activation and a study to detect single strand breaks in DNA of V79 Chinese hamster cells,
were negative.
Impairment of Fertility: See Use in Pregnancy.
Use in Pregnancy: Teratogenic Effects: Pregnancy Category B.
Reproduction studies with lidocaine have been performed in rats and have revealed no evidence of
harm to the fetus (30 mg/kg subcutaneously; 22 times SDA). Reproduction studies with prilocaine
have been performed in rats and have revealed no evidence of impaired fertility or harm to the fetus
(300 mg/kg intramuscularly; 188 times SDA). There are, however, no adequate and well-controlled
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 11
studies in pregnant women. Because animal reproduction studies are not always predictive of human
response, EMLA Cream should be used during pregnancy only if clearly needed.
Reproduction studies have been performed in rats receiving subcutaneous administration of an aqueous
mixture containing lidocaine HCl and prilocaine HCl at 1:1 (w/w). At 40 mg/kg each, a dose
equivalent to 29 times SDA lidocaine and 25 times SDA prilocaine, no teratogenic, embryotoxic or
fetotoxic effects were observed.
Labor and Delivery: Neither lidocaine nor prilocaine are contraindicated in labor and delivery.
Should EMLA Cream be used concomitantly with other products containing lidocaine and/or
prilocaine, cumulative doses from all formulations must be considered.
Nursing Mothers: Lidocaine, and probably prilocaine, are excreted in human milk. Therefore,
caution should be exercised when EMLA Cream is administered to a nursing mother since the milk:
plasma ratio of lidocaine is 0.4 and is not determined for prilocaine.
Pediatric Use: Controlled studies of EMLA Cream in children under the age of seven years have
shown less overall benefit than in older children or adults. These results illustrate the importance of
emotional and psychological support of younger children undergoing medical or surgical procedures.
EMLA Cream should be used with care in patients with conditions or therapy associated with
methemoglobinemia (see Methemoglobinemia subsection of WARNINGS).
When using EMLA Cream in young children, especially infants under the age of 3 months, care must
be taken to insure that the caregiver understands the need to limit the dose and area of application, and
to prevent accidental ingestion (see DOSAGE AND ADMINISTRATION and Methemoglobinemia).
In neonates (minimum gestation age: 37 weeks) and children weighing less than 20 kg, the area
and duration of application should be limited (see TABLE 2 in Individualization of Dose).
Studies have not demonstrated the efficacy of EMLA Cream for heel lancing in neonates.
Geriatric Use: Of the total number of patients in clinical studies of EMLA Cream, 180 were age 65
to 74 and 138 were 75 and over. No overall differences in safety or efficacy were observed between
these patients and younger patients. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.
Plasma levels of lidocaine and prilocaine in geriatric and non-geriatric patients following application
of a thick layer of EMLA Cream are very low and well below potentially toxic levels. However, there
are no sufficient data to evaluate quantitative differences in systemic plasma levels of lidocaine and
prilocaine between geriatric and non-geriatric patients following application of EMLA Cream.
Consideration should be given for those elderly patients who have enhanced sensitivity to systemic
absorption. (See PRECAUTIONS.)
After intravenous dosing, the elimination half-life of lidocaine is significantly longer in elderly patients
(2.5 hours) than in younger patients (1.5 hours). (See CLINICAL PHARMACOLOGY.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 12
ADVERSE REACTIONS
Localized Reactions: During or immediately after treatment with EMLA Cream on intact skin, the
skin at the site of treatment may develop erythema or edema or may be the locus of abnormal
sensation. Rare cases of discrete purpuric or petechial reactions at the application site have been
reported. Rare cases of hyperpigmentation following the use of EMLA Cream have been reported. The
relationship to EMLA Cream or the underlying procedure has not been established. In clinical studies
on intact skin involving over 1,300 EMLA Cream-treated subjects, one or more such local reactions
were noted in 56% of patients, and were generally mild and transient, resolving spontaneously within 1
or 2 hours. There were no serious reactions that were ascribed to EMLA Cream.
Two recent reports describe blistering on the foreskin in neonates about to undergo circumcision. Both
neonates received 1.0 g of EMLA Cream.
In patients treated with EMLA Cream on intact skin, local effects observed in the trials included:
paleness (pallor or blanching) 37%, redness (erythema) 30%, alterations in temperature sensations 7%,
edema 6%, itching 2% and rash, less than 1%.
In clinical studies on genital mucous membranes involving 378 EMLA Cream-treated patients, one or
more application site reactions, usually mild and transient, were noted in 41% of patients. The most
common application site reactions were redness (21%), burning sensation (17%) and edema (10%).
Allergic Reactions: Allergic and anaphylactoid reactions associated with lidocaine or prilocaine can
occur. They are characterized by urticaria, angioedema, bronchospasm, and shock. If they occur they
should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful
value.
Systemic (Dose Related) Reactions: Systemic adverse reactions following appropriate use of
EMLA Cream are unlikely due to the small dose absorbed (see Pharmacokinetics subsection of
CLINICAL PHARMACOLOGY). Systemic adverse effects of lidocaine and/or prilocaine are similar
in nature to those observed with other amide local anesthetic agents including CNS excitation and/or
depression (light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness,
tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors,
convulsions, unconsciousness, respiratory depression and arrest). Excitatory CNS reactions may be
brief or not occur at all, in which case the first manifestation may be drowsiness merging into
unconsciousness. Cardiovascular manifestations may include bradycardia, hypotension and
cardiovascular collapse leading to arrest.
OVERDOSAGE
Peak blood levels following a 60 g application to 400 cm2 of intact skin for 3 hours are 0.05 to 0.16
µg/mL for lidocaine and 0.02 to 0.10 µg/mL for prilocaine. Toxic levels of lidocaine (>5 µg/mL)
and/or prilocaine (>6 µg/mL) cause decreases in cardiac output, total peripheral resistance and mean
arterial pressure. These changes may be attributable to direct depressant effects of these local
anesthetic agents on the cardiovascular system. In the absence of massive topical overdose or oral
ingestion, evaluation should include evaluation of other etiologies for the clinical effects or overdosage
from other sources of lidocaine, prilocaine or other local anesthetics. Consult the package inserts for
parenteral Xylocaine (lidocaine HCl) or Citanest (prilocaine HCl) for further information for the
management of overdose.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 13
DOSAGE AND ADMINISTRATION
Adult Patients – Intact Skin
A thick layer of EMLA Cream is applied to intact skin and covered with an occlusive dressing (see
INSTRUCTIONS FOR APPLICATION).
Minor Dermal Procedures: For minor procedures such as intravenous cannulation and
venipuncture, apply 2.5 grams of EMLA Cream (1/2 the 5 g tube) over 20 to 25 cm2 of skin surface for
at least 1 hour. In controlled clinical trials using EMLA Cream, two sites were usually prepared in case
there was a technical problem with cannulation or venipuncture at the first site.
Major Dermal Procedures: For more painful dermatological procedures involving a larger skin
area such as split thickness skin graft harvesting, apply 2 grams of EMLA Cream per 10 cm2 of skin
and allow to remain in contact with the skin for at least 2 hours.
Adult Male Genital Skin: As an adjunct prior to local anesthetic infiltration, apply a thick layer of
EMLA Cream (1 g/10 cm2) to the skin surface for 15 minutes. Local anesthetic infiltration should be
performed immediately after removal of EMLA Cream.
Dermal analgesia can be expected to increase for up to 3 hours under occlusive dressing and persist for
1 to 2 hours after removal of the cream. The amount of lidocaine and prilocaine absorbed during the
period of application can be estimated from the information in Table 2, ** footnote, in
Individualization of Dose.
Adult Female Patients – Genital Mucous Membranes
For minor procedures on the female external genitalia, such as removal of condylomata acuminata, as
well as for use as pretreatment for anesthetic infiltration, apply a thick layer (5-10 grams) of EMLA
Cream for 5 to 10 minutes.
Occlusion is not necessary for absorption, but may be helpful to keep the cream in place. Patients
should be lying down during the EMLA Cream application, especially if no occlusion is used. The
procedure or the local anesthetic infiltration should be performed immediately after the removal of
EMLA Cream.
Pediatric Patients – Intact Skin
The following are the maximum recommended doses, application areas and application times for
EMLA Cream based on a child’s age and weight:
Age and Body Weight
Requirements
Maximum
Total
Dose of
EMLA
Cream
Maximum
Application
Area
Maximum
Application Time
0 up to 3 months or < 5 kg
1 g
10 cm2
1 hour
3 up to 12 months and > 5 kg
2 g
20 cm2
4 hours
1 to 6 years and > 10 kg
10 g
100 cm2
4 hours
7 to 12 years and > 20 kg
20 g
200 cm2
4 hours
Please note: If a patient greater than 3 months old does not meet the minimum weight requirement, the maximum total dose of EMLA Cream should be
restricted to that which corresponds to the patient’s weight. (see INSTRUCTION FOR APPLICATION).
Practitioners should carefully instruct caregivers to avoid application of excessive amounts of EMLA
Cream (see PRECAUTIONS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 14
When applying EMLA Cream to the skin of young children, care must be taken to maintain careful
observation of the child to prevent accidental ingestion of EMLA Cream or the occlusive dressing. A
secondary protective covering to prevent inadvertent disruption of the application site may be useful.
EMLA Cream should not be used in neonates with a gestational age less than 37 weeks nor in
infants under the age of 12 months who are receiving treatment with methemoglobin-inducing
agents (see Methemoglobinemia subsection of WARNINGS).
When EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is used concomitantly with other products
containing local anesthetic agents, the amount absorbed from all formulations must be considered (see
Individualization of Dose). The amount absorbed in the case of EMLA Cream is determined by the
area over which it is applied and the duration of application under occlusion (see Table 2, ** footnote,
in Individualization of Dose).
Although the incidence of systemic adverse reactions with EMLA Cream is very low, caution should
be exercised, particularly when applying it over large areas and leaving it on for longer than 2 hours.
The incidence of systemic adverse reactions can be expected to be directly proportional to the area and
time of exposure (see Individualization of Dose).
INSTRUCTIONS FOR APPLICATION:
To measure 1 gram of EMLA, the Cream should be gently squeezed out of the tube as a narrow strip
that is 1.5 inches (3.8 cm) long and 0.2 inches (5 mm) wide. The strip of EMLA cream should be
contained within the lines of the diagram shown below.
≈ 1 g strip
1.5 X 0.2 inches
Use the number of strips that equals your dose, like the examples in the table below.
Dosing Information
1 gram
=
1 strip
2 grams
=
2 strips
2.5 grams
=
2.5 strips
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-941/S-018
Page 15
For adult and pediatric
patients, apply ONLY as
prescribed by your
physician.
If your child is below the
age of 3 months or small
for their age, please
inform your doctor before
applying EMLA Cream,
which can be harmful, if
applied over too much
skin at one time in young
children.
When applying EMLA to
the intact skin of young
children, it is important
that they be carefully
observed by an adult in
order to prevent the
accidental ingestion of or
eye contact with EMLA
Cream.
EMLA® Cream
must be applied to
intact skin at least 1
hour before the start
of a routine
procedure and for 2
hours before the
start of a painful
procedure. A
protective covering
of the Cream is not
necessary for
absorption but may
be helpful to keep
the cream in place.
If using a protective
covering, your doctor will
Rremove it, wipe off the
EMLA® Cream, clean the
entire area with an antiseptic
solution before the
procedure. The duration of
effective skin anesthesia will
be at least 1 hour after
removal of the protective
covering.
PRECAUTIONS
1. Do not apply near eyes or on open wounds.
2. Keep out of reach of children.
3. If your child becomes very dizzy, excessively sleepy, or develops duskiness of the face or lips after
applying EMLA Cream, remove the cream and contact the child’s physician at once.
HOW SUPPLIED
EMLA Cream is available as the following:
NDC 0186-1515-01 5 gram tube, box of 1
NDC 0186-1515-01
Product No. 0186-1515-03 5 gram tube, box of 5
NDC 0186-1516-01
30 gram tube box of 1,
the 30 gram tube of EMLA Cream is packaged in a child resistant tube.
NOT FOR OPHTHALMIC USE.
KEEP CONTAINER TIGHTLY CLOSED AT ALL TIMES WHEN NOT IN USE.
Store at controlled room temperature 15–30°C (59–86°F).
EMLA is a registered trademark of the AstraZeneca group of companies.
© AstraZeneca 2005
AstraZeneca LP, Wilmington, DE 19850
30531
30533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:20.775400
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019941s018lbl.pdf', 'application_number': 19941, 'submission_type': 'SUPPL ', 'submission_number': 18}
|
12,082
|
LUPRON DEPOT - leuprolide acetate injection, powder, lyophilized, for suspension
Abbott Laboratories
-
LUPRON DEPOT® 3.75 mg
(leuprolide acetate for depot suspension)
Rx only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring
gonadotropin-releasing hormone (GnRH or LH-RH). The analog possesses greater
potency than the natural hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L
tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate
(salt) with the following structural formula: structural formula
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile
lyophilized microspheres which, when mixed with diluent, become a suspension
intended as a monthly intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe
contains leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic
acids copolymer (33.1 mg), and D-mannitol (6.6 mg). The second chamber of diluent
contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1
mg), water for injection, USP, and glacial acetic acid, USP to control pH.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the
peptide.
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON
DEPOT 3.75 mg results in an initial stimulation followed by a prolonged suppression of
pituitary gonadotropins.
Repeated dosing at monthly intervals results in decreased secretion of gonadal
steroids; consequently, tissues and functions that depend on gonadal steroids for their
maintenance become quiescent. This effect is reversible on discontinuation of drug
therapy.
Leuprolide acetate is not active when given orally. Intramuscular injection of the depot
formulation provides plasma concentrations of leuprolide over a period of one month.
Pharmacokinetics
Absorption
A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection
to healthy female volunteers. The absorption of leuprolide was characterized by an
initial increase in plasma concentration, with peak concentration ranging from 4.6 to
10.2 ng/mL at four hours postdosing. However, intact leuprolide and an inactive
metabolite could not be distinguished by the assay used in the study. Following the
initial rise, leuprolide concentrations started to plateau within two days after dosing and
remained relatively stable for about four to five weeks with plasma concentrations of
about 0.30 ng/mL.
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus
administration to healthy male volunteers was 27 L. In vitro binding to human plasma
proteins ranged from 43% to 49%.
Metabolism
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously
revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-
life of approximately 3 hours based on a two compartment model.
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized
to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II
and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer
patients reached maximum concentration 2 to 6 hours after dosing and were
approximately 6% of the peak parent drug concentration. One week after dosing, mean
plasma M-I concentrations were approximately 20% of mean leuprolide concentrations.
Excretion
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the
dose was recovered as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients have not
been determined.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with
LUPRON DEPOT. However, because leuprolide acetate is a peptide that is primarily
degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific
studies, and the drug is only about 46% bound to plasma proteins, drug interactions
would not be expected to occur.
CLINICAL STUDIES
Endometriosis
In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was
shown to be comparable to danazol 800 mg/day in relieving the clinical sign/symptoms
of endometriosis (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and
induration) and in reducing the size of endometrial implants as evidenced by
laparoscopy. The clinical significance of a decrease in endometriotic lesions is not
known at this time, and in addition laparoscopic staging of endometriosis does not
necessarily correlate with the severity of symptoms.
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the
patients after the first and second treatment months respectively. Most of the remaining
patients reported episodes of only light bleeding or spotting. In the first, second and
third post-treatment months, normal menstrual cycles resumed in 7%, 71% and 95% of
patients, respectively, excluding those who became pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment
visit and sustained relief at 6 and 12 months following discontinuation of treatment for
the various symptoms evaluated during two controlled clinical studies. This included all
patients at end of treatment and those who elected to participate in the follow-up period.
This might provide a slight bias in the results at follow-up as 75% of the original patients
entered the follow-up study, and 36% were evaluated at 6 months and 26% at 12
months. graph
Hormonal replacement therapy
Two clinical studies with a treatment duration of 12 months indicate that concurrent
hormonal therapy (norethindrone acetate 5 mg daily) is effective in significantly reducing
the loss of bone mineral density associated with LUPRON, without compromising the
efficacy of LUPRON in relieving symptoms of endometriosis. (All patients in these
studies received calcium supplementation with 1000 mg elemental calcium). One
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
controlled, randomized and double-blind study included 51 women treated with
LUPRON DEPOT alone and 55 women treated with LUPRON plus norethindrone
acetate 5 mg daily. The second study was an open label study in which 136 women
were treated with LUPRON plus norethindrone acetate 5 mg daily. This study confirmed
the reduction in loss of bone mineral density that was observed in the controlled study.
Suppression of menses was maintained throughout treatment in 84% and 73% of
patients receiving LD/N in the controlled study and open label study, respectively. The
median time for menses resumption after treatment with LD/N was 8 weeks.
Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study. graph
Uterine Leiomyomata (Fibroids)
In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of
three or six months was shown to decrease uterine and fibroid volume, thus allowing for
relief of clinical symptoms (abdominal bloating, pelvic pain, and pressure). Excessive
vaginal bleeding (menorrhagia and menometrorrhagia) decreased, resulting in
improvement in hematologic parameters.
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In three clinical trials, enrollment was not based on hematologic status. Mean uterine
volume decreased by 41% and myoma volume decreased by 37% at final visit as
evidenced by ultrasound or MRI. These patients also experienced a decrease in
symptoms including excessive vaginal bleeding and pelvic discomfort. Benefit occurred
by three months of therapy, but additional gain was observed with an additional three
months of LUPRON DEPOT 3.75 mg. Ninety-five percent of these patients became
amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second,
and third treatment months respectively.
Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT
3.75 mg patients among the 77% who demonstrated a ≥ 25% decrease in uterine
volume while on therapy. Menses usually returned within two months of cessation of
therapy. Mean time to return to pretreatment uterine size was 8.3 months. Regrowth did
not appear to be related to pretreatment uterine volume.
In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or
hemoglobin ≤ 10.2 g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly
with iron, produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of
patients at three months of therapy. The mean change in hematocrit was 10.1% and the
mean change in hemoglobin was 4.2 g/dL. Clinical response was judged to be a
hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood
donation prior to surgery. At three months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or
menometrorrhagia. As with the previous studies, episodes of spotting and menstrual-
like bleeding were noted in some patients.
In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in
60% and 54% of patients respectively. LUPRON DEPOT 3.75 mg was found to relieve
symptoms of bloating, pelvic pain, and pressure.
There is no evidence that pregnancy rates are enhanced or adversely affected by the
use of LUPRON DEPOT 3.75 mg.
Reference ID: 2857097
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INDICATIONS AND USAGE
Endometriosis
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain
relief and reduction of endometriotic lesions. LUPRON DEPOT monthly with
norethindrone acetate 5 mg daily is also indicated for initial management of
endometriosis and for management of recurrence of symptoms. (Refer also to
norethindrone acetate prescribing information for WARNINGS, PRECAUTIONS,
CONTRAINDICATIONS and ADVERSE REACTIONS associated with norethindrone
acetate). Duration of initial treatment or retreatment should be limited to 6 months.
Uterine Leiomyomata (Fibroids)
LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the
preoperative hematologic improvement of patients with anemia caused by uterine
leiomyomata. The clinician may wish to consider a one-month trial period on iron alone
inasmuch as some of the patients will respond to iron alone. (See Table 1.) LUPRON
may be added if the response to iron alone is considered inadequate. Recommended
duration of therapy with LUPRON DEPOT 3.75 mg is up to three months.
Experience with LUPRON DEPOT in females has been limited to women 18 years of
age and older.
Table 1 PERCENT OF PATIENTS ACHIEVING HEMOGLOBIN ≥ 12 GM/DL
Treatment Group
Week 4
Week 8
Week 12
LUPRON DEPOT 3.75 mg with Iron
41*
71†
79*
Iron Alone
17
40
56
*
P-Value < 0.01
†
P-Value < 0.001
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in
LUPRON DEPOT.
2. Undiagnosed abnormal vaginal bleeding.
3. LUPRON DEPOT is contraindicated in women who are or may become pregnant
while receiving the drug. LUPRON DEPOT may cause fetal harm when
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administered to a pregnant woman. Major fetal abnormalities were observed in
rabbits but not in rats after administration of LUPRON DEPOT throughout
gestation. There was increased fetal mortality and decreased fetal weights in rats
and rabbits. (See Pregnancy section.) The effects on fetal mortality are expected
consequences of the alterations in hormonal levels brought about by the drug. If
this drug is used during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to the
fetus.
4. Use in women who are breast-feeding. (See Nursing Mothers section.)
5. Norethindrone acetate is contraindicated in women with the following conditions:
o Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past
history of these conditions
o Markedly impaired liver function or liver disease
o Known or suspected carcinoma of the breast
WARNINGS
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been
established clinically. Before starting treatment with LUPRON DEPOT, pregnancy must
be excluded.
When used monthly at the recommended dose, LUPRON DEPOT usually inhibits
ovulation and stops menstruation. Contraception is not insured, however, by taking
LUPRON DEPOT. Therefore, patients should use non-hormonal methods of
contraception.
Patients should be advised to see their physician if they believe they may be pregnant.
If a patient becomes pregnant during treatment, the drug must be discontinued and the
patient must be apprised of the potential risk to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because
of the physiologic effect of the drug. Therefore, an increase in clinical signs and
symptoms may be observed during the initial days of therapy, but these will dissipate
with continued therapy.
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Symptoms consistent with an anaphylactoid or asthmatic process have been rarely
reported post-marketing.
The following applies to co-treatment with LUPRON and norethindrone acetate:
Norethindrone acetate treatment should be discontinued if there is a sudden partial or
complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. If
examination reveals papilledema or retinal vascular lesions, medication should be
withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in
patients taking progestogens, the physician should be alert to the earliest
manifestations of the disease in women taking norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is
recommended prior to initiation of add-back therapy with norethindrone acetate.
Norethindrone acetate should be used with caution in women with risk factors, including
lipid abnormalities or cigarette smoking.
PRECAUTIONS
Information for Patients
An information pamphlet for patients is included with the product. Patients should be
aware of the following information:
1. Since menstruation usually stops with effective doses of LUPRON DEPOT, the
patient should notify her physician if regular menstruation persists. Patients
missing successive doses of LUPRON DEPOT may experience breakthrough
bleeding.
2. Patients should not use LUPRON DEPOT if they are pregnant, breast feeding,
have undiagnosed abnormal vaginal bleeding, or are allergic to any of the
ingredients in LUPRON DEPOT.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore,
a non-hormonal method of contraception should be used during treatment.
Patients should be advised that if they miss successive doses of LUPRON
DEPOT, breakthrough bleeding or ovulation may occur with the potential for
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conception. If a patient becomes pregnant during treatment, she should
discontinue treatment and consult her physician.
4. Adverse events occurring in clinical studies with LUPRON DEPOT that are
associated with hypoestrogenism include: hot flashes, headaches, emotional
lability, decreased libido, acne, myalgia, reduction in breast size, and vaginal
dryness. Estrogen levels returned to normal after treatment was discontinued.
5. Patients should be counseled on the possibility of the development or worsening
of depression and the occurrence of memory disorders.
6. The induced hypoestrogenic state also results in a loss in bone density over the
course of treatment, some of which may not be reversible. For a period up to six
months, this bone loss should not be clinically significant. Clinical studies show
that concurrent hormonal therapy with norethindrone acetate 5 mg daily is
effective in reducing loss of bone mineral density that occurs with LUPRON. (All
patients received calcium supplementation with 1000 mg elemental calcium.)
(See Changes in Bone Density section).
7. If the symptoms of endometriosis recur after a course of therapy, retreatment
with a six-month course of LUPRON DEPOT and norethindrone acetate 5 mg
daily may be considered. Retreatment beyond this one six month course cannot
be recommended. It is recommended that bone density be assessed before
retreatment begins to ensure that values are within normal limits. Retreatment
with LUPRON DEPOT alone is not recommended.
8. In patients with major risk factors for decreased bone mineral content such as
chronic alcohol and/or tobacco use, strong family history of osteoporosis, or
chronic use of drugs that can reduce bone mass such as anticonvulsants or
corticosteroids, LUPRON DEPOT therapy may pose an additional risk. In these
patients, the risks and benefits must be weighed carefully before therapy with
LUPRON DEPOT alone is instituted, and concomitant treatment with
norethindrone acetate 5 mg daily should be considered. Retreatment with
gonadotropin-releasing hormone analogs, including LUPRON is not advisable in
patients with major risk factors for loss of bone mineral content.
9. Because norethindrone acetate may cause some degree of fluid retention,
conditions which might be influenced by this factor, such as epilepsy, migraine,
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asthma, cardiac or renal dysfunctions require careful observation during
norethindrone acetate add-back therapy.
10.Patients who have a history of depression should be carefully observed during
treatment with norethindrone acetate and norethindrone acetate should be
discontinued if severe depression occurs.
Laboratory Tests
See ADVERSE REACTIONS section.
Drug Interactions
See CLINICAL PHARMACOLOGY, Pharmacokinetics.
Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT in therapeutic doses results in suppression of the
pituitary-gonadal system. Normal function is usually restored within three months after
treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic and
gonadal functions conducted during treatment and for up to three months after
discontinuation of LUPRON DEPOT may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related
increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24
months when the drug was administered subcutaneously at high daily doses (0.6 to 4
mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell
adenomas in females and of testicular interstitial cell adenomas in males (highest
incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or
pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years.
Patients have been treated with leuprolide acetate for up to three years with doses as
high as 10 mg/day and for two years with doses as high as 20 mg/day without
demonstrable pituitary abnormalities.
Mutagenicity studies have been performed with leuprolide acetate using bacterial and
mammalian systems. These studies provided no evidence of a mutagenic potential.
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Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and
similar analogs have shown reversibility of fertility suppression when the drug is
discontinued after continuous administration for periods of up to 24 weeks. Although no
clinical studies have been completed in children to assess the full reversibility of fertility
suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide
acetate and other GnRH analogs have shown functional recovery.
Pregnancy
Teratogenic Effects
Pregnancy Category X (see CONTRAINDICATIONS section).
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and
0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, LUPRON DEPOT produced a
dose-related increase in major fetal abnormalities. Similar studies in rats failed to
demonstrate an increase in fetal malformations. There was increased fetal mortality and
decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits and
with the highest dose (0.024 mg/kg) in rats.
Nursing Mothers
It is not known whether LUPRON DEPOT is excreted in human milk. Because many
drugs are excreted in human milk, and because the effects of LUPRON DEPOT on
lactation and/or the breast-fed child have not been determined, LUPRON DEPOT
should not be used by nursing mothers.
Pediatric Use
Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has been
limited to women 18 years of age and older. See LUPRON DEPOT-PED® (leuprolide
acetate for depot suspension) labeling for the safety and effectiveness in children with
central precocious puberty.
Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in
this population.
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ADVERSE REACTIONS
Clinical Trials
Estradiol levels may increase during the first weeks following the initial injection of
LUPRON, but then decline to menopausal levels. This transient increase in estradiol
can be associated with a temporary worsening of signs and symptoms (see
WARNINGS section).
As would be expected with a drug that lowers serum estradiol levels, the most
frequently reported adverse reactions were those related to hypoestrogenism.
The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical
trials that studied the drug in 166 endometriosis and 166 uterine fibroids patients.
Adverse events reported in ≥5% of patients in either of these populations and thought to
be potentially related to drug are noted in the following table.
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Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN ≥ 5% OF
PATIENTS
Endometriosis (2 Studies)
Uterine Fibroids (4 Studies)
LUPRON
DEPOT
3.75 mg
N=166
Danazol
N=136
Placebo
N=31
N
(%)
N
(%) N
(%)
LUPRON
DEPOT
3.75 mg
N=166
Placebo
N=163
N
(%)
N
(%)
Body as a Whole
Asthenia
5
(3)
9
(7)
0
(0)
14
(8.4)
8
(4.9)
General pain
31
(19)
22 (16) 1
(3)
14
(8.4)
10
(6.1)
Headache*
Cardiovascular System
53
(32)
30 (22) 2
(6)
43
(25.9)
29
(17.8)
Hot flashes/sweats*
Gastrointestinal System
139
(84)
77 (57) 9
(29)
121
(72.9)
29
(17.8)
Nausea/vomiting
21
(13)
17 (13) 1
(3)
8
(4.8)
6
(3.7)
GI disturbances*
Metabolic and Nutritional
Disorders
11
(7)
8
(6)
1
(3)
5
(3.0)
2
(1.2)
Edema
12
(7)
17 (13) 1
(3)
9
(5.4)
2
(1.2)
Weight gain/loss
Endocrine System
22
(13)
36 (26) 0
(0)
5
(3.0)
2
(1.2)
Acne
17
(10)
27 (20) 0
(0)
0
(0)
0
(0)
Hirsutism
Musculoskeletal System
2
(1)
9
(7)
1
(3)
1
(0.6)
0
(0)
Joint disorder*
14
(8)
11
(8)
0
(0)
13
(7.8)
5
(3.1)
Myalgia*
Nervous System
1
(1)
7
(5)
0
(0)
1
(0.6)
0
(0)
Decreased libido*
19
(11)
6
(4)
0
(0)
3
(1.8)
0
(0)
Depression/emotional lability*
36
(22)
27 (20) 1
(3)
18
(10.8)
7
(4.3)
Dizziness
19
(11)
4
(3)
0
(0)
3
(1.8)
6
(3.7)
Nervousness*
8
(5)
11
(8)
0
(0)
8
(4.8)
1
(0.6)
Neuromuscular disorders*
11
(7)
17 (13) 0
(0)
3
(1.8)
0
(0)
Paresthesias
Skin and Appendages
12
(7)
11
(8)
0
(0)
2
(1.2)
1
(0.6)
Skin reactions
Urogenital System
17
(10)
20 (15) 1
(3)
5
(3.0)
2
(1.2)
Breast
changes/tenderness/pain*
10
(6)
12
(9)
0
(0)
3
(1.8)
7
(4.3)
Vaginitis*
46
(28)
23 (17) 0
(0)
19
(11.4)
3
(1.8)
In these same studies, symptoms reported in <5% of patients included: Body as a Whole -
Body odor, Flu syndrome, Injection site reactions; Cardiovascular System - Palpitations,
Syncope, Tachycardia; Digestive System - Appetite changes, Dry mouth, Thirst; Endocrine
System - Androgen-like effects; Hemic and Lymphatic System - Ecchymosis,
Lymphadenopathy; Nervous System – Anxiety*, Insomnia/Sleep disorders*, Delusions,
Memory disorder, Personality disorder; Respiratory System - Rhinitis; Skin and Appendages
- Alopecia, Hair disorder, Nail disorder; Special Senses - Conjunctivitis, Ophthalmologic
disorders*, Taste perversion; Urogenital System - Dysuria*, Lactation, Menstrual disorders.
* = Possible effect of decreased estrogen.
Reference ID: 2857097
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In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT,
patients diagnosed with uterine fibroids received a higher dose (7.5 mg) of LUPRON
DEPOT. Events seen with this dose that were thought to be potentially related to drug
and were not seen at the lower dose included glossitis, hypesthesia, lactation,
pyelonephritis, and urinary disorders. Generally, a higher incidence of hypoestrogenic
effects was observed at the higher dose.
Table 3 lists the potentially drug-related adverse events observed in at least 5% of
patients in any treatment group during the first 6 months of treatment in the add-back
clinical studies.
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55
(87%) patients in the LD/N group reported experiencing hot flashes on one or more
occasions during treatment. During Month 6 of treatment, 32 of 37 (86%) patients in the
LD group and 22 of 38 (58%) patients in the LD/N group reported having experienced
hot flashes. The mean number of days on which hot flashes were reported during this
month of treatment was 19 and 7 in the LD and LD/N treatment groups, respectively.
The mean maximum number of hot flashes in a day during this month of treatment was
5.8 and 1.9 in the LD and LD/N treatment groups, respectively.
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Table 3 TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN ≥5% OF
PATIENTS
Controlled Study
Open Label
Study
LD - Only*
N=51
LD/N†
N=55
LD/N†
N=136
Adverse Events
N
(%)
N
(%)
N
(%)
Any Adverse Event
50
(98)
53
(96)
126
(93)
Body as a Whole
Asthenia
9
(18)
10
(18)
15
(11)
Headache/Migraine
33
(65)
28
(51)
63
(46)
Injection Site Reaction
1
(2)
5
(9)
4
(3)
Pain
12
(24)
16
(29)
29
(21)
Cardiovascular System
Hot flashes/sweats
50
(98)
48
(87)
78
(57)
Digestive System
Altered Bowel Function
7
(14)
8
(15)
14
(10)
Changes in Appetite
2
(4)
0
(0)
8
(6)
GI Disturbance
2
(4)
4
(7)
6
(4)
Nausea/Vomiting
13
(25)
16
(29)
17
(13)
Metabolic and Nutritional Disorders
Edema
0
(0)
5
(9)
9
(7)
Weight Changes
6
(12)
7
(13)
6
(4)
Nervous System
Anxiety
3
(6)
0
(0)
11
(8)
Depression/Emotional Lability
16
(31)
15
(27)
46
(34)
Dizziness/Vertigo
8
(16)
6
(11)
10
(7)
Insomnia/Sleep Disorder
16
(31)
7
(13)
20
(15)
Libido Changes
5
(10)
2
(4)
10
(7)
Memory Disorder
3
(6)
1
(2)
6
(4)
Nervousness
4
(8)
2
(4)
15
(11)
Neuromuscular Disorder
1
(2)
5
(9)
4
(3)
Skin and Appendages
Alopecia
0
(0)
5
(9)
4
(3)
Androgen-Like Effects
2
(4)
3
(5)
24
(18)
Skin/Mucous Membrane Reaction
2
(4)
5
(9)
15
(11)
Urogenital System
Breast Changes/Pain/Tenderness
3
(6)
7
(13)
11
(8)
Menstrual Disorders
1
(2)
0
(0)
7
(5)
Vaginitis
10
(20)
8
(15)
11
(8)
*
LD-Only = LUPRON DEPOT 3.75 mg
†
LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy) or
uterine fibroids (three months of therapy) were treated with LUPRON DEPOT 3.75 mg.
In endometriosis patients, vertebral bone density as measured by dual energy x-ray
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absorptiometry (DEXA) decreased by an average of 3.2% at six months compared with
the pretreatment value.
Clinical studies demonstrate that concurrent hormonal therapy (norethindrone acetate 5
mg daily) and calcium supplementation is effective in significantly reducing the loss of
bone mineral density that occurs with LUPRON treatment, without compromising the
efficacy of LUPRON in relieving symptoms of endometriosis.
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two
clinical trials. The results from this regimen were similar in both studies. LUPRON
DEPOT 3.75 mg was used as a control group in one study. The bone mineral density
data of the lumbar spine from these two studies are presented in Table 4.
Table 4 MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF
LUMBAR SPINE
LUPRON DEPOT
3.75mg
LUPRON DEPOT 3.75 mg plus norethindrone
acetate 5 mg daily
Controlled Study
Controlled Study
Open Label Study
N
Change
N
Change
N
Change
Week 24*
41
-3.2%
42
-0.3%
115
-0.2%
Week 52†
29
-6.3%
32
-1.0%
84
-1.1%
* Includes on-treatment measurements that fell within 2–252 days after the first day of
treatment.
† Includes on-treatment measurements >252 days after the first day of treatment.
When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid
patients, vertebral trabecular bone mineral density as assessed by quantitative digital
radiography (QDR) revealed a mean decrease of 2.7% compared with baseline. Six
months after discontinuation of therapy, a trend toward recovery was observed. Use of
LUPRON DEPOT for longer than three months (uterine fibroids) or six months
(endometriosis) or in the presence of other known risk factors for decreased bone
mineral content may cause additional bone loss and is not recommended.
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Changes in Laboratory Values During Treatment
Plasma Enzymes
Endometriosis
During early clinical trials with LUPRON DEPOT 3.75 mg, regular laboratory monitoring
revealed that AST levels were more than twice the upper limit of normal in only one
patient. There was no clinical or other laboratory evidence of abnormal liver function.
In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus
norethindrone acetate 5 mg daily for up to 12 months developed an elevated (at least
twice the upper limit of normal) SGPT or GGT. Five of the 6 increases were observed
beyond 6 months of treatment. None were associated with elevated bilirubin
concentration.
Uterine Leiomyomata (Fibroids)
In clinical trials with LUPRON DEPOT 3.75 mg, five (3%) patients had a post-treatment
transaminase value that was at least twice the baseline value and above the upper limit
of the normal range. None of the laboratory increases were associated with clinical
symptoms.
Lipids
Endometriosis
In earlier clinical studies, 4% of the LUPRON DEPOT 3.75 mg patients and 1% of the
danazol patients had total cholesterol values above the normal range at enrollment.
These patients also had cholesterol values above the normal range at the end of
treatment.
Of those patients whose pretreatment cholesterol values were in the normal range, 7%
of the LUPRON DEPOT 3.75 mg patients and 9% of the danazol patients had post
treatment values above the normal range.
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The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8
(2.9) mg/dL in the LUPRON DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the
danazol group. At the end of treatment, the mean values for total cholesterol from all
patients were 193.3 mg/dL in the LUPRON DEPOT 3.75 mg group and 194.4 mg/dL in
the danazol group. These increases from the pretreatment values were statistically
significant (p<0.03) in both groups.
Triglycerides were increased above the upper limit of normal in 12% of the patients who
received LUPRON DEPOT 3.75 mg and in 6% of the patients who received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the
normal range in 2% of the LUPRON DEPOT 3.75 mg patients compared with 54% of
those receiving danazol. LDL cholesterol fractions increased above the upper limit of
the normal range in 6% of the patients receiving LUPRON DEPOT 3.75 mg compared
with 23% of those receiving danazol. There was no increase in the LDL/HDL ratio in
patients receiving LUPRON DEPOT 3.75 mg but there was approximately a two-fold
increase in the LDL/HDL ratio in patients receiving danazol.
In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
daily was evaluated for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as
a control group in one study. Percent changes from baseline for serum lipids and
percentages of patients with serum lipid values outside of the normal range in the two
studies are summarized in the tables below.
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Table 5 SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT
TREATMENT WEEK 24
LUPRON
LUPRON plus norethindrone acetate 5 mg daily
Controlled Study (n=39) Controlled Study (n=41)
Open Label Study
(n=117)
Baseline
Wk 24
Baseline
Wk 24
Baseline
Wk 24
Value*
%
Value*
%
Value*
%
Change
Change
Change
Total
170.5
9.2%
179.3
0.2%
181.2
2.8%
Cholesterol
HDL Cholesterol
52.4
7.4%
51.8
-18.8%
51.0
-14.6%
LDL Cholesterol
96.6
10.9%
101.5
14.1%
109.1
13.1%
LDL/HDL Ratio
2.0†
5.0%
2.1†
43.4%
2.3†
39.4%
Triglycerides
107.8
17.5%
130.2
9.5%
105.4
13.8%
*
mg/dL
†
ratio
Changes from baseline tended to be greater at Week 52. After treatment, mean serum
lipid levels from patients with follow up data returned to pretreatment values.
Table 6 PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE
NORMAL RANGE
LUPRON
LUPRON plus norethindrone acetate 5
mg daily
Controlled Study Controlled Study Open Label Study
(n=39)
(n=41)
(n=117)
Wk 0
Wk 24*
Wk 0
Wk 24*
Wk 0
Wk 24*
Total Cholesterol (>240 mg/dL)
15%
23%
15%
20%
6%
7%
HDL Cholesterol (<40 mg/dL)
15%
10%
15%
44%
15%
41%
LDL Cholesterol (>160 mg/dL)
0%
8%
5%
7%
9%
11%
LDL/HDL Ratio (>4.0)
0%
3%
2%
15%
7%
21%
Triglycerides (>200 mg/dL)
13%
13%
12%
10%
5%
9%
*
Includes all patients regardless of baseline value.
Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are
recognized risk factors for cardiovascular disease. The long-term significance of the
observed treatment-related changes in serum lipids in women with endometriosis is
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
unknown. Therefore assessment of cardiovascular risk factors should be considered
prior to initiation of concurrent treatment with LUPRON and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
In patients receiving LUPRON DEPOT 3.75 mg, mean changes in cholesterol (+11
mg/dL to +29 mg/dL), LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to
+6 mg/dL), and the LDL/HDL ratio (-0.1 to +0.5) were observed across studies. In the
one study in which triglycerides were determined, the mean increase from baseline was
32 mg/dL.
Other Changes
Endometriosis
The following changes were seen in approximately 5% to 8% of patients. In the earlier
comparative studies, LUPRON DEPOT 3.75 mg was associated with elevations of LDH
and phosphorus, and decreases in WBC counts. Danazol therapy was associated with
increases in hematocrit, platelet count, and LDH. In the hormonal add-back studies
LUPRON DEPOT in combination with norethindrone acetate was associated with
elevations of GGT and SGPT.
Uterine Leiomyomata (Fibroids)
Hematology: (see CLINICAL STUDIES section) In LUPRON DEPOT 3.75 mg treated
patients, although there were statistically significant mean decreases in platelet counts
from baseline to final visit, the last mean platelet counts were within the normal range.
Decreases in total WBC count and neutrophils were observed, but were not clinically
significant.
Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN,
creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and
phosphorus. None of these increases were clinically significant.
Reference ID: 2857097
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Postmarketing
During postmarketing surveillance, the following adverse events were reported. Like
other drugs in this class, mood swings, including depression, have been reported. There
have been rare reports of suicidal ideation and attempt. Many, but not all, of these
patients had a history of depression or other psychiatric illness. Patients should be
counseled on the possibility of development or worsening of depression during
treatment with LUPRON.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely
reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of
injection. Symptoms consistent with fibromyalgia (eg: joint and muscle pain, headaches,
sleep disorder, gastrointestinal distress, and shortness of breath) have been reported
individually and collectively.
Other events reported are:
Cardiovascular System – Hypotension, Pulmonary embolism;
Cases of serious venous and arterial thromboembolism have been reported, including
deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient
ischemic attack. Although a temporal relationship was reported in some cases, most
cases were confounded by risk factors or concomitant medication use. It is unknown if
there is a casual association between the use of GnRH analogs and these events.
Hemic and Lymphatic System - Decreased WBC;
Central/Peripheral Nervous System - Convulsion, Peripheral neuropathy, Spinal
fracture/paralysis;
Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System - Prostate
pain.
Pituitary apoplexy
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome
secondary to infarction of the pituitary gland) have been reported after the
Reference ID: 2857097
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For current labeling information, please visit https://www.fda.gov/drugsatfda
administration of gonadotropin-releasing hormone agonists. In a majority of these
cases, a pituitary adenoma was diagnosed, with a majority of pituitary apoplexy cases
occurring within 2 weeks of the first dose, and some within the first hour. In these cases,
pituitary apoplexy has presented as sudden headache, vomiting, visual changes,
ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse.
Immediate medical attention has been required.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events
reported in different patient populations.
OVERDOSAGE
In rats subcutaneous administration of 250 to 500 times the recommended human dose,
expressed on a per body weight basis, resulted in dyspnea, decreased activity, and
local irritation at the injection site. There is no evidence that there is a clinical
counterpart of this phenomenon. In early clinical trials using daily subcutaneous
leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to
two years caused no adverse effects differing from those observed with the 1 mg/day
dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
Endometriosis
The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in
combination with norethindrone acetate is six months. The choice of LUPRON DEPOT
alone or LUPRON DEPOT plus norethindrone acetate therapy for initial management of
the symptoms and signs of endometriosis should be made by the health care
professional in consultation with the patient and should take into consideration the risks
and benefits of the addition of norethindrone to LUPRON DEPOT alone.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-
month course of LUPRON DEPOT monthly and norethindrone acetate 5 mg daily may
be considered. Retreatment beyond this one six-month course cannot be
recommended. It is recommended that bone density be assessed before retreatment
Reference ID: 2857097
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For current labeling information, please visit https://www.fda.gov/drugsatfda
begins to ensure that values are within normal limits. LUPRON DEPOT alone is not
recommended for retreatment. If norethindrone acetate is contraindicated for the
individual patient, then retreatment is not recommended.
An assessment of cardiovascular risk and management of risk factors such as cigarette
smoking is recommended before beginning treatment with LUPRON DEPOT and
norethindrone acetate.
Uterine Leiomyomata (Fibroids)
Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months.
The symptoms associated with uterine leiomyomata will recur following discontinuation
of therapy. If additional treatment with LUPRON DEPOT 3.75 mg is contemplated, bone
density should be assessed prior to initiation of therapy to ensure that values are within
normal limits.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot
formulation. The lyophilized microspheres are to be reconstituted and administered
monthly as a single intramuscular injection.
For optimal performance of the prefilled dual chamber syringe (PDS), read and follow
the following instructions:
1. The LUPRON DEPOT powder should be visually inspected and the syringe
should NOT BE USED if clumping or caking is evident. A thin layer of powder on
the wall of the syringe is considered normal. The diluent should appear clear.
2. To prepare for injection, screw the white plunger into the end stopper until the
stopper begins to turn.
3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8
seconds) the plunger until the first stopper is at the blue line in the middle of the
barrel.
4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to
form a uniform suspension. The suspension will appear milky. If the powder
adheres to the stopper or caking/clumping is present, tap the syringe with your
finger to disperse. DO NOT USE if any of the powder has not gone into
suspension.
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward
without twisting.
6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the
syringe.
7. Inject the entire contents of the syringe intramuscularly at the time of
reconstitution. The suspension settles very quickly following reconstitution;
therefore, LUPRON DEPOT should be mixed and used immediately.
NOTE: Aspirated blood would be visible just below the luer lock connection if a
blood vessel is accidentally penetrated. If present, blood can be seen through the
transparent LuproLoc™ safety device.
AFTER INJECTION
8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by
pushing the arrow forward with the thumb or finger until the device is fully
extended and a CLICK is heard or felt.
Since the product does not contain a preservative, the suspension should be discarded
if not used immediately.
As with other drugs administered by injection, the injection site should be varied
periodically.
HOW SUPPLIED
Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains:
•
one prefilled dual-chamber syringe
•
one plunger
•
two alcohol swabs
•
instructions for how to mix and administer
•
an information pamphlet for patients
•
a complete prescribing information enclosure
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated
in a biodegradable copolymer of lactic and glycolic acids. When mixed with diluent,
LUPRON DEPOT 3.75 mg is administered as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled
Room Temperature]
REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. 2004. U.S. Department of Health and
Human Services, Public Health Service, Centers for Disease Control and
Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH)
Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling
Occupational Exposure to Hazardous Drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling
hazardous drugs. Am J Health-Syst Pharm. 2006; 63; 1172-1193.
4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and
biotherapy guidelines and recommendations for practice (2nd. Ed.) Pittsburgh, PA:
Oncology Nursing Society.
Manufactured for
Abbott Laboratories
North Chicago, IL 60064
by Takeda Pharmaceutical Company Limited
Osaka, Japan 540-8645
™ - Trademark
® - Registered Trademark
(No. 3641)
Revised: October, 2010
©2008, Abbott Laboratories
Reference ID: 2857097
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019943s030,020011s037lbl.pdf', 'application_number': 19943, 'submission_type': 'SUPPL ', 'submission_number': 30}
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1
23-4526-00-1
PATIENT INFORMATION
DIFLUCAN (fluconazole tablets)
This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not
meant to take the place of your doctor's instructions. Read this information carefully before
you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this
information or if you want to know more about DIFLUCAN.
What Is DIFLUCAN?
DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast
called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the
yeast infection goes away.
DIFLUCAN is different from other treatments for vaginal yeast infections because it is a
tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet
is only about using DIFLUCAN for vaginal yeast infections. For information about using
DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet
for information about vaginal yeast infections.
What Is A Vaginal Yeast Infection?
It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much
yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast
infections are common. About three out of every four adult women will have at least one
vaginal yeast infection during their life.
Some medicines and medical conditions can increase your chance of getting a yeast
infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you
may get yeast infections more often than other women. Personal hygiene and certain types
of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips
on what you can do to help prevent vaginal yeast infections.
If you get a vaginal yeast infection, you may have any of the following symptoms:
• itching
• a burning feeling when you urinate
• redness
• soreness
• a thick white vaginal discharge that looks like cottage cheese
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
What To Tell Your Doctor Before You Start DIFLUCAN?
Do not take Diflucan if you take certain medicines. They can cause serious problems.
Therefore, tell your doctor about all the medicines you take including:
• diabetes medicines you take by mouth such as glyburide, tolbutamide, glipizide
• blood thinners such as warfarin
• cyclosporine (used to prevent rejection of organ transplants)
• rifampin or rifabutin (used for tuberculosis)
• astemizole (used for allergies)
• tacrolimus (used to prevent rejection of organ transplants)
• phenytoin (used for seizures)
• theophylline (used for asthma)
• cisapride (Propulsid®; used for stomach acid problems)
• terfenadine (Seldane®; used for allergies)
Since there are many brand names for these medicines, check with your doctor or
pharmacist if you have any questions.
• are taking any over-the-counter medicines you can buy without a prescription,
including natural or herbal remedies
• have any liver problems.
• have any other medical conditions
• are pregnant, plan to become pregnant, or think you might be pregnant. Your
doctor will discuss whether DIFLUCAN is right for you.
• are breast-feeding. DIFLUCAN can pass through breast milk to the baby.
• are allergic to any other medicines including those used to treat yeast and other
fungal infections.
• are allergic to any of the ingredients in DIFLUCAN. The main ingredient of
DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask
your doctor or pharmacist.
Who Should Not Take DIFLUCAN?
To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking cisapride
(Propulsid®) since it can cause changes in heartbeat in some people if taken with
DIFLUCAN.
How Should I Take DIFLUCAN
Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time
of the day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms
start to go away after 24 hours. However, it may take several days for your symptoms to go
away completely. If there is no change in your symptoms after a few days, call your doctor.
[caption on the right of the illustration]
Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection.
What Should I Avoid While Taking DIFLUCAN?
Some medicines can affect how well DIFLUCAN works. Check with your doctor before
starting any new medicines within seven days of taking DIFLUCAN.
What Are The Possible Side Effects of DIFLUCAN?
Like all medicines, DIFLUCAN may cause some side effects that are usually mild to
moderate.
The most common side effects of DIFLUCAN are:
• headache
• diarrhea
• nausea or upset stomach
• dizziness
• stomach pain
• changes in the way food tastes
Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right
away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency
room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing;
fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck,
or any other part of the body; or skin rash, hives, blisters or skin peeling.
Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in
patients with serious medical problems. Call your doctor if your skin or eyes become
yellow, your urine turns a darker color, your stools (bowel movements) are light-colored,
or if you vomit or feel like vomiting or if you have severe skin itching.
In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with
skin peeling have been reported. Tell your doctor right away if you get a rash while taking
DIFLUCAN.
DIFLUCAN may cause other less common side effects besides those listed here. If you
develop any side effects that concern you, call your doctor. For a list of all side effects, ask
your doctor or pharmacist.
What To Do For An Overdose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
In case of an accidental overdose, call your doctor right away or go to the nearest emergency
room.
How To Store DIFLUCAN
Keep DIFLUCAN and all medicines out of the reach of children.
General Advice About Prescription Medicines
Medicines are sometimes prescribed for conditions that are mentioned in patient information
leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not
give DIFLUCAN to other people, even if they have the same symptoms you have. It may
harm them.
This leaflet summarizes the most important information about DIFLUCAN. If you would
like more information, talk with your doctor. You can ask your pharmacist or doctor for
information about DIFLUCAN that is written for health professionals.
You can also visit the DIFLUCAN Internet site at www.diflucan.com.
p U.S. Pharmaceuticals
2003, Pfizer Inc
Revised June 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The
structural formula is:
str
uct
ural
f
or
mu
la
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
(fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal
indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken
without regard to meals. (see DOSAGE AND ADMINISTRATION.)
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean(%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(μg/mL)
Vdss
(L/kg)
9 Months-
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months-
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4+ 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
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There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18-31%)
and 13% (95% C.I. range 8-18%), respectively relative to placebo. Fluconazole treatment did not
cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to
placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3
of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
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Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9%
(range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to
72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See
PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
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half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg
and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%)
of placebo treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was
a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide
Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of
19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
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fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Microbiology
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 dependent enzyme
lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The
subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in
fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell
demethylation is much less sensitive to fluconazole inhibition.
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Activity In Vitro and In Clinical Infections
Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
(≥16µg/ml). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/ml, see Table 1), the
highest dose is recommended (see Dosage and Administration). For resistant isolates alternative therapy is
recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
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concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
Table 1: Susceptibility Interpretive Criteria for Fluconazole
Broth Dilution at 48 hours
(MIC in µg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
Antifungal agent
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Fluconazole*
≤ 8.0
16-32
≥64
≥19
15-18
≤14
* Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be
interpreted using this scale.
** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for
fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
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Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results
QC Strain
Macrodilution
(MIC in µg/mL)
@ 48 hours
Microdilution
(MIC in µg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
Candida parapsilosis ATCC 22019
2.0-8.0
1.0-4.0
22-33
Candida krusei ATCC 6258
16-64
16-128
---*
Candida albicans ATCC 90028
---*
---*
28-39
Candida tropicalis ATCC 750
---*
---*
26-37
---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
Activity In Vivo
Fungistatic activity has also been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for
systemic infections due to Candida albicans.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to
fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was
active in a variety of animal models of fungal infection using standard laboratory strains of fungi.
Activity has been demonstrated against fungal infections caused by Aspergillus flavus and
Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal
models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary
infections in normal mice; one model of Coccidioides immitis intracranial infections in normal
mice; and several models of Histoplasma capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results obtained in these studies is
unknown.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The
clinical significance of results obtained in these studies is unknown.
Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target
enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination
of these mechanisms.
Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target
with decreased affinity for azoles. Overexpression of ERG11 results in the production of high
concentrations of the target enzyme, creating the need for higher intracellular drug
concentrations to inhibit all of the enzyme molecules in the cell.
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The second major mechanism of drug resistance involves active efflux of fluconazole out of the
cell through the activation of two types of multidrug efflux transporters; the major facilitators
(encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR
genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of
CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in
resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to
32 µg/mL), the highest fluconazole dose is recommended.
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
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CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic erad.
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
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Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 ( 4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 ( 7%)
Headache
58 (13%)
28 ( 7%)
Gastrointestinal
68 (15%)
13 ( 3%)
Abdominal pain
25 ( 6%)
7 ( 2%)
Nausea
30 ( 7%)
3 ( 1%)
Diarrhea
12 ( 3%)
2 (<1%)
Application site event
0 ( 0%)
19 ( 5%)
Taste Perversion
6 ( 1%)
0 ( 0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23%
for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of cisapride is
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contraindicated in patients receiving DIFLUCAN (fluconazole). (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN has been associated with rare cases of serious hepatic
toxicity, including fatalities primarily in patients with serious underlying medical
conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to
total daily dose, duration of therapy, sex or age of the patient has been observed.
DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation
of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy
should be monitored for the development of more severe hepatic injury. DIFLUCAN
should be discontinued if clinical signs and symptoms consistent with liver disease develop
that may be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) Clinically or potentially significant drug interactions between
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DIFLUCAN and the following agents/classes have been observed. These are described in greater
detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Tacrolimus
Short-acting benzodiazepines
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring of cyclosporine concentrations
and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
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Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200-mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400-mg and
800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events, including torsade de pointes in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: The use of fluconazole in patients concurrently taking astemizole or other drugs
metabolized by the cytochrome P450 system may be associated with elevations in serum levels
of these drugs. In the absence of definitive information, caution should be used when
coadministering fluconazole. Patients should be carefully monitored.
Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were
coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully
monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and
tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly
should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
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metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should
be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral
contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels;
however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and
levonorgestrel levels. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The
data presently available indicate that the decreases in some individual ethinyl estradiol and
levonorgestrel AUC values with fluconazole treatment are likely the result of random variation.
While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and
levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or
levonorgestrel metabolism. The clinical significance of these effects is presently unknown.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20 and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still-born pups
and decrease of neonatal survival at these dose levels. The effects on parturition in rats are
consistent with the species specific estrogen-lowering property produced by high doses of
fluconazole. Such a hormone change has not been observed in women treated with fluconazole.
(See CLINICAL PHARMACOLOGY.)
Pregnancy
Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant
rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg,
respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at
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75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were
detected. In several studies in which pregnant rats were treated orally with fluconazole during
organogenesis, maternal weight gain was impaired and placental weights were increased at
25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants
(supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and
50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the
recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal
abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These
effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of
known effects of lowered estrogen on pregnancy, organogenesis and parturition.
There are no adequate and well controlled studies in pregnant women. There have been reports
of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more
months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an
unindicated use). The relationship between fluconazole use and these events is unclear.
DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk
to the fetus.
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of
DIFLUCAN in nursing mothers is not recommended.
Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
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The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
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In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during postmarketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
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Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic
epidermal necrolysis (see WARNINGS), alopecia.
Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Dyspepsia, vomiting.
Other Senses: Taste perversion.
Adverse Reactions in Children:
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
OVERDOSAGE
There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient
infected with human immunodeficiency virus developed hallucinations and exhibited paranoid
behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the
hospital, and his condition resolved within 48 hours.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
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In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions.
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
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Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis of patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
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Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
>50
100%
≤50 (no dialysis)
50%
Regular dialysis
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males:
Weight (kg) × (140-age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K ×
linear length or height (cm)
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
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Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be
taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of
intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a
maximum rate of approximately 200 mg/hour, given as a continuous infusion.
DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
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Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
HOW SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN Tablets are supplied as follows:
DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG”
on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86°F (30°C).
DIFLUCAN for Oral Suspension: DIFLUCAN for oral suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6
Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.
Rx only
REFERENCES
1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27
A2, 2002 Volume 22, No 15, CLSI, Wayne, PA, August 2002.
2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion
Susceptibllity Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume
24, No. 15 CLSI, Wayne, PA, May 2004.
3. Pfaller, M. A., Messer,S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1,
D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to
Voriconazole among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and
Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of
Clinical Microbiology. 45:70–75. company logo
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LAB-0099-11.0
Revised August, 2010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension, and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The
structural formula is:
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
Reference ID: 2938710
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diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
(fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal
indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken
without regard to meals. (see DOSAGE AND ADMINISTRATION.)
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
Reference ID: 2938710
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Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean (%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(μg/mL)
Vdss
(L/kg)
9 Months-
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months-
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
Reference ID: 2938710
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There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%)
and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did
not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study
compared to placebo dosing. The individual AUC values of norethindrone decreased very
slightly (<5%) in 3 of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
Reference ID: 2938710
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Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent
oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life
decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
Reference ID: 2938710
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For current labeling information, please visit https://www.fda.gov/drugsatfda
half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg
and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22
(40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was
a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide
Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of
19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
Reference ID: 2938710
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fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes.
Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for
2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy
male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57%
(90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical
study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and
fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole
and fluconazole at any dose is not recommended. Close monitoring for adverse events related to
voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially
within 24 h of the last dose of fluconazole. (See PRECAUTIONS.)
Reference ID: 2938710
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Microbiology
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme
lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The
subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in
fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell
demethylation is much less sensitive to fluconazole inhibition.
Activity In Vitro and In Clinical Infections
Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
(≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the
highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative
therapy is recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well-controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
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Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
Table 1: Susceptibility Interpretive Criteria for Fluconazole
Broth Dilution at 48 hours
(MIC in µg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
Antifungal agent
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Fluconazole*
≤ 8.0
16-32
≥64
≥19
15-18
≤14
* Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be
interpreted using this scale.
** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for
fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
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resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results
QC Strain
Macrodilution
(MIC in µg/mL)
@ 48 hours
Microdilution
(MIC in µg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
Candida parapsilosis ATCC 22019
2.0-8.0
1.0-4.0
22-33
Candida krusei ATCC 6258
16-64
16-128
---*
Candida albicans ATCC 90028
---*
---*
28-39
Candida tropicalis ATCC 750
---*
---*
26-37
---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
Activity In Vivo
Fungistatic activity has also been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for
systemic infections due to Candida albicans.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to
fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was
active in a variety of animal models of fungal infection using standard laboratory strains of fungi.
Activity has been demonstrated against fungal infections caused by Aspergillus flavus and
Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal
models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary
infections in normal mice; one model of Coccidioides immitis intracranial infections in normal
mice; and several models of Histoplasma capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results obtained in these studies is
unknown.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The
clinical significance of results obtained in these studies is unknown.
Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target
enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination
of these mechanisms.
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Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target
with decreased affinity for azoles. Overexpression of ERG11 results in the production of high
concentrations of the target enzyme, creating the need for higher intracellular drug
concentrations to inhibit all of the enzyme molecules in the cell.
The second major mechanism of drug resistance involves active efflux of fluconazole out of the
cell through the activation of two types of multidrug efflux transporters; the major facilitators
(encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR
genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of
CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in
resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to
32 µg/mL), the highest fluconazole dose is recommended.
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
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Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic eradication
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
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Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 (4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 (7%)
Headache
58 (13%)
28 (7%)
Gastrointestinal
68 (15%)
13 (3%)
Abdominal pain
25 (6%)
7 (2%)
Nausea
30 (7%)
3 (1%)
Diarrhea
12 (3%)
2 (<1%)
Application site event
0 (0%)
19 (5%)
Taste Perversion
6 (1%)
0 (0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and
23% for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
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between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of other drugs
known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as
cisapride, astemizole, pimozide, and quinidine are contraindicated in patients receiving fluconazole..
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver
dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity,
including fatalities primarily in patients with serious underlying medical conditions. In
cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose,
duration of therapy, sex, or age of the patient has been observed. DIFLUCAN
hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy.
Patients who develop abnormal liver function tests during DIFLUCAN therapy should be
monitored for the development of more severe hepatic injury. DIFLUCAN should be
discontinued if clinical signs and symptoms consistent with liver disease develop that may
be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities, and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Concomitant use of fluconazole and erythromycin has the potential to increase the risk of
cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death.
This combination should be avoided.
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Fluconazole should be administered with caution to patients with renal dysfunction.
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole
treated patients who are concomitantly treated with drugs with a narrow therapeutic window
metabolized through CYP2C9 and CYP3A4 should be monitored.
DIFLUCAN Capsules contain lactose and should not be given to patients with rare hereditary
problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients
with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.
DIFLUCAN Syrup contains glycerol. Glycerol may cause headache, stomach upset, and
diarrhea.
When driving vehicles or operating machines, it should be taken into account that occasionally
dizziness or seizures may occur.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
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Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP)
isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented
interactions mentioned below, there is a risk of increased plasma concentration of other compounds
metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should
be exercised when using these combinations and the patients should be carefully monitored. The
enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole
treatment due to the long half-life of fluconazole. Clinically or potentially significant drug
interactions between DIFLUCAN and the following agents/classes have been observed. These
are described in greater detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Triazolam
Oral Contraceptives
Pimozide
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
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Vitamin A
Zidovudine
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose
adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug
Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring of cyclosporine concentrations
and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and
800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
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contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the
clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT
prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and
astemizole is contraindicated. .
Rifabutin: There have been reports that an interaction exists when fluconazole is administered
concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There
have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered.
Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring
for adverse events and toxicity related to voriconazole is recommended; especially, if
voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus
up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No
significant pharmacokinetic changes have been observed when tacrolimus is given intravenously.
Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered
tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should
be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
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Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20
32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage
adjustments of triazolam may be necessary.
Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been
performed using multiple doses of fluconazole. There were no relevant effects on hormone level in
the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and
levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at
these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
.
Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma
concentrations can lead to QT prolongation and rare occurrences of torsade de pointes.
Coadministration of fluconazole and pimozide is contraindicated.
Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose
hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of
fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole
dose regimen in subjects receiving concomitant diuretics.
Alfentanil: A study observed a reduction in clearance and distribution volume as well as
prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible
mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil
may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-
nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and
after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal
and immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical
significance of results obtained in these studies is unknown.
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a
single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the
pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction
between fluconazole and azithromycin.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum
carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity.
Dosage adjustment of carbamazepine may be necessary depending on concentration
measurements/effect.
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Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine,
isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the
potential to increase the systemic exposure of the calcium channel antagonists. Frequent
monitoring for adverse events is recommended.
Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200
mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the
celecoxib dose may be necessary when combined with fluconazole.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an
increase in serum bilirubin and serum creatinine. The combination may be used while taking
increased consideration to the risk of increased serum bilirubin and serum creatinine.
Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author
judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover
study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of
fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory
effect on CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when
fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through
CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If
concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and
rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors
should be discontinued if a marked increase in creatinine kinase is observed or
myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74)
which is responsible for most of the angiotensin Il-receptor antagonism which occurs during
treatment with losartan. Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage
adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by
23% and 81%, respectively, when coadministered with fluconazole compared to administration
of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S
(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was
coadministered with racemic ibuprofen (400 mg) compared to administration of racemic
ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure
of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam,
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diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is
recommended. Adjustment of dosage of NSAIDs may be needed.
Prednisone: There was a case report that a liver-transplanted patient treated with prednisone
developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was
discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity
which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole
and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is
discontinued.
Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by
approximately 55%, and decreases clearance of saquinavir by approximately 50% due to
inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein.
Dosage adjustment of saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting
the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used
with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca
alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an
inhibitory effect on CYP3A4.
Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans
retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have
developed in the form of pseudotumour cerebri, which disappeared after discontinuation of
fluconazole treatment. This combination may be used but the incidence of CNS related
undesirable effects should be borne in mind.
Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%,
respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of
zidovudine was likewise prolonged by approximately 128% following combination therapy with
fluconazole. Patients receiving this combination should be monitored for the development of
zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
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(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still born pups and
decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent
with the species specific estrogen-lowering property produced by high doses of fluconazole.
Such a hormone change has not been observed in women treated with fluconazole. (See
CLINICAL PHARMACOLOGY.)
Pregnancy
Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant
rabbits during organogenesis in two studies at 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg,
respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at
75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were
detected. In several studies in which pregnant rats were treated orally with fluconazole during
organogenesis, maternal weight gain was impaired and placental weights were increased at
25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants
(supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and
50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the
recommended human dose) to 320 mg/kg, embryolethality in rats was increased and fetal
abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These
effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of
known effects of lowered estrogen on pregnancy, organogenesis, and parturition.
Data from several hundred pregnant women treated with doses <200 mg/day of fluconazole,
administered as a single or repeated dosage in the first trimester, show no undesired effects in the
fetus.
There have been reports of multiple congenital abnormalities in infants whose mothers were
being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for
coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these
events is unclear. DIFLUCAN should be used in pregnancy only if the potential benefit justifies
the possible risk to the fetus.
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of
DIFLUCAN in nursing mothers is not recommended.
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Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
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Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
DIFLUCAN is generally well tolerated.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer,
changes in renal and hematological function test results and hepatic abnormalities have been
observed during treatment with fluconazole and comparative agents, but the clinical significance
and relationship to treatment is uncertain.
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
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Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Body as a Whole: Asthenia, fatigue, fever, malaise.
Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.
Other Senses: Taste perversion.
Musculoskeletal System: myalgia.
Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.
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Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased
sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal
necrolysis (see WARNINGS), alopecia.
Adverse Reactions in Children:
The pattern and incidence of adverse events and laboratory abnormalities recorded during
pediatric clinical trials are comparable to those seen in adults.
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
OVERDOSAGE
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid
behavior.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions.
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DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
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for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
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recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
>50
100%
≤50 (no dialysis)
50%
Regular dialysis
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males:
Weight (kg) × (140 – age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K ×
linear length or height (cm)
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be
taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of
intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a
maximum rate of approximately 200 mg/hour, given as a continuous infusion.
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DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
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HOW SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN Tablets are supplied as follows:
DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG”
on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86°F (30°C).
DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
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company logo
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6
Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.
Rx only
REFERENCES
1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27
A2, 2002 Volume 22, No. 15, CLSI, Wayne, PA, August 2002.
2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion
Susceptibility Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume
24, No. 15, CLSI, Wayne, PA, May 2004.
3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and
Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and
Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by
Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods.
2007. Journal of Clinical Microbiology. 45:70–75.
LAB-0099-13.0
Revised April 2011
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
DIFLUCAN® (fluconazole tablets)
This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not
meant to take the place of your doctor's instructions. Read this information carefully
before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand
any of this information or if you want to know more about DIFLUCAN.
What Is DIFLUCAN?
DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast
called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so
the yeast infection goes away.
DIFLUCAN is different from other treatments for vaginal yeast infections because it is a
tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this
leaflet is only about using DIFLUCAN for vaginal yeast infections. For information
about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the
section of this leaflet for information about vaginal yeast infections.
What Is a Vaginal Yeast Infection?
It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much
yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast
infections are common. About three out of every four adult women will have at least one
vaginal yeast infection during their life.
Some medicines and medical conditions can increase your chance of getting a yeast
infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics
you may get yeast infections more often than other women. Personal hygiene and certain
types of clothing may increase your chances of getting a yeast infection. Ask your doctor
for tips on what you can do to help prevent vaginal yeast infections.
If you get a vaginal yeast infection, you may have any of the following symptoms:
• itching
• a burning feeling when you urinate
• redness
• soreness
• a thick white vaginal discharge that looks like cottage cheese
Reference ID: 2938710
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What To Tell Your Doctor Before You Start DIFLUCAN?
Do not take Diflucan if you take certain medicines. They can cause serious problems.
Therefore, tell your doctor about all the medicines you take including:
• diabetes medicines such as glyburide, tolbutamide, glipizide
• blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine
or felodipine
• blood thinners such as warfarin
• cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants)
• rifampin or rifabutin for tuberculosis
• astemizole for allergies
• phenytoin or carbamazepine to control seizures
• theophylline to control asthma
• cisapride for heartburn
• quinidine (used to correct disturbances in heart rhythm)
• amitriptyline or nortriptyline for depression
• pimozide for psychiatric illness
• amphotericin B or voriconazole for fungal infections
• erythromycin for bacterial infections
• cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment
of cancer
• fentanyl, afentanil or methadone for chronic pain
• halofantrine for malaria
• lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin
• non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen
• prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory
disorders
• antiviral medications used to treat HIV like saquinavir or zidovudine
• vitamin A nutritional supplement
Since there are many brand names for these medicines, check with your doctor or
pharmacist if you have any questions.
• are taking any over-the-counter medicines you can buy without a prescription,
including natural or herbal remedies
• have any liver problems.
• have any other medical conditions
• are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor
will discuss whether DIFLUCAN is right for you.
• are breast-feeding. DIFLUCAN can pass through breast milk to the baby.
• are allergic to any other medicines including those used to treat yeast and other
fungal infections.
• are allergic to any of the ingredients in DIFLUCAN. The main ingredient of
DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your
doctor or pharmacist.
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Who Should Not Take DIFLUCAN?
To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking
erythromycin, astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can
cause changes in heartbeat in some people if taken with DIFLUCAN.
How Should I Take DIFLUCAN
Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any
time of the day.
DIFLUCAN keeps working for several days to treat the infection. Generally the
symptoms start to go away after 24 hours. However, it may take several days for your
symptoms to go away completely. If there is no change in your symptoms after a few
days, call your doctor.
[caption on the right of the illustration]
Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection.
What Should I Avoid while Taking DIFLUCAN?
Some medicines can affect how well DIFLUCAN works. Check with your doctor before
starting any new medicines within seven days of taking DIFLUCAN.
What Are the Possible Side Effects of DIFLUCAN?
Like all medicines, DIFLUCAN may cause some side effects that are usually mild to
moderate.
The most common side effects of DIFLUCAN are:
• headache
• diarrhea
• nausea or upset stomach
• dizziness
• stomach pain
• changes in the way food tastes
Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated
right away by a doctor. If you cannot reach your doctor, go to the nearest hospital
emergency room. Signs of an allergic reaction can include shortness of breath; coughing;
wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face,
mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling.
Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly
in patients with serious medical problems. Call your doctor if your skin or eyes become
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
yellow, your urine turns a darker color, your stools (bowel movements) are light-colored,
or if you vomit or feel like vomiting or if you have severe skin itching.
In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes
with skin peeling have been reported. Tell your doctor right away if you get a rash while
taking DIFLUCAN.
DIFLUCAN may cause other less common side effects besides those listed here. If you
develop any side effects that concern you, call your doctor. For a list of all side effects,
ask your doctor or pharmacist.
What to Do For an Overdose
In case of an accidental overdose, call your doctor right away or go to the nearest
emergency room.
How to Store DIFLUCAN
Keep DIFLUCAN and all medicines out of the reach of children.
General Advice about Prescription Medicines
Medicines are sometimes prescribed for conditions that are mentioned in patient
information leaflets. Do not use DIFLUCAN for a condition for which it was not
prescribed. Do not give DIFLUCAN to other people, even if they have the same
symptoms you have. It may harm them.
This leaflet summarizes the most important information about DIFLUCAN. If you
would like more information, talk with your doctor. You can ask your pharmacist or
doctor for information about DIFLUCAN that is written for health professionals.
You can also visit the DIFLUCAN Internet site at www.diflucan.com. company logo
LAB-0380-4.0
Revised April 2011
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension, and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-,1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The
structural formula is:
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
Reference ID: 3373589
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 g/mL (range: 4.12 to 8.08 g/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
(fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal
indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken
without regard to meals. (see DOSAGE AND ADMINISTRATION.)
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 g/mL (range: 1.57 to 3.65 g/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
Reference ID: 3373589
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
Reference ID: 3373589
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean (%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(g/mL)
Vdss
(L/kg)
9 Months
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4 20.3 mcgh/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
Reference ID: 3373589
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For current labeling information, please visit https://www.fda.gov/drugsatfda
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%)
and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did
not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study
compared to placebo dosing. The individual AUC values of norethindrone decreased very
slightly (<5%) in 3 of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent
Reference ID: 3373589
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For current labeling information, please visit https://www.fda.gov/drugsatfda
oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life
decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
Reference ID: 3373589
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg
and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22
(40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a
mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax
increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23%
(range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
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Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes.
Concurrent administration of oral Voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for
2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy
male subjects resulted in an increase in Cmax and AUC of voriconazole by an average of 57%
(90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical
study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and
fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole
and fluconazole at any dose is not recommended. Close monitoring for adverse events related to
voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially
within 24 h of the last dose of fluconazole. (See PRECAUTIONS)
Tofacitinib: Co-administration of fluconazole (400 mg on Day 1 and 200 mg once daily for 6
days [Days 2-7]) and tofacitinib (30 mg single dose on Day 5) in healthy subjects resulted in
increased mean tofacitinib AUC and Cmax values of approximately 79% (90% CI: 64% – 96%)
and 27% (90% CI: 12% – 44%), respectively, compared to administration of tofacitinib alone.
(See PRECAUTIONS)
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Microbiology
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme
lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The
subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in
fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell
demethylation is much less sensitive to fluconazole inhibition.
Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target
enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination
of these mechanisms.
Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target
with decreased affinity for azoles. Overexpression of ERG11 results in the production of high
concentrations of the target enzyme, creating the need for higher intracellular drug
concentrations to inhibit all of the enzyme molecules in the cell.
The second major mechanism of drug resistance involves active efflux of fluconazole out of the
cell through the activation of two types of multidrug efflux transporters; the major facilitators
(encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR
genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of
CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in
resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to
32 µg/mL), the highest fluconazole dose is recommended.
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
Activity In Vitro and In Clinical Infections
Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
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* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
(≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the
highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative
therapy is recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well-controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
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Table 1: Susceptibility Interpretive Criteria for Fluconazole
Broth Dilution at 48 hours
(MIC in µg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
Antifungal agent
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Fluconazole*
≤ 8.0
16-32
≥64
≥19
15-18
≤14
* Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be
interpreted using this scale.
** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for
fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results
QC Strain
Macrodilution
(MIC in µg/mL)
@ 48 hours
Microdilution
(MIC in µg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
Candida parapsilosis ATCC 22019
2.0-8.0
1.0-4.0
22-33
Candida krusei ATCC 6258
16-64
16-128
---*
Candida albicans ATCC 90028
---*
---*
28-39
Candida tropicalis ATCC 750
---*
---*
26-37
---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
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INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
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Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic eradication
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 (4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 (7%)
Headache
58 (13%)
28 (7%)
Gastrointestinal
68 (15%)
13 (3%)
Abdominal pain
25 (6%)
7 (2%)
Nausea
30 (7%)
3 (1%)
Diarrhea
12 (3%)
2 (<1%)
Application site event
0 (0%)
19 (5%)
Taste Perversion
6 (1%)
0 (0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
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Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and
23% for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of other drugs
known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as
cisapride, astemizole, pimozide, and quinidine are contraindicated in patients receiving fluconazole..
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver
dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity,
including fatalities primarily in patients with serious underlying medical conditions. In
cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose,
duration of therapy, sex, or age of the patient has been observed. DIFLUCAN
hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy.
Patients who develop abnormal liver function tests during DIFLUCAN therapy should be
monitored for the development of more severe hepatic injury. DIFLUCAN should be
discontinued if clinical signs and symptoms consistent with liver disease develop that may
be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
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(4) Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN in
pregnant women. Available human data do not suggest an increased risk of congenital anomalies
following a single maternal dose of 150 mg. A few published case reports describe a rare pattern
of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole
(400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar
to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes
pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus
(See PRECAUTIONS, Pregnancy.)
PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities, and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Concomitant use of fluconazole and erythromycin has the potential to increase the risk of
cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death.
This combination should be avoided.
Fluconazole should be administered with caution to patients with renal dysfunction.
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole
treated patients who are concomitantly treated with drugs with a narrow therapeutic window
metabolized through CYP2C9 and CYP3A4 should be monitored.
DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients
with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.
When driving vehicles or operating machines, it should be taken into account that occasionally
dizziness or seizures may occur.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP)
isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented
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interactions mentioned below, there is a risk of increased plasma concentration of other compounds
metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should
be exercised when using these combinations and the patients should be carefully monitored. The
enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole
treatment due to the long half-life of fluconazole. Clinically or potentially significant drug
interactions between DIFLUCAN and the following agents/classes have been observed. These
are described in greater detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Tofacitinib
Triazolam
Oral Contraceptives
Pimozide
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
Vitamin A
Zidovudine
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Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose
adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug
Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring of cyclosporine concentrations
and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and
800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
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Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the
clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT
prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and
astemizole is contraindicated. .
Rifabutin: There have been reports that an interaction exists when fluconazole is administered
concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There
have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered.
Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring
for adverse events and toxicity related to voriconazole is recommended; especially, if
voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus
up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No
significant pharmacokinetic changes have been observed when tacrolimus is given intravenously.
Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered
tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should be
appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Tofacitinib: Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with
fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of
tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once
daily as instructed in the XELJANZ® [tofacitinib] label). (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax
by 20-32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage
adjustments of triazolam may be necessary.
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Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been
performed using multiple doses of fluconazole. There were no relevant effects on hormone level in
the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and
levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at
these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma
concentrations can lead to QT prolongation and rare occurrences of torsade de pointes.
Coadministration of fluconazole and pimozide is contraindicated.
Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose
hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of
fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole
dose regimen in subjects receiving concomitant diuretics.
Alfentanil: A study observed a reduction in clearance and distribution volume as well as
prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible
mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil
may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5
nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and
after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal
and immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical
significance of results obtained in these studies is unknown.
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a
single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the
pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction
between fluconazole and azithromycin.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum
carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity.
Dosage adjustment of carbamazepine may be necessary depending on concentration
measurements/effect.
Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine,
isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the
potential to increase the systemic exposure of the calcium channel antagonists. Frequent
monitoring for adverse events is recommended.
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Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200
mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the
celecoxib dose may be necessary when combined with fluconazole.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an
increase in serum bilirubin and serum creatinine. The combination may be used while taking
increased consideration to the risk of increased serum bilirubin and serum creatinine.
Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author
judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover
study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of
fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory
effect on CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when
fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through
CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If
concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and
rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors
should be discontinued if a marked increase in creatinine kinase is observed or
myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74)
which is responsible for most of the angiotensin Il-receptor antagonism which occurs during
treatment with losartan. Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage
adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by
23% and 81%, respectively, when coadministered with fluconazole compared to administration
of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S
(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was
coadministered with racemic ibuprofen (400 mg) compared to administration of racemic
ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure
of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam,
diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is
recommended. Adjustment of dosage of NSAIDs may be needed.
Prednisone: There was a case report that a liver-transplanted patient treated with prednisone
developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was
discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity
which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole
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and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is
discontinued.
Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by
approximately 55%, and decreases clearance of saquinavir by approximately 50% due to
inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein.
Dosage adjustment of saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting
the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used
with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca
alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an
inhibitory effect on CYP3A4.
Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans
retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have
developed in the form of pseudotumour cerebri, which disappeared after discontinuation of
fluconazole treatment. This combination may be used but the incidence of CNS related
undesirable effects should be borne in mind.
Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%,
respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of
zidovudine was likewise prolonged by approximately 128% following combination therapy with
fluconazole. Patients receiving this combination should be monitored for the development of
zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
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(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still born pups and
decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent
with the species specific estrogen-lowering property produced by high doses of fluconazole.
Such a hormone change has not been observed in women treated with fluconazole. (See
CLINICAL PHARMACOLOGY.)
Pregnancy
Teratogenic Effects.Pregnancy Category C:
Single 150 mg tablet use for Vaginal Candidiasis:
There are no adequate and well-controlled studies of Diflucan in pregnant women. Available
human data do not suggest an increased risk of congenital anomalies following a single maternal
dose of 150 mg.
Pregnancy Category D:
All other indications:
A few published case reports describe a rare pattern of distinct congenital anomalies in infants
exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the
first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient
should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy.)
Human Data
Several published epidemiologic studies do not suggest an increased risk of congenital anomalies
associated with low dose exposure to fluconazole in pregnancy (most subjects received a single
oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth
defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during
most or all of the first trimester of pregnancy. The features seen in these infants include:
brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing,
thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to
those seen in animal studies.
Animal Data
Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at
doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was
impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on
BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose
based on BSA); no adverse fetal effects were observed.
In several studies in which pregnant rats received fluconazole orally during organogenesis,
maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There
were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs,
renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher
doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical
dose based on BSA), embryolethality in rats was increased and fetal abnormalities included
wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with
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the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered
estrogen on pregnancy, organogenesis, and parturition
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to maternal plasma
concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing
woman.
Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
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Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
DIFLUCAN is generally well tolerated.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer,
changes in renal and hematological function test results and hepatic abnormalities have been
observed during treatment with fluconazole and comparative agents, but the clinical significance
and relationship to treatment is uncertain.
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
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In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Body as a Whole: Asthenia, fatigue, fever, malaise.
Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
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Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.
Other Senses: Taste perversion.
Musculoskeletal System: myalgia.
Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.
Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased
sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal
necrolysis (see WARNINGS), alopecia.
Adverse Reactions in Children:
The pattern and incidence of adverse events and laboratory abnormalities recorded during
pediatric clinical trials are comparable to those seen in adults.
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
OVERDOSAGE
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid
behavior.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
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Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions.
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
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Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
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Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
>50
100%
50 (no dialysis)
50%
Regular dialysis
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males:
Weight (kg) (140 – age)
72 serum creatinine (mg/100 mL)
Females: 0.85 above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K
linear length or height (cm)
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be
taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of
intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a
maximum rate of approximately 200 mg/hour, given as a continuous infusion.
Reference ID: 3373589
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DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86F
(30C) and 41F (5C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
Reference ID: 3373589
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HOW SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN Tablets are supplied as follows:
DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG”
on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86F (30C).
DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86F (30C). Store reconstituted suspension between 86F
(30C) and 41F (5C) and discard unused portion after 2 weeks. Protect from freezing.
DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
Reference ID: 3373589
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DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL 6
Storage: Store between 86F (30C) and 41F (5C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL 6
Storage: Store between 77F (25C) and 41F (5C). Brief exposure up to 104F (40C) does
not adversely affect the product. Protect from freezing.
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution
Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI
Document M27-A3, Clinical and Laboratory Standards Institute, 940 West Valley Road,
Suite 1400, Wayne, PA,19087-1898 USA, 2008
2. Clinical and Laboratory Standards Institute (CLSI). Methods for Antifungal Disk
Diffusion Susceptibility Testing of Yeasts; Approved Guideline-Second Edition. CLSI
Document M44-A2, Clinical and Laboratory Standards Institute, 940 West Valley Road,
Suite 1400, Wayne, PA, 19087-1898 USA, 2009
3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and
Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and
Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by
Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods.
2007. Journal of Clinical Microbiology. 45:70–75. company logo
LAB-0099-17.0
Revised September 2013
Reference ID: 3373589
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
DIFLUCAN (fluconazole tablets)
This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant
to take the place of your doctor's instructions. Read this information carefully before you take
DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or
if you want to know more about DIFLUCAN.
What Is DIFLUCAN?
DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called
Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast
infection goes away.
DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet
taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only
about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN
for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information
about vaginal yeast infections.
What Is a Vaginal Yeast Infection?
It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast
starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are
common. About three out of every four adult women will have at least one vaginal yeast
infection during their life.
Some medicines and medical conditions can increase your chance of getting a yeast infection. If
you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast
infections more often than other women. Personal hygiene and certain types of clothing may
increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do
to help prevent vaginal yeast infections.
If you get a vaginal yeast infection, you may have any of the following symptoms:
itching
a burning feeling when you urinate
redness
soreness
a thick white vaginal discharge that looks like cottage cheese
What To Tell Your Doctor Before You Start DIFLUCAN?
Do not take Diflucan if you take certain medicines. They can cause serious problems.
Therefore, tell your doctor about all the medicines you take including:
Reference ID: 3373589
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diabetes medicines such as glyburide, tolbutamide, glipizide
blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or
felodipine
blood thinners such as warfarin
cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants)
rifampin or rifabutin for tuberculosis
astemizole for allergies
phenytoin or carbamazepine to control seizures
theophylline to control asthma
cisapride for heartburn
quinidine (used to correct disturbances in heart rhythm)
amitriptyline or nortriptyline for depression
pimozide for psychiatric illness
amphotericin B or voriconazole for fungal infections
erythromycin for bacterial infections
cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of
cancer
fentanyl, afentanil or methadone for chronic pain
halofantrine for malaria
lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin
non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen
prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory
disorders
antiviral medications used to treat HIV like saquinavir or zidovudine
tofacitinib for rheumatoid arthritis
vitamin A nutritional supplement
Since there are many brand names for these medicines, check with your doctor or pharmacist
if you have any questions.
are taking any over-the-counter medicines you can buy without a prescription, including
natural or herbal remedies
have any liver problems.
have any other medical conditions
are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor
will discuss whether DIFLUCAN is right for you.
are breast-feeding. DIFLUCAN can pass through breast milk to the baby.
are allergic to any other medicines including those used to treat yeast and other fungal
infections.
are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is
fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist.
Reference ID: 3373589
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Who Should Not Take DIFLUCAN?
To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking erythromycin,
astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can cause changes in
heartbeat in some people if taken with DIFLUCAN.
How Should I Take DIFLUCAN
Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the
day.
DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms start
to go away after 24 hours. However, it may take several days for your symptoms to go away
completely. If there is no change in your symptoms after a few days, call your doctor.
Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection.
What Should I Avoid while Taking DIFLUCAN?
Some medicines can affect how well DIFLUCAN works. Check with your doctor before
starting any new medicines within seven days of taking DIFLUCAN.
What Are the Possible Side Effects of DIFLUCAN?
Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate.
The most common side effects of DIFLUCAN are:
headache
diarrhea
nausea or upset stomach
dizziness
stomach pain
changes in the way food tastes
Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right away
by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs
of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills;
throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the
body; or skin rash, hives, blisters or skin peeling.
Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in
patients with serious medical problems. Call your doctor if your skin or eyes become yellow,
your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit
or feel like vomiting or if you have severe skin itching.
Reference ID: 3373589
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In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin
peeling have been reported. Tell your doctor right away if you get a rash while taking
DIFLUCAN.
DIFLUCAN may cause other less common side effects besides those listed here. If you develop
any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor
or pharmacist.
What to Do For an Overdose
In case of an accidental overdose, call your doctor right away or go to the nearest emergency
room.
How to Store DIFLUCAN
Keep DIFLUCAN and all medicines out of the reach of children.
General Advice about Prescription Medicines
Medicines are sometimes prescribed for conditions that are mentioned in patient information
leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give
DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about DIFLUCAN. If you would like
more information, talk with your doctor. You can ask your pharmacist or doctor for information
about DIFLUCAN that is written for health professionals.
You can also visit the DIFLUCAN Internet site at www.diflucan.com. company logo
LAB-0380-6.0
Revised March 2013
Reference ID: 3373589
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension, and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The
structural formula is:
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
Reference ID: 3476158
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The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
(fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal
indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken
without regard to meals. (see DOSAGE AND ADMINISTRATION.)
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
Reference ID: 3476158
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A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
Reference ID: 3476158
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Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean (%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(µg/mL)
Vdss
(L/kg)
9 Months
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
Reference ID: 3476158
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administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%)
and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did
not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study
compared to placebo dosing. The individual AUC values of norethindrone decreased very
slightly (<5%) in 3 of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent
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oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life
decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
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change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg
and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole
with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been
associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration
of fluconazole and quinidine is contraindicated. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22
(40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a
mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide Cmax
increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of 19% ± 23%
(range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
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doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes.
Concurrent administration of oral Voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for
2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy
male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57%
(90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical
study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and
fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole
and fluconazole at any dose is not recommended. Close monitoring for adverse events related to
voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially
within 24 h of the last dose of fluconazole. (See PRECAUTIONS)
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Tofacitinib: Co-administration of fluconazole (400 mg on Day 1 and 200 mg once daily for 6
days [Days 2-7]) and tofacitinib (30 mg single dose on Day 5) in healthy subjects resulted in
increased mean tofacitinib AUC and Cmax values of approximately 79% (90% CI: 64% – 96%)
and 27% (90% CI: 12% – 44%), respectively, compared to administration of tofacitinib alone.
(See PRECAUTIONS)
Microbiology
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme
lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The
subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in
fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell
demethylation is much less sensitive to fluconazole inhibition.
Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target
enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination
of these mechanisms.
Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target
with decreased affinity for azoles. Overexpression of ERG11 results in the production of high
concentrations of the target enzyme, creating the need for higher intracellular drug
concentrations to inhibit all of the enzyme molecules in the cell.
The second major mechanism of drug resistance involves active efflux of fluconazole out of the
cell through the activation of two types of multidrug efflux transporters; the major facilitators
(encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR
genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of
CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in
resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to
32 µg/mL), the highest fluconazole dose is recommended.
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
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Activity In Vitro and In Clinical Infections
Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
(≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the
highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative
therapy is recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well-controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
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Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
Table 1: Susceptibility Interpretive Criteria for Fluconazole
Broth Dilution at 48 hours
(MIC in µg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
Antifungal agent
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Fluconazole*
≤ 8.0
16-32
≥64
≥19
15-18
≤14
* Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be
interpreted using this scale.
** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for
fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results
QC Strain
Macrodilution
(MIC in µg/mL)
@ 48 hours
Microdilution
(MIC in µg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
Candida parapsilosis ATCC 22019
2.0-8.0
1.0-4.0
22-33
Candida krusei ATCC 6258
16-64
16-128
---*
Candida albicans ATCC 90028
---*
---*
28-39
Candida tropicalis ATCC 750
---*
---*
26-37
---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
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INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
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Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic eradication
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 (4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 (7%)
Headache
58 (13%)
28 (7%)
Gastrointestinal
68 (15%)
13 (3%)
Abdominal pain
25 (6%)
7 (2%)
Nausea
30 (7%)
3 (1%)
Diarrhea
12 (3%)
2 (<1%)
Application site event
0 (0%)
19 (5%)
Taste Perversion
6 (1%)
0 (0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
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Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and
23% for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of other drugs
known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as
cisapride, astemizole, erythromycin, pimozide, and quinidine are contraindicated in patients
receiving fluconazole.. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver
dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity,
including fatalities primarily in patients with serious underlying medical conditions. In
cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose,
duration of therapy, sex, or age of the patient has been observed. DIFLUCAN
hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy.
Patients who develop abnormal liver function tests during DIFLUCAN therapy should be
monitored for the development of more severe hepatic injury. DIFLUCAN should be
discontinued if clinical signs and symptoms consistent with liver disease develop that may
be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Exfoliative skin disorders during treatment with DIFLUCAN have been
reported. Fatal outcomes have been reported in patients with serious underlying diseases.
Patients with deep seated fungal infections who develop rashes during treatment with
DIFLUCAN should be monitored closely and the drug discontinued if lesions progress.
Fluconazole should be discontinued in patients treated for superficial fungal infection who
develop a rash that may be attributed to fluconazole.
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(4) Use in Pregnancy: There are no adequate and well-controlled studies of DIFLUCAN in
pregnant women. Available human data do not suggest an increased risk of congenital anomalies
following a single maternal dose of 150 mg. A few published case reports describe a rare pattern
of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole
(400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar
to those seen in animal studies. If this drug is used during pregnancy or if the patient becomes
pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus
(See PRECAUTIONS, Pregnancy.)
PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities, and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Concomitant use of fluconazole and erythromycin has the potential to increase the risk of
cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death.
This combination should be avoided.
Fluconazole should be administered with caution to patients with renal dysfunction.
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole
treated patients who are concomitantly treated with drugs with a narrow therapeutic window
metabolized through CYP2C9 and CYP3A4 should be monitored.
DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients
with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.
When driving vehicles or operating machines, it should be taken into account that occasionally
dizziness or seizures may occur.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
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Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP)
isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented
interactions mentioned below, there is a risk of increased plasma concentration of other compounds
metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should
be exercised when using these combinations and the patients should be carefully monitored. The
enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole
treatment due to the long half-life of fluconazole. Clinically or potentially significant drug
interactions between DIFLUCAN and the following agents/classes have been observed. These
are described in greater detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Tofacitinib
Triazolam
Oral Contraceptives
Pimozide
Quinidine
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
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Vitamin A
Zidovudine
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose
adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug
Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN significantly increases cyclosporine levels in renal transplant patients
with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum
creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies). This combination may be used
by reducing the dosage of cyclosporine depending on cyclosporine concentration.
Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and
800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
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contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the
clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT
prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and
astemizole is contraindicated. .
Rifabutin: There have been reports that an interaction exists when fluconazole is administered
concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There
have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered.
Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring
for adverse events and toxicity related to voriconazole is recommended; especially, if
voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus
up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No
significant pharmacokinetic changes have been observed when tacrolimus is given intravenously.
Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered
tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should be
appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Tofacitinib: Systemic exposure to tofacitinib is increased when tofacitinib is coadministered with
fluconazole, a combined moderate CYP3A4 and potent CYP2C19 inhibitor. Reduce the dose of
tofacitinib when given concomitantly with fluconazole (i.e., from 5 mg twice daily to 5 mg once
daily as instructed in the XELJANZ® [tofacitinib] label). (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
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Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax
by 20-32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage
adjustments of triazolam may be necessary.
Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been
performed using multiple doses of fluconazole. There were no relevant effects on hormone level in
the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and
levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at
these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma
concentrations can lead to QT prolongation and rare occurrences of torsade de pointes.
Coadministration of fluconazole and pimozide is contraindicated.
Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated
with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole
and quinidine is contraindicated. (See CONTRAINDICATIONS.)
Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose
hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of
fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole
dose regimen in subjects receiving concomitant diuretics.
Alfentanil: A study observed a reduction in clearance and distribution volume as well as
prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible
mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil
may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5
nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and
after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal
and immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical
significance of results obtained in these studies is unknown.
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a
single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the
pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction
between fluconazole and azithromycin.
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Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum
carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity.
Dosage adjustment of carbamazepine may be necessary depending on concentration
measurements/effect.
Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine,
isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the
potential to increase the systemic exposure of the calcium channel antagonists. Frequent
monitoring for adverse events is recommended.
Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200
mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the
celecoxib dose may be necessary when combined with fluconazole.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an
increase in serum bilirubin and serum creatinine. The combination may be used while taking
increased consideration to the risk of increased serum bilirubin and serum creatinine.
Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author
judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover
study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of
fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory
effect on CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when
fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through
CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If
concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and
rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors
should be discontinued if a marked increase in creatinine kinase is observed or
myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74)
which is responsible for most of the angiotensin Il-receptor antagonism which occurs during
treatment with losartan. Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage
adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by
23% and 81%, respectively, when coadministered with fluconazole compared to administration
of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S
(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was
coadministered with racemic ibuprofen (400 mg) compared to administration of racemic
ibuprofen alone.
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Although not specifically studied, fluconazole has the potential to increase the systemic exposure
of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam,
diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is
recommended. Adjustment of dosage of NSAIDs may be needed.
Prednisone: There was a case report that a liver-transplanted patient treated with prednisone
developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was
discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity
which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole
and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is
discontinued.
Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by
approximately 55%, and decreases clearance of saquinavir by approximately 50% due to
inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein.
Dosage adjustment of saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting
the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used
with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca
alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an
inhibitory effect on CYP3A4.
Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans
retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have
developed in the form of pseudotumour cerebri, which disappeared after discontinuation of
fluconazole treatment. This combination may be used but the incidence of CNS related
undesirable effects should be borne in mind.
Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%,
respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of
zidovudine was likewise prolonged by approximately 128% following combination therapy with
fluconazole. Patients receiving this combination should be monitored for the development of
zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
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Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still born pups and
decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent
with the species specific estrogen-lowering property produced by high doses of fluconazole.
Such a hormone change has not been observed in women treated with fluconazole. (See
CLINICAL PHARMACOLOGY.)
Pregnancy
Teratogenic Effects.Pregnancy Category C:
Single 150 mg tablet use for Vaginal Candidiasis:
There are no adequate and well-controlled studies of Diflucan in pregnant women. Available
human data do not suggest an increased risk of congenital anomalies following a single maternal
dose of 150 mg.
Pregnancy Category D:
All other indications:
A few published case reports describe a rare pattern of distinct congenital anomalies in infants
exposed in utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the
first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient
should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy.)
Human Data
Several published epidemiologic studies do not suggest an increased risk of congenital anomalies
associated with low dose exposure to fluconazole in pregnancy (most subjects received a single
oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth
defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during
most or all of the first trimester of pregnancy. The features seen in these infants include:
brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing,
thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to
those seen in animal studies.
Animal Data
Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at
doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was
impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on
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BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose
based on BSA); no adverse fetal effects were observed.
In several studies in which pregnant rats received fluconazole orally during organogenesis,
maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There
were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs,
renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher
doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical
dose based on BSA), embryolethality in rats was increased and fetal abnormalities included
wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with
the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered
estrogen on pregnancy, organogenesis, and parturition
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to maternal plasma
concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing
woman.
Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
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Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
DIFLUCAN is generally well tolerated.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer,
changes in renal and hematological function test results and hepatic abnormalities have been
observed during treatment with fluconazole and comparative agents, but the clinical significance
and relationship to treatment is uncertain.
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
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In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Body as a Whole: Asthenia, fatigue, fever, malaise.
Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
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Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.
Other Senses: Taste perversion.
Musculoskeletal System: myalgia.
Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.
Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased
sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal
necrolysis (see WARNINGS), alopecia.
Adverse Reactions in Children:
The pattern and incidence of adverse events and laboratory abnormalities recorded during
pediatric clinical trials are comparable to those seen in adults.
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
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OVERDOSAGE
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid
behavior.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions.
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
>50
Percent of Recommended Dose
100%
≤50 (no dialysis)
Regular dialysis
50%
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males:
Weight (kg) × (140 – age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K ×
linear length or height (cm)
serum creatinine (mg/100 mL)
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be
taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of
intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a
maximum rate of approximately 200 mg/hour, given as a continuous infusion.
DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
HOW SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN Tablets are supplied as follows:
DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG”
on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86°F (30°C).
DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6
Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution
Antifungal Susceptibility Testing of Yeasts; Approved Standard-Third Edition. CLSI
Document M27-A3, Clinical and Laboratory Standards Institute, 940 West Valley Road,
Suite 1400, Wayne, PA,19087-1898 USA, 2008
2. Clinical and Laboratory Standards Institute (CLSI). Methods for Antifungal Disk
Diffusion Susceptibility Testing of Yeasts; Approved Guideline-Second Edition. CLSI
Document M44-A2, Clinical and Laboratory Standards Institute, 940 West Valley Road,
Suite 1400, Wayne, PA, 19087-1898 USA, 2009
3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and
Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and
Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by
Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods.
2007. Journal of Clinical Microbiology. 45:70–75.
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
LAB-0099-19.0
Revised March 2014
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
DIFLUCAN (fluconazole tablets)
This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not meant
to take the place of your doctor's instructions. Read this information carefully before you take
DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this information or
if you want to know more about DIFLUCAN.
What Is DIFLUCAN?
DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast called
Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the yeast
infection goes away.
DIFLUCAN is different from other treatments for vaginal yeast infections because it is a tablet
taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet is only
about using DIFLUCAN for vaginal yeast infections. For information about using DIFLUCAN
for other reasons, ask your doctor or pharmacist. See the section of this leaflet for information
about vaginal yeast infections.
What Is a Vaginal Yeast Infection?
It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much yeast
starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast infections are
common. About three out of every four adult women will have at least one vaginal yeast
infection during their life.
Some medicines and medical conditions can increase your chance of getting a yeast infection. If
you are pregnant, have diabetes, use birth control pills, or take antibiotics you may get yeast
infections more often than other women. Personal hygiene and certain types of clothing may
increase your chances of getting a yeast infection. Ask your doctor for tips on what you can do
to help prevent vaginal yeast infections.
If you get a vaginal yeast infection, you may have any of the following symptoms:
• itching
• a burning feeling when you urinate
• redness
• soreness
• a thick white vaginal discharge that looks like cottage cheese
What To Tell Your Doctor Before You Start DIFLUCAN?
Do not take Diflucan if you take certain medicines. They can cause serious problems.
Therefore, tell your doctor about all the medicines you take including:
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• diabetes medicines such as glyburide, tolbutamide, glipizide
• blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine or
felodipine
• blood thinners such as warfarin
• cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants)
• rifampin or rifabutin for tuberculosis
• astemizole for allergies
• phenytoin or carbamazepine to control seizures
• theophylline to control asthma
• cisapride for heartburn
• quinidine (used to correct disturbances in heart rhythm)
• amitriptyline or nortriptyline for depression
• pimozide for psychiatric illness
• amphotericin B or voriconazole for fungal infections
• erythromycin for bacterial infections
• cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment of
cancer
• fentanyl, afentanil or methadone for chronic pain
• halofantrine for malaria
• lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin
• non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen
• prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory
disorders
• antiviral medications used to treat HIV like saquinavir or zidovudine
• tofacitinib for rheumatoid arthritis
• vitamin A nutritional supplement
Since there are many brand names for these medicines, check with your doctor or pharmacist
if you have any questions.
• are taking any over-the-counter medicines you can buy without a prescription, including
natural or herbal remedies
• have any liver problems.
• have any other medical conditions
• are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor
will discuss whether DIFLUCAN is right for you.
• are breast-feeding. DIFLUCAN can pass through breast milk to the baby.
• are allergic to any other medicines including those used to treat yeast and other fungal
infections.
• are allergic to any of the ingredients in DIFLUCAN. The main ingredient of DIFLUCAN is
fluconazole. If you need to know the inactive ingredients, ask your doctor or pharmacist.
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Who Should Not Take DIFLUCAN?
To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking erythromycin,
astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can cause changes in
heartbeat in some people if taken with DIFLUCAN.
How Should I Take DIFLUCAN
Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time of the
day.
DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms start
to go away after 24 hours. However, it may take several days for your symptoms to go away
completely. If there is no change in your symptoms after a few days, call your doctor.
Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection.
What Should I Avoid while Taking DIFLUCAN?
Some medicines can affect how well DIFLUCAN works. Check with your doctor before
starting any new medicines within seven days of taking DIFLUCAN.
What Are the Possible Side Effects of DIFLUCAN?
Like all medicines, DIFLUCAN may cause some side effects that are usually mild to moderate.
The most common side effects of DIFLUCAN are:
• headache
• diarrhea
• nausea or upset stomach
• dizziness
• stomach pain
• changes in the way food tastes
Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right away
by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency room. Signs
of an allergic reaction can include shortness of breath; coughing; wheezing; fever; chills;
throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck, or any other part of the
body; or skin rash, hives, blisters or skin peeling.
Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in
patients with serious medical problems. Call your doctor if your skin or eyes become yellow,
your urine turns a darker color, your stools (bowel movements) are light-colored, or if you vomit
or feel like vomiting or if you have severe skin itching.
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with skin
peeling have been reported. Tell your doctor right away if you get a rash while taking
DIFLUCAN.
DIFLUCAN may cause other less common side effects besides those listed here. If you develop
any side effects that concern you, call your doctor. For a list of all side effects, ask your doctor
or pharmacist.
What to Do For an Overdose
In case of an accidental overdose, call your doctor right away or go to the nearest emergency
room.
How to Store DIFLUCAN
Keep DIFLUCAN and all medicines out of the reach of children.
General Advice about Prescription Medicines
Medicines are sometimes prescribed for conditions that are mentioned in patient information
leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not give
DIFLUCAN to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about DIFLUCAN. If you would like
more information, talk with your doctor. You can ask your pharmacist or doctor for information
about DIFLUCAN that is written for health professionals.
You can also visit the DIFLUCAN Internet site at www.diflucan.com. company logo
LAB-0380-6.0
Revised March 2014
Reference ID: 3476158
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019949s058,019950s062,020090s042lbl.pdf', 'application_number': 19949, 'submission_type': 'SUPPL ', 'submission_number': 58}
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12,089
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1
23-4526-00-1
PATIENT INFORMATION
DIFLUCAN (fluconazole tablets)
This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not
meant to take the place of your doctor's instructions. Read this information carefully before
you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand any of this
information or if you want to know more about DIFLUCAN.
What Is DIFLUCAN?
DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast
called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so the
yeast infection goes away.
DIFLUCAN is different from other treatments for vaginal yeast infections because it is a
tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this leaflet
is only about using DIFLUCAN for vaginal yeast infections. For information about using
DIFLUCAN for other reasons, ask your doctor or pharmacist. See the section of this leaflet
for information about vaginal yeast infections.
What Is A Vaginal Yeast Infection?
It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much
yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast
infections are common. About three out of every four adult women will have at least one
vaginal yeast infection during their life.
Some medicines and medical conditions can increase your chance of getting a yeast
infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics you
may get yeast infections more often than other women. Personal hygiene and certain types
of clothing may increase your chances of getting a yeast infection. Ask your doctor for tips
on what you can do to help prevent vaginal yeast infections.
If you get a vaginal yeast infection, you may have any of the following symptoms:
• itching
• a burning feeling when you urinate
• redness
• soreness
• a thick white vaginal discharge that looks like cottage cheese
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
What To Tell Your Doctor Before You Start DIFLUCAN?
Do not take Diflucan if you take certain medicines. They can cause serious problems.
Therefore, tell your doctor about all the medicines you take including:
• diabetes medicines you take by mouth such as glyburide, tolbutamide, glipizide
• blood thinners such as warfarin
• cyclosporine (used to prevent rejection of organ transplants)
• rifampin or rifabutin (used for tuberculosis)
• astemizole (used for allergies)
• tacrolimus (used to prevent rejection of organ transplants)
• phenytoin (used for seizures)
• theophylline (used for asthma)
• cisapride (Propulsid®; used for stomach acid problems)
• terfenadine (Seldane®; used for allergies)
Since there are many brand names for these medicines, check with your doctor or
pharmacist if you have any questions.
• are taking any over-the-counter medicines you can buy without a prescription,
including natural or herbal remedies
• have any liver problems.
• have any other medical conditions
• are pregnant, plan to become pregnant, or think you might be pregnant. Your
doctor will discuss whether DIFLUCAN is right for you.
• are breast-feeding. DIFLUCAN can pass through breast milk to the baby.
• are allergic to any other medicines including those used to treat yeast and other
fungal infections.
• are allergic to any of the ingredients in DIFLUCAN. The main ingredient of
DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask
your doctor or pharmacist.
Who Should Not Take DIFLUCAN?
To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking cisapride
(Propulsid®) since it can cause changes in heartbeat in some people if taken with
DIFLUCAN.
How Should I Take DIFLUCAN
Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any time
of the day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
DIFLUCAN keeps working for several days to treat the infection. Generally the symptoms
start to go away after 24 hours. However, it may take several days for your symptoms to go
away completely. If there is no change in your symptoms after a few days, call your doctor.
[caption on the right of the illustration]
Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection.
What Should I Avoid While Taking DIFLUCAN?
Some medicines can affect how well DIFLUCAN works. Check with your doctor before
starting any new medicines within seven days of taking DIFLUCAN.
What Are The Possible Side Effects of DIFLUCAN?
Like all medicines, DIFLUCAN may cause some side effects that are usually mild to
moderate.
The most common side effects of DIFLUCAN are:
• headache
• diarrhea
• nausea or upset stomach
• dizziness
• stomach pain
• changes in the way food tastes
Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated right
away by a doctor. If you cannot reach your doctor, go to the nearest hospital emergency
room. Signs of an allergic reaction can include shortness of breath; coughing; wheezing;
fever; chills; throbbing of the heart or ears; swelling of the eyelids, face, mouth, neck,
or any other part of the body; or skin rash, hives, blisters or skin peeling.
Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly in
patients with serious medical problems. Call your doctor if your skin or eyes become
yellow, your urine turns a darker color, your stools (bowel movements) are light-colored,
or if you vomit or feel like vomiting or if you have severe skin itching.
In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes with
skin peeling have been reported. Tell your doctor right away if you get a rash while taking
DIFLUCAN.
DIFLUCAN may cause other less common side effects besides those listed here. If you
develop any side effects that concern you, call your doctor. For a list of all side effects, ask
your doctor or pharmacist.
What To Do For An Overdose
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
In case of an accidental overdose, call your doctor right away or go to the nearest emergency
room.
How To Store DIFLUCAN
Keep DIFLUCAN and all medicines out of the reach of children.
General Advice About Prescription Medicines
Medicines are sometimes prescribed for conditions that are mentioned in patient information
leaflets. Do not use DIFLUCAN for a condition for which it was not prescribed. Do not
give DIFLUCAN to other people, even if they have the same symptoms you have. It may
harm them.
This leaflet summarizes the most important information about DIFLUCAN. If you would
like more information, talk with your doctor. You can ask your pharmacist or doctor for
information about DIFLUCAN that is written for health professionals.
You can also visit the DIFLUCAN Internet site at www.diflucan.com.
p U.S. Pharmaceuticals
2003, Pfizer Inc
Revised June 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:46:22.061796
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19949slr037,19950slr039,20090slr019_diflucan_lbl.pdf', 'application_number': 19950, 'submission_type': 'SUPPL ', 'submission_number': 39}
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The
structural formula is:
CH2
CH2
C
N
N
N
N
N
N
OH
F
F
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
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diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Mode of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14
alpha-demethylation. Mammalian cell demethylation is much less sensitive to fluconazole
inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14
alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole.
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
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regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
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Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean(%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(µg/mL)
Vdss
(L/kg)
9 Months-
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months-
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4+ 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
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There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18-31%)
and 13% (95% C.I. range 8-18%), respectively relative to placebo. Fluconazole treatment did not
cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to
placebo dosing. The individual AUC individual values of norethindrone decreased very slightly
(<5%) in 3 of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
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Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9%
(range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to
72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See
PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
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half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg
and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%)
of placebo treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was
a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide
Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of
19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
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fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Microbiology
Fluconazole exhibits in vitro activity against Cryptococcus neoformans and Candida spp.
Fungistatic activity has also been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for
systemic infections due to Candida albicans.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to
fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was
active in a variety of animal models of fungal infection using standard laboratory strains of fungi.
Activity has been demonstrated against fungal infections caused by Aspergillus flavus and
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Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal
models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary
infections in normal mice; one model of Coccidioides immitis intracranial infections in normal
mice; and several models of Histoplasma capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results obtained in these studies is
unknown.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cr. neoformans,
and antagonism of the two drugs in systemic infection with Asp. fumigatus. The clinical
significance of results obtained in these studies is unknown.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
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CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic erad.
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
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Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 ( 4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 ( 7%)
Headache
58 (13%)
28 ( 7%)
Gastrointestinal
68 (15%)
13 ( 3%)
Abdominal pain
25 ( 6%)
7 ( 2%)
Nausea
30 ( 7%)
3 ( 1%)
Diarrhea
12 ( 3%)
2 (<1%)
Application site event
0 ( 0%)
19 ( 5%)
Taste Perversion
6 ( 1%)
0 ( 0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23%
for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of cisapride is
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contraindicated in patients receiving DIFLUCAN (fluconazole). (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN has been associated with rare cases of serious hepatic
toxicity, including fatalities primarily in patients with serious underlying medical
conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to
total daily dose, duration of therapy, sex or age of the patient has been observed.
DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation
of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy
should be monitored for the development of more severe hepatic injury. DIFLUCAN
should be discontinued if clinical signs and symptoms consistent with liver disease develop
that may be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) Clinically or potentially significant drug interactions between
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DIFLUCAN and the following agents/classes have been observed. These are described in greater
detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Tacrolimus
Short-acting benzodiazepines
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring of cyclosporine concentrations
and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
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Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200-mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400-mg and
800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events, including torsade de pointes in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval.The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: The use of fluconazole in patients concurrently taking astemizole or other drugs
metabolized by the cytochrome P450 system may be associated with elevations in serum levels
of these drugs. In the absence of definitive information, caution should be used when
coadministering fluconazole. Patients should be carefully monitored.
Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were
coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully
monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and
tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly
should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
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metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should
be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral
contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels;
however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and
levonorgestrel levels. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The
data presently available indicate that the decreases in some individual ethinyl estradiol and
levonorgestrel AUC values with fluconazole treatment are likely the result of random variation.
While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and
levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or
levonorgestrel metabolism. The clinical significance of these effects is presently unknown.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
(human lymphocytes exposed to fluconazole at 1000 µg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20 and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still-born pups
and decrease of neonatal survival at these dose levels. The effects on parturition in rats are
consistent with the species specific estrogen-lowering property produced by high doses of
fluconazole. Such a hormone change has not been observed in women treated with fluconazole.
(See CLINICAL PHARMACOLOGY.)
Pregnancy
Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant
rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg,
respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at
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75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were
detected. In several studies in which pregnant rats were treated orally with fluconazole during
organogenesis, maternal weight gain was impaired and placental weights were increased at
25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants
(supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and
50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the
recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal
abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These
effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of
known effects of lowered estrogen on pregnancy, organogenesis and parturition.
There are no adequate and well controlled studies in pregnant women. There have been reports
of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more
months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an
unindicated use). The relationship between fluconazole use and these events is unclear.
DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk
to the fetus.
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of
DIFLUCAN in nursing mothers is not recommended.
Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
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The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
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In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
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Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic
epidermal necrolysis (see WARNINGS), alopecia.
Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Dyspepsia, vomiting.
Other Senses: Taste perversion.
Adverse Reactions in Children:
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
OVERDOSAGE
There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient
infected with human immunodeficiency virus developed hallucinations and exhibited paranoid
behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the
hospital, and his condition resolved within 48 hours.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
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Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions.
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
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Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis of patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy.
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Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
>50
100%
≤50 (no dialysis)
50%
Regular dialysis
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males: Weight (kg) × (140-age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K ×
linear length or height (cm)
serum creatinine (mg/100 mL)
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(Where K=0.55 for children older than 1 year and 0.45 for infants.)
Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN injection
has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of
DIFLUCAN should be administered at a maximum rate of approximately 200 mg/hour, given as
a continuous infusion.
DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
HOW SUPPLIED
DIFLUCAN® Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN® Tablets are supplied as follows:
DIFLUCAN® 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and
“ROERIG” on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN® 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN® 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN® 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86°F (30°C).
DIFLUCAN® for Oral Suspension: DIFLUCAN® for oral suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DIFLUCAN® Injections: DIFLUCAN® injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN®
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN® Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN® Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6
Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.Rx only
2004
PFIZER INC
LAB-0099 –6.1
Revised August2004
Roerig
Division of Pfizer Inc, NY, NY 10017
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:22.383075
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19949s30,32,35,19950s31,33,37,20090s12,14,17lbl.pdf', 'application_number': 19950, 'submission_type': 'SUPPL ', 'submission_number': 37}
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12,090
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The
structural formula is:
str
uct
ural
f
or
mu
la
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
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diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
(fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal
indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken
without regard to meals. (see DOSAGE AND ADMINISTRATION.)
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
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regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
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Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean(%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(μg/mL)
Vdss
(L/kg)
9 Months-
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months-
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4+ 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%) and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
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There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18-31%)
and 13% (95% C.I. range 8-18%), respectively relative to placebo. Fluconazole treatment did not
cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to
placebo dosing. The individual AUC values of norethindrone decreased very slightly (<5%) in 3
of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
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Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9%
(range: –13 to –42%). Apparent oral clearance of fluconazole increased 32% ± 17% (range: 16 to
72%). Fluconazole half-life decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See
PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
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half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400-mg
and 800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%)
of placebo treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was
a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide
Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of
19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
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fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Microbiology
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 dependent enzyme
lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The
subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in
fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell
demethylation is much less sensitive to fluconazole inhibition.
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Activity In Vitro and In Clinical Infections
Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
(≥16µg/ml). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/ml, see Table 1), the
highest dose is recommended (see Dosage and Administration). For resistant isolates alternative therapy is
recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
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concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
Table 1: Susceptibility Interpretive Criteria for Fluconazole
Broth Dilution at 48 hours
(MIC in µg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
Antifungal agent
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Fluconazole*
≤ 8.0
16-32
≥64
≥19
15-18
≤14
* Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be
interpreted using this scale.
** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for
fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
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Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results
QC Strain
Macrodilution
(MIC in µg/mL)
@ 48 hours
Microdilution
(MIC in µg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
Candida parapsilosis ATCC 22019
2.0-8.0
1.0-4.0
22-33
Candida krusei ATCC 6258
16-64
16-128
---*
Candida albicans ATCC 90028
---*
---*
28-39
Candida tropicalis ATCC 750
---*
---*
26-37
---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
Activity In Vivo
Fungistatic activity has also been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for
systemic infections due to Candida albicans.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to
fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was
active in a variety of animal models of fungal infection using standard laboratory strains of fungi.
Activity has been demonstrated against fungal infections caused by Aspergillus flavus and
Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal
models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary
infections in normal mice; one model of Coccidioides immitis intracranial infections in normal
mice; and several models of Histoplasma capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results obtained in these studies is
unknown.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The
clinical significance of results obtained in these studies is unknown.
Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target
enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination
of these mechanisms.
Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target
with decreased affinity for azoles. Overexpression of ERG11 results in the production of high
concentrations of the target enzyme, creating the need for higher intracellular drug
concentrations to inhibit all of the enzyme molecules in the cell.
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The second major mechanism of drug resistance involves active efflux of fluconazole out of the
cell through the activation of two types of multidrug efflux transporters; the major facilitators
(encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR
genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of
CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in
resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to
32 µg/mL), the highest fluconazole dose is recommended.
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
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CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic erad.
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
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Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 ( 4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 ( 7%)
Headache
58 (13%)
28 ( 7%)
Gastrointestinal
68 (15%)
13 ( 3%)
Abdominal pain
25 ( 6%)
7 ( 2%)
Nausea
30 ( 7%)
3 ( 1%)
Diarrhea
12 ( 3%)
2 (<1%)
Application site event
0 ( 0%)
19 ( 5%)
Taste Perversion
6 ( 1%)
0 ( 0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment the percentages of patients with clinical relapse were 22% for DIFLUCAN and 23%
for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of cisapride is
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contraindicated in patients receiving DIFLUCAN (fluconazole). (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN has been associated with rare cases of serious hepatic
toxicity, including fatalities primarily in patients with serious underlying medical
conditions. In cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to
total daily dose, duration of therapy, sex or age of the patient has been observed.
DIFLUCAN hepatotoxicity has usually, but not always, been reversible on discontinuation
of therapy. Patients who develop abnormal liver function tests during DIFLUCAN therapy
should be monitored for the development of more severe hepatic injury. DIFLUCAN
should be discontinued if clinical signs and symptoms consistent with liver disease develop
that may be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) Clinically or potentially significant drug interactions between
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DIFLUCAN and the following agents/classes have been observed. These are described in greater
detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Tacrolimus
Short-acting benzodiazepines
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring of cyclosporine concentrations
and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
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Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200-mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400-mg and
800-mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events, including torsade de pointes in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: The use of fluconazole in patients concurrently taking astemizole or other drugs
metabolized by the cytochrome P450 system may be associated with elevations in serum levels
of these drugs. In the absence of definitive information, caution should be used when
coadministering fluconazole. Patients should be carefully monitored.
Rifabutin: There have been reports of uveitis in patients to whom fluconazole and rifabutin were
coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully
monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: There have been reports of nephrotoxicity in patients to whom fluconazole and
tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly
should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
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metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should
be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-containing oral
contraceptives produced an overall mean increase in ethinyl estradiol and levonorgestrel levels;
however, in some patients there were decreases up to 47% and 33% of ethinyl estradiol and
levonorgestrel levels. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) The
data presently available indicate that the decreases in some individual ethinyl estradiol and
levonorgestrel AUC values with fluconazole treatment are likely the result of random variation.
While there is evidence that fluconazole can inhibit the metabolism of ethinyl estradiol and
levonorgestrel, there is no evidence that fluconazole is a net inducer of ethinyl estradiol or
levonorgestrel metabolism. The clinical significance of these effects is presently unknown.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20 and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still-born pups
and decrease of neonatal survival at these dose levels. The effects on parturition in rats are
consistent with the species specific estrogen-lowering property produced by high doses of
fluconazole. Such a hormone change has not been observed in women treated with fluconazole.
(See CLINICAL PHARMACOLOGY.)
Pregnancy
Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant
rabbits during organogenesis in two studies, at 5, 10 and 20 mg/kg and at 5, 25, and 75 mg/kg,
respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at
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75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were
detected. In several studies in which pregnant rats were treated orally with fluconazole during
organogenesis, maternal weight gain was impaired and placental weights were increased at
25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants
(supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and
50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the
recommended human dose) to 320 mg/kg embryolethality in rats was increased and fetal
abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These
effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of
known effects of lowered estrogen on pregnancy, organogenesis and parturition.
There are no adequate and well controlled studies in pregnant women. There have been reports
of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more
months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an
unindicated use). The relationship between fluconazole use and these events is unclear.
DIFLUCAN should be used in pregnancy only if the potential benefit justifies the possible risk
to the fetus.
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of
DIFLUCAN in nursing mothers is not recommended.
Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
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The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
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In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during postmarketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
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Dermatologic: Exfoliative skin disorders including Stevens-Johnson syndrome and toxic
epidermal necrolysis (see WARNINGS), alopecia.
Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Dyspepsia, vomiting.
Other Senses: Taste perversion.
Adverse Reactions in Children:
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
OVERDOSAGE
There have been reports of overdosage with DIFLUCAN (fluconazole). A 42-year-old patient
infected with human immunodeficiency virus developed hallucinations and exhibited paranoid
behavior after reportedly ingesting 8200 mg of DIFLUCAN. The patient was admitted to the
hospital, and his condition resolved within 48 hours.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
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In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions.
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
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Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis of patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
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Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
>50
100%
≤50 (no dialysis)
50%
Regular dialysis
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males:
Weight (kg) × (140-age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K ×
linear length or height (cm)
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
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Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be
taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of
intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a
maximum rate of approximately 200 mg/hour, given as a continuous infusion.
DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
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Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
HOW SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100 or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN Tablets are supplied as follows:
DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG”
on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86°F (30°C).
DIFLUCAN for Oral Suspension: DIFLUCAN for oral suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
This label may not be the latest approved by FDA.
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DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6
Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.
Rx only
REFERENCES
1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27
A2, 2002 Volume 22, No 15, CLSI, Wayne, PA, August 2002.
2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion
Susceptibllity Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume
24, No. 15 CLSI, Wayne, PA, May 2004.
3. Pfaller, M. A., Messer,S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and Diekema1,
D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to
Voriconazole among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and
Laboratory Standard Institute-Recommended Broth Microdilution Methods. 2007. Journal of
Clinical Microbiology. 45:70–75. company logo
This label may not be the latest approved by FDA.
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LAB-0099-11.0
Revised August, 2010
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:46:22.576711
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019949s048,019950s053,020090s031lbl.pdf', 'application_number': 19950, 'submission_type': 'SUPPL ', 'submission_number': 53}
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12,091
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension, and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The
structural formula is:
OH
str
uctu
ra
l
fo
rm
ul
a
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
Reference ID: 2956251
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diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
(fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal
indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken
without regard to meals. (see DOSAGE AND ADMINISTRATION.)
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
Reference ID: 2956251
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For current labeling information, please visit https://www.fda.gov/drugsatfda
regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
Reference ID: 2956251
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Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean (%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(μg/mL)
Vdss
(L/kg)
9 Months-
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months-
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
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There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%)
and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did
not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study
compared to placebo dosing. The individual AUC values of norethindrone decreased very
slightly (<5%) in 3 of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
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Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent
oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life
decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
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half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg
and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22
(40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was
a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide
Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of
19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
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fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes.
Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for
2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy
male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57%
(90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical
study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and
fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole
and fluconazole at any dose is not recommended. Close monitoring for adverse events related to
voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially
within 24 h of the last dose of fluconazole. (See PRECAUTIONS.)
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Microbiology
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme
lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The
subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in
fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell
demethylation is much less sensitive to fluconazole inhibition.
Activity In Vitro and In Clinical Infections
Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
(≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the
highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative
therapy is recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well-controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
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Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
Table 1: Susceptibility Interpretive Criteria for Fluconazole
Broth Dilution at 48 hours
(MIC in µg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
Antifungal agent
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Fluconazole*
≤ 8.0
16-32
≥64
≥19
15-18
≤14
* Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be
interpreted using this scale.
** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for
fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
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resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results
QC Strain
Macrodilution
(MIC in µg/mL)
@ 48 hours
Microdilution
(MIC in µg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
Candida parapsilosis ATCC 22019
2.0-8.0
1.0-4.0
22-33
Candida krusei ATCC 6258
16-64
16-128
---*
Candida albicans ATCC 90028
---*
---*
28-39
Candida tropicalis ATCC 750
---*
---*
26-37
---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
Activity In Vivo
Fungistatic activity has also been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for
systemic infections due to Candida albicans.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to
fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was
active in a variety of animal models of fungal infection using standard laboratory strains of fungi.
Activity has been demonstrated against fungal infections caused by Aspergillus flavus and
Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal
models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary
infections in normal mice; one model of Coccidioides immitis intracranial infections in normal
mice; and several models of Histoplasma capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results obtained in these studies is
unknown.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The
clinical significance of results obtained in these studies is unknown.
Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target
enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination
of these mechanisms.
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Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target
with decreased affinity for azoles. Overexpression of ERG11 results in the production of high
concentrations of the target enzyme, creating the need for higher intracellular drug
concentrations to inhibit all of the enzyme molecules in the cell.
The second major mechanism of drug resistance involves active efflux of fluconazole out of the
cell through the activation of two types of multidrug efflux transporters; the major facilitators
(encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR
genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of
CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in
resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to
32 µg/mL), the highest fluconazole dose is recommended.
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
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Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic eradication
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
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Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 (4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 (7%)
Headache
58 (13%)
28 (7%)
Gastrointestinal
68 (15%)
13 (3%)
Abdominal pain
25 (6%)
7 (2%)
Nausea
30 (7%)
3 (1%)
Diarrhea
12 (3%)
2 (<1%)
Application site event
0 (0%)
19 (5%)
Taste Perversion
6 (1%)
0 (0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and
23% for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
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between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of other drugs
known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as
cisapride, astemizole, pimozide, and quinidine are contraindicated in patients receiving fluconazole..
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver
dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity,
including fatalities primarily in patients with serious underlying medical conditions. In
cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose,
duration of therapy, sex, or age of the patient has been observed. DIFLUCAN
hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy.
Patients who develop abnormal liver function tests during DIFLUCAN therapy should be
monitored for the development of more severe hepatic injury. DIFLUCAN should be
discontinued if clinical signs and symptoms consistent with liver disease develop that may
be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
(4) Use in Pregnancy: There are no adequate and well-controlled studies of Diflucan in pregnant
women. Available human data do not suggest an increased risk of congenital anomalies
following a single maternal dose of 150 mg. A few published case reports describe a rare pattern
of distinct congenital anomalies in infants exposed in-utero to high dose maternal fluconazole
(400-800 mg/day) during most or all of the first trimester. These reported anomalies are similar
to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking the drug, the patient should be informed of the potential hazard to the
fetus. (See PRECAUTIONS, Pregnancy)
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PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities, and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Concomitant use of fluconazole and erythromycin has the potential to increase the risk of
cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death.
This combination should be avoided.
Fluconazole should be administered with caution to patients with renal dysfunction.
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole
treated patients who are concomitantly treated with drugs with a narrow therapeutic window
metabolized through CYP2C9 and CYP3A4 should be monitored.
DIFLUCAN Capsules contain lactose and should not be given to patients with rare hereditary
problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients
with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.
DIFLUCAN Syrup contains glycerol. Glycerol may cause headache, stomach upset, and
diarrhea.
When driving vehicles or operating machines, it should be taken into account that occasionally
dizziness or seizures may occur.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP)
isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented
interactions mentioned below, there is a risk of increased plasma concentration of other compounds
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metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should
be exercised when using these combinations and the patients should be carefully monitored. The
enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole
treatment due to the long half-life of fluconazole. Clinically or potentially significant drug
interactions between DIFLUCAN and the following agents/classes have been observed. These
are described in greater detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Triazolam
Oral Contraceptives
Pimozide
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
Vitamin A
Zidovudine
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
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in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose
adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug
Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring of cyclosporine concentrations
and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and
800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
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Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the
clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT
prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and
astemizole is contraindicated. .
Rifabutin: There have been reports that an interaction exists when fluconazole is administered
concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There
have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered.
Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring
for adverse events and toxicity related to voriconazole is recommended; especially, if
voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus
up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No
significant pharmacokinetic changes have been observed when tacrolimus is given intravenously.
Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered
tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should
be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20
32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage
adjustments of triazolam may be necessary.
Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been
performed using multiple doses of fluconazole. There were no relevant effects on hormone level in
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the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and
levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at
these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
.
Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma
concentrations can lead to QT prolongation and rare occurrences of torsade de pointes.
Coadministration of fluconazole and pimozide is contraindicated.
Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose
hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of
fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole
dose regimen in subjects receiving concomitant diuretics.
Alfentanil: A study observed a reduction in clearance and distribution volume as well as
prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible
mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil
may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-
nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and
after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal
and immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical
significance of results obtained in these studies is unknown.
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a
single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the
pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction
between fluconazole and azithromycin.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum
carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity.
Dosage adjustment of carbamazepine may be necessary depending on concentration
measurements/effect.
Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine,
isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the
potential to increase the systemic exposure of the calcium channel antagonists. Frequent
monitoring for adverse events is recommended.
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Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200
mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the
celecoxib dose may be necessary when combined with fluconazole.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an
increase in serum bilirubin and serum creatinine. The combination may be used while taking
increased consideration to the risk of increased serum bilirubin and serum creatinine.
Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author
judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover
study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of
fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory
effect on CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when
fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through
CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If
concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and
rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors
should be discontinued if a marked increase in creatinine kinase is observed or
myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74)
which is responsible for most of the angiotensin Il-receptor antagonism which occurs during
treatment with losartan. Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage
adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by
23% and 81%, respectively, when coadministered with fluconazole compared to administration
of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S
(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was
coadministered with racemic ibuprofen (400 mg) compared to administration of racemic
ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure
of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam,
diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is
recommended. Adjustment of dosage of NSAIDs may be needed.
Prednisone: There was a case report that a liver-transplanted patient treated with prednisone
developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was
discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity
which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole
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and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is
discontinued.
Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by
approximately 55%, and decreases clearance of saquinavir by approximately 50% due to
inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein.
Dosage adjustment of saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting
the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used
with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca
alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an
inhibitory effect on CYP3A4.
Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans
retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have
developed in the form of pseudotumour cerebri, which disappeared after discontinuation of
fluconazole treatment. This combination may be used but the incidence of CNS related
undesirable effects should be borne in mind.
Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%,
respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of
zidovudine was likewise prolonged by approximately 128% following combination therapy with
fluconazole. Patients receiving this combination should be monitored for the development of
zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and
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40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still born pups and
decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent
with the species specific estrogen-lowering property produced by high doses of fluconazole.
Such a hormone change has not been observed in women treated with fluconazole. (See
CLINICAL PHARMACOLOGY.)
PRECAUTIONS/Pregnancy:
Teratogenic Effects.
Pregnancy Category C
Single 150 mg tablet use for Vaginal Candidiasis:
There are no adequate and well-controlled studies of Diflucan in pregnant women. Available
human data do not suggest an increased risk of congenital anomalies following a single maternal
dose of 150 mg.
Pregnancy Category D:
All other indications:
A few published case reports describe a rare pattern of distinct congenital anomalies in infants
exposed in-utero to high dose maternal fluconazole (400-800 mg/day) during most or all of the
first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient
should be informed of the potential hazard to the fetus. (See WARNINGS, Use in Pregnancy)
Human Data
Several published epidemiologic studies do not suggest an increased risk of congenital anomalies
associated with low dose exposure to fluconazole in pregnancy (most subjects received a single
oral dose of 150 mg). A few published case reports describe a distinctive and rare pattern of birth
defects among infants whose mothers received high-dose (400-800 mg/day) fluconazole during
most or all of the first trimester of pregnancy. The features seen in these infants include:
brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing,
thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to
those seen in animal studies.
Animal Data
Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at
doses of 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg, respectively. Maternal weight gain was
impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on
BSA), and abortions occurred at 75 mg/kg (approximately 4 times the 400 mg clinical dose
based on BSA); no adverse fetal effects were observed.
In several studies in which pregnant rats received fluconazole orally during organogenesis,
maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There
were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs,
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renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher
doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical
dose based on BSA), embryolethality in rats was increased and fetal abnormalities included
wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with
the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered
estrogen on pregnancy, organogenesis, and parturition.
PRECAUTIONS/Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to maternal plasma
concentrations. Caution should be exercised when DIFLUCAN is administered to a nursing
woman.
Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
Geriatric Use
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In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
DIFLUCAN is generally well tolerated.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer,
changes in renal and hematological function test results and hepatic abnormalities have been
observed during treatment with fluconazole and comparative agents, but the clinical significance
and relationship to treatment is uncertain.
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
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In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Body as a Whole: Asthenia, fatigue, fever, malaise.
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Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.
Other Senses: Taste perversion.
Musculoskeletal System: myalgia.
Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.
Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased
sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal
necrolysis (see WARNINGS), alopecia.
Adverse Reactions in Children:
The pattern and incidence of adverse events and laboratory abnormalities recorded during
pediatric clinical trials are comparable to those seen in adults.
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
OVERDOSAGE
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There have been reports of overdose with fluconazole accompanied by hallucination and paranoid
behavior.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions.
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
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Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
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Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
>50
100%
≤50 (no dialysis)
50%
Regular dialysis
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males:
Weight (kg) × (140 – age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
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Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K ×
linear length or height (cm)
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be
taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of
intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a
maximum rate of approximately 200 mg/hour, given as a continuous infusion.
DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
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To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
HOW SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN Tablets are supplied as follows:
DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG”
on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86°F (30°C).
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DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6
Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.
Rx only
REFERENCES
1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27
A2, 2002 Volume 22, No. 15, CLSI, Wayne, PA, August 2002.
2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion
Susceptibility Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume
24, No. 15, CLSI, Wayne, PA, May 2004.
Reference ID: 2956251
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3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and
Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and
Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by
Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods.
2007. Journal of Clinical Microbiology. 45:70–75. Pfizer
LAB-0099-13.0
Revised May 2011
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019950s056lbl.pdf', 'application_number': 19950, 'submission_type': 'SUPPL ', 'submission_number': 56}
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DIFLUCAN®
(Fluconazole Tablets)
(Fluconazole Injection - for intravenous infusion only)
(Fluconazole for Oral Suspension)
DESCRIPTION
DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is
available as tablets for oral administration, as a powder for oral suspension, and as a sterile
solution for intravenous use in glass and in Viaflex® Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight of 306.3. The
structural formula is:
Fluconazole is a white crystalline solid which is slightly soluble in water and saline.
DIFLUCAN Tablets contain 50, 100, 150, or 200 mg of fluconazole and the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone,
croscarmellose sodium, FD&C Red No. 40 aluminum lake dye, and magnesium stearate.
DIFLUCAN for Oral Suspension contains 350 mg or 1400 mg of fluconazole and the following
inactive ingredients: sucrose, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate,
titanium dioxide, colloidal silicon dioxide, xanthan gum, and natural orange flavor. After
reconstitution with 24 mL of distilled water or Purified Water (USP), each mL of reconstituted
suspension contains 10 mg or 40 mg of fluconazole.
DIFLUCAN Injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a
sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium
chloride or 56 mg of dextrose, hydrous. The pH ranges from 4.0 to 8.0 in the sodium chloride
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diluent and from 3.5 to 6.5 in the dextrose diluent. Injection volumes of 100 mL and 200 mL are
packaged in glass and in Viaflex® Plus plastic containers.
The Viaflex® Plus plastic container is fabricated from a specially formulated polyvinyl chloride
(PL 146® Plastic) (Viaflex and PL 146 are registered trademarks of Baxter International, Inc.).
The amount of water that can permeate from inside the container into the overwrap is insufficient
to affect the solution significantly. Solutions in contact with the plastic container can leach out
certain of its chemical components in very small amounts within the expiration period, e.g.,
di-2-ethylhexylphthalate (DEHP), up to 5 parts per million. However, the suitability of the
plastic has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar following administration by the
intravenous or oral routes. In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration. Bioequivalence was
established between the 100 mg tablet and both suspension strengths when administered as a
single 200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after
oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN
(fluconazole) leads to a mean Cmax of 6.72 μg/mL (range: 4.12 to 8.08 μg/mL) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional.
The Cmax and AUC data from a food-effect study involving administration of DIFLUCAN
(fluconazole) tablets to healthy volunteers under fasting conditions and with a high-fat meal
indicated that exposure to the drug is not affected by food. Therefore, DIFLUCAN may be taken
without regard to meals. (see DOSAGE AND ADMINISTRATION.)
Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating
women resulted in a mean Cmax of 2.61 μg/mL (range: 1.57 to 3.65 μg/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg
given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose
results in plasma concentrations close to steady-state by the second day. The apparent volume of
distribution of fluconazole approximates that of total body water. Plasma protein binding is low
(11-12%). Following either single- or multiple oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see table below). In normal volunteers, saliva
concentrations of fluconazole were equal to or slightly greater than plasma concentrations
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regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum
concentrations of fluconazole following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole
concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal
tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours
following dosing.
A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal
fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following
dosing.
Ratio of Fluconazole
Tissue (Fluid)/Plasma
Tissue or Fluid
Concentration*
Cerebrospinal fluid†
0.5-0.9
Saliva
1
Sputum
1
Blister fluid
1
Urine
10
Normal skin
10
Nails
1
Blister skin
2
Vaginal tissue
1
Vaginal fluid
0.4-0.7
* Relative to concurrent concentrations in plasma in subjects with normal renal function.
† Independent of degree of meningeal inflammation.
In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately
80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose
is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There
is an inverse relationship between the elimination half-life and creatinine clearance. The dose of
DIFLUCAN may need to be reduced in patients with impaired renal function. (See DOSAGE
AND ADMINISTRATION.) A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, DIFLUCAN administration (doses ranging from 200 mg to 400 mg once
daily for up to 14 days) was associated with small and inconsistent effects on testosterone
concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol
response.
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Pharmacokinetics in Children
In children, the following pharmacokinetic data {Mean (%cv)} have been reported:
Age
Studied
Dose
(mg/kg)
Clearance
(mL/min/kg)
Half-life
(Hours)
Cmax
(μg/mL)
Vdss
(L/kg)
9 Months-
13 years
Single-Oral
2 mg/kg
0.40 (38%)
N=14
25.0
2.9 (22%)
N=16
___
9 Months-
13 years
Single-Oral
8 mg/kg
0.51 (60%)
N=15
19.5
9.8 (20%)
N=15
___
5-15 years
Multiple IV
2 mg/kg
0.49 (40%)
N=4
17.4
5.5 (25%)
N=5
0.722 (36%)
N=4
5-15 years
Multiple IV
4 mg/kg
0.59 (64%)
N=5
15.2
11.4 (44%)
N=6
0.729 (33%)
N=5
5-15 years
Multiple IV
8 mg/kg
0.66 (31%)
N=7
17.6
14.1 (22%)
N=8
1.069 (37%)
N=7
Clearance corrected for body weight was not affected by age in these studies. Mean body
clearance in adults is reported to be 0.23 (17%) mL/min/kg.
In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within
36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of
0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later.
Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six
days later and 46.6 hours 12 days later.
Pharmacokinetics in Elderly
A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a
single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving
diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was
76.4 ± 20.3 mcg⋅h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic
parameter values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine
clearance (74 mL/min), the percent of drug recovered unchanged in urine (0-24 hr, 22%), and the
fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower
than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group. A plot of each
subject’s terminal elimination half-life versus creatinine clearance compared with the predicted
half-life – creatinine clearance curve derived from normal subjects and subjects with varying
degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life – creatinine clearance curves. These results are consistent with the
hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects
compared with normal young male volunteers are due to the decreased kidney function that is
expected in the elderly.
Drug Interaction Studies
Oral contraceptives: Oral contraceptives were administered as a single dose both before and
after the oral administration of DIFLUCAN 50 mg once daily for 10 days in 10 healthy women.
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There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the
administration of 50 mg of DIFLUCAN. The mean increase in ethinyl estradiol AUC was 6%
(range: –47 to 108%) and levonorgestrel AUC increased 17% (range: –33 to 141%).
In a second study, twenty-five normal females received daily doses of both 200 mg DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all
subjects receiving DIFLUCAN during one cycle and placebo during the other. The order of
study treatment was random. Single doses of an oral contraceptive tablet containing
levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both
cycles. Following administration of 200 mg of DIFLUCAN, the mean percentage increase of
AUC for levonorgestrel compared to placebo was 25% (range: –12 to 82%) and the mean
percentage increase for ethinyl estradiol compared to placebo was 38% (range: –11 to 101%).
Both of these increases were statistically significantly different from placebo.
A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to
21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In
this placebo-controlled, double-blind, randomized, two-way crossover study carried out over
three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the
mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The
mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range: 18-31%)
and 13% (95% C.I. range: 8-18%), respectively, relative to placebo. Fluconazole treatment did
not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study
compared to placebo dosing. The individual AUC values of norethindrone decreased very
slightly (<5%) in 3 of the 21 subjects after fluconazole treatment.
Cimetidine: DIFLUCAN 100 mg was administered as a single oral dose alone and two hours
after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration
of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean
± SD decrease in fluconazole AUC of 13% ± 11% (range: –3.4 to –31%) and Cmax decreased
19% ± 14% (range: –5 to –40%). However, the administration of cimetidine 600 mg to 900 mg
intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of
DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in
24 healthy male volunteers.
Antacid: Administration of Maalox® (20 mL) to 14 normal male volunteers immediately prior to
a single dose of DIFLUCAN 100 mg had no effect on the absorption or elimination of
fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in
fluconazole AUC and Cmax compared to DIFLUCAN given alone. There was a mean ± SD
increase in fluconazole AUC and Cmax of 45% ± 31% (range: 19 to 114%) and 43% ± 31%
(range: 19 to 122%), respectively. These changes are attributed to a mean ± SD reduction in
renal clearance of 30% ± 12% (range: –10 to –50%).
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Rifampin: Administration of a single oral 200 mg dose of DIFLUCAN after 15 days of rifampin
administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease
in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There
was a mean ± SD reduction in fluconazole AUC of 23% ± 9% (range: –13 to –42%). Apparent
oral clearance of fluconazole increased 32% ± 17% (range: 16 to 72%). Fluconazole half-life
decreased from 33.4 ± 4.4 hours to 26.8 ± 3.9 hours. (See PRECAUTIONS.)
Warfarin: There was a significant increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to
13 normal male volunteers following oral DIFLUCAN 200 mg administered daily for 14 days as
compared to the administration of warfarin alone. There was a mean ± SD increase in the
prothrombin time response (area under the prothrombin time-time curve) of 7% ± 4% (range: –2
to 13%). (See PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for one dose) both with and without the
administration of fluconazole (oral DIFLUCAN 200 mg daily for 16 days) in 10 normal male
volunteers. There was a significant increase in phenytoin AUC. The mean ± SD increase in
phenytoin AUC was 88% ± 68% (range: 16 to 247%). The absolute magnitude of this interaction
is unknown because of the intrinsically nonlinear disposition of phenytoin. (See
PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on
cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks.
There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and
a significant reduction in apparent oral clearance following the administration of fluconazole.
The mean ± SD increase in AUC was 92% ± 43% (range: 18 to 147%). The Cmax increased
60% ± 48% (range: –5 to 133%). The Cmin increased 157% ± 96% (range: 33 to 360%). The
apparent oral clearance decreased 45% ± 15% (range: –15 to –60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and
following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were
on a stable zidovudine dose for at least two weeks. There was a significant increase in
zidovudine AUC following the administration of fluconazole. The mean ± SD increase in AUC
was 20% ± 32% (range: –27 to 104%). The metabolite, GZDV, to parent drug ratio significantly
decreased after the administration of fluconazole, from 7.6 ± 3.6 to 5.7 ± 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg
daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline
AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean ± SD
theophylline AUC increased 21% ± 16% (range: –5 to 48%). The Cmax increased 13% ± 17%
(range: –13 to 40%). Theophylline clearance decreased 16% ± 11% (range: –32 to 5%). The
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half-life of theophylline increased from 6.6 ± 1.7 hours to 7.9 ± 1.5 hours. (See
PRECAUTIONS.)
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine
plasma concentrations. Terfenadine acid metabolite AUC increased 36% ± 36% (range: 7 to
102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no
change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg
and 800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg
per day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
(See CONTRAINDICATIONS and PRECAUTIONS.)
Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral
hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three
placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a
single dose and again as a single dose following the administration of DIFLUCAN 100 mg daily
for 7 days. In these three studies, 22/46 (47.8%) of DIFLUCAN treated patients and 9/22
(40.1%) of placebo-treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration of fluconazole. There was
a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%). Tolbutamide
Cmax increased 11% ± 9% (range: –6 to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal male volunteers. There was a mean
± SD increase in AUC of 49% ± 13% (range: 27 to 73%) and an increase in Cmax of
19% ± 23% (range: –11 to 79%). (See PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal male volunteers. There was a mean
± SD increase in AUC of 44% ± 29% (range: –13 to 115%) and Cmax increased 19% ± 19%
(range: –23 to 62%). Five subjects required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
Rifabutin: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. (See
PRECAUTIONS.)
Tacrolimus: There have been published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.
(See PRECAUTIONS.)
Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential
interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered
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fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days
of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101%
increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple
doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in
the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving
cisapride 20 mg four times daily for 5 days. (See CONTRAINDICATIONS and
PRECAUTIONS.)
Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of
midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study,
subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2
to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day,
0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day.
Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing,
fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the
sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased after oral
administration of midazolam but not significantly affected following intravenous midazolam.
A second randomized, double-dummy, placebo-controlled, cross over study in three phases was
performed to determine the effect of route of administration of fluconazole on the interaction
between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400
mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo
and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo. The
AUC and Cmax of midazolam were significantly higher after oral than IV administration of
fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%,
respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%,
respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of
midazolam. (See PRECAUTIONS.)
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a
single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the
pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
Voriconazole: Voriconazole is a substrate for both CYP2C9 and CYP3A4 isoenzymes.
Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for
2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy
male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57%
(90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical
study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and
fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole
and fluconazole at any dose is not recommended. Close monitoring for adverse events related to
voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially
within 24 h of the last dose of fluconazole. (See PRECAUTIONS.)
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Microbiology
Mechanism of Action
Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme
lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The
subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in
fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell
demethylation is much less sensitive to fluconazole inhibition.
Activity In Vitro and In Clinical Infections
Fluconazole has been shown to be active against most strains of the following microorganisms
both in vitro and in clinical infections.
Candida albicans
Candida glabrata (Many strains are intermediately susceptible)*
Candida parapsilosis
Candida tropicalis
Cryptococcus neoformans
* In a majority of the studies, fluconazole MIC90 values against C. glabrata were above the susceptible breakpoint
(≥16 µg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to
multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 µg/mL, see Table 1), the
highest dose is recommended (see DOSAGE AND ADMINISTRATION). For resistant isolates, alternative
therapy is recommended.
The following in vitro data are available, but their clinical significance is unknown.
Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 µg/mL or
less against most (≥90%) strains of the following microorganisms, however, the safety and
effectiveness of fluconazole in treating clinical infections due to these microorganisms have not
been established in adequate and well-controlled trials.
Candida dubliniensis
Candida guilliermondii
Candida kefyr
Candida lusitaniae
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
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Susceptibility Testing Methods
Cryptococcus neoformans and filamentous fungi:
No interpretive criteria have been established for Cryptococcus neoformans and filamentous
fungi.
Candida species:
Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum
inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida
spp. to antifungal agents. MICs should be determined using a standardized procedure.
Standardized procedures are based on a dilution method (broth)1 with standardized inoculum
concentrations of fluconazole powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also
provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One
such standardized procedure2 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 25 µg of fluconazole to test the susceptibility of
yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1.
Table 1: Susceptibility Interpretive Criteria for Fluconazole
Broth Dilution at 48 hours
(MIC in µg/mL)
Disk Diffusion at 24 hours
(Zone Diameters in mm)
Antifungal agent
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Susceptible
(S)
Intermediate
(I)**
Resistant
(R)
Fluconazole*
≤ 8.0
16-32
≥64
≥19
15-18
≤14
* Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be
interpreted using this scale.
** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for
fluconazole.
The susceptible category implies that isolates are inhibited by the usually achievable
concentrations of antifungal agent tested when the recommended dosage is used. The
intermediate category implies that an infection due to the isolate may be appropriately treated in
body sites where the drugs are physiologically concentrated or when a high dosage of drug is
used. The resistant category implies that isolates are not inhibited by the usually achievable
concentrations of the agent with normal dosage schedules and clinical efficacy of the agent
against the isolate has not been reliably shown in treatment studies.
Quality Control
Standardized susceptibility test procedures require the use of quality control organisms to control
the technical aspects of the test procedures. Standardized fluconazole powder and 25 µg disks
should provide the following range of values noted in Table 2. NOTE: Quality control
microorganisms are specific strains of organisms with intrinsic biological properties relating to
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resistance mechanisms and their genetic expression within fungi; the specific strains used for
microbiological control are not clinically significant.
Table 2: Acceptable Quality Control Ranges for Fluconazole to be Used in Validation of Susceptibility Test Results
QC Strain
Macrodilution
(MIC in µg/mL)
@ 48 hours
Microdilution
(MIC in µg/mL)
@ 48 hours
Disk Diffusion
(Zone Diameter in mm)
@ 24 hours
Candida parapsilosis ATCC 22019
2.0-8.0
1.0-4.0
22-33
Candida krusei ATCC 6258
16-64
16-128
---*
Candida albicans ATCC 90028
---*
---*
28-39
Candida tropicalis ATCC 750
---*
---*
26-37
---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
Activity In Vivo
Fungistatic activity has also been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for
systemic infections due to Candida albicans.
In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to
fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was
active in a variety of animal models of fungal infection using standard laboratory strains of fungi.
Activity has been demonstrated against fungal infections caused by Aspergillus flavus and
Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal
models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary
infections in normal mice; one model of Coccidioides immitis intracranial infections in normal
mice; and several models of Histoplasma capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results obtained in these studies is
unknown.
Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis.
Concurrent administration of fluconazole and amphotericin B in infected normal and
immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The
clinical significance of results obtained in these studies is unknown.
Drug Resistance
Fluconazole resistance may arise from a modification in the quality or quantity of the target
enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination
of these mechanisms.
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Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target
with decreased affinity for azoles. Overexpression of ERG11 results in the production of high
concentrations of the target enzyme, creating the need for higher intracellular drug
concentrations to inhibit all of the enzyme molecules in the cell.
The second major mechanism of drug resistance involves active efflux of fluconazole out of the
cell through the activation of two types of multidrug efflux transporters; the major facilitators
(encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR
genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of
CDR genes may lead to resistance to multiple azoles.
Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in
resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to
32 µg/mL), the highest fluconazole dose is recommended.
Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei
appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent.
There have been reports of cases of superinfection with Candida species other than C. albicans,
which are often inherently not susceptible to DIFLUCAN (e.g., Candida krusei). Such cases may
require alternative antifungal therapy.
INDICATIONS AND USAGE
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively
small numbers of patients, DIFLUCAN was also effective for the treatment of Candida
urinary tract infections, peritonitis, and systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS patients
with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing
DIFLUCAN to amphotericin B in non-HIV infected patients have not been conducted.
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Prophylaxis. DIFLUCAN is also indicated to decrease the incidence of candidiasis in patients
undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation
therapy.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be
instituted before the results of the cultures and other laboratory studies are known; however,
once these results become available, anti-infective therapy should be adjusted accordingly.
CLINICAL STUDIES
Cryptococcal meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day) to
amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in patients with AIDS,
a multivariate analysis revealed three pretreatment factors that predicted death during the course
of therapy: abnormal mental status, cerebrospinal fluid cryptococcal antigen titer greater than
1:1024, and cerebrospinal fluid white blood cell count of less than 20 cells/mm3. Mortality
among high risk patients was 33% and 40% for amphotericin B and DIFLUCAN patients,
respectively (p=0.58), with overall deaths 14% (9 of 63 subjects) and 18% (24 of 131 subjects)
for the 2 arms of the study (p=0.48). Optimal doses and regimens for patients with acute
cryptococcal meningitis and at high risk for treatment failure remain to be determined. (Saag, et
al. N Engl J Med 1992; 326:83-9.)
Vaginal candidiasis: Two adequate and well-controlled studies were conducted in the U.S. using
the 150 mg tablet. In both, the results of the fluconazole regimen were comparable to the control
regimen (clotrimazole or miconazole intravaginally for 7 days) both clinically and statistically at
the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and symptoms of vaginal
candidiasis (clinical cure), along with a negative KOH examination and negative culture for
Candida (microbiologic eradication), was 55% in both the fluconazole group and the vaginal
products group.
Fluconazole PO 150 mg tablet
Vaginal Product qhs x 7 days
Enrolled
448
422
Evaluable at Late Follow-up
347 (77%)
327 (77%)
Clinical cure
239/347 (69%)
235/327 (72%)
Mycologic eradication
213/347 (61%)
196/327 (60%)
Therapeutic cure
190/347 (55%)
179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4 episodes/12 months)
and achieved 80% clinical cure, 67% mycologic eradication, and 59% therapeutic cure when
treated with a 150 mg DIFLUCAN tablet administered orally. These rates were comparable to
control products. The remaining one-fourth of enrolled patients had recurrent vaginitis
(>4 episodes/12 months) and achieved 57% clinical cure, 47% mycologic eradication, and 40%
therapeutic cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent vaginitis.
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Substantially more gastrointestinal events were reported in the fluconazole group compared to
the vaginal product group. Most of the events were mild to moderate. Because fluconazole was
given as a single dose, no discontinuations occurred.
Parameter
Fluconazole PO
Vaginal Products
Evaluable patients
448
422
With any adverse event
141 (31%)
112 (27%)
Nervous System
90 (20%)
69 (16%)
Gastrointestinal
73 (16%)
18 (4%)
With drug-related event
117 (26%)
67 (16%)
Nervous System
61 (14%)
29 (7%)
Headache
58 (13%)
28 (7%)
Gastrointestinal
68 (15%)
13 (3%)
Abdominal pain
25 (6%)
7 (2%)
Nausea
30 (7%)
3 (1%)
Diarrhea
12 (3%)
2 (<1%)
Application site event
0 (0%)
19 (5%)
Taste Perversion
6 (1%)
0 (0%)
Pediatric Studies
Oropharyngeal candidiasis: An open-label, comparative study of the efficacy and safety of
DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times daily) in
immunocompromised children with oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole treated patients
compared to 46% of nystatin treated patients. Mycologically, 76% of fluconazole treated patients
had the infecting organism eradicated compared to 11% for nystatin treated patients.
Fluconazole
Nystatin
Enrolled
96
90
Clinical Cure
76/88 (86%)
36/78 (46%)
Mycological eradication*
55/72 (76%)
6/54 (11%)
* Subjects without follow-up cultures for any reason were considered nonevaluable for
mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of treatment was 14% for
subjects receiving DIFLUCAN and 16% for subjects receiving nystatin. At 4 weeks after the end
of treatment, the percentages of patients with clinical relapse were 22% for DIFLUCAN and
23% for nystatin.
CONTRAINDICATIONS
DIFLUCAN (fluconazole) is contraindicated in patients who have shown hypersensitivity to
fluconazole or to any of its excipients. There is no information regarding cross-hypersensitivity
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between fluconazole and other azole antifungal agents. Caution should be used in prescribing
DIFLUCAN to patients with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses of 400 mg or
higher based upon results of a multiple dose interaction study. Coadministration of other drugs
known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as
cisapride, astemizole, pimozide, and quinidine are contraindicated in patients receiving fluconazole..
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS.)
WARNINGS
(1) Hepatic injury: DIFLUCAN should be administered with caution to patients with liver
dysfunction. DIFLUCAN has been associated with rare cases of serious hepatic toxicity,
including fatalities primarily in patients with serious underlying medical conditions. In
cases of DIFLUCAN-associated hepatotoxicity, no obvious relationship to total daily dose,
duration of therapy, sex, or age of the patient has been observed. DIFLUCAN
hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy.
Patients who develop abnormal liver function tests during DIFLUCAN therapy should be
monitored for the development of more severe hepatic injury. DIFLUCAN should be
discontinued if clinical signs and symptoms consistent with liver disease develop that may
be attributable to DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with
DIFLUCAN. In patients with serious underlying diseases (predominantly AIDS and
malignancy), these have rarely resulted in a fatal outcome. Patients who develop rashes during
treatment with DIFLUCAN should be monitored closely and the drug discontinued if lesions
progress.
PRECAUTIONS
General
Some azoles, including fluconazole, have been associated with prolongation of the QT interval
on the electrocardiogram. During post-marketing surveillance, there have been rare cases of QT
prolongation and torsade de pointes in patients taking fluconazole. Most of these reports
involved seriously ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities, and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarrhythmic
conditions.
Concomitant use of fluconazole and erythromycin has the potential to increase the risk of
cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death.
This combination should be avoided.
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Fluconazole should be administered with caution to patients with renal dysfunction.
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole
treated patients who are concomitantly treated with drugs with a narrow therapeutic window
metabolized through CYP2C9 and CYP3A4 should be monitored.
DIFLUCAN Capsules contain lactose and should not be given to patients with rare hereditary
problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
DIFLUCAN Powder for Oral Suspension contains sucrose and should not be used in patients
with hereditary fructose, glucose/galactose malabsorption, and sucrase-isomaltase deficiency.
DIFLUCAN Syrup contains glycerol. Glycerol may cause headache, stomach upset, and
diarrhea.
When driving vehicles or operating machines, it should be taken into account that occasionally
dizziness or seizures may occur.
Single Dose
The convenience and efficacy of the single dose oral tablet of fluconazole regimen for the
treatment of vaginal yeast infections should be weighed against the acceptability of a higher
incidence of drug related adverse events with DIFLUCAN (26%) versus intravaginal agents
(16%) in U.S. comparative clinical studies. (See ADVERSE REACTIONS and CLINICAL
STUDIES.)
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Drug Interactions: (See CLINICAL PHARMACOLOGY: Drug Interaction Studies and
CONTRAINDICATIONS.) DIFLUCAN is a potent inhibitor of cytochrome P450 (CYP)
isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented
interactions mentioned below, there is a risk of increased plasma concentration of other compounds
metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore, caution should
be exercised when using these combinations and the patients should be carefully monitored. The
enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole
treatment due to the long half-life of fluconazole. Clinically or potentially significant drug
interactions between DIFLUCAN and the following agents/classes have been observed. These
are described in greater detail below:
Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Terfenadine
Cisapride
Astemizole
Rifabutin
Voriconazole
Tacrolimus
Short-acting benzodiazepines
Triazolam
Oral Contraceptives
Pimozide
Hydrochlorothiazide
Alfentanil
Amitriptyline, nortriptyline
Amphotericin B
Azithromycin
Carbamazepine
Calcium Channel Blockers
Celecoxib
Cyclophosphamide
Fentanyl
Halofantrine
HMG-CoA reductase inhibitors
Losartan
Methadone
Non-steroidal anti-inflammatory drugs
Prednisone
Saquinavir
Sirolimus
Vinca Alkaloids
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Vitamin A
Zidovudine
Oral hypoglycemics: Clinically significant hypoglycemia may be precipitated by the use of
DIFLUCAN with oral hypoglycemic agents; one fatality has been reported from hypoglycemia
in association with combined DIFLUCAN and glyburide use. DIFLUCAN reduces the
metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of
these agents. When DIFLUCAN is used concomitantly with these or other sulfonylurea oral
hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose
of the sulfonylurea should be adjusted as necessary. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Coumarin-type anticoagulants: Prothrombin time may be increased in patients receiving
concomitant DIFLUCAN and coumarin-type anticoagulants. In post-marketing experience, as
with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding,
hematuria, and melena) have been reported in association with increases in prothrombin time in
patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin
time in patients receiving DIFLUCAN and coumarin-type anticoagulants is recommended. Dose
adjustment of warfarin may be necessary. (See CLINICAL PHARMACOLOGY: Drug
Interaction Studies.)
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful monitoring of
phenytoin concentrations in patients receiving DIFLUCAN and phenytoin is recommended. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Cyclosporine: DIFLUCAN may significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring of cyclosporine concentrations
and serum creatinine is recommended in patients receiving DIFLUCAN and cyclosporine. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Rifampin: Rifampin enhances the metabolism of concurrently administered DIFLUCAN.
Depending on clinical circumstances, consideration should be given to increasing the dose of
DIFLUCAN when it is administered with rifampin. (See CLINICAL PHARMACOLOGY:
Drug Interaction Studies.)
Theophylline: DIFLUCAN increases the serum concentrations of theophylline. Careful
monitoring of serum theophylline concentrations in patients receiving DIFLUCAN and
theophylline is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to
prolongation of the QTc interval in patients receiving azole antifungals in conjunction with
terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of
fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and
800 mg daily dose of fluconazole demonstrated that DIFLUCAN taken in doses of 400 mg per
day or greater significantly increases plasma levels of terfenadine when taken concomitantly.
The combined use of fluconazole at doses of 400 mg or greater with terfenadine is
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contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug
Interaction Studies.) The coadministration of fluconazole at doses lower than 400 mg/day with
terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events, including torsade de pointes, in patients to
whom fluconazole and cisapride were coadministered. A controlled study found that concomitant
fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The combined use of
fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Astemizole: Concomitant administration of fluconazole with astemizole may decrease the
clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT
prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and
astemizole is contraindicated. .
Rifabutin: There have been reports that an interaction exists when fluconazole is administered
concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There
have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered.
Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored. (See
CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
Voriconazole: Avoid concomitant administration of voriconazole and fluconazole. Monitoring
for adverse events and toxicity related to voriconazole is recommended; especially, if
voriconazole is started within 24 h after the last dose of fluconazole. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus
up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No
significant pharmacokinetic changes have been observed when tacrolimus is given intravenously.
Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered
tacrolimus should be decreased depending on tacrolimus concentration. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.)
Short-acting Benzodiazepines: Following oral administration of midazolam, fluconazole resulted
in substantial increases in midazolam concentrations and psychomotor effects. This effect on
midazolam appears to be more pronounced following oral administration of fluconazole than
with fluconazole administered intravenously. If short-acting benzodiazepines, which are
metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole,
consideration should be given to decreasing the benzodiazepine dosage, and the patients should
be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.)
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Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax by 20
32%, and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage
adjustments of triazolam may be necessary.
Oral Contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been
performed using multiple doses of fluconazole. There were no relevant effects on hormone level in
the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and
levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at
these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
.
Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with
pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma
concentrations can lead to QT prolongation and rare occurrences of torsade de pointes.
Coadministration of fluconazole and pimozide is contraindicated.
Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple dose
hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of
fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole
dose regimen in subjects receiving concomitant diuretics.
Alfentanil: A study observed a reduction in clearance and distribution volume as well as
prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible
mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil
may be necessary.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5-
nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and
after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal
and immunosuppressed mice showed the following results: a small additive antifungal effect in
systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus
neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical
significance of results obtained in these studies is unknown.
Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects
assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a
single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the
pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction
between fluconazole and azithromycin.
Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum
carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity.
Dosage adjustment of carbamazepine may be necessary depending on concentration
measurements/effect.
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Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine,
isradipine, amlodipine, and felodipine) are metabolized by CYP3A4. Fluconazole has the
potential to increase the systemic exposure of the calcium channel antagonists. Frequent
monitoring for adverse events is recommended.
Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200
mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the
celecoxib dose may be necessary when combined with fluconazole.
Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an
increase in serum bilirubin and serum creatinine. The combination may be used while taking
increased consideration to the risk of increased serum bilirubin and serum creatinine.
Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author
judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover
study with 12 healthy volunteers it was shown that fluconazole delayed the elimination of
fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory
effect on CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when
fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through
CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If
concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and
rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors
should be discontinued if a marked increase in creatinine kinase is observed or
myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74)
which is responsible for most of the angiotensin Il-receptor antagonism which occurs during
treatment with losartan. Patients should have their blood pressure monitored continuously.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage
adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen were increased by
23% and 81%, respectively, when coadministered with fluconazole compared to administration
of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S
(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was
coadministered with racemic ibuprofen (400 mg) compared to administration of racemic
ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure
of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam,
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diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is
recommended. Adjustment of dosage of NSAIDs may be needed.
Prednisone: There was a case report that a liver-transplanted patient treated with prednisone
developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was
discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity
which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole
and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is
discontinued.
Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by
approximately 55%, and decreases clearance of saquinavir by approximately 50% due to
inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein.
Dosage adjustment of saquinavir may be necessary.
Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting
the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used
with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Vinca Alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca
alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an
inhibitory effect on CYP3A4.
Vitamin A: Based on a case report in one patient receiving combination therapy with all-trans
retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have
developed in the form of pseudotumour cerebri, which disappeared after discontinuation of
fluconazole treatment. This combination may be used but the incidence of CNS related
undesirable effects should be borne in mind.
Zidovudine:. Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%,
respectively, due to an approximately 45% decrease in oral zidovudine clearance. The half-life of
zidovudine was likewise prolonged by approximately 128% following combination therapy with
fluconazole. Patients receiving this combination should be monitored for the development of
zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.
Physicians should be aware that interaction studies with medications other than those listed in the
CLINICAL PHARMACOLOGY section have not been conducted, but such interactions may
occur.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for
24 months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2-7x the recommended human
dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular
adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in
4 strains of S. typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro
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(human lymphocytes exposed to fluconazole at 1000 μg/mL) showed no evidence of
chromosomal mutations.
Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5,
10, or 20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg, although the onset of parturition
was slightly delayed at 20 mg/kg PO. In an intravenous perinatal study in rats at 5, 20, and
40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg
(approximately 5-15x the recommended human dose) and 40 mg/kg, but not at 5 mg/kg. The
disturbances in parturition were reflected by a slight increase in the number of still born pups and
decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent
with the species specific estrogen-lowering property produced by high doses of fluconazole.
Such a hormone change has not been observed in women treated with fluconazole. (See
CLINICAL PHARMACOLOGY.)
Pregnancy
Teratogenic Effects. Pregnancy Category C: Fluconazole was administered orally to pregnant
rabbits during organogenesis in two studies at 5, 10, and 20 mg/kg and at 5, 25, and 75 mg/kg,
respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at
75 mg/kg (approximately 20-60x the recommended human dose); no adverse fetal effects were
detected. In several studies in which pregnant rats were treated orally with fluconazole during
organogenesis, maternal weight gain was impaired and placental weights were increased at
25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants
(supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and
50 mg/kg and higher doses. At doses ranging from 80 mg/kg (approximately 20-60x the
recommended human dose) to 320 mg/kg, embryolethality in rats was increased and fetal
abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These
effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of
known effects of lowered estrogen on pregnancy, organogenesis, and parturition.
Data from several hundred pregnant women treated with doses <200 mg/day of fluconazole,
administered as a single or repeated dosage in the first trimester, show no undesired effects in the
fetus.
There have been reports of multiple congenital abnormalities in infants whose mothers were
being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for
coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these
events is unclear. DIFLUCAN should be used in pregnancy only if the potential benefit justifies
the possible risk to the fetus.
Nursing Mothers
Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, the use of
DIFLUCAN in nursing mothers is not recommended.
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Pediatric Use
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective in the
treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. (See CLINICAL
STUDIES.)
The use of DIFLUCAN in children with cryptococcal meningitis, Candida esophagitis, or
systemic Candida infections is supported by the efficacy shown for these indications in adults and
by the results from several small noncomparative pediatric clinical studies. In addition,
pharmacokinetic studies in children (see CLINICAL PHARMACOLOGY) have established a
dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.)
In a noncomparative study of children with serious systemic fungal infections, most of which
were candidemia, the effectiveness of DIFLUCAN was similar to that reported for the treatment
of candidemia in adults. Of 17 subjects with culture-confirmed candidemia, 11 of 14 (79%) with
baseline symptoms (3 were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed at 10 and 18 days,
respectively, following cessation of therapy.
The efficacy of DIFLUCAN for the suppression of cryptococcal meningitis was successful in 4
of 5 children treated in a compassionate-use study of fluconazole for the treatment of
life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole
for primary treatment of cryptococcal meningitis in children.
The safety profile of DIFLUCAN in children has been studied in 577 children ages 1 day to
17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See
ADVERSE REACTIONS.)
Efficacy of DIFLUCAN has not been established in infants less than 6 months of age. (See
CLINICAL PHARMACOLOGY.) A small number of patients (29) ranging in age from 1 day
to 6 months have been treated safely with DIFLUCAN.
Geriatric Use
In non-AIDS patients, side effects possibly related to fluconazole treatment were reported in
fewer patients aged 65 and older (9%, n =339) than for younger patients (14%, n=2240).
However, there was no consistent difference between the older and younger patients with respect
to individual side effects. Of the most frequently reported (>1%) side effects, rash, vomiting, and
diarrhea occurred in greater proportions of older patients. Similar proportions of older patients
(2.4%) and younger patients (1.5%) discontinued fluconazole therapy because of side effects. In
post-marketing experience, spontaneous reports of anemia and acute renal failure were more
frequent among patients 65 years of age or older than in those between 12 and 65 years of age.
Because of the voluntary nature of the reports and the natural increase in the incidence of anemia
and renal failure in the elderly, it is however not possible to establish a casual relationship to
drug exposure.
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Controlled clinical trials of fluconazole did not include sufficient numbers of patients aged 65
and older to evaluate whether they respond differently from younger patients in each indication.
Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.
Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients
are more likely to have decreased renal function, care should be taken to adjust dose based on
creatinine clearance. It may be useful to monitor renal function. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
DIFLUCAN is generally well tolerated.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer,
changes in renal and hematological function test results and hepatic abnormalities have been
observed during treatment with fluconazole and comparative agents, but the clinical significance
and relationship to treatment is uncertain.
In Patients Receiving a Single Dose for Vaginal Candidiasis:
During comparative clinical studies conducted in the United States, 448 patients with vaginal
candidiasis were treated with DIFLUCAN, 150 mg single dose. The overall incidence of side
effects possibly related to DIFLUCAN was 26%. In 422 patients receiving active comparative
agents, the incidence was 16%. The most common treatment-related adverse events reported in
the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%),
nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or
greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion
(1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema
and anaphylactic reaction have been reported in marketing experience.
In Patients Receiving Multiple Doses for Other Infections:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in clinical trials of
7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due
to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in
non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected
patients were similar. The proportions of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events occurred at an incidence of 1% or greater
in 4048 patients receiving DIFLUCAN for 7 or more days in clinical trials: nausea 3.7%,
headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%.
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Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases
of serious hepatic reactions during treatment with DIFLUCAN. (See WARNINGS.) The
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to
clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal
hepatic reactions were noted to occur primarily in patients with serious underlying medical
conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant
medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each of these cases, liver function returned to
baseline on discontinuation of DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN for the suppression of relapse of
cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT)
levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the
other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of
normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations
occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most
of whom were receiving multiple concomitant medications, including many known to be
hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients
taking DIFLUCAN concomitantly with one or more of the following medications: rifampin,
phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
Post-Marketing Experience
In addition, the following adverse events have occurred during post-marketing experience.
Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has
been reported.
Body as a Whole: Asthenia, fatigue, fever, malaise.
Cardiovascular: QT prolongation, torsade de pointes. (See PRECAUTIONS.)
Central Nervous System: Seizures, dizziness.
Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia.
Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia.
Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting.
Other Senses: Taste perversion.
Musculoskeletal System: myalgia.
Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo.
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Skin and Appendages: Acute generalized exanthematous-pustulosis, drug eruption, increased
sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal
necrolysis (see WARNINGS), alopecia.
Adverse Reactions in Children:
The pattern and incidence of adverse events and laboratory abnormalities recorded during
pediatric clinical trials are comparable to those seen in adults.
In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients,
ages 1 day to 17 years were treated with DIFLUCAN at doses up to 15 mg/kg/day for up to
1,616 days. Thirteen percent of children experienced treatment-related adverse events. The most
commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea
(2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4%
of patients due to laboratory test abnormalities. The majority of treatment-related laboratory
abnormalities were elevations of transaminases or alkaline phosphatase.
Percentage of Patients With Treatment-Related Side Effects
Fluconazole
Comparative Agents
(N=577)
(N=451)
With any side effect
13.0
9.3
Vomiting
5.4
5.1
Abdominal pain
2.8
1.6
Nausea
2.3
1.6
Diarrhea
2.1
2.2
OVERDOSAGE
There have been reports of overdose with fluconazole accompanied by hallucination and paranoid
behavior.
In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if
clinically indicated) should be instituted.
Fluconazole is largely excreted in urine. A three-hour hemodialysis session decreases plasma
levels by approximately 50%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species
included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence,
loss of righting reflex, and cyanosis; death was sometimes preceded by clonic convulsions.
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
Dosage and Administration in Adults:
Single Dose
Vaginal candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis is 150 mg
as a single oral dose.
Multiple Dose
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE
OF DIFLUCAN (FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND
SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of
twice the daily dose is recommended on the first day of therapy to result in plasma
concentrations close to steady-state by the second day of therapy.
The daily dose of DIFLUCAN for the treatment of infections other than vaginal candidiasis
should be based on the infecting organism and the patient’s response to therapy. Treatment
should be continued until clinical parameters or laboratory tests indicate that active fungal
infection has subsided. An inadequate period of treatment may lead to recurrence of active
infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of
oropharyngeal candidiasis generally resolves within several days, but treatment should be
continued for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: The recommended dosage of DIFLUCAN for esophageal candidiasis is
200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used,
based on medical judgment of the patient’s response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least two weeks following
resolution of symptoms.
Systemic Candida infections: For systemic Candida infections including candidemia,
disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers of patients, doses
of up to 400 mg daily have been used.
Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and
peritonitis, daily doses of 50-200 mg have been used in open, noncomparative studies of small
numbers of patients.
Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal
meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once
daily.
Prophylaxis in patients undergoing bone marrow transplantation: The recommended
DIFLUCAN daily dosage for the prevention of candidiasis in patients undergoing bone marrow
transplantation is 400 mg, once daily. Patients who are anticipated to have severe
granulocytopenia (less than 500 neutrophils per cu mm) should start DIFLUCAN prophylaxis
several days before the anticipated onset of neutropenia, and continue for 7 days after the
neutrophil count rises above 1000 cells per cu mm.
Dosage and Administration in Children:
The following dose equivalency scheme should generally provide equivalent exposure in
pediatric and adult patients:
Pediatric Patients
Adults
3 mg/kg
100 mg
6 mg/kg
200 mg
12* mg/kg
400 mg
* Some older children may have clearances similar to that of adults. Absolute doses exceeding
600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.) Based on the prolonged half-life seen in
premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of
life, should receive the same dosage (mg/kg) as in older children, but administered every
72 hours. After the first two weeks, these children should be dosed once daily. No information
regarding DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal candidiasis: The recommended dosage of DIFLUCAN for oropharyngeal
candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment
should be administered for at least 2 weeks to decrease the likelihood of relapse.
Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage
of DIFLUCAN in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up
to 12 mg/kg/day may be used, based on medical judgment of the patient’s response to therapy.
Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at
least 2 weeks following the resolution of symptoms.
Systemic Candida infections: For the treatment of candidemia and disseminated Candida
infections, daily doses of 6-12 mg/kg/day have been used in an open, noncomparative study of a
small number of children.
Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended
dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg once
daily may be used, based on medical judgment of the patient’s response to therapy. The
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks
after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal
meningitis in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
Dosage In Patients With Impaired Renal Function:
Fluconazole is cleared primarily by renal excretion as unchanged drug. There is no need to adjust
single dose therapy for vaginal candidiasis because of impaired renal function. In patients with
impaired renal function who will receive multiple doses of DIFLUCAN, an initial loading dose
of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication)
should be based on the following table:
Creatinine Clearance (mL/min)
Percent of Recommended Dose
>50
100%
≤50 (no dialysis)
50%
Regular dialysis
100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following administration of
multiple doses. Further adjustment may be needed depending upon clinical condition.
When serum creatinine is the only measure of renal function available, the following formula
(based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance
in adults:
Males:
Weight (kg) × (140 – age)
72 × serum creatinine (mg/100 mL)
Females: 0.85 × above value
Although the pharmacokinetics of fluconazole has not been studied in children with renal
insufficiency, dosage reduction in children with renal insufficiency should parallel that
recommended for adults. The following formula may be used to estimate creatinine clearance in
children:
K ×
linear length or height (cm)
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
Administration
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN can be
taken with or without food. DIFLUCAN injection has been used safely for up to fourteen days of
intravenous therapy. The intravenous infusion of DIFLUCAN should be administered at a
maximum rate of approximately 200 mg/hour, given as a continuous infusion.
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DIFLUCAN injections in glass and Viaflex® Plus plastic containers are intended only for
intravenous administration using sterile equipment.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Directions for Mixing the Oral Suspension
Prepare a suspension at time of dispensing as follows: tap bottle until all the powder flows freely.
To reconstitute, add 24 mL of distilled water or Purified Water (USP) to fluconazole bottle and
shake vigorously to suspend powder. Each bottle will deliver 35 mL of suspension. The
concentrations of the reconstituted suspensions are as follows:
Fluconazole Content per Bottle
Concentration of Reconstituted Suspension
350 mg
10 mg/mL
1400 mg
40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
Directions for IV Use of DIFLUCAN in Viaflex® Plus Plastic Containers
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The
inner bag maintains the sterility of the product.
CAUTION: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found, discard
solution as sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
DIFLUCAN Tablets: Pink trapezoidal tablets containing 50, 100, or 200 mg of fluconazole are
packaged in bottles or unit dose blisters. The 150 mg fluconazole tablets are pink and oval
shaped, packaged in a single dose unit blister.
DIFLUCAN Tablets are supplied as follows:
DIFLUCAN 50 mg Tablets: Engraved with “DIFLUCAN” and “50” on the front and “ROERIG”
on the back.
NDC 0049-3410-30
Bottles of 30
DIFLUCAN 100 mg Tablets: Engraved with “DIFLUCAN” and “100” on the front and
“ROERIG” on the back.
NDC 0049-3420-30
Bottles of 30
NDC 0049-3420-41
Unit dose package of 100
DIFLUCAN 150 mg Tablets: Engraved with “DIFLUCAN” and “150” on the front and
“ROERIG” on the back.
NDC 0049-3500-79
Unit dose package of 1
DIFLUCAN 200 mg Tablets: Engraved with “DIFLUCAN” and “200” on the front and
“ROERIG” on the back.
NDC 0049-3430-30
Bottles of 30
NDC 0049-3430-41
Unit dose package of 100
Storage: Store tablets below 86°F (30°C).
DIFLUCAN for Oral Suspension: DIFLUCAN for Oral Suspension is supplied as an
orange-flavored powder to provide 35 mL per bottle as follows:
NDC 0049-3440-19
Fluconazole 350 mg per bottle
NDC 0049-3450-19
Fluconazole 1400 mg per bottle
Storage: Store dry powder below 86°F (30°C). Store reconstituted suspension between 86°F
(30°C) and 41°F (5°C) and discard unused portion after 2 weeks. Protect from freezing.
DIFLUCAN Injections: DIFLUCAN injections for intravenous infusion administration are
formulated as sterile iso-osmotic solutions containing 2 mg/mL of fluconazole. They are
supplied in glass bottles or in Viaflex® Plus plastic containers containing volumes of 100 mL or
200 mL, affording doses of 200 mg and 400 mg of fluconazole, respectively. DIFLUCAN
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
injections in Viaflex® Plus plastic containers are available in both sodium chloride and dextrose
diluents.
DIFLUCAN Injections in Glass Bottles:
NDC 0049-3371-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3372-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
Storage: Store between 86°F (30°C) and 41°F (5°C). Protect from freezing.
DIFLUCAN Injections in Viaflex® Plus Plastic Containers:
NDC 0049-3435-26 Fluconazole in Sodium Chloride Diluent 200 mg/100 mL × 6
NDC 0049-3436-26 Fluconazole in Sodium Chloride Diluent 400 mg/200 mL × 6
NDC 0049-3437-26 Fluconazole in Dextrose Diluent 200 mg/100 mL × 6
NDC 0049-3438-26 Fluconazole in Dextrose Diluent 400 mg/200 mL × 6
Storage: Store between 77°F (25°C) and 41°F (5°C). Brief exposure up to 104°F (40°C) does
not adversely affect the product. Protect from freezing.
Rx only
REFERENCES
1. Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts; Approved Standard-Second Edition. CLSI Document M27
A2, 2002 Volume 22, No. 15, CLSI, Wayne, PA, August 2002.
2. Clinical and Laboratory Standards Institute. Methods for Antifungal Disk Diffusion
Susceptibility Testing of Yeasts; Approved Guideline. CLSI Document M44-A, 2004 Volume
24, No. 15, CLSI, Wayne, PA, May 2004.
3. Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., and
Diekema1, D. J. Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and
Resistance to Voriconazole Among 13,338 Clinical Isolates of Candida spp. Tested by
Clinical and Laboratory Standard Institute-Recommended Broth Microdilution Methods.
2007. Journal of Clinical Microbiology. 45:70–75.
LAB-0099-13.0
Revised April 2011
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
DIFLUCAN® (fluconazole tablets)
This leaflet contains important information about DIFLUCAN (dye-FLEW-kan). It is not
meant to take the place of your doctor's instructions. Read this information carefully
before you take DIFLUCAN. Ask your doctor or pharmacist if you do not understand
any of this information or if you want to know more about DIFLUCAN.
What Is DIFLUCAN?
DIFLUCAN is a tablet you swallow to treat vaginal yeast infections caused by a yeast
called Candida. DIFLUCAN helps stop too much yeast from growing in the vagina so
the yeast infection goes away.
DIFLUCAN is different from other treatments for vaginal yeast infections because it is a
tablet taken by mouth. DIFLUCAN is also used for other conditions. However, this
leaflet is only about using DIFLUCAN for vaginal yeast infections. For information
about using DIFLUCAN for other reasons, ask your doctor or pharmacist. See the
section of this leaflet for information about vaginal yeast infections.
What Is a Vaginal Yeast Infection?
It is normal for a certain amount of yeast to be found in the vagina. Sometimes too much
yeast starts to grow in the vagina and this can cause a yeast infection. Vaginal yeast
infections are common. About three out of every four adult women will have at least one
vaginal yeast infection during their life.
Some medicines and medical conditions can increase your chance of getting a yeast
infection. If you are pregnant, have diabetes, use birth control pills, or take antibiotics
you may get yeast infections more often than other women. Personal hygiene and certain
types of clothing may increase your chances of getting a yeast infection. Ask your doctor
for tips on what you can do to help prevent vaginal yeast infections.
If you get a vaginal yeast infection, you may have any of the following symptoms:
• itching
• a burning feeling when you urinate
• redness
• soreness
• a thick white vaginal discharge that looks like cottage cheese
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What To Tell Your Doctor Before You Start DIFLUCAN?
Do not take Diflucan if you take certain medicines. They can cause serious problems.
Therefore, tell your doctor about all the medicines you take including:
• diabetes medicines such as glyburide, tolbutamide, glipizide
• blood pressure medicines like hydrochlorothiazide, losartan, amlodipine, nifedipine
or felodipine
• blood thinners such as warfarin
• cyclosporine, tacrolimus or sirolimus (used to prevent rejection of organ transplants)
• rifampin or rifabutin for tuberculosis
• astemizole for allergies
• phenytoin or carbamazepine to control seizures
• theophylline to control asthma
• cisapride for heartburn
• quinidine (used to correct disturbances in heart rhythm)
• amitriptyline or nortriptyline for depression
• pimozide for psychiatric illness
• amphotericin B or voriconazole for fungal infections
• erythromycin for bacterial infections
• cyclophosphamide or vinca alkaloids such as vincristine or vinblastine for treatment
of cancer
• fentanyl, afentanil or methadone for chronic pain
• halofantrine for malaria
• lipid lowering drugs such as atorvastatin, simvastatin, and fluvastatin
• non-steroidal anti-inflammatory drugs including celecoxib, ibuprofen, and naproxen
• prednisone, a steroid used to treat skin, gastrointestinal, hematological or respiratory
disorders
• antiviral medications used to treat HIV like saquinavir or zidovudine
• vitamin A nutritional supplement
Since there are many brand names for these medicines, check with your doctor or
pharmacist if you have any questions.
• are taking any over-the-counter medicines you can buy without a prescription,
including natural or herbal remedies
• have any liver problems.
• have any other medical conditions
• are pregnant, plan to become pregnant, or think you might be pregnant. Your doctor
will discuss whether DIFLUCAN is right for you.
• are breast-feeding. DIFLUCAN can pass through breast milk to the baby.
• are allergic to any other medicines including those used to treat yeast and other
fungal infections.
• are allergic to any of the ingredients in DIFLUCAN. The main ingredient of
DIFLUCAN is fluconazole. If you need to know the inactive ingredients, ask your
doctor or pharmacist.
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Who Should Not Take DIFLUCAN?
To avoid a possible serious reaction, do NOT take DIFLUCAN if you are taking
erythromycin, astemizole, pimozide, quinidine, and cisapride (Propulsid®) since it can
cause changes in heartbeat in some people if taken with DIFLUCAN.
How Should I Take DIFLUCAN
Take DIFLUCAN by mouth with or without food. You can take DIFLUCAN at any
time of the day.
DIFLUCAN keeps working for several days to treat the infection. Generally the
symptoms start to go away after 24 hours. However, it may take several days for your
symptoms to go away completely. If there is no change in your symptoms after a few
days, call your doctor.
[caption on the right of the illustration]
Just swallow 1 DIFLUCAN tablet to treat your vaginal yeast infection.
What Should I Avoid while Taking DIFLUCAN?
Some medicines can affect how well DIFLUCAN works. Check with your doctor before
starting any new medicines within seven days of taking DIFLUCAN.
What Are the Possible Side Effects of DIFLUCAN?
Like all medicines, DIFLUCAN may cause some side effects that are usually mild to
moderate.
The most common side effects of DIFLUCAN are:
• headache
• diarrhea
• nausea or upset stomach
• dizziness
• stomach pain
• changes in the way food tastes
Allergic reactions to DIFLUCAN are rare, but they can be very serious if not treated
right away by a doctor. If you cannot reach your doctor, go to the nearest hospital
emergency room. Signs of an allergic reaction can include shortness of breath; coughing;
wheezing; fever; chills; throbbing of the heart or ears; swelling of the eyelids, face,
mouth, neck, or any other part of the body; or skin rash, hives, blisters or skin peeling.
Diflucan has been linked to rare cases of serious liver damage, including deaths, mostly
in patients with serious medical problems. Call your doctor if your skin or eyes become
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
yellow, your urine turns a darker color, your stools (bowel movements) are light-colored,
or if you vomit or feel like vomiting or if you have severe skin itching.
In patients with serious conditions such as AIDS or cancer, rare cases of severe rashes
with skin peeling have been reported. Tell your doctor right away if you get a rash while
taking DIFLUCAN.
DIFLUCAN may cause other less common side effects besides those listed here. If you
develop any side effects that concern you, call your doctor. For a list of all side effects,
ask your doctor or pharmacist.
What to Do For an Overdose
In case of an accidental overdose, call your doctor right away or go to the nearest
emergency room.
How to Store DIFLUCAN
Keep DIFLUCAN and all medicines out of the reach of children.
General Advice about Prescription Medicines
Medicines are sometimes prescribed for conditions that are mentioned in patient
information leaflets. Do not use DIFLUCAN for a condition for which it was not
prescribed. Do not give DIFLUCAN to other people, even if they have the same
symptoms you have. It may harm them.
This leaflet summarizes the most important information about DIFLUCAN. If you
would like more information, talk with your doctor. You can ask your pharmacist or
doctor for information about DIFLUCAN that is written for health professionals.
You can also visit the DIFLUCAN Internet site at www.diflucan.com. company logo
LAB-0380-4.0
Revised April 2011
Reference ID: 2938710
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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NDA 19-951 RETROVIR IV Infusion
Page 3
PRODUCT INFORMATION
RETROVIR®
(zidovudine)
IV Infusion
FOR INTRAVENOUS INFUSION ONLY
WARNING: RETROVIR (ZIDOVUDINE) HAS BEEN ASSOCIATED WITH
HEMATOLOGIC TOXICITY, INCLUDING NEUTROPENIA AND SEVERE ANEMIA,
PARTICULARLY IN PATIENTS WITH ADVANCED HIV DISEASE (SEE WARNINGS).
PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED WITH SYMPTOMATIC
MYOPATHY.
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING
FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE
ANALOGUES ALONE OR IN COMBINATION, INCLUDING RETROVIR AND OTHER
ANTIRETROVIRALS (SEE WARNINGS).
DESCRIPTION: RETROVIR is the brand name for zidovudine (formerly called azidothymidine
[AZT]), a pyrimidine nucleoside analogue active against human immunodeficiency virus (HIV).
RETROVIR IV Infusion is a sterile solution for intravenous infusion only. Each mL contains 10 mg
zidovudine in Water for Injection. Hydrochloric acid and/or sodium hydroxide may have been added to
adjust the pH to approximately 5.5. RETROVIR IV Infusion contains no preservatives.
The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural
formula:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-951 RETROVIR IV Infusion
Page 4
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a
solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
MICROBIOLOGY:
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue of the naturally occurring
nucleoside, thymidine, in which the 3′-hydroxy (-OH) group is replaced by an azido (-N3) group.
Within cells, zidovudine is converted to the active metabolite, zidovudine 5′-triphosphate (AztTP), by
the sequential action of the cellular enzymes. Zidovudine 5′-triphosphate inhibits the activity of the
HIV reverse transcriptase both by competing for utilization with the natural substrate, deoxythymidine
5′-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3′- OH group in the
incorporated nucleoside analogue prevents the formation of the 5′ to 3′ phosphodiester linkage
essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The active
metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and mitochondrial
polymerase-gamma and has been reported to be incorporated into the DNA of cells in culture.
In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zidovudine was assessed by infecting
cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and
clinical isolates of HIV. The IC50 and IC90 values (50% and 90% inhibitory concentrations) were 0.003
to 0.013 and 0.03 to 0.13 mcg/mL, respectively (1 nM = 0.27 ng/mL).The IC50 and IC90 values of HIV
isolates recovered from 18 untreated AIDS/ARC patients were in the range of 0.003 to 0.013 mcg/mL
and 0.03 to 0.3 mcg/mL, respectively. Zidovudine showed antiviral activity in all acutely infected cell
lines; however, activity was substantially less in chronically infected cell lines. In drug combination
studies with zalcitabine, didanosine, lamivudine, saquinavir, indinavir, ritonavir, nevirapine,
delavirdine, or interferon-alpha, zidovudine showed additive to synergistic activity in cell culture. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-951 RETROVIR IV Infusion
Page 5
relationship between the in vitro susceptibility of HIV to reverse transcriptase inhibitors and the
inhibition of HIV replication in humans has not been established.
Drug Resistance: HIV isolates with reduced sensitivity to zidovudine have been selected in vitro and
were also recovered from patients treated with RETROVIR. Genetic analysis of the isolates showed
mutations that result in 5 amino acid substitutions (Met41→Leu, A67→Asn, Lys70→Arg,
Thr215→Tyr or Phe, and Lys219→Gln) in the viral reverse transcriptase. In general, higher levels of
resistance were associated with greater number of mutations, with 215 mutation being the most
significant.
Cross-Resistance: The potential for cross-resistance between HIV reverse transcriptase inhibitors and
protease inhibitors is low because of the different enzyme targets involved. Combination therapy with
zidovudine plus zalcitabine or didanosine does not appear to prevent the emergence of zidovudine-
resistant isolates. Combination therapy with RETROVIR plus EPIVIR delayed the emergence of
mutations conferring resistance to zidovudine. In some patients harboring zidovudine-resistant virus,
combination therapy with RETROVIR plus EPIVIR restored phenotypic sensitivity to zidovudine by
12 weeks of treatment. HIV isolates with multidrug resistance to zidovudine, didanosine, zalcitabine,
stavudine, and lamivudine were recovered from a small number of patients treated for ≥1 year with the
combination of zidovudine and didanosine or zalcitabine. The pattern of resistant mutations in the
combination therapy was different (Ala62→Val, Val75→Ile, Phe77→116Tyr, and Gln→151Met)
from monotherapy, with mutation 151 being most significant for multidrug resistance. Site-directed
mutagenesis studies showed that these mutations could also result in resistance to zalcitabine,
lamivudine, and stavudine.
CLINICAL PHARMACOLOGY:
Pharmacokinetics: Adults: The pharmacokinetics of zidovudine have been evaluated in 22 adult
HIV-infected patients in a Phase 1 dose-escalation study. Following intravenous (IV) dosing,
dose-independent kinetics was observed over the range of 1 to 5 mg/kg.). The major metabolite of
zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV area under
the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recover of zidovudine and
GZDV accounts for 18% and 60%, respectively, following IV dosing. A second metabolite, 3′-amino-
3′-deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration
of zidovudine. The AMT AUC was one fifth of the zidovudine AUC.
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The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg/kg every 4 hours
were 1.06 and 0.12 mcg/mL, respectively.
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in 39 patients
receiving chronic therapy with RETROVIR. The median ratio measured in 50 paired samples drawn 1
to 8 hours after the last dose of RETROVIR was 0.6.
Table 1: Zidovudine Pharmacokinetic Parameters following Intravenous Administration in
HIV-Infected Patients
Parameter
Mean ± SD
(except where noted)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 11)
Plasma protein binding (%)
<38
CSF:plasma ratio*
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/h/kg)
1.6 (0.8 to 2.7)
(n =18)
Renal clearance (L/h/kg)
0.34 ± 0.05
(n = 16)
Elimination half-life (h)†
1.1 (0.5 to 2.9)
(n = 19)
*Median [range].
†Approximate range.
Adults with Impaired Renal Function: Zidovudine clearance was decreased resulting in increased
zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14) following a
single 200-mg oral dose (Table 2). Plasma concentrations of AMT were not determined. A dose
adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.
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Table 2: Zidovudine Pharmacokinetic Parameters in Patients
With Severe Renal Impairment*
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•h/mL)
1400 ± 200
3100 ± 300
Zidovudine half-life (h)
1.0 ± 0.2
1.4 ± 0.1
*Data are expressed as mean ± standard deviation.
The pharmacokinetics and tolerance of oral zidovudine were evaluated in a multiple-dose study in
patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to
200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite
significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was
approximately 50% of that reported in patients with normal renal function. Hemodialysis and
peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV
elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis
or peritoneal dialysis (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Adults with Impaired Hepatic Function: Data describing the effect of hepatic impairment on the
pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily by
hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma
concentrations would be increased following administration of the recommended adult doses to
patients with hepatic impairment (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Pediatrics: Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric patients
(Table 3).
Patients from 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in pediatric
patients >3 months of age are similar to those in adult patients. Proportional increases in plasma
zidovudine concentrations were observed following administration of oral solution from 90 to
240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable
to adult values. As in adult patients, the major route of elimination was by metabolism to GZDV. After
intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the
dose was excreted as GZDV (see DOSAGE AND ADMINISTRATION: Pediatrics).
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Patients Younger Than 3 Months of Age: Zidovudine pharmacokinetics have been evaluated in
pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately
following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was
13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body clearance was
slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for
neonates, see DOSAGE AND ADMINISTRATION: Neonatal Dosing.
Table 3: Zidovudine Pharmacokinetic Parameters in Pediatric Patients*
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.26 ± 0.17†
(n = 28)
CL (L/h/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (h)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
*Data presented as mean ± standard deviation except where noted.
†CSF ratio determined at steady-state on constant intravenous infusion.
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women during
the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation.
Zidovudine pharmacokinetics were similar to that of nonpregnant adults. Consistent with passive
transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth
were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone
maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.
However, in another patient population, a potential for interaction has been identified (see
PRECAUTIONS).
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean
concentration of zidovudine was similar in human milk and serum (see PRECAUTIONS: Nursing
Mothers).
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients over 65 years of
age.
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Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no
differences in zidovudine exposure (AUC) when a single dose of zidovudine was administered as the
300-mg RETROVIR Tablet.
Drug Interactions: See Table 4 and PRECAUTIONS: Drug Interactions:
Zidovudine Plus Lamivudine: No clinically significant alterations in lamivudine or zidovudine
pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single oral
dose of zidovudine (200 mg) in combination with multiple oral doses of lamivudine (300 mg every
12 hours).
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Table 4: Effect of Coadministered Drugs on Zidovudine AUC*
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH
COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Zidovudine
Oral
Zidovudine
Concentrations
Concentration of
Coadministered
Drug and Dose
Dose
n
AUC
Variability
Drug
Atovaquone
750 mg q 12 h
with food
200 mg q 8 h
14
↑ AUC
31%
Range
23% to 78%**
↔
Fluconazole
400 mg daily
200 mg q 8 h
12
↑ AUC
74%
95% CI:
54% to 98%
Not Reported
Methadone
30 to 90 mg daily
200 mg q 4 h
9
↑ AUC
43%
Range
16% to 64%**
↔
Nelfinavir
750 mg q 8 h
x 7 to 10 days
single 200 mg
11
↓ AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 h
x 2 days
2 mg/kg q 8 h
x 3 days
3
↑ AUC
106%
Range
100% to
170%**
Not Assessed
Ritonavir
300 mg q 6 h
x 4 days
200 mg q 8 h
x 4 days
9
↓ AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 h x 4 days
100 mg q 8 h
x 4 days
6
↑ AUC
80%
Range
64% to
130%**
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus
time curve; CI = confidence interval.
* This table is not all inclusive.
**Estimated range of percent difference.
INDICATIONS AND USAGE: RETROVIR IV Infusion in combination with other antiretroviral
agents is indicated for the treatment of HIV infection.
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of maternal-fetal
HIV transmission as part of a regimen that includes oral RETROVIR beginning between 14 and
34 weeks of gestation, intravenous RETROVIR during labor, and administration of RETROVIR Syrup
to the neonate after birth. The efficacy of this regimen for preventing HIV transmission in women who
have received RETROVIR for a prolonged period before pregnancy has not been evaluated. The safety
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of RETROVIR for the mother or fetus during the first trimester of pregnancy has not been assessed
(see Description of Clinical Studies).
Description of Clinical Studies: Therapy with RETROVIR has been shown to prolong survival and
decrease the incidence of opportunistic infections in patients with advanced HIV disease at the
initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients.
RETROVIR in combination with other antiretroviral agents has been shown to be superior to
monotherapy in one or more of the following endpoints: delaying death, delaying development of
AIDS, increasing CD4 cell counts, and decreasing plasma HIV-1 RNA. The complete prescribing
information for each drug should be consulted before combination therapy that includes RETROVIR is
initiated.
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled
trial (ACTG 076) conducted in HIV-infected pregnant women with CD4 cell counts of 200 to 1818
cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to
RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks
of therapy) followed by intravenous administration of RETROVIR during labor and delivery.
Following birth, neonates received oral RETROVIR Syrup for 6 weeks. The study showed a
statistically significant difference in the incidence of HIV infection in the neonates (based on viral
culture from peripheral blood) between the group receiving RETROVIR and the group receiving
placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV infection was 7.8% in the
group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk
of 68.7%. RETROVIR was well tolerated by mothers and infants. There was no difference in
pregnancy-related adverse events between the treatment groups.
CONTRAINDICATIONS: RETROVIR IV Infusion is contraindicated for patients who have
potentially life-threatening allergic reactions to any of the components of the formulation.
WARNINGS: COMBIVIR and TRIZIVIR are combination product tablets that contain zidovudine
as one of their components. RETROVIR should not be administered concomitantly with COMBIVIR
or TRIZIVIR.
The incidence of adverse reactions appears to increase with disease progression; patients should be
monitored carefully, especially as disease progression occurs.
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Bone Marrow Suppression: RETROVIR should be used with caution in patients who have bone
marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL. In
patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant
adverse events observed. There have been reports of pancytopenia associated with the use of
RETROVIR, which was reversible in most instances, after discontinuance of the drug. However,
significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or
blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other
antiretrovirals.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are
treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV
disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage
adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
disease, have been associated with prolonged use of RETROVIR.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with
steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in
combination, including zidovudine and other antiretrovirals. A majority of these cases have been in
women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors.
Particular caution should be exercised when administering RETROVIR to any patient with known risk
factors for liver disease; however, cases have also been reported in patients with no known risk factors.
Treatment with RETROVIR should be suspended in any patient who develops clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly
and steatosis even in the absence of marked transaminase elevations).
PRECAUTIONS:
General: Zidovudine is eliminated from the body primarily by renal excretion following metabolism
in the liver (glucuronidation). In patients with severely impaired renal function (CrCl<15 mL/min),
dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to
be increased in patients with severely impaired hepatic function which may increase the risk of
hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND
ADMINISTRATION).
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Information for Patients: RETROVIR is not a cure for HIV infection, and patients may continue to
acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients
should be advised to seek medical care for any significant change in their health status.
The safety and efficacy of RETROVIR in treating women, intravenous drug users, and racial
minorities is not significantly different than that observed in white males.
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or anemia.
The frequency and severity of these toxicities are greater in patients with more advanced disease and in
those who initiate therapy later in the course of their infection. They should be told that if toxicity
develops, they may require transfusions or drug discontinuation. They should be told of the extreme
importance of having their blood counts followed closely while on therapy, especially for patients with
advanced symptomatic HIV disease. They should be cautioned about the use of other medications,
including ganciclovir and interferon-alpha, which may exacerbate the toxicity of RETROVIR (see
PRECAUTIONS: Drug Interactions). Patients should be informed that other adverse effects of
RETROVIR include nausea and vomiting. Patients should also be encouraged to contact their
physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or
pancreatitis, or any other unexpected adverse events while being treated with RETROVIR.
Pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV
transmission to their infants should be advised that transmission may still occur in some cases despite
therapy. The long-term consequences of in utero and neonatal exposure to RETROVIR are unknown,
including the possible risk of cancer.
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission
of HIV to a child who may not yet be infected.
Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of
transmission of HIV to others through sexual contact or blood contamination.
Drug Interactions: See CLINICAL PHARMACOLOGY section (Table 4) for information on
zidovudine concentrations when coadministered with other drugs. For patients experiencing
pronounced anemia or other severe zidovudine-associated events while receiving chronic
administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4,
zidovudine dose reduction may be considered.
Antiretroviral Agents: Concomitant use of zidovudine with stavudine should be avoided since an
antagonistic relationship has been demonstrated in vitro.
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro
antiviral activity of RETROVIR against HIV; concomitant use of such drugs should be avoided.
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Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an
antagonistic relationship has been demonstrated in vitro (see CLINICAL PHARMACOLOGY for
additional drug interactions).
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
RETROVIR, while in 1 case a high level was documented. However, in a pharmacokinetic interaction
study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone and during
steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was
observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a
30% decrease in oral zidovudine clearance was observed with phenytoin.
Overlapping Toxicities: Coadministration of ganciclovir, interferon-alpha, and other bone marrow
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered orally at
3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial
single daily doses were 30, 60, and 120 mg/kg per day in mice and 80, 220, and 600 mg/kg per day in
rats. The doses in mice were reduced to 20, 30, and 40 mg/kg per day after day 90 because of
treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg per day on
day 91, and then to 300 mg/kg per day on day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell
carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest
dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No
vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in
rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by
AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the
recommended therapeutic dose of 100 mg every 4 hours.
Two transplacental carcinogenicity studies were conducted in mice. One study administered
zidovudine at doses of 20 mg/kg per day or 40 mg/kg per day from gestation day 10 through
parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of
zidovudine employed in this study produced zidovudine exposures approximately 3 times the
estimated human exposure at recommended doses. After 24 months, an increase in incidence of
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vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either
gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as
described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day
or 25 mg/day (∼1000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to
pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in
the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level
of zidovudine. It is not known how predictive the results of rodent carcinogenicity studies may be for
humans.
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and
positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic
study in rats given a single dose.
Zidovudine, administered to male and female rats at doses up to seven times the usual adult dose
based on body surface area considerations, had no effect on fertility judged by conception rates.
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to
500 mg/kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment
resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats
given 150 or 450 mg/kg per day and rabbits given 500 mg/kg per day. The doses used in the teratology
studies resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after
one sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an
in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent
reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3000 mg/kg per
day (very near the oral median lethal dose in rats of 3683 mg/kg) caused marked maternal toxicity and
an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma
concentrations 350 times peak human plasma concentrations. (Estimated area-under-the-curve [AUC]
in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day.) No evidence
of teratogenicity was seen in this experiment at doses of 600 mg/kg per day or less.
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
Mutagenesis, Impairment of Fertility).
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV transmission
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(see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities
occurred with similar frequency between neonates born to mothers who received RETROVIR and
neonates born to mothers who received placebo. Abnormalities were either problems in embryogenesis
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study
drug.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are
encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV.
Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics:
Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
receiving RETROVIR (see Pediatric Use and INDICATIONS AND USAGE: Maternal-Fetal HIV
Transmission).
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age
who had HIV-related symptoms or who were asymptomatic with abnormal laboratory values
indicating significant HIV-related immunosuppression. RETROVIR has also been studied in neonates
perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION,
INDICATIONS AND USAGE: Description of Clinical Studies, and CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Geriatric Use: Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS: The adverse events reported during intravenous administration of
RETROVIR IV Infusion are similar to those reported with oral administration; neutropenia and anemia
were reported most frequently. Long-term intravenous administration beyond 2 to 4 weeks has not
been studied in adults and may enhance hematologic adverse events. Local reaction, pain, and slight
irritation during intravenous administration occur infrequently.
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Adults: The frequency and severity of adverse events associated with the use of RETROVIR are greater
in patients with more advanced infection at the time of initiation of therapy.
Table 5 summarizes events reported at a statistically significantly greater incidence for patients
receiving RETROVIR orally in a monotherapy study:
Table 5: Percentage (%) of Patients with Adverse Events*
in Asymptomatic HIV Infection (ACTG 019)
Adverse Event
RETROVIR
500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a Whole
Asthenia
Headache
Malaise
8.6%
62.5%
53.2%
5.8%
52.6%
44.9%
GastrointestinalL
Anorexia
Constipation
Nausea
Vomiting
20.1%
6.4†%
51.4%
17.2%
10.5%
3.5
29.9
9.8
* Reported in ≥5% of study population.
† Not statistically significant versus placebo.
In addition to the adverse events listed in table 5, other adverse events observed in clinical studies
were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia,
insomnia, musculoskeletal pain, myalgia, and neuropathy.
Selected laboratory abnormalities observed during a clinical study of monotherapy with oral
RETROVIR are shown in Table 6.
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Table 6: Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with
Asymptomatic HIV Infection (ACTG 019)
Adverse Event
RETROVIR
500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
1.1%
0.2%
Granulocytopenia (<750 cells/mm3)
1.8%
1.6%
Thrombocytopenia (platelets<50,000/mm3)
0%
0.5%
ALT (>5 x ULN)
3.1%
2.6%
AST (>5 x ULN)
0.9%
1.6%
Alkaline phosphatase (>5 x ULN)
0%
0%
ULN = Upper limit of normal.
Pediatrics: Study ACTG300: Selected clinical adverse events and physical findings with a ≥5%
frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2 orally
3 times daily compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy) pediatric
patients are listed in Table 7.
Table 7: Selected Clinical Adverse Events and Physical Findings (≥5% Frequency)
in Pediatric Patients in Study ACTG300
Adverse Event
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a Whole
Fever
25%
32%
Digestive
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
5%
8%
Respiratory
Cough
15%
18%
Abnormal breath sounds/wheezing
7%
9%
Ear, Nose, and Throat
Signs or symptoms of ears*
7%
6%
Nasal discharge or congestion
8%
11%
Other
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
*Includes pain, discharge, erythema, or swelling of an ear.
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NDA 19-951 RETROVIR IV Infusion
Page 19
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy)
pediatric patients are listed in Table 8.
TABLE 8: FREQUENCIES OF SELECTED (GRADE 3/4) LABORATORY ABNORMALITIES IN PEDIATRIC
PATIENTS IN STUDY ACTG300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
8%
3%
Anemia (Hgb<7.0 g/dL)
4%
2%
Thrombocytopenia (platelets<50,000/mm3)
1%
3%
ALT (>10 x ULN)
1%
3%
AST (>10 x ULN)
2%
4%
Lipase (>2.5 x ULN)
3%
3%
Total amylase (>2.5 x ULN)
3%
3%
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR
180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema,
hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
pediatric patients.
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized, double-blind,
placebo-controlled trial in HIV-infected women and their neonates conducted to determine the utility
of RETROVIR for the prevention of maternal-fetal HIV transmission, RETROVIR Syrup at 2 mg/kg
was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth.
The most commonly reported adverse experiences were anemia (hemoglobin <9.0 g/dL) and
neutropenia (<1000 cells/mm3). Anemia occurred in 22% of the neonates who received RETROVIR
and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less
than 1.0 g/dL for neonates receiving RETROVIR compared to neonates receiving placebo. No
neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal
within 6 weeks after completion of therapy with RETROVIR. Neutropenia was reported with similar
frequency in the group that received RETROVIR (21%) and in the group that received placebo (27%).
The long-term consequences of in utero and infant exposure to RETROVIR are unknown.
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during use of RETROVIR in clinical practice. Because they are
reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These
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NDA 19-951 RETROVIR IV Infusion
Page 20
events have been chosen for inclusion due to either their seriousness, frequency of reporting, potential
causal connection to RETROVIR, or a combination of these factors.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain.
Cardiovascular: Cardiomyopathy, syncope.
Endocrine: Gynecomastia.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosal pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy,
pancytopenia with marrow hypoplasia.
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic
acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with
pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia,
seizures, somnolence, vertigo.
Respiratory: Cough, dyspnea, rhinitis, sinusitis.
Skin: Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic
epidemal necrolysis, sweat, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Urogenital: Urinary frequency, urinary hesitancy.
OVERDOSAGE: Acute overdoses of zidovudine have been reported in pediatric patients and adults.
These involved exposures up to 50 grams. No specific symptoms or signs have been identified
following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue,
headache, vomiting, and occasional reports of hematological disturbances. All patients recovered
without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on
the removal of zidovudine, while elimination of its primary metabolite, GZDV, is enhanced.
DOSAGE AND ADMINISTRATION:
Adults: The recommended intravenous dose is 1 mg/kg infused over 1 hour. This dose should be
administered 5 to 6 times daily (5 to 6 mg/kg daily). The effectiveness of this dose compared to higher
dosing regimens in improving the neurologic dysfunction associated with HIV disease is unknown. A
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NDA 19-951 RETROVIR IV Infusion
Page 21
small randomized study found a greater effect of higher doses of RETROVIR on improvement of
neurological symptoms in patients with pre-existing neurological disease.
Patients should receive RETROVIR IV Infusion only until oral therapy can be administered. The
intravenous dosing regimen equivalent to the oral administration of 100 mg every 4 hours is
approximately 1 mg/kg intravenously every 4 hours.
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to pregnant
women (>14 weeks of pregnancy) and their neonates is:
Maternal Dosing: 100 mg orally 5 times per day until the start of labor. During labor and delivery,
intravenous RETROVIR should be administered at 2 mg/kg (total body weight) over 1 hour
followed by a continuous intravenous infusion of 1 mg/kg per hour (total body weight) until
clamping of the umbilical cord.
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing
through 6 weeks of age. Neonates unable to receive oral dosing may be administered RETROVIR
intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See PRECAUTIONS if hepatic
disease or renal insufficiency is present.)
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone marrow
reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly in
patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is
recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who experience
hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia
usually occurs after 6 to 8 weeks.
Dose Adjustment: Anemia: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of
baseline) and/or significant neutropenia (granulocyte count of <750 cells/mm3 or reduction of >50%
from baseline) may require a dose interruption until evidence of marrow recovery is observed (see
WARNINGS). In patients who develop significant anemia, dose interruption does not necessarily
eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption
in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses,
depending on hematologic indices such as serum erythropoetin level and patient tolerance.
For patients experiencing pronounced anemia while receiving chronic coadministration of
zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose
reduction may be considered.
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NDA 19-951 RETROVIR IV Infusion
Page 22
End-stage Renal Disease: In patients maintained on hemodialysis or peritoneal dialysis (CrCl
<15 mL/min), recommended dosing is 1 mg/kg every 6 to 8 hours (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
Hepatic Impairment: There are insufficient data to recommend dose adjustment of RETROVIR in
patients with mild to moderate impaired hepatic function or liver cirrhosis. Since RETROVIR is
primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these
patients. Frequent monitoring of hematologic toxicities is advised (see CLINICAL
PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).
Method of Preparation: RETROVIR IV Infusion must be diluted prior to administration. The
calculated dose should be removed from the 20-mL vial and added to 5% Dextrose Injection solution
to achieve a concentration no greater than 4 mg/mL. Admixture in biologic or colloidal fluids (e.g.,
blood products, protein solutions, etc.) is not recommended.
After dilution, the solution is physically and chemically stable for 24 hours at room temperature and
48 hours if refrigerated at 2° to 8°C (36° to 46°F). Care should be taken during admixture to prevent
inadvertent contamination. As an additional precaution, the diluted solution should be administered
within 8 hours if stored at 25°C (77°F) or 24 hours if refrigerated at 2° to 8°C to minimize potential
administration of a microbially contaminated solution.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior
to administration whenever solution and container permit. Should either be observed, the solution
should be discarded and fresh solution prepared.
Administration: RETROVIR IV Infusion is administered intravenously at a constant rate over 1 hour.
Rapid infusion or bolus injection should be avoided. RETROVIR IV Infusion should not be given
intramuscularly.
HOW SUPPLIED: RETROVIR IV Infusion, 10 mg zidovudine in each mL.
20-mL Single-Use Vial, Tray of 10 (NDC 0173-0107-93).
Store vials at 15° to 25°C (59° to 77°F) and protect from light.
GlaxoSmithKline
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NDA 19-951 RETROVIR IV Infusion
Page 23
Manufactured by
Catalytica Pharmaceuticals, Inc.
Greenville, NC 27834
for GlaxoSmithKline
Research Triangle Park, NC 27709
2001, GlaxoSmithKline
All rights reserved.
October 2001
RL-1023
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:23.107769
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19951slr018_retrovir_lbl.pdf', 'application_number': 19951, 'submission_type': 'SUPPL ', 'submission_number': 18}
|
12,095
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RETROVIR safely and effectively. See full prescribing information for
RETROVIR.
RETROVIR® (zidovudine) tablets, for oral use
RETROVIR® (zidovudine) capsules, for oral use
RETROVIR® (zidovudine) syrup, for oral use
RETROVIR® (zidovudine) injection, for intravenous use
Initial U.S. Approval: 1987
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
• Hematologic toxicity including neutropenia and severe anemia have
been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine.
(5.3)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues
including RETROVIR. Suspend treatment if clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity
occur. (5.4)
----------------------------INDICATIONS AND USAGE ---------------------------
RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for:
• Treatment of Human Immunodeficiency Virus (HIV-1) infection in
combination with other antiretroviral agents. (1.1)
• Prevention of maternal-fetal HIV-1 transmission. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
• Treatment of HIV-1 infection:
Adults: Recommended oral dosage is 300 mg twice a day with other
antiretroviral agents. For patients who are unable to take the oral
formulations, the recommended intravenous dose is 1 mg per kg infused
over 1 hour every 4 hours. (2.1)
Pediatric patients (aged 4 weeks to less than 18 years): Dosage should be
calculated based on body weight not to exceed adult dose. (2.2)
• Prevention of maternal-fetal HIV-1 transmission:
Specific dosage instructions for mother and infant. (2.3)
• Patients with severe anemia and/or neutropenia:
Dosage interruption may be necessary. (2.4)
• Renal impairment: Recommended oral dosage in hemodialysis or
peritoneal dialysis or in patients with creatinine clearance (CrCl) less than
15 mL per minute is 100 mg every 6 to 8 hours. Equivalent intraveneous
dosing is approximately 1 mg per kg every 6 to 8 hours. (2.5)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
• Tablets: 300 mg (3)
• Capsules: 100 mg (3)
• Syrup: 10 mg per mL (3)
• Injection: (10 mg per mL) 20-mL single-use vial (3)
-------------------------------CONTRAINDICATIONS ------------------------------
Hypersensitivity to zidovudine or any of the components (e.g., anaphylaxis,
Stevens-Johnson syndrome). (4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• See boxed warning for information about the following: hematologic
toxicity, myopathy, and lactic acidosis and severe hepatomegaly (5.1, 5.3,
5.4)
• The vial stoppers for RETROVIR injection contain natural rubber latex
which may cause allergic reactions in latex-sensitive individuals. (5.2)
• Exacerbation of anemia has been reported in HIV-1/HCV co-infected
patients receiving ribavirin and zidovudine. Coadministration of ribavirin
and zidovudine is not advised. (5.5)
• Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV
co-infected patients receiving combination antiretroviral therapy and
interferon alfa with/without ribavirin. Discontinue zidovudine as medically
appropriate and consider dose reduction or discontinuation of interferon
alfa, ribavirin, or both. (5.5)
• RETROVIR should not be administered with other zidovudine-containing
combination products. (5.6)
• Immune reconstitution syndrome (5.7) and redistribution/accumulation of
body fat (5.8) have been reported in patients treated with combination
antiretroviral therapy.
------------------------------ ADVERSE REACTIONS -----------------------------
• Most commonly reported adverse reactions (incidence greater than or
equal to 15%) in adult HIV-1 clinical trials were headache, malaise,
nausea, anorexia, and vomiting. (6.1)
• Most commonly reported adverse reactions (incidence greater than or
equal to 15%) in pediatric HIV-1 clinical trials were fever and cough. (6.1)
• Most commonly reported adverse reactions in neonates (incidence greater
than or equal to 15%) in the prevention of maternal-fetal transmission of
HIV-1 clinical trial were anemia and neutropenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact ViiV
Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• Stavudine: Concomitant use with zidovudine should be avoided. (7.1)
• Doxorubicin: Use with zidovudine should be avoided. (7.2)
• Bone marrow suppressive/cytotoxic agents: May increase the hematologic
toxicity of zidovudine. (7.3)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 12/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
2
DOSAGE AND ADMINISTRATION
2.1
Adults – Treatment of HIV-1 Infection
2.2
Pediatric Patients (Aged 4 Weeks to Less than
18 Years)
2.3
Prevention of Maternal-Fetal HIV-1 Transmission
2.4
Patients with Severe Anemia and/or Neutropenia
2.5
Patients with Renal Impairment
2.6
Patients with Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
5.2
Latex
5.3
Myopathy
5.4
Lactic Acidosis/Severe Hepatomegaly with Steatosis
5.5
Use with Interferon- and Ribavirin-based Regimens in
HIV-1/HCV Co-infected Patients
5.6
Use with Other Zidovudine-containing Products
5.7
Immune Reconstitution Syndrome
5.8
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
7.2
Doxorubicin
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic
Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
1
Reference ID: 3678046
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For current labeling information, please visit https://www.fda.gov/drugsatfda
12.4 Microbiology
14.2 Pediatric Patients
13 NONCLINICAL TOXICOLOGY
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
13.2 Animal Toxicology and/or Pharmacology Studies
17 PATIENT COUNSELING INFORMATION
14 CLINICAL STUDIES
*Sections or subsections omitted from the full prescribing information are not listed.
14.1 Adults
FULL PRESCRIBING INFORMATION
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC
ACIDOSIS
Hematologic Toxicity
RETROVIR® (zidovudine) tablets, capsules, syrup, and injection have been associated with
hematologic toxicity including neutropenia and severe anemia, particularly in patients with
advanced HIV-1 disease [see Warnings and Precautions (5.1)].
Myopathy
Prolonged use of RETROVIR has been associated with symptomatic myopathy [see
Warnings and Precautions (5.3)].
Lactic Acidosis and Severe Hepatomegaly
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogues alone or in combination, including
RETROVIR and other antiretrovirals. Suspend treatment if clinical or laboratory findings
suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and
Precautions (5.4)].
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other
antiretroviral agents for the treatment of HIV-1 infection.
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see Dosage
and Administration (2.3)]. The indication is based on a dosing regimen that included
3 components:
1.
antepartum therapy of HIV-1 infected mothers
2.
intrapartum therapy of HIV-1 infected mothers
3.
post-partum therapy of HIV-1 exposed neonate
Points to consider prior to initiating RETROVIR in pregnant women for the prevention of
maternal-fetal HIV-1 transmission include:
• In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be
given in combination with other antiretroviral drugs.
2
Reference ID: 3678046
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Prevention of HIV-1 transmission in women who have received RETROVIR for a prolonged
period before pregnancy has not been evaluated.
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the
first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are
not fully known, women in the first trimester of pregnancy who do not require immediate
initiation of antiretroviral therapy for their own health may consider delaying use; this
indication is based on use after 14 weeks gestation.
2
DOSAGE AND ADMINISTRATION
2.1
Adults – Treatment of HIV-1 Infection
Oral Dosing
The recommended oral dose of RETROVIR is 300 mg twice daily in combination with other
antiretroviral agents.
Intravenous (IV) Dosing
The recommended intravenous dose is 1 mg per kg infused at a constant rate over 1 hour every 4
hours. Patients should receive RETROVIR injection only until oral therapy can be administered.
• RETROVIR injection must be diluted prior to administration. The calculated dose should be
removed from the 20-mL vial and added to 5% Dextrose injection solution to achieve a
concentration no greater than 4 mg per mL.
• After dilution, the solution is physically and chemically stable for 24 hours at room
temperature and 48 hours if refrigerated at 2° to 8°C (36° to 46°F). As an additional
precaution, the diluted solution should be administered within 8 hours if stored at 25°C
(77°F) or 24 hours if refrigerated at 2° to 8°C to minimize potential administration of a
microbially contaminated solution.
• Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit and discarded if either is
observed.
• Rapid infusion or bolus injection should be avoided. RETROVIR injection should not be
given intramuscularly.
2.2
Pediatric Patients (Aged 4 Weeks to Less than 18 Years)
Healthcare professionals should pay special attention to accurate calculation of the dose of
RETROVIR, transcription of the medication order, dispensing information, and dosing
instructions to minimize risk for medication dosing errors.
Prescribers should calculate the appropriate dose of RETROVIR for each child based on body
weight (kg) and should not exceed the recommended adult dose.
3
Reference ID: 3678046
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Before prescribing RETROVIR capsules or tablets, children should be assessed for the ability to
swallow capsules or tablets. If a child is unable to reliably swallow a RETROVIR capsule or
tablet, the RETROVIR syrup formulation should be prescribed.
The recommended oral dosage in pediatric patients aged 4 weeks to less than 18 years and
weighing greater than or equal to 4 kg is provided in Table 1. RETROVIR syrup should be used
to provide accurate dosage when whole tablets or capsules are not appropriate.
Table 1. Recommended Pediatric Oral Dosage of RETROVIR
Body Weight
(kg)
Total Daily
Dose
Dosage Regimen and Dose
Twice Daily
Three Times Daily
4 to <9
24 mg/kg/day
12 mg/kg
8 mg/kg
≥9 to <30
18 mg/kg/day
9 mg/kg
6 mg/kg
≥30
600 mg/day
300 mg
200 mg
Alternatively, dosing for RETROVIR can be based on body surface area (BSA) for each child.
The recommended oral dose of RETROVIR is 480 mg per m2 per day in divided doses (240 mg
per m2 twice daily or 160 mg per m2 three times daily). In some cases the dose calculated by mg
per kg will not be the same as that calculated by BSA.
2.3
Prevention of Maternal-Fetal HIV-1 Transmission
The recommended dosage regimen for administration to pregnant women (greater than 14 weeks
of pregnancy) and their neonates is:
Maternal Dosing
100 mg orally 5 times per day until the start of labor [see Clinical Studies (14.3)]. During labor
and delivery, intravenous RETROVIR should be administered at 2 mg per kg (total body weight)
over 1 hour followed by a continuous intravenous infusion of 1 mg per kg per hour (total body
weight) until clamping of the umbilical cord.
Neonatal Dosing
Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates
unable to receive oral dosing may be administered RETROVIR intravenously. See Table 2.
Table 2. Recommended Neonatal Dosages of RETROVIR
Route
Total Daily Dose
Dose and Dosage Regimen
Oral
8 mg/kg/day
2 mg/kg every 6 hours
Intravenous
6 mg/kg/day
1.5 mg/kg infused over 30 minutes, every 6 hours
4
Reference ID: 3678046
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.4
Patients with Severe Anemia and/or Neutropenia
Significant anemia (hemoglobin less than 7.5 g per dL or reduction greater than 25% of baseline)
and/or significant neutropenia (granulocyte count less than 750 cells per mm3 or reduction
greater than 50% from baseline) may require a dose interruption until evidence of marrow
recovery is observed [see Warnings and Precautions (5.1)]. In patients who develop significant
anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow
recovery occurs following dose interruption, resumption in dose may be appropriate using
adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic
indices such as serum erythropoietin level and patient tolerance.
2.5
Patients with Renal Impairment
In patients maintained on hemodialysis or peritoneal dialysis or with creatinine clearance (CrCl)
by Cockcroft-Gault less than 15 mL per min, the recommended oral dosage is 100 mg every 6 to
8 hours. The intravenous dosing regimen equivalent to the oral administration of 100 mg every 6
to 8 hours is approximately 1 mg per kg every 6 to 8 hours [see Use in Specific Populations
(8.6), Clinical Pharmacology (12.3)].
2.6
Patients with Hepatic Impairment
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is
advised [see Use in Specific Populations (8.7)].
3
DOSAGE FORMS AND STRENGTHS
• RETROVIR tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
zidovudine, one side engraved “GX CW3” and “300” on the other side.
• RETROVIR capsules 100 mg (white, opaque cap and body) containing 100 mg zidovudine
and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on body.
• RETROVIR syrup (colorless to pale yellow, strawberry-flavored) containing 10 mg
zidovudine in each mL.
• RETROVIR injection is a clear, nearly colorless, sterile aqueous solution with a pH of
approximately 5.5. Each vial contains 200 mg of zidovudine in 20 mL solution (10 mg per
mL).
4
CONTRAINDICATIONS
RETROVIR is contraindicated in patients who have had a potentially life-threatening
hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the
components of the formulations.
5
Reference ID: 3678046
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
RETROVIR should be used with caution in patients who have bone marrow compromise
evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 g per
dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose
and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and
neutropenia were the most significant adverse events observed. In patients who experience
hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and
neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia
associated with the use of RETROVIR, which was reversible in most instances after
discontinuance of the drug. However, significant anemia, in many cases requiring dose
adjustment, discontinuation of RETROVIR, and/or blood transfusions, has occurred during
treatment with RETROVIR alone or in combination with other antiretrovirals.
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in
patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease
who are treated with RETROVIR. For HIV–1-infected individuals and patients with
asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or
neutropenia develops, dosage interruption may be needed [see Dosage and Administration
(2.4)].
5.2
Latex
The vial stoppers for RETROVIR injection contain natural rubber latex which may cause allergic
reactions in latex-sensitive individuals.
5.3
Myopathy
Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease,
have been associated with prolonged use of RETROVIR.
5.4
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported
with the use of nucleoside analogues alone or in combination, including zidovudine and other
antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure
to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised
when administering RETROVIR to any patient with known risk factors for liver disease;
however, cases have also been reported in patients with no known risk factors. Treatment with
RETROVIR should be suspended in any patient who develops clinical or laboratory findings
suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and
steatosis even in the absence of marked transaminase elevations).
6
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5.5
Use with Interferon- and Ribavirin-based Regimens in HIV-1/HCV
Co-infected Patients
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside
analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic
interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was
coadministered with zidovudine in HIV-1/HCV co-infected subjects [see Clinical Pharmacology
(12.3)], exacerbation of anemia due to ribavirin has been reported when zidovudine is part of the
HIV regimen. Coadministration of ribavirin and zidovudine is not advised. Consideration should
be given to replacing zidovudine in established combination HIV-1/HCV therapy, especially in
patients with a known history of zidovudine-induced anemia.
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving
combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.
Patients receiving interferon alfa with or without ribavirin and zidovudine should be closely
monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia,
and anemia.
Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or
discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening
clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than
6) (see the complete prescribing information for interferon and ribavirin).
5.6
Use with Other Zidovudine-containing Products
RETROVIR should not be administered with combination products that contain zidovudine as
one of their components (e.g., COMBIVIR® [lamivudine and zidovudine] tablets or TRIZIVIR®
[abacavir sulfate, lamivudine, and zidovudine] tablets).
5.7
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including RETROVIR. During the initial phase of combination
antiretroviral treatment, patients whose immune systems respond may develop an inflammatory
response to indolent or residual opportunistic infections (such as Mycobacterium avium
infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)
have also been reported to occur in the setting of immune reconstitution; however, the time to
onset is more variable, and can occur many months after initiation of treatment.
5.8
Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement
(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid
7
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appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and
long-term consequences of these events are currently unknown. A causal relationship has not
been established.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and
Precautions (5.1)].
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.3)].
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
Precautions (5.4)].
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings
and Precautions (5.5)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
Adults
The frequency and severity of adverse reactions associated with the use of RETROVIR are
greater in patients with more advanced infection at the time of initiation of therapy.
Table 3 summarizes adverse reactions reported at a statistically significant greater incidence for
subjects receiving oral RETROVIR in a monotherapy trial.
8
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Table 3. Percentage (%) of Subjects with Adverse Reactions (Greater than or Equal to 5%
Frequency) in Asymptomatic HIV-1 Infection (ACTG 019)
Adverse Reaction
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
Headache
Malaise
Gastrointestinal
Anorexia
Constipation
Nausea
Vomiting
9%
a
63%
53%
20%
6%
a
51%
17%
6%
53%
45%
11%
4%
30%
10%
a Not statistically significant versus placebo.
In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence
of greater than or equal to 5% in any treatment arm in clinical trials (NUCA3001, NUCA3002,
NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills,
dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in
these trials hyperbilirubinemia was reported at an incidence of less than or equal to 0.8%.
Selected laboratory abnormalities observed during a clinical trial of monotherapy with oral
RETROVIR are shown in Table 4.
Table 4. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Subjects with
Asymptomatic HIV-1 Infection (ACTG 019)
Test
(Abnormal Level)
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
Granulocytopenia (<750 cells/mm3)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>5 x ULN)
AST (>5 x ULN)
1%
2%
0%
3%
1%
<1%
2%
<1%
3%
2%
ULN = Upper limit of normal.
The adverse reactions reported during IV administration of RETROVIR injection are similar to
those reported with oral administration; neutropenia and anemia were reported most frequently.
Long-term IV administration beyond 2 to 4 weeks has not been studied in adults and may
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enhance hematologic adverse reactions. Local reaction, pain, and slight irritation during IV
administration occur infrequently.
Pediatrics
The clinical adverse reactions reported among adult recipients of RETROVIR may also occur in
pediatric patients.
Trial ACTG 300: Selected clinical adverse reactions and physical findings with a greater than or
equal to 5% frequency during therapy with EPIVIR® (lamivudine) oral suspension 4 mg per kg
twice daily plus RETROVIR 160 mg per m2 3 times daily compared with didanosine in therapy-
naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in
Table 5.
Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or Equal
to 5% Frequency) in Pediatric Subjects in Trial ACTG 300
Adverse Reaction
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
Digestive
25%
32%
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
Respiratory
5%
8%
Cough
15%
18%
Abnormal breath sounds/wheezing
Ear, Nose, and Throat
7%
9%
Signs or symptoms of earsa
7%
6%
Nasal discharge or congestion
Other
8%
11%
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
a Includes pain, discharge, erythema, or swelling of an ear.
Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of
antiretroviral therapy) pediatric subjects are listed in Table 6.
10
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Table 6. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric
Subjects in Trial ACTG 300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
Anemia (Hgb<7.0 g/dL)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>10 x ULN)
AST (>10 x ULN)
Lipase (>2.5 x ULN)
Total amylase (>2.5 x ULN)
8%
4%
1%
1%
2%
3%
3%
3%
2%
3%
3%
4%
3%
3%
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Macrocytosis was reported in the majority of pediatric subjects receiving RETROVIR 180 mg
per m2 every 6 hours in open-label trials. Additionally, adverse reactions reported at an incidence
of less than 6% in these trials were congestive heart failure, decreased reflexes, ECG
abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
Use for the Prevention of Maternal-Fetal Transmission of HIV-1
In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their
neonates conducted to determine the utility of RETROVIR for the prevention of maternal-fetal
HIV-1 transmission, RETROVIR syrup at 2 mg per kg was administered every 6 hours for
6 weeks to neonates beginning within 12 hours following birth. The most commonly reported
adverse reactions were anemia (hemoglobin less than 9.0 g per dL) and neutropenia (less than
1,000 cells per mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in
12% of the neonates who received placebo. The mean difference in hemoglobin values was less
than 1.0 g per dL for neonates receiving RETROVIR compared with neonates receiving placebo.
No neonates with anemia required transfusion and all hemoglobin values spontaneously returned
to normal within 6 weeks after completion of therapy with RETROVIR. Neutropenia in neonates
was reported with similar frequency in the group that received RETROVIR (21%) and in the
group that received placebo (27%). The long-term consequences of in utero and infant exposure
to RETROVIR are unknown.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of RETROVIR.
Because these reactions are reported voluntarily from a population of unknown size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
11
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Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
redistribution/accumulation of body fat [see Warnings and Precautions (5.8)].
Cardiovascular: Cardiomyopathy, syncope.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hematologic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia
with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with
pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia,
seizures, somnolence, vertigo.
Reproductive System and Breast: Gynecomastia.
Respiratory: Dyspnea, rhinitis, sinusitis.
Skin and Subcutaneous Tissue: Changes in skin and nail pigmentation, pruritus,
Stevens-Johnson syndrome, toxic epidermal necrolysis, sweating, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Renal and Urinary: Urinary frequency, urinary hesitancy.
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
Stavudine
Concomitant use of zidovudine with stavudine should be avoided since an antagonistic
relationship has been demonstrated in vitro.
Nucleoside Analogues Affecting DNA Replication
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro
antiviral activity of RETROVIR against HIV-1; concomitant use of such drugs should be
avoided.
7.2
Doxorubicin
Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic
relationship has been demonstrated in vitro.
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7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or
cytotoxic agents may increase the hematologic toxicity of zidovudine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C.
In humans, treatment with RETROVIR during pregnancy reduced the rate of maternal-fetal
HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants
born to mothers treated with RETROVIR [see Clinical Studies (14.3)]. There were no
differences in pregnancy-related adverse events between the treatment groups. Animal
reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal
malformations.
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant
women to determine the utility of RETROVIR for the prevention of maternal-fetal
HIV-1-transmission [see Clinical Studies (14.3)]. Congenital abnormalities occurred with similar
frequency between neonates born to mothers who received RETROVIR and neonates born to
mothers who received placebo. The observed abnormalities included problems in embryogenesis
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of
study drug.
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine
that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the
mean steady-state peak human plasma concentration following a single 100-mg dose of
zidovudine. There were no other reported developmental anomalies. In another developmental
toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak
plasma concentrations 350 times peak human plasma concentrations (300 times the daily
exposure [AUC] in humans given 600 mg per day zidovudine). This dose was associated with
marked maternal toxicity and an increased incidence of fetal malformations. However, there
were no signs of teratogenicity at doses up to one-fifth the lethal dose [see Nonclinical
Toxicology (13.2)].
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to RETROVIR, an
Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register
patients by calling 1-800-258-4263.
8.3
Nursing Mothers
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Zidovudine is excreted in human milk. After administration of a single dose of 200 mg
zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in
human milk and serum.
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the
United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1
infection. Because of both the potential for HIV-1 transmission and the potential for serious
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
receiving RETROVIR.
8.4
Pediatric Use
RETROVIR has been studied in HIV-1-infected pediatric subjects aged at least 6 weeks who had
HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating
significant HIV-1-related immunosuppression. RETROVIR has also been studied in neonates
perinatally exposed to HIV-1 [see Dosage and Administration (2.2), Adverse Reactions (6.1),
Clinical Pharmacology (12.3), Clinical Studies (14.2, 14.3)].
8.5
Geriatric Use
Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
drug therapy.
8.6
Renal Impairment
Unchanged zidovudine and its glucuronide metabolite (formed in the liver) are primarily
eliminated from the body by renal excretion. In patients with severely impaired renal function
(CrCl less than 15 mL per min), dosage reduction is recommended [see Dosage and
Administration (2.5), Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
RETROVIR is primarily eliminated by hepatic metabolism and zidovudine concentrations
appear to be increased in patients with impaired hepatic function, which may increase the risk of
hematologic toxicity. Frequent monitoring of hematologic toxicities is advised. There are
insufficient data to recommend dose adjustment of RETROVIR in patients with impaired hepatic
function or liver cirrhosis [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].
10
OVERDOSAGE
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These
involved exposures up to 50 grams. No specific symptoms or signs have been identified
following acute overdosage with zidovudine apart from those listed as adverse events such as
14
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fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3′-
azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced. If overdose
occurs, the patient should be monitored for evidence of toxicity and given standard supportive
treatment as required.
11
DESCRIPTION
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′-
azido-3′-deoxythymidine; it has the following structural formula:
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and
a solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C10H13N5O4.
RETROVIR tablets are for oral administration. Each film-coated tablet contains 300 mg of
zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
RETROVIR capsules are for oral administration. Each capsule contains 100 mg of zidovudine
and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose, and
sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink,
consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin,
and titanium dioxide.
RETROVIR syrup is for oral administration. Each mL of RETROVIR syrup contains 10 mg of
zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a preservative), citric
acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to adjust pH.
RETROVIR injection is a sterile solution for IV infusion only. Each mL contains 10 mg
zidovudine in water for injection. Hydrochloric acid and/or sodium hydroxide may have been
added to adjust the pH to approximately 5.5. RETROVIR injection contains no preservatives.
The vial stoppers for RETROVIR injection contain natural rubber latex.
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12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Zidovudine is an antiviral agent [see Microbiology (12.4)].
12.3 Pharmacokinetics
Absorption and Bioavailability
Following IV dosing, dose-independent kinetics was observed over the range of 1 to 5 mg per
kg. The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg per kg every
4 hours were 1.1 and 0.1 mcg per mL, respectively.
In adults, following oral administration, zidovudine is rapidly absorbed and extensively
distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was
equivalent when zidovudine was administered as RETROVIR tablets or syrup compared with
RETROVIR capsules. The pharmacokinetic properties of zidovudine in fasting adult subjects are
summarized in Table 7.
Table 7. Zidovudine Pharmacokinetic Parameters in Adult Subjects
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Cerebrospinal fluid (CSF):plasma ratioa
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/h/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/h/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (h)b
0.5 to 3
(n = 19)
a Median [range] for 50 paired samples drawn 1 to 8 hours after the last dose in subjects on
chronic therapy with RETROVIR.
b Approximate range.
Distribution
The apparent volume of distribution of zidovudine, is 1.6 ± 0.6 L per kg (Table 7); and binding
to plasma protein is low (less than 38%).
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Metabolism and Elimination
Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine
is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of
zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral
administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3′-
amino-3′-deoxythymidine (AMT), has been identified in the plasma following single-dose IV
administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC.
Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from
2 mg per kg every 8 hours to 10 mg per kg every 4 hours.
Effect of Food on Absorption
RETROVIR may be administered with or without food. The zidovudine AUC was similar when
a single dose of zidovudine was administered with food.
Special Populations
Renal Impairment: Zidovudine clearance was decreased resulting in increased zidovudine and
GZDV half-life and AUC in subjects with impaired renal function (n = 14) following a single
200-mg oral dose (Table 8). Plasma concentrations of AMT were not determined. No dose
adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min.
Table 8. Zidovudine Pharmacokinetic Parameters in Subjects with Severe Renal
Impairmenta
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Subjects with Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•h/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (h)
1.0 ± 0.2
1.4 ± 0.1
a Data are expressed as mean ± standard deviation.
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of zidovudine
were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal
dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily
doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma
concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in
subjects with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a
negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis
[see Dosage and Administration (2.5)].
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Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics
of zidovudine are limited. However, zidovudine is eliminated primarily by hepatic metabolism
and it appears that zidovudine clearance is decreased and plasma concentrations are increased in
subjects with hepatic impairment. There are insufficient data to recommend dose adjustment of
RETROVIR in patients with impaired hepatic function or liver cirrhosis [see Dosage and
Administration (2.6)].
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in HIV-1-infected
pediatric subjects (Table 9).
Patients Aged 3 Months to 12 Years: Overall, zidovudine pharmacokinetics in
pediatric patients older than 3 months are similar to those in adult patients. Proportional
increases in plasma zidovudine concentrations were observed following administration of oral
solution from 90 to 240 mg per m2 every 6 hours. Oral bioavailability, terminal half-life, and oral
clearance were comparable to adult values. As in adult subjects, the major route of elimination
was by metabolism to GZDV. After IV dosing, about 29% of the dose was excreted in the urine
unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and Administration
(2.2)].
Patients Aged Less than 3 Months: Zidovudine pharmacokinetics have been
evaluated in pediatric subjects from birth to 3 months of life. Zidovudine elimination was
determined immediately following birth in 8 neonates who were exposed to zidovudine in utero.
The half-life was 13.0 ± 5.8 hours. In neonates less than or equal to 14 days old, bioavailability
was greater, total body clearance was slower, and half-life was longer than in pediatric subjects
older than 14 days. For dose recommendations for neonates [see Dosage and Administration
(2.3)].
Table 9. Zidovudine Pharmacokinetic Parameters in Pediatric Subjectsa
Parameter
Birth to 14 Days
Aged 14 Days to
3 Months
Aged 3 Months to
12 Years
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]b
(n = 38)
CL (L/h/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (h)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
a Data presented as mean ± standard deviation except where noted.
b Median [range].
18
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Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I trial of 8 women
during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of
nonpregnant adults. Consistent with passive transmission of the drug across the placenta,
zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal
plasma at delivery [see Use in Specific Populations (8.1)].
Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear
to alter zidovudine pharmacokinetics.
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in subjects over
65 years of age.
Gender: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects showed
no differences in zidovudine AUC when a single dose of zidovudine was administered as the
300-mg RETROVIR tablet.
Drug Interactions
[See Drug Interactions (7).]
19
Reference ID: 3678046
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 10. Effect of Coadministered Drugs on Zidovudine AUCa
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED
WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Drug and Dose
Zidovudine
Oral Dose
n
Zidovudine
Concentrations
Concentration of
Coadministered
Drug
AUC
Variability
Atovaquone
750 mg every 12 h
with food
200 mg every
8 h
14
↑AUC
31%
Range:
23% to 78%b
↔
Clarithromycin
500 mg twice daily
100 mg every
4 h x 7 days
4
↓AUC
12%
Range:
↓34% to ↑14%b
Not Reported
Fluconazole
400 mg daily
200 mg every
8 h
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Lamivudine
300 mg every 12 h
single 200 mg
12
↑AUC
13%
90% CI:
2% to 27%
↔
Methadone
30 to 90 mg daily
200 mg every
4 h
9
↑AUC
43%
Range:
16% to 64%b
↔
Nelfinavir
750 mg every 8 h
x 7 to 10 days
single 200 mg
11
↓AUC
35%
Range:
28% to 41%b
↔
Probenecid
500 mg every 6 h
x 2 days
2 mg/kg every
8 h x 3 days
3
↑AUC
106%
Range:
100% to 170%b
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 h x
14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg every 6 h
x 4 days
200 mg every
8 h x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
every 8 h x 4 days
100 mg every
8 h x 4 days
6
↑AUC
80%
Range:
64% to 130%b
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration
versus time curve; CI = confidence interval.
a This table is not all inclusive.
b Estimated range of percent difference.
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
20
Reference ID: 3678046
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For current labeling information, please visit https://www.fda.gov/drugsatfda
interaction trial in which 12 HIV-1-positive volunteers received a single 300-mg phenytoin dose
alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in
phenytoin kinetics was observed. Although not designed to optimally assess the effect of
phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed
with phenytoin.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and
zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular
triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of
HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine
(n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug
regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions (5.5)].
12.4 Microbiology
Mechanism of Action
Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to
its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of
action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after
incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA
polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
Antiviral Activity
The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines
(including monocytes and fresh human peripheral blood lymphocytes). The EC50 and EC90
values for zidovudine were 0.01 to 0.49 µM (1 µM = 0.27 mcg per mL) and 0.1 to 9 µM,
respectively. HIV-1 from therapy-naive subjects with no mutations associated with resistance
gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92 baseline
samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram Biosciences
(n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against different
HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from 0.00049
to 0.004 µM. In cell culture drug combination studies, zidovudine demonstrates synergistic
activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and lamivudine;
the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease
inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon
alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.
Resistance
Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated
subjects showed mutations in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L,
D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general,
higher levels of resistance were associated with greater number of amino acid substitutions. In
21
Reference ID: 3678046
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some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to
zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination
therapy with lamivudine plus zidovudine delayed the emergence of substitutions conferring
resistance to zidovudine.
Cross-Resistance
In a trial of 167 HIV-1-infected subjects, isolates (n = 2) with multi-drug resistance to
didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from subjects
treated for at least 1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The
pattern of resistance-associated amino acid substitutions with such combination therapies was
different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy,
with the Q151M substitution being most commonly associated with multi-drug resistance. The
substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116 results in a
virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and
zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer
cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats
(60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per
kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were
reduced to 20, 30, and 40 mg per kg per day after day 90 because of treatment-related anemia,
whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to
300 mg per kg per day on Day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous
cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given
the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a
middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle
dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by
AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at
the recommended therapeutic dose of 100 mg every 4 hours.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
22
Reference ID: 3678046
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Two transplacental carcinogenicity studies were conducted in mice. One study administered
zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10
through parturition and lactation with dosing continuing in offspring for 24 months postnatally.
The doses of zidovudine administered in this study produced zidovudine exposures
approximately 3 times the estimated human exposure at recommended doses. After 24 months,
an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or
lung or any other organ in either gender. These findings are consistent with results of the
standard oral carcinogenicity study in mice, as described earlier. A second study administered
zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately
1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight)
to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of
tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the
higher dose level of zidovudine.
Mutagenesis
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and
positive in mouse and rat micronucleus tests after repeated doses. It was negative in a
cytogenetic study in rats given a single dose.
Impairment of Fertility
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose
based on body surface area, had no effect on fertility judged by conception rates.
13.2 Animal Toxicology and/or Pharmacology
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg per kg per day revealed
no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal
toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or
450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology
studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in
rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma
concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose
(100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine
exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional
teratology study in rats, a dose of 3,000 mg per kg per day (very near the oral median lethal dose
in rats of 3,683 mg per kg) caused marked maternal toxicity and an increase in the incidence of
fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak
human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily
AUC in humans given 600 mg per day.) No evidence of teratogenicity was seen in this
experiment at doses of 600 mg per kg per day or less.
23
Reference ID: 3678046
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14
CLINICAL STUDIES
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence of
opportunistic infections in patients with advanced HIV-1 disease and to delay disease
progression in asymptomatic HIV-1-infected patients.
14.1 Adults
Combination Therapy
RETROVIR in combination with other antiretroviral agents has been shown to be superior to
monotherapy for one or more of the following endpoints: delaying death, delaying development
of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
The clinical efficacy of a combination regimen that includes RETROVIR was demonstrated in
trial ACTG 320. This trial was a multi-center, randomized, double-blind, placebo-controlled trial
that compared RETROVIR 600 mg per day plus EPIVIR 300 mg per day with RETROVIR plus
EPIVIR plus indinavir 800 mg three times daily. The incidence of AIDS-defining events or death
was lower in the triple-drug–containing arm compared with the 2-drug–containing arm (6.1%
versus 10.9%, respectively).
Monotherapy
In controlled trials of treatment-naive subjects conducted between 1986 and 1989, monotherapy
with RETROVIR, as compared with placebo, reduced the risk of HIV-1 disease progression, as
assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining
events, or death. These trials enrolled subjects with advanced disease (BW 002), and
asymptomatic or mildly symptomatic disease in subjects with CD4+ cell counts between 200 and
500 cells per mm3 (ACTG 016 and ACTG 019). A survival benefit for monotherapy with
RETROVIR was not demonstrated in the latter 2 trials. Subsequent trials showed that the clinical
benefit of monotherapy with RETROVIR was time limited.
14.2 Pediatric Patients
ACTG 300 was a multi-center, randomized, double-blind trial that provided for comparison of
EPIVIR plus RETROVIR to didanosine monotherapy. A total of 471 symptomatic,
HIV-1-infected therapy-naive pediatric subjects were enrolled in these 2 treatment arms. The
median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline CD4+ cell count was
868 cells per mm3, and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies per mL. The
median duration that subjects remained on trial was approximately 10 months. Results are
summarized in Table 11.
24
Reference ID: 3678046
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Table 11. Number of Subjects (%) Reaching a Primary Clinical Endpoint (Disease
Progression or Death)
Endpoint
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
The utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission was
demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in
HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm3 (median
in the treated group: 560 cells per mm3) who had little or no previous exposure to RETROVIR.
Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of
therapy) followed by IV administration of RETROVIR during labor and delivery. Following
birth, neonates received oral RETROVIR syrup for 6 weeks. The trial showed a statistically
significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture
from peripheral blood) between the group receiving RETROVIR and the group receiving
placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV-1 infection was 7.8%
in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in
transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was
no difference in pregnancy-related adverse events between the treatment groups.
16
HOW SUPPLIED/STORAGE AND HANDLING
RETROVIR 300-mg tablets are supplied as white, biconvex, round, film-coated tablets
containing 300 mg zidovudine per tablet. Each tablet has one side engraved “GX CW3” and
“300” on the other side.
Bottles of 60 (NDC 49702-214-18).
Store at 15° to 25°C (59° to 77°F).
RETROVIR 100-mg capsules are supplied as white, opaque cap and body capsules containing
100 mg zidovudine per capsule. Each capsule is printed with “Wellcome” and unicorn logo on
cap and “Y9C” and “100” on body.
Bottles of 100 (NDC 49702-211-20).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
25
Reference ID: 3678046
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RETROVIR syrup is supplied as a colorless to pale yellow, strawberry-flavored syrup containing
10 mg zidovudine in each mL.
Bottle of 240 mL (NDC 49702-212-48) with child-resistant cap.
Store at 15° to 25°C (59° to 77°F).
RETROVIR injection, 10 mg zidovudine in each mL.
20-mL Single-use Vial (NDC 49702-213-01), Tray of 10 (NDC 49702-213-05).
Store vials at 15° to 25°C (59° to 77°F) and protect from light.
17
PATIENT COUNSELING INFORMATION
Hypersensitivity Reactions
Inform patients that potentially life-threatening hypersensitivity reactions (e.g., anaphylaxis,
Stevens-Johnson syndrome) can occur while receiving RETROVIR. Instruct patients to
immediately contact their healthcare provider if they develop rash, as it may be a sign of a more
serious reaction. Advise patients that it is very important that they remain under a healthcare
provider’s care during treatment with RETROVIR.
Neutropenia and Anemia
Inform patients that the major toxicities of RETROVIR are neutropenia and/or anemia. The
frequency and severity of these toxicities are greater in patients with more advanced disease and
in those who initiate therapy later in the course of their infection. Advise patients that if toxicity
develops, they may require transfusions or drug discontinuation. Advise patients of the extreme
importance of having their blood counts followed closely while on therapy, especially for
patients with advanced symptomatic HIV-1 disease [see Boxed Warning, Warnings and
Precautions (5.1)].
Myopathy
Inform patients that myopathy and myositis with pathological changes, similar to that produced
by HIV-1 disease, have been associated with prolonged use of RETROVIR [see Boxed Warning,
Warnings and Precautions (5.3)].
Lactic Acidosis/Hepatomegaly
Inform patients that some HIV medicines, including RETROVIR, can cause a rare, but serious
condition called lactic acidosis with liver enlargement (hepatomegaly) [see Boxed Warning,
Warnings and Precautions (5.4)].
HIV-1/HCV Co-infection
Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has
occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for
HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.5)].
26
Reference ID: 3678046
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Use with Other Zidovudine-containing Products
RETROVIR should not be administered with combination products that contain zidovudine as
one of their components (e.g., COMBIVIR [lamivudine and zidovudine] tablets or TRIZIVIR
[abacavir sulfate, lamivudine, and zidovudine] tablets) [see Warnings and Precautions (5.6)].
Immune Reconstitution Syndrome
In some patients with advanced HIV infection, signs and symptoms of inflammation from
previous infections may occur soon after anti-HIV treatment is started. It is believed that these
symptoms are due to an improvement in the body's immune response, enabling the body to fight
infections that may have been present with no obvious symptoms. Advise patients to inform their
healthcare provider immediately of any symptoms of infection [see Warnings and Precautions
(5.7)].
Redistribution/Accumulation of Body Fat
Inform patients that redistribution or accumulation of body fat may occur in patients receiving
antiretroviral therapy and that the cause and long-term health effects of these conditions are not
known at this time [see Warnings and Precautions (5.8)].
Common Adverse Reactions
Inform patients that the most commonly reported adverse reactions in adult patients being treated
with RETROVIR were headache, malaise, nausea, anorexia, and vomiting. The most commonly
reported adverse reactions in pediatric patients receiving RETROVIR were fever, cough, and
digestive disorders. Patients also should be encouraged to contact their physician if they
experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any
other unexpected adverse events while being treated with RETROVIR [see Adverse Reactions
(6)].
Drug Interactions
Caution patients about the use of other medications, including ganciclovir, interferon alfa, and
ribavirin, which may exacerbate the toxicity of RETROVIR [see Drug Interactions (7)].
Pregnancy
Inform pregnant women considering the use of RETROVIR during pregnancy for prevention of
HIV-1 transmission to their infants that transmission may still occur in some cases despite
therapy. The long-term consequences of in utero and infant exposure to RETROVIR are
unknown, including the possible risk of cancer [see Use in Specific Populations (8.1)].
Advise HIV-1-infected pregnant women not to breastfeed to avoid postnatal transmission of HIV
to a child who may not yet be infected [see Use in Specific Populations (8.3)].
Information about HIV-1 Infection
27
Reference ID: 3678046
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RETROVIR is not a cure for HIV-1 infection, and patients may continue to experience illnesses
associated with HIV-1 infection, including opportunistic infections. Patients must remain on
continuous HIV therapy to control HIV-1 infection and decrease HIV-1-related illness. Patients
should be told that sustained decreases in plasma HIV-1 RNA have been associated with a
reduced risk of progression to AIDS and death. Patients should remain under the care of a
physician when using RETROVIR.
Patients should be informed to take all HIV medications exactly as prescribed.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like
toothbrushes and razor blades.
• Continue to practice safe sex by using a latex or polyurethane condom or other barrier
method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Female patients should be advised not to breastfeed. Zidovudine is excreted in human
breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to
the baby in the breast milk.
Instruct patients that if they miss a dose, they should just take their next dose at the usual time.
Patients should not double their next dose.
RETROVIR, COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of the ViiV
Healthcare group of companies.
Manufactured for:
ViiV Healthcare
Research Triangle Park, NC 27709
by:
28
Reference ID: 3678046
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GlaxoSmithKline
Research Triangle Park, NC 27709
©2014, the ViiV Healthcare group of companies. All rights reserved.
RTR: XPI
29
Reference ID: 3678046
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019910s041lbl.pdf', 'application_number': 19951, 'submission_type': 'SUPPL ', 'submission_number': 32}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HEPARIN SODIUM IN 5% DEXTROSE INJECTION safely and
effectively. See full prescribing information for HEPARIN SODIUM
IN 5% DEXTROSE INJECTION.
HEPARIN SODIUM IN 5% DEXTROSE INJECTION, for intravenous
use
Initial U.S. Approval: 1992
--------------------------- INDICATIONS AND USAGE --------------------------
Heparin sodium is indicated for: (1)
•
Prophylaxis and treatment of venous thrombosis and pulmonary
embolism;
•
Prophylaxis and treatment of thromboembolic complications
associated with atrial fibrillation;
•
Treatment of acute and chronic consumption coagulopathies
(disseminated intravascular coagulation);
•
Prevention of clotting in arterial and cardiac surgery;
•
Prophylaxis and treatment of peripheral arterial embolism;
•
Anticoagulant use in blood transfusions, extracorporeal
circulation, and dialysis procedures.
------------------ DOSAGE AND ADMINISTRATION --------------------
Recommended Adult Dosages:
•
Therapeutic Anticoagulant Effect with Full-Dose Heparin* (2.3)
Intermittent
Initial Dose
10,000 Units
Intravenous
Injection
Every 4 to 6
hours
5,000 – 10,000 Units
Continuous
Initial Dose
5,000 Units by IV injection
Intravenous
Infusion
Continuous
20,000 – 40,000 Units/24
hours
*Based on 150 lb. (68 kg) patient.
•
Intravascular via
Total Body
Perfusion
>150 units/kg;
Initial Dose
adjust for longer
procedures
•
Extracorporeal Dialysis (2.8)
Intravascular via
Follow equipment manufacturer’s
Extracorporeal
operating directions carefully.
Dialysis
For pediatric dosing see section 2.4 of full prescribing information.
Surgery of the Heart and Blood Vessels (2.5)
-------------------- DOSAGE FORMS AND STRENGTHS ------------------
•
Heparin Sodium 20,000 USP units per 500 mL (40 USP units per
mL) in 5% Dextrose Injection (3)
•
Heparin Sodium 25,000 USP units per 500 mL (50 USP units per
mL) in 5% Dextrose Injection (3)
•
Heparin Sodium 25,000 USP units per 250 mL (100 USP units per
mL) in 5% Dextrose Injection (3)
------------------------ CONTRAINDICATIONS ---------------------------
•
History of Heparin-induced Thrombocytopenia (HIT) (With or
Without Thrombosis) (4)
•
Known hypersensitivity to heparin or pork products (4)
•
In whom suitable blood coagulation tests cannot be performed at
appropriate intervals (4)
---------------------- WARNINGS AND PRECAUTIONS --------------------
•
Fatal Medication Errors: Confirm choice of correct strength prior
to administration. (5.1)
•
Hemorrhage: Fatal cases have occurred. Use caution in
conditions with increased risk of hemorrhage. (5.2)
•
HIT (With or Without Thrombosis): Monitor for signs and
symptoms and discontinue if indicative of HIT (With or Without
Thrombosis). (5.3)
•
Monitoring: Blood coagulation tests guide therapy for full-dose
heparin. Monitor platelet count and hematocrit in all patients
receiving heparin. (5.5)
------------------------ ADVERSE REACTIONS -------------------------------
Most common adverse reactions are: hemorrhage,
thrombocytopenia, HIT (with or without thrombosis),
hypersensitivity reactions, and elevations of aminotransferase
levels. (6.1)
report SUSPECTED ADVERSE REACTIONS, contact B. Braun
dical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or
ww.fda.gov/medwatch.
--------------------------- DRUG INTERACTIONS --------------------------
Drugs that interfere with coagulation, platelet aggregation or
drugs that counteract coagulation may induce bleeding. (7)
e 17 for PATIENT COUNSELING INFORMATION
Revised: 05/2016
FULL PRESCRIBING INFORMATION: CONTENTS *
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
2.2 Laboratory Monitoring for Efficacy and Safety
2.3 Therapeutic Anticoagulant Effect with Full-Dose
Heparin
2.4 Pediatric Use
2.5 Cardiovascular Surgery
2.6 Converting to Warfarin
2.7 Converting to Oral Anticoagulants other than Warfarin
2.8 Extracorporeal Dialysis
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Fatal Medication Errors
5.2 Hemorrhage
5.3 Heparin-induced Thrombocytopenia (HIT) (With or
Without Thrombosis)
5.4 Thrombocytopenia
5.5 Coagulation Testing and Monitoring
5.6 Heparin Resistance
5.7 Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Oral Anticoagulants
7.2 Platelet Inhibitors
7.3 Other Interactions
7.4 Drug/Laboratory Tests Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Heparin sodium is indicated for:
•
Prophylaxis and treatment of venous thrombosis and pulmonary embolism;
•
Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation;
•
Treatment of acute and chronic consumption coagulopathies (disseminated intravascular
coagulation);
•
Prevention of clotting in arterial and cardiac surgery;
•
Prophylaxis and treatment of peripheral arterial embolism;
•
Anticoagulant use in blood transfusions, extracorporeal circulation, and dialysis procedures.
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
Confirm the selection of the correct formulation and strength prior to administration of the drug.
Do not use Heparin Sodium in 5% Dextrose Injection as a “catheter lock flush” product.
Do not admix with other drugs.
Do not use plastic containers in series connection.
This product should not be infused under pressure.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
2.2 Laboratory Monitoring for Efficacy and Safety
Adjust the dosage of heparin sodium according to the patient’s coagulation test results. W hen heparin is
given by continuous intravenous infusion, determine the coagulation time approximately every 4 hours in
the early stages of treatment. When the drug is administered intermittently by intravenous injection,
perform coagulation tests before each injection during the early stages of treatment and at appropriate
intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time
(APTT) is 1.5 to 2 times the normal or when the whole blood clotting time is elevated approximately 2.5 to
3 times the control value.
Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended during the
entire course of heparin therapy.
2.3 Therapeutic Anticoagulant Effect with Full-Dose Heparin
The dosing recommendations in Table 1 are based on clinical experience. Although dosage must be
adjusted for the individual patient according to the results of suitable laboratory tests, the following
dosage schedules may be used as guidelines:
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Table 1: Recommended Adult Full-Dose Heparin Regimens for Therapeutic Anticoagulant Effect
Method of
Administration
Frequency
Recommended Dose*
Intermittent Intravenous
Initial Dose
10,000 Units
Injection
Every 4 to 6 hours
5,000 – 10,000 Units
Continuous
Initial Dose
5,000 Units by IV injection
Intravenous Infusion
Continuous
20,000 – 40,000 Units/24 hours
* Based on 150 lb. (68 kg) patient.
2.4 Pediatric Use
There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing
recommendations are based on clinical experience. In general, the following dosage schedule may be
used as a guideline in pediatric patients:
Initial Dose
75 to 100 units/kg (IV bolus over 10 minutes)
Maintenance Dose
Infants: 25 to 30 units/kg/hour;
Infants < 2 months have the highest requirements (average 28 units/kg/hour)
Children > 1 year of age: 18 to 20 units/kg/hour;
Older children may require less heparin, similar to weight-adjusted adult dosage
Monitoring
Adjust heparin to maintain APTT of 60 to 85 seconds, assuming this reflects an
anti-Factor Xa level of 0.35 to 0.70.
2.5 Cardiovascular Surgery
Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less
than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per
kilogram is used for procedures estimated to last less than 60 minutes or 400 units per kilogram for those
estimated to last longer than 60 minutes.
2.6 Converting to Warfarin
To ensure continuous anticoagulation when converting from HEPARIN SODIUM to warfarin, continue full
heparin therapy for several days until the INR (prothrombin time) has reached a stable therapeutic range.
Heparin therapy may then be discontinued without tapering [see Drug Interactions (7.4)].
2.7 Converting to Oral Anticoagulants other than Warfarin
For patients currently receiving intravenous heparin, stop intravenous infusion of heparin sodium
immediately after administering the first dose of oral anticoagulant; or for intermittent intravenous
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administration of heparin sodium, start oral anticoagulant 0 to 2 hours before the time that the next dose
of heparin was to have been administered.
2.8 Extracorporeal Dialysis
Follow equipment manufacturer’s operating directions carefully. A dose of 25 to 30 units/kg followed by
an infusion rate of 1,500 to 2,000 units/hour is suggested based on pharmacodynamic data if specific
manufacturers’ recommendations are not available.
3 DOSAGE FORMS AND STRENGTHS
HEPARIN SODIUM IN 5% DEXTROSE INJECTION is available as:
• Heparin Sodium 20,000 USP units per 500 mL (40 USP units per mL) in 5% Dextrose Injection.
• Heparin Sodium 25,000 USP units per 500 mL (50 USP units per mL) in 5% Dextrose Injection.
• Heparin Sodium 25,000 USP units per 250 mL (100 USP units per mL) in 5% Dextrose Injection.
4 CONTRAINDICATIONS
The use of HEPARIN SODIUM is contraindicated in patients:
• With history of heparin-induced thrombocytopenia (HIT) (With or Without Thrombosis) [see Warnings
and Precautions (5.3)]
• With a known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse
Reactions (6.1)]
• In whom suitable blood coagulation tests — e.g., the whole blood clotting time, partial thromboplastin
time, etc., — cannot be performed at appropriate intervals (this contraindication refers to full-dose
heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose
heparin) [see Warnings and Precautions (5.5)]
5 WARNINGS AND PRECAUTIONS
5.1 Fatal Medication Errors
Do not use this product as a “catheter lock flush” product. Heparin is supplied in various strengths. Fatal
hemorrhages have occurred due to medication errors. Carefully examine all heparin products to confirm
the correct container choice prior to administration of the drug.
5.2 Hemorrhage
Hemorrhage, including fatal events, has occurred in patients receiving HEPARIN SODIUM. Avoid using
heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the
potential risks.
Hemorrhage can occur at virtually any site in patients receiving heparin. Adrenal hemorrhage (with
resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have
occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1)]. A higher incidence of
bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical
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Pharmacology (12.3)]. An unexplained fall in hematocrit or fall in blood pressure should lead to serious
consideration of a hemorrhagic event.
Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage,
including:
•
Cardiovascular — Subacute bacterial endocarditis. Severe hypertension.
•
Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery,
especially involving the brain, spinal cord or eye.
•
Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia,
thrombocytopenia and some vascular purpuras.
•
Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – The
anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in
patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, reduce the heparin
dose during concomitant treatment with antithrombin III (human).
•
Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine.
Other — Menstruation, liver disease with impaired hemostasis.
5.3 Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis)
HIT is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may
progress to the development of venous and arterial thromboses, a condition known as HIT with
thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious
thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis,
limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric
thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to
amputation, and possibly death. Monitor thrombocytopenia of any degree closely. If the platelet count falls
below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT,
and, if necessary, administer an alternative anticoagulant.
HIT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with
thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT.
5.4 Thrombocytopenia
Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of
up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Obtain
platelet counts before and periodically during heparin therapy. Monitor thrombocytopenia of any degree
closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue
heparin, evaluate for HIT, and, if necessary, administer an alternative anticoagulant [see Warnings and
Precautions (5.3)].
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5.5 Coagulation Testing and Monitoring
When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation
tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be
discontinued promptly [see Overdosage (10)]. Periodic platelet counts, hematocrits are recommended
during the entire course of heparin therapy [see Dosage and Administration (2.2)].
5.6 Heparin Resistance
Increased resistance to heparin is frequently encountered in fever, thrombosis, thrombophlebitis,
infections with thrombosing tendencies, myocardial infarction, cancer and in postsurgical patients, and
patients with antithrombin III deficiency. Close monitoring of coagulation tests is recommended in these
cases. Adjustment of heparin doses based on anti-Factor Xa levels may be warranted.
5.7 Hypersensitivity Reactions
Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-
threatening situations [see Adverse Reactions (6.1)].
Because Heparin Sodium in 5% Dextrose Injection is derived from animal tissue, monitor for signs and
symptoms of hypersensitivity when it is used in patients with a history of allergy.
This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible
people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably
low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling:
•
Fatal Medication Errors [see Warnings and Precautions (5.1)]
•
Hemorrhage [see Warnings and Precautions (5.2)]
•
Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) [see Warnings and
Precautions (5.3)]
•
Thrombocytopenia [see Warnings and Precautions (5.4)]
•
Heparin Resistance [see Warnings and Precautions (5.6)]
•
Hypersensitivity [see Warnings and Precautions (5.7)]
6.1 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of heparin sodium.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency.
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•
Hemorrhage - Hemorrhage is the chief complication that may result from heparin therapy [see
Warnings and Precautions (5.2)]. Gastrointestinal or urinary tract bleeding during anticoagulant
therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but
certain specific hemorrhagic complications may be difficult to detect:
-
Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin
therapy, including fatal cases. Ovarian (corpus luteum) hemorrhage developed in a number of
women of reproductive age receiving short- or long-term anticoagulant therapy.
-
Retroperitoneal hemorrhage.
•
Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and
Thrombocytopenia: [see Warnings and Precautions (5.3 and 5.4)]
•
Hypersensitivity - Generalized hypersensitivity reactions have been reported with chills, fever, and
urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and
vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning,
especially on the plantar site of the feet, may occur [see Warnings and Precautions (5.7)].
•
Elevations of serum aminotransferases –Significant elevations of aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received
heparin.
•
Others - Osteoporosis following long-term administration of high-doses of heparin, cutaneous
necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient
alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been
reported.
7 DRUG INTERACTIONS
7.1 Oral Anticoagulants
Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given
with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours
after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be
obtained.
7.2 Platelet Inhibitors
Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole,
hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic
defense of heparinized patients) may induce bleeding and should be used with caution in patients
receiving heparin sodium.
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7.3 Other Interactions
Digitalis, tetracyclines, nicotine, antihistamines, or IV nitroglycerine may partially counteract the
anticoagulant action of heparin sodium. Intravenous nitroglycerin administered to heparinized patients
may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon
discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of
heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin.
7.4 Drug/Laboratory Tests Interactions
Prothrombin time – Heparin sodium may prolong the one-stage prothrombin time. Therefore, when
heparin sodium is given with warfarin, allow a period of at least 5 hours after the last intravenous dose or
24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain a valid
prothrombin time.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of
adverse maternal or fetal outcomes in humans. No teratogenicity was observed in animal reproduction
studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses
up to 10,000 USP units/kg/day, approximately 10 times the maximum recommended human dose (MRHD)
of 40,000 USP units/24 hours infusion [see Data]. In pregnant animals, doses up to 10 times higher than
the maximum human daily dose based on body weight resulted in increased resorptions. Consider the
benefits and risks of HEPARIN SODIUM IN 5% DEXTROSE INJECTION to a pregnant woman and
possible risks to the fetus when prescribing HEPARIN SODIUM IN 5% DEXTROSE INJECTION.
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Human Data
The maternal and fetal outcomes associated with uses of heparin via various dosing methods
and administration routes during pregnancy have been investigated in numerous studies. These
studies generally reported normal deliveries with no maternal or fetal bleeding and no other
complications.
Animal Data
In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously
during organogenesis at a dose of 10,000 USP units/kg/day, approximately 10 times the maximum human
daily dose based on body weight. The number of early resorptions increased in both species. There was
no evidence of teratogenic effects.
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8.2 Lactation
Risk Summary
There is no information regarding the presence of HEPARIN SODIUM IN 5% DEXTROSE INJECTION in
human milk, the effects on the breastfed infant, or the effects on milk production. Due to its large
molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be
orally absorbed by a nursing infant. The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for HEPARIN SODIUM IN 5% DEXTROSE INJECTION
and any potential adverse effects on the breastfed infant from HEPARIN SODIUM IN 5% DEXTROSE
INJECTION or from the underlying maternal condition [see Use in Specific Populations (8.4)].
8.4 Pediatric Use
There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing
recommendations are based on clinical experience [see Dosage and Administration (2.4)].
8.5 Geriatric Use
There are limited adequate and well-controlled studies in patients 65 years and older. However, a higher
incidence of bleeding has been reported in patients over 60 years of age, especially women [see Warnings
and Precautions (5.2)]. Lower doses of heparin may be indicated in these patients [see Clinical
Pharmacology (12.3)].
10 OVERDOSAGE
Bleeding is the chief sign of heparin overdosage.
Neutralization of heparin effect:
When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution)
by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very
slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP Heparin
Units. The amount of protamine required decreases over time as heparin is metabolized. Although the
metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to
have a half-life of about 1/2 hour after intravenous injection.
Because fatal reactions often resembling anaphylaxis have been reported, protamine sulfate should be
given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.
For additional information, consult the prescribing information for Protamine Sulfate Injection, USP.
11 DESCRIPTION
Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called
glycosaminoglycans having anticoagulant properties. It is composed of polymers of alternating derivations
of alpha-L-iduronic acid 2-sulfate (1), 2-deoxy-2-sulfamino- alpha-D-glucose 6-sulfate (2), beta-D
glucuronic acid (3), 2-acetamido-2- deoxy-alpha-D-glucose (4), and alpha-L-iduronic acid (5).
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Structure of Heparin Sodium (representative subunits): structural formula
Heparin Sodium in 5% Dextrose Injection is a sterile, nonpyrogenic solution prepared from heparin
sodium (derived from porcine intestinal mucosa and standardized for use as an anticoagulant) and
Hydrous Dextrose USP in Water for Injection USP. It is to be administered by intravenous injection. The
potency is determined by a biological assay using a USP reference standard based on units of heparin
activity per milligram.
The pH range is 5.6 (4.5 – 7.0) and the osmolarity mOsmol/L (calc.) is 315. The concentration of
electrolytes is 38 mEq/L Sodium, 30 mEq/L Phosphate, and 15 mEq/L Citrate.
40 USP units/mL: Each 100 mL of the 20,000 USP units per 500 mL preparation contains: 4,000 USP
units of heparin sodium, 5 g Hydrous Dextrose USP, 0.41 g Dibasic Sodium Phosphate, 0.093 g Citric
Acid Anhydrous USP, 0.0686 g Sodium Metabisulfite NF (antioxidant), and Water for Injection USP until
quantity sufficient.
50 USP units/mL: Each 100 mL of the 25,000 USP units per 500 mL preparation contains: 5,000 USP
units of heparin sodium, 5 g Hydrous Dextrose USP, 0.41 g Dibasic Sodium Phosphate, 0.093 g Citric
Acid Anhydrous USP, 0.0686 g Sodium Metabisulfite NF (antioxidant), and Water for Injection USP until
quantity sufficient.
100 USP units/mL: Each 100 mL of the 25,000 USP units per 250 mL preparation contains: 10,000 USP
units of heparin sodium, 5 g Hydrous Dextrose USP, 0.41 g Dibasic Sodium Phosphate, 0.093 g Citric
Acid Anhydrous USP, 0.0686 g Sodium Metabisulfite NF (antioxidant), and Water for Injection USP until
quantity sufficient.
The plastic container is made from a multilayered film specifically developed for parenteral drugs. It
contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized
copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-
solution unit is a closed system and is not dependent upon entry of external air during administration.
The container is overwrapped to provide protection from the physical environment and to provide an
additional moisture barrier when necessary.
The plastic container is not made with natural rubber latex, PVC or DEHP.
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The closure system has two ports; the one for the administration set has a tamper evident plastic
protector.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and
in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in
combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor
X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger
amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion
of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation
of the fibrin stabilizing factor. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing
clots.
12.2 Pharmacodynamics
Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of
heparin; in most cases it is not measurably affected by low doses of heparin.
12.3 Pharmacokinetics
Plasma Concentrations
Peak plasma levels of heparin are achieved 2-4 hours following subcutaneous administration, although
there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time for
a wide range of dose levels are linear which suggests the absence of zero order processes. Liver and the
reticuloendothelial system are the sites of biotransformation. The biphasic elimination curve, a rapidly
declining alpha phase (t½ = 10 minutes) and after the age of 40 a slower beta phase, indicates uptake in
organs. The absence of a relationship between anticoagulant half-life and concentration half-life may
reflect factors such as protein binding of heparin.
Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of
heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years
of age.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals to evaluate the carcinogenic potential, reproduction studies in animals to
determine effects on fertility of males and females, and the studies to determine mutagenic potential have
not been conducted.
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16 HOW SUPPLIED/STORAGE AND HANDLING
Heparin Sodium in 5% Dextrose Injection is supplied sterile and nonpyrogenic in EXCEL®
Containers packaged 24 per case.
NDC
REF
Concentration
Size
0264-9567-10
P5671
Heparin Sodium
20,000 USP units per
500 mL (40 USP units
per mL) in 5%
Dextrose Injection
500 mL
0264-9577-10
P5771
Heparin Sodium
25,000 USP units per
500 mL (50 USP units
per mL) in 5%
Dextrose Injection
500 mL
0264-9587-20
P5872
Heparin Sodium
25,000 USP units per
250 mL (100 USP units
per mL) in 5%
Dextrose Injection
250 mL
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from
freezing. It is recommended that the product be stored at room temperature (25°C); however, brief
exposure up to 40°C does not adversely affect the product.
Storage in automated dispensing machines: Brief exposure up to 2 weeks to ultraviolet or fluorescent light
does not adversely affect the product labeling legibility; prolonged exposure can cause fading of the red
label. Rotate stock frequently.
17 PATIENT COUNSELING INFORMATION
Hemorrhage
Inform patients that it may take them longer than usual to stop bleeding, that they may bruise and/or
bleed more easily when they are treated with heparin, and that they should report any unusual bleeding
or bruising to their physician. Hemorrhage can occur at virtually any site in patients receiving heparin.
Fatal hemorrhages have occurred [see Warnings and Precautions (5.2)].
Prior to Surgery
Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is
scheduled [see Warnings and Precautions (5.2)].
Heparin-Induced Thrombocytopenia
Inform patients of the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the
development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia
and thrombosis (HITT). HIT (With or Without Thrombosis) can occur up to several weeks after the
discontinuation of heparin therapy [see Warnings and Precautions (5.3 and 5.4)].
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Hypersensitivity
Inform patients that generalized hypersensitivity reactions have been reported. Necrosis of the skin has
been reported at the site of subcutaneous injection of heparin [see Warnings and Precautions (5.7),
Adverse Reactions (6)].
Other Medications
Because of the risk of hemorrhage, advise patients to inform their physicians and dentists of all
medications they are taking, including non-prescription medications, and before starting any new
medication [see Drug Interactions (7.2)].
EXCEL is a registered trademark of B. Braun Medical Inc.
B. Braun Medical Inc.
Bethlehem, PA 18018-3524 USA
1-800-227-2862
Y36-002-900
LD-239-6
Reference ID: 3937270
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|
custom-source
|
2025-02-12T13:46:23.336113
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019952s033lbl.pdf', 'application_number': 19952, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
12,093
|
RETROVIR® (zidovudine) IV Infusion
1
PRODUCT INFORMATION
1
2
RETROVIR®
3
(zidovudine)
4
IV Infusion
5
FOR INTRAVENOUS INFUSION ONLY
6
7
WARNING: RETROVIR (ZIDOVUDINE) MAY BE ASSOCIATED WITH HEMATOLOGIC TOXICITY
8
INCLUDING NEUTROPENIA AND SEVERE ANEMIA PARTICULARLY IN PATIENTS WITH
9
ADVANCED HIV DISEASE (SEE WARNINGS). PROLONGED USE OF RETROVIR HAS BEEN
10
ASSOCIATED WITH SYMPTOMATIC MYOPATHY SIMILAR TO THAT PRODUCED BY HUMAN
11
IMMUNODEFICIENCY VIRUS.
12
RARE OCCURRENCES OF POTENTIALLY FATAL LACTIC ACIDOSIS IN THE ABSENCE OF
13
HYPOXEMIA, AND SEVERE HEPATOMEGALY WITH STEATOSIS HAVE BEEN REPORTED
14
WITH THE USE OF CERTAIN ANTIRETROVIRAL NUCLEOSIDE ANALOGUES (SEE
15
WARNINGS).
16
17
DESCRIPTION: RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]),
18
a pyrimidine nucleoside analogue active against human immunodeficiency virus (HIV). RETROVIR IV
19
Infusion is a sterile solution for intravenous infusion only. Each mL contains 10 mg zidovudine in
20
Water for Injection. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the
21
pH to approximately 5.5. RETROVIR IV Infusion contains no preservatives.
22
The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural
23
formula:
24
25
26
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
2
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a
28
solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
29
30
MICROBIOLOGY: Mechanism of Action: Zidovudine is a synthetic nucleoside analogue of the
31
naturally occurring nucleoside, thymidine, in which the 3′-hydroxy (-OH) group is replaced by an azido
32
(-N3) group. Within cells, zidovudine is converted to the active metabolite, zidovudine 5′-triphosphate
33
(AztTP), by the sequential action of the cellular enzymes. Zidovudine 5′-triphosphate inhibits the
34
activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate,
35
deoxythymidine 5′-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3′- OH
36
group in the incorporated nucleoside analogue prevents the formation of the 5′ to 3′ phosphodiester
37
linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The
38
active metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and
39
mitochondrial polymerase-gamma and has been reported to be incorporated into the DNA of cells in
40
culture.
41
In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zidovudine was assessed by infecting cell
42
lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and
43
clinical isolates of HIV. The IC50 and IC90 values (50% and 90% inhibitory concentrations) were 0.003
44
to 0.013 and 0.03 to 0.13 mcg/mL, respectively (1 nM = 0.27 ng/mL). The IC50 and IC90 values of HIV
45
isolates recovered from 18 untreated AIDS/ARC patients were in the range of 0.003 to 0.013 mcg/mL
46
and 0.03 to 0.3 mcg/mL, respectively. Zidovudine showed antiviral activity in all acutely infected cell
47
lines; however, activity was substantially less in chronically infected cell lines. In drug combination
48
studies with zalcitabine, didanosine, lamivudine, saquinavir, indinavir, ritonavir, nevirapine,
49
delavirdine, or interferon-alpha, zidovudine showed additive to synergistic activity in cell culture. The
50
relationship between the in vitro susceptibility of HIV to reverse transcriptase inhibitors and the
51
inhibition of HIV replication in humans has not been established.
52
Drug Resistance: HIV isolates with reduced sensitivity to zidovudine have been selected in vitro and
53
were also recovered from patients treated with RETROVIR. Genetic analysis of the isolates showed
54
mutations which result in five amino acid substitutions (Met41→Leu, A67→Asn, Lys70→Arg,
55
Thr215→Tyr or Phe, and Lys219→Gln) in the viral reverse transcriptase. In general, higher levels of
56
resistance were associated with greater number of mutations with 215 mutation being the most
57
significant.
58
Cross-Resistance: The potential for cross-resistance between HIV reverse transcriptase inhibitors
59
and protease inhibitors is low because of the different enzyme targets involved. Combination therapy
60
with zidovudine plus zalcitabine or didanosine does not appear to prevent the emergence of
61
zidovudine-resistant isolates. Combination therapy with RETROVIR plus EPIVIR delayed the
62
emergence of mutations conferring resistance to zidovudine. In some patients harboring zidovudine-
63
resistant virus, combination therapy with RETROVIR plus EPIVIR restored phenotypic sensitivity to
64
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For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
3
zidovudine by 12 weeks of treatment. HIV isolates with multidrug resistance to zidovudine,
65
didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number of patients
66
treated for ≥1 year with the combination of zidovudine and didanosine or zalcitabine. The pattern of
67
resistant mutations in the combination therapy was different (Ala62→Val, Val75→Ile,
68
Phe77→116Tyr, and Gln→151Met) from monotherapy, with mutation 151 being most significant for
69
multidrug resistance. Site-directed mutagenesis studies showed that these mutations could also
70
result in resistance to zalcitabine, lamivudine, and stavudine.
71
72
CLINICAL PHARMACOLOGY:
73
Pharmacokinetics: Adults: The pharmacokinetics of zidovudine has been evaluated in 22 adult
74
HIV-infected patients in a Phase 1 dose-escalation study. Following intravenous dosing,
75
dose-independent kinetics was observed over the range of 1 to 5 mg/kg with a mean zidovudine
76
half-life of 1.1 hours (range 0.48 to 2.86 hours). Total body clearance averaged 1900 mL/min per
77
70 kg, and the apparent volume of distribution was 1.6 L/kg. At a dose of 7.5 mg/kg every 4 hours,
78
total body clearance was calculated to be about 1200 mL/min per 70 kg, with no change in half-life.
79
Renal clearance is estimated to be 400 mL/min per 70 kg, indicating glomerular filtration and active
80
tubular secretion by the kidneys. Zidovudine plasma protein binding is 34% to 38%, indicating that
81
drug interactions involving binding site displacement are not anticipated.
82
The mean steady-state peak and trough concentrations of zidovudine at 2.5 mg/kg every 4 hours
83
were 1.06 and 0.12 mcg/mL, respectively.
84
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in
85
39 patients receiving chronic therapy with RETROVIR. The median ratio measured in 50 paired
86
samples drawn 1 to 8 hours after the last dose of RETROVIR was 0.6.
87
Zidovudine is rapidly metabolized to GZDV which has an apparent elimination half-life of 1 hour
88
(range 0.61 to 1.73 hours). A second metabolite, 3′-amino-3′-deoxythymidine (AMT), has been
89
identified in the plasma following single-dose intravenous administration of zidovudine. AMT
90
area-under-the-curve (AUC) was one fifth of the AUC of zidovudine and had a half-life of
91
2.7 ± 0.7 hours. In comparison, GZDV AUC was about threefold greater than the AUC of zidovudine.
92
Following intravenous administration, urinary recoveries of zidovudine and GZDV accounted for 18%
93
and 60% of the dose, respectively, and the total urinary recovery averaged 77% (range 64% to 98%).
94
Adults with Impaired Renal Function: The pharmacokinetics of zidovudine has been evaluated
95
in patients with impaired renal function following a single 200-mg oral dose. In 14 patients (mean
96
creatinine clearance 18 ± 2 mL/min) the half-life of zidovudine was 1.4 hours compared to 1.0 hour
97
for control subjects with normal renal function; AUC values were approximately twice those of
98
controls. Additionally, GZDV half-life in these patients was 8.0 hours (versus 0.9 hours for control)
99
and AUC was 17 times higher than for control subjects. The pharmacokinetics and tolerance were
100
evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis
101
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RETROVIR® (zidovudine) IV Infusion
4
(n = 6). Patients received escalating oral doses of zidovudine up to 200 mg five times daily for
102
8 weeks. Daily oral doses of 500 mg or less were well tolerated despite significantly elevated plasma
103
levels of GZDV. Apparent oral clearance of zidovudine was approximately 50% of that reported in
104
patients with normal renal function. The plasma concentrations of AMT are not known in patients with
105
renal insufficiency. Daily doses of 300 to 400 mg should be appropriate in HIV-infected patients with
106
severe renal dysfunction (see DOSAGE AND ADMINISTRATION: Dose Adjustment). Hemodialysis
107
and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, whereas
108
GZDV elimination is enhanced.
109
Pediatrics: The pharmacokinetics and bioavailability of zidovudine have been evaluated in
110
21 HIV-infected pediatric patients, aged 6 months through 12 years, following intravenous doses
111
administered over the range of 80 to 160 mg/m2 every 6 hours, and following oral doses of the
112
intravenous solution administered over the range of 90 to 240 mg/m2 every 6 hours. After
113
discontinuation of the IV infusion, zidovudine plasma concentrations decayed biexponentially,
114
consistent with two-compartment pharmacokinetics. Proportional increases in AUC and in zidovudine
115
concentrations were observed with increasing dose, consistent with dose-independent kinetics over
116
the dose range studied. The mean terminal half-life and total body clearance across all dose levels
117
administered were 1.5 hours and 30.9 mL/min per kg, respectively. These values compare to mean
118
half-life and total body clearance in adults of 1.1 hours and 27.1 mL/min per kg.
119
The pharmacokinetics of zidovudine has been studied in pediatric patients from birth to 3 months
120
of life. In one study of the pharmacokinetics of zidovudine in women during the last trimester of
121
pregnancy, zidovudine elimination was determined immediately after birth in eight neonates who were
122
exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In another study, the
123
pharmacokinetics of zidovudine was evaluated in pediatric patients (ranging in age of 1 day to
124
3 months) of normal birth weight for gestational age and with normal renal and hepatic function. In
125
neonates less than or equal to 14 days old, mean ± SD total body clearance was 10.9 ± 4.8 mL/min
126
per kg (n = 18) and half-life was 3.1 ± 1.2 hours (n = 21). In neonates and infants greater than
127
14 days old, total body clearance was 19.0 ± 4.0 mL/min per kg (n = 16) and half-life was
128
1.9 ± 0.7 hours (n = 18).
129
Concentrations of zidovudine in cerebrospinal fluid were measured after both intermittent oral and
130
IV drug administration in 21 pediatric patients during Phase 1 and Phase 2 studies. The mean
131
zidovudine CSF/plasma concentration ratio measured at an average time of 2.2 hours postdose at
132
oral doses of 120 to 240 mg/m2 was 0.52 ± 0.44 (n = 28); after an IV infusion of doses of 80 to
133
160 mg/m2 over 1 hour, the mean CSF/plasma concentration ratio was 0.87 ± 0.66 (n = 23) at
134
3.2 hours after the start of the infusion. During continuous IV infusion, mean steady-state
135
CSF/plasma ratio was 0.26 ± 0.17 (n = 28).
136
As in adult patients, the major route of elimination in pediatric patients was by metabolism to
137
GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged and about 45%
138
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RETROVIR® (zidovudine) IV Infusion
5
of the dose was excreted as GZDV. Overall, the pharmacokinetics of zidovudine in pediatric patients
139
greater than 3 months of age is similar to that of zidovudine in adult patients.
140
Pregnancy: The pharmacokinetics of zidovudine has been studied in a Phase 1 study of eight
141
women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of
142
drug accumulation. The pharmacokinetics of zidovudine was similar to that of nonpregnant adults.
143
Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in
144
infant plasma at birth were essentially equal to those in maternal plasma at delivery. Although data
145
are limited, methadone maintenance therapy in five pregnant women did not appear to alter
146
zidovudine pharmacokinetics. However, in another patient population, a potential for interaction has
147
been identified (see PRECAUTIONS).
148
Nursing Mothers: The US Public Health Service Centers for Disease Control and Prevention
149
advises HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who
150
may not yet be infected. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected
151
women, the mean concentration of zidovudine was similar in human milk and serum (see
152
PRECAUTIONS: Nursing Mothers).
153
154
INDICATIONS AND USAGE: RETROVIR IV Infusion is indicated for the treatment of HIV infection
155
when antiretroviral therapy is warranted (see Description of Clinical Studies).
156
The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in
157
antiretroviral therapy should be considered if disease progression occurs during treatment.
158
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of maternal-fetal
159
HIV transmission as part of a regimen that includes oral RETROVIR beginning between 14 and
160
34 weeks of gestation, intravenous RETROVIR during labor, and administration of RETROVIR Syrup
161
to the neonate after birth. The efficacy of this regimen for preventing HIV transmission in women who
162
have received RETROVIR for a prolonged period before pregnancy has not been evaluated. The
163
safety of RETROVIR for the mother or fetus during the first trimester of pregnancy has not been
164
assessed (see Description of Clinical Studies).
165
Description of Clinical Studies: RETROVIR has been shown to prolong survival and decrease the
166
incidence of opportunistic infections in patients with advanced HIV disease at the initiation of therapy
167
and to delay disease progression in asymptomatic HIV-infected patients.
168
Other randomized studies suggest that the duration of the clinical benefit of monotherapy with
169
RETROVIR is time-limited.
170
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
171
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled
172
trial (ACTG 076) conducted in HIV-infected pregnant women with CD4 cell counts of 200 to 1818
173
cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to
174
RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks
175
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RETROVIR® (zidovudine) IV Infusion
6
of therapy) followed by intravenous administration of RETROVIR during labor and delivery. After
176
birth, neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
177
significant difference in the incidence of HIV infection in the neonates (based on viral culture from
178
peripheral blood) between the group receiving RETROVIR and the group receiving placebo. Of
179
363 neonates evaluated in the study, the estimated risk of HIV infection was 7.8% in the group
180
receiving RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of
181
68.7%. RETROVIR was well tolerated by mothers and infants. There was no difference in
182
pregnancy-related adverse events between the treatment groups.
183
184
CONTRAINDICATIONS: RETROVIR IV Infusion is contraindicated for patients who have potentially
185
life-threatening allergic reactions to any of the components of the formulation.
186
187
WARNINGS: The incidence of adverse reactions appears to increase with disease progression, and
188
patients should be monitored carefully, especially as disease progression occurs.
189
Bone Marrow Suppression: RETROVIR should be used with caution in patients who have bone
190
marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL. In
191
patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant
192
adverse events observed (see ADVERSE REACTIONS). There have been reports of pancytopenia
193
associated with the use of RETROVIR, which was reversible in most instances after discontinuance
194
of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation
195
of RETROVIR, and/or blood transfusions has occurred during treatment with RETROVIR alone or in
196
combination with other antiretrovirals.
197
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are
198
treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV
199
disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage
200
adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
201
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
202
disease, have been associated with prolonged use of RETROVIR.
203
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Rare occurrences of potentially fatal lactic
204
acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported
205
with the use of certain antiretroviral nucleoside analogues. Lactic acidosis should be considered
206
whenever a patient receiving therapy with RETROVIR develops unexplained tachypnea, dyspnea, or
207
fall in serum bicarbonate level. Under these circumstances, therapy with RETROVIR should be
208
suspended until the diagnosis of lactic acidosis has been excluded. Caution should be exercised
209
when administering RETROVIR to any patient, particularly obese women, with hepatomegaly,
210
hepatitis, or other known risk factor for liver disease. These patients should be followed closely while
211
on therapy with RETROVIR. The significance of elevated aminotransferase levels suggesting hepatic
212
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
7
injury in HIV-infected patients prior to starting RETROVIR or while on RETROVIR is unclear.
213
Treatment with RETROVIR should be suspended in the setting of rapidly elevating aminotransferase
214
levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown etiology.
215
Other Serious Adverse Reactions: Several serious adverse events have been reported with use of
216
RETROVIR in clinical practice. Reports of pancreatitis, sensitization reactions (including anaphylaxis
217
in one patient), vasculitis, and seizures have been rare. These adverse events, except for
218
sensitization, have also been associated with HIV disease. Changes in skin and nail pigmentation
219
have been associated with the use of RETROVIR.
220
221
PRECAUTIONS:
222
General: Zidovudine is eliminated from the body primarily by renal excretion following metabolism in
223
the liver (glucuronidation). In patients with severely impaired renal function, dosage reduction is
224
recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND
225
ADMINISTRATION). Although very little data are available, patients with severely impaired hepatic
226
function may be at greater risk of toxicity.
227
Information for Patients: RETROVIR is not a cure for HIV infection, and patients may continue to
228
acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients
229
should be advised to seek medical care for any significant change in their health status.
230
The safety and efficacy of RETROVIR in treating women, intravenous drug users, and racial
231
minorities is not significantly different than that observed in white males.
232
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or
233
anemia. The frequency and severity of these toxicities are greater in patients with more advanced
234
disease and in those who initiate therapy later in the course of their infection. They should be told that
235
if toxicity develops, they may require transfusions or dose modifications including possible
236
discontinuation. They should be told of the extreme importance of having their blood counts followed
237
closely while on therapy, especially for patients with advanced symptomatic HIV disease. They
238
should be cautioned about the use of other medications, including ganciclovir and interferon-alpha,
239
that may exacerbate the toxicity of RETROVIR (see PRECAUTIONS: Drug Interactions). Patients
240
should be informed that other adverse effects of RETROVIR include nausea and vomiting. Patients
241
should also be encouraged to contact their physician if they experience muscle weakness, shortness
242
of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being
243
treated with RETROVIR.
244
Pregnant women considering the use of RETROVIR during pregnancy for prevention of
245
HIV-transmission to their infants should be advised that transmission may still occur in some cases
246
despite therapy. The long-term consequences of in utero and neonatal exposure to RETROVIR are
247
unknown, including the possible risk of cancer.
248
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
8
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission
249
of HIV to a child who may not yet be infected.
250
Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of
251
transmission of HIV to others through sexual contact or blood contamination.
252
Drug Interactions: Ganciclovir: Use of RETROVIR in combination with ganciclovir increases the
253
risk of hematologic toxicities in some patients with advanced HIV disease. Should the use of this
254
combination become necessary in the treatment of patients with HIV disease, dose reduction or
255
interruption of one or both agents may be necessary to minimize hematologic toxicity. Hematologic
256
parameters, including hemoglobin, hematocrit, and white blood cell count with differential, should be
257
monitored frequently in all patients receiving this combination.
258
Interferon-alpha: Hematologic toxicities have also been seen when RETROVIR is used
259
concomitantly with interferon-alpha. As with the concomitant use of RETROVIR and ganciclovir, dose
260
reduction or interruption of one or both agents may be necessary, and hematologic parameters
261
should be monitored frequently.
262
Bone Marrow Suppressive Agents/Cytotoxic Agents: Coadministration of RETROVIR with
263
drugs that are cytotoxic or which interfere with RBC/WBC number or function (e.g., dapsone,
264
flucytosine, vincristine, vinblastine, or adriamycin) may increase the risk of hematologic toxicity.
265
Probenecid: Limited data suggest that probenecid may increase zidovudine levels by inhibiting
266
glucuronidation and/or by reducing renal excretion of zidovudine. Some patients who have used
267
RETROVIR concomitantly with probenecid have developed flu-like symptoms consisting of myalgia,
268
malaise, and/or fever and maculopapular rash.
269
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
270
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
271
interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone
272
and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin
273
kinetics was observed. Although not designed to optimally assess the effect of phenytoin on
274
zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
275
Methadone: In a pharmacokinetic study of nine HIV-positive patients receiving
276
methadone-maintenance (30 to 90 mg daily) concurrent with 200 mg of RETROVIR every 4 hours,
277
no changes were observed in the pharmacokinetics of methadone upon initiation of therapy with
278
RETROVIR and after 14 days of treatment with RETROVIR. No adjustments in
279
methadone-maintenance requirements were reported. For four patients, the mean zidovudine AUC
280
was elevated twofold, while for five patients, the value was equal to that of control patients. The exact
281
mechanism and clinical significance of these data are unknown.
282
Fluconazole: The coadministration of fluconazole with RETROVIR has been reported to interfere
283
with the oral clearance and metabolism of RETROVIR. In a pharmacokinetic interaction study in
284
which 12 HIV-positive men received RETROVIR 200 mg every 8 hours alone and in combination with
285
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
9
fluconazole 400 mg daily, fluconazole increased the zidovudine AUC (74%; range 28% to 173%) and
286
the zidovudine half-life (128%; range -4% to 189%) at steady state. The clinical significance of this
287
interaction is unknown.
288
Atovaquone: Data from 14 HIV-infected volunteers who were given atovaquone tablets 750 mg
289
every 12 hours with zidovudine 200 mg every 8 hours showed a 24% ± 12% decrease in zidovudine
290
oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide
291
metabolite:parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1
292
when zidovudine was administered with atovaquone tablets. Zidovudine had no effect on atovaquone
293
pharmacokinetics.
294
Valproic Acid: The concomitant administration of valproic acid 250 mg (n = 5) or 500 mg (n = 1)
295
every 8 hours and zidovudine 100 mg orally every 8 hours for 4 days to six HIV-infected,
296
asymptomatic male volunteers resulted in a 79% ± 61% (mean ± SD) increase in the plasma
297
zidovudine AUC and a 22% ± 10% decrease in the plasma GZDV AUC as compared to the
298
administration of zidovudine in the absence of valproic acid. The GZDV/zidovudine urinary excretion
299
ratio decreased 58% ± 12%. Because no change in the zidovudine plasma half-life occurred, these
300
results suggest that valproic acid may increase the oral bioavailability of zidovudine through inhibition
301
of first-pass metabolism. Although the clinical significance of this interaction is unknown, patients
302
should be monitored more closely for a possible increase in zidovudine-related adverse effects. The
303
effect of zidovudine on the pharmacokinetics of valproic acid was not evaluated.
304
Lamivudine: RETROVIR and lamivudine were coadministered to 12 asymptomatic HIV-positive
305
patients in a single-center, open-label, randomized, crossover study. No significant differences were
306
observed in AUC∞ or total clearance for lamivudine or zidovudine when the two drugs were
307
administered together. Coadministration of RETROVIR with lamivudine resulted in an increase of
308
39% ± 62% (mean ± SD) in Cmax of zidovudine.
309
Other Agents: Preliminary data from a drug interaction study (n = 10) suggest that
310
coadministration of 200 mg RETROVIR and 600 mg rifampin decreases the area under the plasma
311
concentration curve by an average of 48% ± 34%. However, the effect of once daily dosing of
312
rifampin on multiple daily doses of RETROVIR is unknown. Some nucleoside analogues affecting
313
DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of RETROVIR against HIV;
314
concomitant use of such drugs should be avoided.
315
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered orally at
316
three dosage levels to separate groups of mice and rats (60 females and 60 males in each group).
317
Initial single daily doses were 30, 60, and 120 mg/kg per day in mice and 80, 220, and 600 mg/kg per
318
day in rats. The doses in mice were reduced to 20, 30, and 40 mg/kg per day after day 90 because of
319
treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg per day on
320
day 91, and then to 300 mg/kg per day on day 279.
321
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
10
In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing
322
squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred in
323
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina
324
of a middle-dose animal. No vaginal tumors were found at the lowest dose.
325
In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
326
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in
327
rats. No other drug-related tumors were observed in either sex of either species.
328
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by
329
AUC) was approximately three times (mouse) and 24 times (rat) the estimated human exposure at
330
the recommended therapeutic dose of 100 mg every 4 hours.
331
Two transplacental carcinogenicity studies were conducted in mice. One study administered
332
zidovudine at doses of 20 mg/kg per day or 40 mg/kg per day from gestation day 10 through
333
parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of
334
zidovudine employed in this study produced zidovudine exposures approximately three times the
335
estimated human exposure at recommended doses. After 24 months, an increase in incidence of
336
vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either
337
gender. These findings are consistent with results of the standard oral carcinogenicity study in mice,
338
as described earlier. A second study administered zidovudine at maximum tolerated doses of
339
12.5 mg/day or 25 mg/day (∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body
340
weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number
341
of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher
342
dose level of zidovudine. It is not known how predictive the results of rodent carcinogenicity studies
343
may be for humans.
344
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
345
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and
346
positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic
347
study in rats given a single dose.
348
Zidovudine, administered to male and female rats at doses up to seven times the usual adult dose
349
based on body surface area considerations, had no effect on fertility judged by conception rates.
350
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to
351
500 mg/kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment
352
resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in
353
rats given 150 or 450 mg/kg per day and rabbits given 500 mg/kg per day. The doses used in the
354
teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose)
355
in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma
356
concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg
357
every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
358
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For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
11
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose
359
of 3000 mg/kg per day (very near the oral median lethal dose in rats of 3683 mg/kg) caused marked
360
maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak
361
zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated
362
area-under-the-curve [AUC] in rats at this dose level was 300 times the daily AUC in humans given
363
600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg
364
per day or less.
365
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
366
Mutagenesis, Impairment of Fertility).
367
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
368
women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-transmission
369
(see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities occurred
370
with similar frequency between neonates born to mothers who received RETROVIR and neonates
371
born to mothers who received placebo. Abnormalities were either problems in embryogenesis (prior
372
to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
373
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
374
exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are
375
encouraged to register patients by calling 1-800-258-4263.
376
Nursing Mothers: The US Public Health Service Centers for Disease Control and Prevention
377
advises HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who
378
may not yet be infected.
379
Zidovudine is excreted in human milk (see Pharmacokinetics).
380
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age
381
who have HIV-related symptoms or who are asymptomatic with abnormal laboratory values indicating
382
significant HIV-related immunosuppression (see ADVERSE REACTIONS, DOSAGE AND
383
ADMINISTRATION, and INDICATIONS AND USAGE: Description of Clinical Studies, and
384
Pharmacokinetics).
385
Geriatric Use: Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
386
and over to determine whether they respond differently from younger subjects. Other reported clinical
387
experience has not identified differences in responses between the elderly and younger patients. In
388
general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of
389
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
390
391
ADVERSE REACTIONS: The adverse events reported during intravenous administration of
392
RETROVIR IV Infusion are similar to those reported with oral administration; neutropenia and anemia
393
were reported most frequently. Long-term intravenous administration beyond 2 to 4 weeks has not
394
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
12
been studied in adults and may enhance hematologic adverse events. Local reaction, pain, and slight
395
irritation during intravenous administration occur infrequently.
396
Adults: The frequency and severity of adverse events associated with the use of oral RETROVIR in
397
adults are greater in patients with more advanced infection at the time of initiation of therapy. Table 1
398
summarizes the relative incidence of hematologic adverse events observed in clinical studies by
399
severity of HIV disease present at the start of treatment with oral RETROVIR:
400
401
Table 1
402
403
Stage of
Disease
RETROVIR
Daily Dose*
(mg)
Neutropenia
(<750 cells/mm3)
Anemia
(Hgb <8.0 g/dL)
Asymptomatic
ACTG 019
500
1.8%†
1.1%†
Early HIV Disease
(CD4 >200 cells/mm3)
ACTG 016
1200
4%
4%
Advanced HIV Disease
(CD4 >200 cells/mm3)
BW 02
(CD4 ≤200 cells/mm3)
ACTG 002
BW 02
1500
600
1500
10%†
37%
47%
3%†‡
29%
29%‡
* The currently recommended oral dose is 500 to 600 mg daily.
404
† Not statistically significant compared to placebo.
405
‡ Anemia = Hgb <7.5 g/dL.
406
407
The anemia reported in patients with advanced HIV disease receiving RETROVIR appeared to be
408
the result of impaired erythrocyte maturation as evidenced by macrocytosis while on drug. Although
409
mean platelet counts in patients receiving RETROVIR were significantly increased compared to
410
mean baseline values, thrombocytopenia did occur in some of these patients with advanced disease.
411
Twelve percent of patients receiving RETROVIR compared to 5% of patients receiving placebo had
412
>50% decreases from baseline platelet count. Mild drug-associated elevations in total bilirubin levels
413
have been reported as an uncommon occurrence in patients treated for asymptomatic HIV infection.
414
The HIV-infected adults participating in these clinical trials often had baseline symptoms and signs
415
of HIV disease and/or experienced adverse events at some time during study. It was often difficult to
416
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
13
distinguish adverse events possibly associated with administration of RETROVIR from underlying
417
signs of HIV disease or intercurrent illnesses. Table 2 summarizes clinical adverse events or
418
symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with
419
1500 mg/day of oral RETROVIR in the original placebo-controlled study. Of the items listed in the
420
table, only severe headache, nausea, insomnia, and myalgia were reported at a significantly greater
421
rate in patients receiving RETROVIR.
422
423
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
14
Table 2: Percentage (%) of Patients with Adverse Events
424
in Advanced HIV Disease (BW 02)
425
426
Adverse Event
RETROVIR
1500 mg/day*
(n = 144) %
Placebo
(n = 137) %
BODY AS A WHOLE
Asthenia
Diaphoresis
Fever
Headache
Malaise
19
5
16
42
8
18
4
12
37
7
GASTROINTESTINAL
Anorexia
Diarrhea
Dyspepsia
GI Pain
Nausea
Vomiting
11
12
5
20
46
6
8
18
4
19
18
3
MUSCULOSKELETAL
Myalgia
8
2
NERVOUS
Dizziness
Insomnia
Paresthesia
Somnolence
6
5
6
8
4
1
3
9
RESPIRATORY
Dyspnea
5
3
SKIN
Rash
17
15
SPECIAL SENSES
Taste Perversion
5
8
* The currently recommended oral dose is 500 to 600 mg daily.
427
428
All events of a severe or life-threatening nature were monitored for adults in the placebo-controlled
429
studies in early HIV disease and asymptomatic HIV infection. Data concerning the occurrence of
430
additional signs or symptoms were also collected. No distinction was made in reporting events
431
between those possibly associated with the administration of the study medication and those due to
432
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
15
the underlying disease. Tables 3 and 4 summarize all those events reported at a statistically
433
significant greater incidence for patients receiving RETROVIR in these studies:
434
435
Table 3: Percentage (%) of Patients with Adverse Events
436
in Early HIV Disease (ACTG 016)
437
438
Adverse Event
RETROVIR
1200 mg/day*
(n = 361) %
Placebo
(n = 352) %
BODY AS A WHOLE
Asthenia
69
62
GASTROINTESTINAL
Dyspepsia
Nausea
Vomiting
6
61
25
1
41
13
* The currently recommended oral dose is 500 to 600 mg daily.
439
440
Table 4: Percentage (%) of Patients with Adverse Events*
441
in Asymptomatic HIV Infection (ACTG 019)
442
443
Adverse Event
RETROVIR
500 mg/day
(n = 453) %
Placebo
(n = 428) %
BODY AS A WHOLE
Asthenia
Headache
Malaise
8.6†
62.5
53.2
5.8
52.6
44.9
GASTROINTESTINAL
Anorexia
Constipation
Nausea
Vomiting
20.1
6.4†
51.4
17.2
10.5
3.5
29.9
9.8
NERVOUS
Dizziness
17.9†
15.2
* Reported in ≥5% of study population.
444
† Not statistically significant versus placebo.
445
446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
16
Several serious adverse events have been reported with the use of RETROVIR in clinical practice.
447
Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have
448
been associated with prolonged use of RETROVIR. Reports of hepatomegaly with steatosis,
449
hepatitis, pancreatitis, lactic acidosis, sensitization reactions (including anaphylaxis in one patient),
450
hyperbilirubinemia, vasculitis, and seizures have been rare. These adverse events, except for
451
sensitization, have also been associated with HIV disease. A single case of macular edema has been
452
reported with the use of RETROVIR.
453
Additional adverse events reported in clinical trials at a rate not significantly different from placebo
454
are listed below. Selected events from post-marketing clinical experience with RETROVIR are also
455
included. Many of these events may also occur as part of HIV disease. The clinical significance of the
456
association between treatment with RETROVIR and these events is unknown.
457
Body as a Whole: Abdominal pain, back pain, body odor, chest pain, chills, edema of the lip,
458
fever, flu syndrome, hyperalgesia.
459
Cardiovascular: Syncope, vasodilation.
460
Gastrointestinal: Bleeding gums, constipation, diarrhea, dysphagia, edema of the tongue,
461
eructation, flatulence, mouth ulcer, rectal hemorrhage.
462
Hemic and Lymphatic: Lymphadenopathy.
463
Musculoskeletal: Arthralgia, muscle spasm, tremor, twitch.
464
Nervous: Anxiety, confusion, depression, dizziness, emotional lability, loss of mental acuity,
465
nervousness, paresthesia, somnolence, vertigo.
466
Respiratory: Cough, dyspnea, epistaxis, hoarseness, pharyngitis, rhinitis, sinusitis.
467
Skin: Acne, changes in skin and nail pigmentation, pruritus, rash, sweat, urticaria.
468
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
469
Urogenital: Dysuria, polyuria, urinary frequency, urinary hesitancy.
470
Pediatrics: Anemia and neutropenia among pediatric patients with advanced HIV disease receiving
471
RETROVIR occurred with similar incidence to that reported for adults with AIDS or advanced ARC
472
(see above). Management of neutropenia and anemia included, in some cases, dose modification
473
and/or blood product transfusions. In the open-label studies, 17% had their dose modified (generally
474
a reduction in dose by 30%) due to anemia and 25% had their dose modified (temporary
475
discontinuation or dose reduction by 30%) for neutropenia. Four pediatric patients had RETROVIR
476
permanently discontinued for neutropenia. Table 5 summarizes the occurrence of anemia (Hgb
477
<7.5 g/dL) and neutropenia (<750 cells/mm3) among 124 pediatric patients receiving oral RETROVIR
478
for a mean of 267 days (range 3 to 855 days):
479
480
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
17
Table 5
481
482
Advanced
Pediatric
Neutropenia
(<750 cells/mm3)
Anemia
(Hgb <7.5 g/dL)
HIV Disease
n
%
n
%
(n = 124)
48
39
28*
23
* Twenty-two pediatric patients received one or more transfusions due to a decline in hemoglobin to
483
<7.5 g/dL; an additional 15 pediatric patients were transfused for hemoglobin levels >7.5 g/dL.
484
Fifty-nine percent of the patients transfused had a prestudy history of anemia or transfusion
485
requirement.
486
487
Macrocytosis was observed among the majority of pediatric patients enrolled in the studies.
488
In the open-label studies involving 124 pediatric patients, 16 clinical adverse events were reported
489
by 24 pediatric patients. No event was reported by more than 5.6% of the study populations. Due to
490
the open-label design of the studies, it was difficult to determine possible events related to the use of
491
RETROVIR versus disease-related events. Therefore, all clinical events reported as associated with
492
therapy with RETROVIR or of unknown relationship to therapy with RETROVIR are presented in
493
Table 6:
494
495
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
18
Table 6: Percentage (%) of Pediatric Patients
496
with Clinical Events in Open-Label Studies
497
498
Adverse Event
n
%
BODY AS A WHOLE
Fever
Phlebitis*/Bacteremia
Headache
4
2
2
3.2
1.6
1.6
GASTROINTESTINAL
Nausea
Vomiting
Abdominal Pain
Diarrhea
Weight Loss
1
6
4
1
1
0.8
4.8
3.2
0.8
0.8
NERVOUS
Insomnia
Nervousness/Irritability
Decreased Reflexes
Seizure
3
2
7
1
2.4
1.6
5.6
0.8
CARDIOVASCULAR
Left Ventricular Dilation
Cardiomyopathy
S3 Gallop
Congestive Heart Failure
Generalized Edema
ECG Abnormality
1
1
1
1
1
3
0.8
0.8
0.8
0.8
0.8
2.4
UROGENITAL
Hematuria/Viral Cystitis
1
0.8
* Peripheral vein IV catheter site.
499
500
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
501
pediatric patients.
502
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized, double-blind,
503
placebo-controlled trial in HIV-infected women and their neonates conducted to determine the utility
504
of RETROVIR for the prevention of maternal-fetal HIV transmission, RETROVIR Syrup at 2 mg/kg
505
was administered every 6 hours for 6 weeks to neonates beginning within 12 hours after birth. The
506
most commonly reported adverse experiences were anemia (hemoglobin <9.0 g/dL) and neutropenia
507
(<1000 cells/mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of
508
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
19
the neonates who received placebo. The mean difference in hemoglobin values was less than
509
1.0 g/dL for neonates receiving RETROVIR compared to neonates receiving placebo. No neonates
510
with anemia required transfusion, and all hemoglobin values spontaneously returned to normal within
511
6 weeks after completion of therapy with RETROVIR. Neutropenia was reported with similar
512
frequency in the group that received RETROVIR (21%) and in the group that received placebo (27%).
513
The long-term consequences of in utero and neonatal exposure to RETROVIR are unknown.
514
515
OVERDOSAGE: Cases of acute overdoses in both pediatric patients and adults have been reported
516
with doses up to 50 grams. None were fatal. The only consistent finding in these cases of overdose
517
was spontaneous or induced nausea and vomiting. Hematologic changes were transient and not
518
severe. Some patients experienced nonspecific CNS symptoms such as headache, dizziness,
519
drowsiness, lethargy, and confusion. One report of a grand mal seizure possibly attributable to
520
RETROVIR occurred in a 35-year-old male 3 hours after ingesting 36 grams of RETROVIR. No other
521
cause could be identified. All patients recovered without permanent sequelae. Hemodialysis appears
522
to have a negligible effect on the removal of zidovudine while elimination of its primary metabolite,
523
GZDV, is enhanced.
524
525
DOSAGE AND ADMINISTRATION:
526
Adults: The recommended intravenous dose is 1 mg/kg infused over 1 hour. This dose should be
527
administered five to six times daily (5 to 6 mg/kg daily). The effectiveness of this dose compared to
528
higher dosing regimens in improving the neurologic dysfunction associated with HIV disease is
529
unknown. A small randomized study found a greater effect of higher doses of RETROVIR on
530
improvement of neurological symptoms in patients with pre-existing neurological disease.
531
Patients should receive RETROVIR IV Infusion only until oral therapy can be administered. The
532
intravenous dosing regimen equivalent to the oral administration of 100 mg every 4 hours is
533
approximately 1 mg/kg intravenously every 4 hours.
534
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to
535
pregnant women (>14 weeks of pregnancy) and their neonates is:
536
Maternal Dosing: 100 mg orally five times per day until the start of labor. During labor and
537
delivery, intravenous RETROVIR should be administered at 2 mg/kg (total body weight) over
538
1 hour followed by a continuous intravenous infusion of 1 mg/kg per hour (total body weight) until
539
clamping of the umbilical cord.
540
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing
541
through 6 weeks of age. Neonates unable to receive oral dosing may be administered RETROVIR
542
intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See PRECAUTIONS if
543
hepatic disease or renal insufficiency is present.)
544
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
20
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone marrow
545
reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly
546
in patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is
547
recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who
548
experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and
549
neutropenia usually occurs after 6 to 8 weeks.
550
Dose Adjustment: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of baseline)
551
and/or significant neutropenia (granulocyte count of <750 cells/mm3 or reduction of >50% from
552
baseline) may require a dose interruption until some evidence of marrow recovery is observed. For
553
less severe anemia or neutropenia, a reduction in daily dose may be adequate. In patients who
554
develop significant anemia, dose modification does not necessarily eliminate the need for
555
transfusion. If marrow recovery occurs following dose modification, gradual increases in dose may be
556
appropriate depending on hematologic indices and patient tolerance.
557
In end-stage renal disease patients maintained on hemodialysis or peritoneal dialysis,
558
recommended dosing is 1 mg/kg every 6 to 8 hours (see CLINICAL PHARMACOLOGY:
559
Pharmacokinetics).
560
There are insufficient data to recommend dose adjustment of zidovudine in patients with impaired
561
hepatic function.
562
Method of Preparation: RETROVIR IV Infusion must be diluted prior to administration. The
563
calculated dose should be removed from the 20-mL vial and added to 5% Dextrose Injection solution
564
to achieve a concentration no greater than 4 mg/mL. Admixture in biologic or colloidal fluids (e.g.,
565
blood products, protein solutions, etc.) is not recommended.
566
After dilution, the solution is physically and chemically stable for 24 hours at room temperature
567
and 48 hours if refrigerated at 2° to 8°C (36° to 46°F). Care should be taken during admixture to
568
prevent inadvertent contamination. As an additional precaution, the diluted solution should be
569
administered within 8 hours if stored at 25°C (77°F) or 24 hours if refrigerated at 2° to 8°C to
570
minimize potential administration of a microbially contaminated solution.
571
Parenteral drug products should be inspected visually for particulate matter and discoloration prior
572
to administration whenever solution and container permit. Should either be observed, the solution
573
should be discarded and fresh solution prepared.
574
Administration: RETROVIR IV Infusion is administered intravenously at a constant rate over one
575
hour. Rapid infusion or bolus injection should be avoided. RETROVIR IV Infusion should not be
576
given intramuscularly.
577
578
HOW SUPPLIED: RETROVIR IV Infusion, 10 mg zidovudine in each mL. 20-mL Single-Use Vial,
579
Tray of 10 (NDC 0173-0107-93).
580
Store vials at 15° to 25°C (59° to 77°F) and protect from light.
581
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) IV Infusion
21
582
US Patent Nos. 4,818,538 (Product Patent)
583
4,724,232; 4,833,130; and 4,837,208 (Use Patents)
584
585
586
587
Manufactured by
588
Catalytica Pharmaceuticals, Inc.
589
Greenville, NC 27834
590
for Glaxo Wellcome Inc.
591
Research Triangle Park, NC 27709
592
Copyright 1996, 2000, Glaxo Wellcome Inc. All rights reserved.
593
594
Date of Issue
RL-
595
596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
--------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
--------------------------------------------------------------------------------------------------------
/s/
---------------------
Jeffrey Murray
9/12/01 05:05:20 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:23.422325
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19951s16lbl.pdf', 'application_number': 19951, 'submission_type': 'SUPPL ', 'submission_number': 16}
|
12,101
|
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 1
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 2
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 3
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 4
4
NovoPen
Junior Instruction
5
Manual
6
7
Dial-A-Dose Insulin Delivery System
8
9
INTRODUCTION
10
11
12
13
14
NovoPen® Junior delivers a minimum dose of 1 unit to a maximum dose of 35
15
units of insulin in half unit steps. A raised circle on the push button makes it easy
16
for you to know your NovoPen Junior from the ordinary NovoPen 3. This booklet
17
includes everything you need to know about using the NovoPen Junior. Please
18
read it carefully before using your NovoPen Junior for the first time.
19
20
The NovoPen Junior is designed for use with:
21
! PenFill® 3 mL cartridges.
22
! NovoFine® disposable needles.
23
NovoFine disposable needles are for single-use only.
24
You will also need alcohol swabs.
25
26
If you have any questions about your NovoPen Junior insulin delivery system,
27
please call Novo Nordisk Pharmaceuticals, Inc. at 1-800-727-6500.
28
29
Please complete and return the NovoPen Junior warranty card.
30
31
32
33
34
See Important Things to Know and Important Notes on pages 33-35.
35
36
2
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 5
HOW TO USE THIS BOOKLET
38
39
This booklet gives you step-by-step instructions for using the NovoPen
40
Junior.
41
42
Begin by reviewing the drawing layout of the parts of the NovoPen Junior, PenFill
43
3 mL cartridge, and NovoFine disposable needle. The inside front cover opens
44
out so you have a handy reference while you read the rest of the booklet.
45
46
Most pages contain a drawing on the right with numbered instructions to the left
47
of the drawing.
48
Important additional information is given below the drawing.
49
50
We suggest that you read the text and look at the drawing to make sure that
51
you understand each step thoroughly.
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
3
81
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NovoPen Junior Final revision
Page 6
TABLE OF CONTENTS
82
83
SECTION 1:
84
Preparing the NovoPen Junior..........................………......................……… 5
85
86
SECTION 2:
87
Inserting the PenFill 3 mL Cartridge............................................................. 8
88
89
SECTION 3:
90
Attaching the NovoFine Disposable Needle................................................ 12
91
92
SECTION 4:
93
Doing an Air Shot ........................................................................................ 16
94
95
SECTION 5:
96
Giving the Injection ..................................................................................... 20
97
98
SECTION 6:
99
Removing the NovoFine Disposable Needle................................................ 24
100
101
SECTION 7:
102
Removing the PenFill 3 mL Cartridge......................................................... 26
103
104
FUNCTION CHECK ................................................................................... 28
105
106
STORAGE..................................................................................................
31
107
108
MAINTENANCE........................................................................................
32
109
110
IMPORTANT THINGS TO KNOW...........................................................
33
111
112
IMPORTANT NOTES.................................................................................
34
113
114
WHAT TO DO IF......................................................................................
36
115
116
WARRANTY .............................................................................................
37
117
Corrections on this page =
118
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NovoPen Junior Final revision
Page 7
SECTION 1
Preparing the NovoPen Junior
119
120
Remove the device cap:
121
1. Remove the NovoPen Junior from the case.
122
2. Gently twist the pen cap until the cap separates from the barrel.
123
3. Pull the pen cap straight up to remove it.
124
125
126
127
If you use more than one insulin product (such as Novolin® R, Novolin® N,
128
Novolin® 70/30, or NovoLog®), use a separate insulin delivery device for each
129
product.
130
131
5
132
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NovoPen Junior Final revision
Page 8
SECTION 1 (cont.)
133
134
Separate the cartridge holder from the barrel:
135
136
4. Unscrew and remove the cartridge holder from the barrel.
137
138
139
140
Make sure the dose indicator window shows zero:
141
142
5. Press the push button all the way in until zero (0) appears in the window.
143
The zero should be lined up with the stripe below the dose indicator
144
window.
145
146
147
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Page 9
6
148
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Page 10
149
SECTION 1 (cont.)
150
151
The end of the piston rod should be flat against the end of the reset mechanism
152
prior to inserting each new PenFill 3 mL cartridge. It should not be sticking out.
153
154
If the piston rod is sticking out:
155
156
Turn the end of the reset mechanism in a clockwise direction until it is no longer
157
sticking out. Never push the piston rod back in.
158
159
160
161
162
You should never reset the piston rod until it is time to remove the used PenFill 3
163
mL cartridge and insert a new one.
164
165
If the reset mechanism locks, it is usually due to improper technique. Gently turn
166
the mechanism side to side until it unlocks. Then call our toll free number (1-800-
167
727-6500) so that we may go over your technique with you.
168
169
7
170
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NovoPen Junior Final revision
Page 11
SECTION 2
Inserting the PenFill 3 mL Cartridge
171
172
1. To remove the PenFill cartridge from its wrapper, push the cartridge
173
through the foil side of the packaging. Always make sure that the PenFill
174
cartridge you use contains the correct type of insulin (such as Novolin R,
175
Novolin N, Novolin 70/30, or NovoLog). If you are treated with more than
176
one type of insulin in PenFill cartridges, you should use a separate insulin
177
delivery device for each type of insulin. Before use, check that the PenFill
178
cartridge is full and intact. If not, do not use it.
179
180
2-1
181
182
2. In the PenFill Information For The Patient leaflet, you will find instructions
183
on how to prepare the insulin if the PenFill contains a suspension insulin
184
(white and cloudy insulin) such as Novolin N or Novolin 70/30.
185
186
1-4
187
Each PenFill 3 mL cartridge contains a total of 300 units of insulin. Make sure
188
you are using the correct type of insulin. On the glass part of the cartridge is the
189
name of the insulin.
190
191
Each PenFill cartridge is for single-person use only. DO NOT share the same
192
cartridge with anyone even if you attach a new disposable needle for each
193
injection. Sharing the cartridge can spread disease.
194
Use only a new PenFill 3 mL cartridge when loading the NovoPen Junior. Never
195
load a partially filled cartridge.
196
Never try to refill a used PenFill 3 mL cartridge.
197
198
8
199
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Page 12
9
200
SECTION 2 (cont.)
201
202
Insert the PenFill cartridge:
203
204
2. Hold the cartridge holder so the wider opening is up.
205
3. Drop the PenFill cartridge into the cartridge holder, plastic cap first.
206
207
208
A threaded plastic cap surrounds the end of the PenFill® cartridge, like the cap
209
on a bottle. In the center is the front rubber stopper.
210
211
The rear rubber stopper is at the other end of the PenFill cartridge.
212
213
10
214
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NovoPen Junior Final revision
Page 13
SECTION 2 (cont.)
215
216
Re-attach the cartridge holder:
217
218
4. Screw the barrel into the cartridge holder completely until it is tight.
219
220
221
222
223
224
You can see the cartridge in the insulin scale window. The cartridge holder has a
225
scale with marks showing about how much insulin is left in the PenFill cartridge.
226
227
11
228
2
229
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Page 14
SECTION 3
Attaching the NovoFine® Disposable Needle
230
231
At the end of the cartridge holder are two inspection windows. You can see the
232
cartridge through these windows.
233
234
If you use a suspension insulin (white and cloudy) such as Novolin® N or
235
Novolin® 70/30, use the windows to check if there is enough insulin left for
236
proper mixing. (see below)
237
238
Check the amount of insulin remaining:
239
240
! If the rear rubber stopper cannot be seen in the inspection window, you
241
have enough insulin for mixing left in the cartridge.
242
! If the rear rubber stopper can be seen in the inspection window, you do
243
not have enough insulin left in the cartridge and must insert a new PenFill
244
3 mL cartridge.
245
246
See Section 7 for instructions on removing a PenFill cartridge and Section 2 for
247
inserting a new one.
248
249
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Page 15
At least
250
12
251
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NovoPen Junior Final revision
Page 16
SECTION 3 (cont.)
252
253
For users of suspension insulin (white and cloudy) such as Novolin N or
254
Novolin 70/30:
255
256
Always remix the insulin before each injection.
257
To remix the insulin, turn the NovoPen Junior up and down between positions A
258
and B 10 times or until the insulin looks uniformly white and cloudy
259
260
261
262
263
13
264
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NovoPen Junior Final revision
Page 17
SECTION 3 (cont.)
265
266
1. Wipe the front rubber stopper with an alcohol swab.
267
1
268
269
270
You must wipe the front rubber stopper with an alcohol swab before each
271
injection, even if you are using the same PenFill cartridge.
272
3-3
273
14
274
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NovoPen Junior Final revision
Page 18
SECTION 3 (cont.)
275
276
2. Remove the protective tab from the NovoFine disposable needle.
277
3. Screw the NovoFine disposable needle firmly onto the PenFill 3 mL
278
cartridge until it is tight.
279
2 33
280
281
282
Never place a NovoFine disposable needle on your NovoPen Junior until you are
283
ready to do an air shot and give an injection.
284
If the NovoFine needle is left on, some liquid may leak out of the PenFill
285
cartridge. This may cause a change in the strength of the suspension insulin
286
such as Novolin N or Novolin 70/30.
287
15
288
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NovoPen Junior Final revision
Page 19
289
SECTION 4
Doing an Air Shot
290
291
The PenFill cartridge may contain an air bubble, and small amounts of air may
292
collect in the needle and PenFill cartridge when you use them. To avoid injecting
293
air and to ensure proper dosing, you must perform an air shot before each
294
injection.
295
296
Before doing the air shot, the dose indicator window must show zero (0).
297
298
If you use a suspension insulin, such as Novolin N or Novolin 70/30 and have
299
used the PenFill cartridge for previous injections, make sure there is enough
300
insulin left in the PenFill cartridge to properly mix the insulin (see page 12). If
301
there is enough insulin left in the PenFill cartridge, see the next page for
302
instructions.
303
304
16
305
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NovoPen Junior Final revision
Page 20
SECTION 4 (cont.)
306
307
Set the NovoPen Junior for the air shot:
308
309
1. Turn the dial-a-dose selector to 2 units. Full units are shown as numbers.
310
Half units are shown as long lines between the numbers.
311
1
312
313
4-1
314
If you dial more than 2 units, DO NOT turn the dial back to zero (0). If you
315
do, the extra insulin will squirt out of the needle. You may complete the air shot
316
with the number of units you have dialed or refer to Section 5 on page 21 for
317
instructions on how to reset the dose to zero.
318
319
17
320
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NovoPen Junior Final revision
Page 21
SECTION 4 (cont.)
321
322
Uncap the NovoFine needle:
323
324
2. Pull off the outer needle cap and set aside.
325
3. Pull off the inner needle cap and discard.
326
2
327
Do not use the needle if it is bent or damaged.
328
329
330
331
4. Hold the NovoPen Junior with the NovoFine needle pointing up.
332
5. Tap the cartridge holder with your finger a few times to raise any air
333
bubbles that may be present to the top of the cartridge.
334
335
336
18-3
337
338
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NovoPen Junior Final revision
Page 22
SECTION 4 (cont.)
339
340
Do the air shot:
341
342
6. Press the push button all the way in. A drop of insulin should appear at the
343
needle tip.
344
345
If no insulin appears, repeat the following steps, until a drop of insulin
346
appears:
347
348
a. Make sure the NovoFine needle is securely attached.
349
b. Dial 2 units.
350
c. Tap the cartridge holder with your finger.
351
d. Press the push button all the way in.
352
353
There may still be some small air bubble(s) in the PenFill cartridge after this, but
354
they will not affect your dose and they will not be injected.
355
356
357
358
When you press the push button, the piston rod presses against the rear rubber
359
stopper. This moves the rear rubber stopper and pushes the correct amount of
360
insulin up through the needle.
361
362
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Page 23
19
363
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NovoPen Junior Final revision
Page 24
SECTION 5
Giving the Injection
364
365
Be sure to do an air shot before giving each injection (see pages 16-19).
366
Select the dose:
367
368
1 Check that the dial-a-dose selector is set to zero. If not, follow the
369
instructions on the next page. Turn the dial-a-dose selector until you see
370
the correct number of units in the dose indicator window. Full units are
371
shown as numbers. Half units are shown as long lines between the
372
numbers.
373
374
1 DO NOT use the clicking sound as a guide for selecting your dose.
375
376
377
4-4
378
The NovoPen Junior can deliver insulin in half unit steps from a minimum dose
379
of 1 unit to a maximum dose of 35 units.
380
381
If you dial more than your dose, DO NOT turn the dial back to zero (0). If you
382
do, the extra insulin will squirt out of the needle. For instructions on how to reset
383
the dose to zero (0) so you can start again, see the next page.
384
385
386
20
387
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NovoPen Junior Final revision
Page 25
SECTION 5 (cont.)
388
389
If you dial a larger dose than you need, pull the barrel and the cartridge holder
390
apart, as shown in the drawing A. While holding them apart, gently press the
391
push button against a hard surface and release your grip B. Your dose indicator
392
window should be back to zero (0).
393
394
You can now dial the correct number of units.
395
396
397
398
21
399
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NovoPen Junior Final revision
Page 26
Corrections on this page =
400
SECTION 5 (cont.)
401
402
Giving the injection:
403
404
2. After the air shot is done and you have chosen the correct number of
405
units, insert the NovoFine needle in the correct injection site on your body.
406
(Use the injection technique recommended by your health care
407
professional). If you use a suspension insulin such as Novolin N or
408
Novolin 70/30, mix the insulin (see page 13, Section 3) and make sure the
409
insulin looks uniformly white and cloudy before you inject.
410
411
3. Press the push button as far as it will go to deliver the insulin. Do not
412
force it.
413
414
To ensure that all the insulin is injected, keep the NovoFine needle in the skin for
415
several seconds after injection with your thumb on the push button. Keep the
416
push button fully depressed until after the NovoFine needle has been withdrawn.
417
418
Important: Never turn the dial-a-dose selector to inject the insulin.
419
420
421
422
When you get near the end of a PenFill cartridge, you may need to give yourself
423
two injections to receive your full dose. Check the dose indicator window after
424
giving an injection. If zero does not appear in the dose indicator window, you did
425
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NovoPen Junior Final revision
Page 27
not receive your full dose. See the next page for instructions on how to get the
426
remaining part of your dose.
427
428
22
429
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NovoPen Junior Final revision
Page 28
430
SECTION 5 (cont.)
431
432
4. Check the dose indicator window to make sure it shows zero (0). If
433
zero does not appear, you did not receive the full dose.
434
435
If the dose indicator window does not show zero, there were not enough units of
436
insulin in the PenFill cartridge for you to receive the full dose. The dose indicator
437
window shows the number of units that you did not receive.
438
439
For example, if you dial 25 units and there are only 20 units left in the PenFill
440
cartridge, after the injection the number in the dose indicator window will be
441
5 (25-20 = 5). If this happens, proceed with the following steps to get the
442
remaining part of your dose:
443
444
a. Note the number of units in the dose indicator window.
445
b. Remove the NovoFine needle (see Section 6).
446
c. Remove the empty PenFill 3 mL cartridge (see Section 7).
447
d. Insert a new PenFill 3 mL cartridge (see Section 2).
448
e. Attach a NovoFine needle (see Section 3).
449
f. Do an air shot (see Section 4).
450
g. Dial the number of units noted in step a.
451
h. Give the injection.
452
453
454
4
455
456
23
457
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NovoPen Junior Final revision
Page 29
SECTION 6
Removing the NovoFine Disposable Needle
458
459
Remove the NovoFine disposable needle:
460
461
1. After the injection, remove the needle without replacing the cap.
462
463
2. Hold the cartridge holder firmly while you unscrew the NovoFine
464
disposable needle.
465
466
3. Place the NovoFine disposable needle in a puncture-resistant disposable
467
container.
468
469
Health care professionals, relatives and other caregivers should also follow the
470
above instructions to eliminate the risk of unintended needle penetration.
471
472
473
474
475
The NovoFine disposable needle must be removed immediately after each
476
injection without replacing the cap. If the NovoFine disposable needle is not
477
removed, some liquid may leak out of the PenFill cartridge. This may cause a
478
change in the strength of suspension insulins (white and cloudy) such as Novolin
479
N or Novolin 70/30.
480
481
For information on how to throw away needle containers properly, contact your
482
local trash company.
483
6-1
484
24
485
Corrections
486
487
SECTION 6 (cont.)
488
489
Replace the pen cap:
490
491
4. After you remove the disposable needle, hold the pen cap so that the clip
492
is lined up with the dose indicator window.
493
494
5. Gently slide the pen cap onto the barrel.
495
496
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NovoPen Junior Final revision
Page 30
497
4
498
25
499
500
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NovoPen Junior Final revision
Page 31
501
SECTION 7
Removing the PenFill 3 mL Cartridge
502
503
You will need to remove the PenFill cartridge for the following reasons:
504
505
! When tThe PenFill cartridge is empty.
506
507
! If you use a suspension insulin such as Novolin N or Novolin 70/30:
508
509
When you see the rear rubber stopper in the inspection window, then you
510
do not have enough insulin left in the PenFill cartridge for proper mixing.
511
512
Remove the barrel:
513
514
1. Remove the pen cap.
515
516
2. Hold the NovoPen Junior with the dose indicator window at the top.
517
518
3. Unscrew the barrel from the cartridge holder.
519
520
7-1
521
522
26
523
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NovoPen Junior Final revision
Page 32
SECTION 7 (cont.)
524
525
Remove the PenFill 3 mL cartridge:
526
527
4. Tip the cartridge holder. The PenFill cartridge will drop out.
528
529
5. Press the push button all the way in until zero (0) appears in the window.
530
531
6. Turn the end of the reset mechanism in a clockwise direction until the
532
piston rod is no longer sticking out (refer to figure 1-4 on page 7).
533
534
7. To insert a new PenFill cartridge, please refer to Section 2.
535
536
537
538
If the reset mechanism locks, it is usually due to improper technique. Gently turn
539
the mechanism side to side until it unlocks and then call our toll free number (1-
540
800-727-6500) so that we may go over your technique with you.
541
5
542
27
543
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NovoPen Junior Final revision
Page 33
FUNCTION CHECK
544
545
You should regularly check the functioning of your NovoPen Junior, (for example,
546
once a month or before starting a new box of PenFill cartridges). The function
547
check is done by delivering 20 units of insulin into the outer needle cap. You will
548
not be injecting insulin into your body.
549
550
Always check the functioning of the NovoPen Junior if you suspect it has been
551
damaged or if you are uncertain that it is delivering the correct dose.
552
553
Do not use NovoPen Junior unless you are sure that it is working properly.
554
Help? Call 1-800-727-6500
555
To perform the function check:
556
557
1. Attach a NovoFine disposable needle (see pages 12-15).
558
559
2. Do an air shot (see pages 16-19).
560
561
28
562
1
563
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NovoPen Junior Final revision
Page 34
564
FUNCTION CHECK (cont.)
565
566
3. Do not replace the inner needle cap. Place the outer needle cap
567
securely over the exposed NovoFine needle.
568
569
570
571
572
Expel 20 units of insulin into the outer needle cap:
573
574
4. Turn the dial-a-dose selector so the dose indicator window shows 20.
575
576
577
578
29
579
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NovoPen Junior Final revision
Page 35
FUNCTION CHECK (cont.)
580
581
5. Hold the NovoPen Junior so the NovoFine disposable needle is pointing
582
down.
583
584
6. Slowly press the push button as far as it will go.
585
586
7. Check the dose indicator window to see if it shows zero (0). If it does not
587
show zero (0), there is not enough insulin in the cartridge to do a function
588
check. Insert a new PenFill cartridge (see pages 8-11) and repeat the
589
function check. If there is enough insulin in the cartridge but the dose
590
indicator window does not show zero, repeat the FUNCTION CHECK. If
591
you do not see zero after repeating the above steps, do not use your
592
NovoPen Junior. Contact Novo Nordisk Pharmaceuticals, Inc. at our toll
593
free number (1-800-727-6500).
594
595
596
597
598
The insulin should fill the bottom part of the outer needle cap. This indicates the
599
device is functioning properly.
600
601
If the insulin does not fill or overfills this part of the cap, review the function
602
check procedure. Then repeat the function check with a new NovoFine
603
disposable needle and outer needle cap.
604
605
If the second function check also shows under- or over-filling, do not use your
606
NovoPen Junior.
607
608
DO NOT try to repair a NovoPen Junior that you think is not working
609
properly.
610
611
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 36
See Warranty section for further information.
612
613
30
614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 37
-3
615
STORAGE
616
617
Guidelines for storing the NovoPen Junior and PenFill 3 mL cartridges:
618
619
! PenFill cartridges should be stored in a cool place, such as in a
620
refrigerator, but not in thea freezer.
621
622
! After the first use of PenFill cartridge in the NovoPen Junior, the NovoPen
623
Junior (with the PenFill cartridge inside) can be kept at room temperature
624
below 86°F (30°C) for the amount of time days specified listed in the
625
PenFill Information for the Patient leaflet for the type of insulin you are
626
using.
627
628
! Do not store the NovoPen 3 Junior (with the PenFill cartridge inside) in a
629
refrigerator or areas where there may be extreme temperatures or
630
moisture, such as in your car.
631
632
! The expiration date printed on the cartridge is for unused cartridges
633
under refrigeration. Never use the cartridge after the expiration date
634
on the cartridge or its box.
635
636
637
638
639
! Store the NovoPen Junior without the NovoFine needle attached and
640
with the pen cap in position.
641
642
! For information on storing PenFill cartridges, see the package leaflet that
643
comes in the PenFill cartridge box.
644
645
646
31
647
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 38
MAINTENANCE
648
649
Guidelines for maintaining the NovoPen Junior.
650
651
Be sure to:
652
653
1. Clean it by wiping with a soft cloth moistened with alcohol.
654
655
2. Protect it from dust, dirt, and moisture when not in its case.
656
657
658
Make certain you:
659
660
1. Do not soak it in alcohol, do not wash it in soap and water, or do not
661
lubricate it, since this may cause damage.
662
663
2. Do not expose it to excessive pressure or blows.
664
665
3. Do not drop it.
666
667
32
668
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 39
IMPORTANT THINGS TO KNOW
669
2
670
! The NovoPen Junior is not recommended for the blind or visually
671
impaired, without the assistance of a sighted individual trained to use it.
672
673
! If you use more than one type of insulin (such as Novolin R, Novolin N,
674
Novolin 70/30, or NovoLog), use a separate insulin delivery device for
675
each type of insulin.
676
677
! Use only a new PenFill 3 mL cartridge when loading the NovoPen Junior.
678
Never load the NovoPen Junior with a partially filled PenFill cartridge.
679
680
! Always keep a spare insulin delivery system available, in case your
681
NovoPen Junior is lost or damaged.
682
683
! Keep the NovoPen Junior, PenFill cartridges, and NovoFine needles out
684
of the reach of children. The American Diabetes Association recommends
685
that insulin should be self-administered. The proper age for initiating this
686
should be assessed by the adult caregiver.
687
688
! Keep the NovoPen Junior away from areas where temperatures may get
689
too hot or too cold such as a car or refrigerator.
690
691
! The NovoPen Junior is designed for use with PenFill 3 mL insulin
692
cartridges and NovoFine single-use disposable needles.
693
694
Novo Nordisk is not responsible for any consequences arising from the use of
695
the NovoPen Junior with products other than PenFill 3 mL insulin cartridges
696
and NovoFine single-use disposable needles.
697
698
33
699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 40
IMPORTANT NOTES
700
701
The following is a review of some important information about the use and
702
care of your NovoPen Junior.
703
704
705
Before each injection, be certain:
706
707
1. The NovoPen Junior contains the correct insulin cartridge (such as
708
Novolin R, Novolin N, Novolin 70/30, or NovoLog), if you use more than
709
one type of insulin.
710
711
2. The PenFill cartridge contains enough insulin for mixing, if you use a
712
suspension insulin (white and cloudy) such as Novolin N or Novolin 70/30.
713
714
3. To do an air shot with the NovoFine needle pointing up before each
715
injection.
716
1
717
2 3
718
Be sure to:
719
720
1. Check the dose indicator window after each injection to make sure you
721
have received your full dose (see page 23, Section 5).
722
723
2. Remove the NovoFine needle immediately after each injection without
724
replacing the cap.
725
726
3. Select your dose only by using the number in the dose indicator window.
727
728
4. Perform the function check regularly or if you think your NovoPen Junior is
729
not working properly.
730
1
731
34
732
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 41
IMPORTANT NOTES (cont.)
733
734
Make certain you:
735
736
1. DO NOT place a NovoFine needle on the NovoPen Junior until you are
737
ready to do an air shot and give an injection or do a function check.
738
Remove the needle immediately after each injection without replacing the
739
cap. If the NovoFine needle is not removed, some liquid may leak out of
740
the PenFill cartridge. This may cause a change in the strength of
741
suspension insulin (white and cloudy) such as Novolin N or Novolin 70/30.
742
743
2. DO NOT use the clicking sound to set your insulin dose.
744
745
3. DO NOT try to refill a PenFill cartridge.
746
747
4. DO NOT share the same PenFill cartridge with anyone else even if you
748
attach a new NovoFine needle for each injection. Sharing the cartridge
749
can spread disease. Each PenFill cartridge is for single-person use only.
750
751
Blood glucose levels should be tested frequently to monitor your insulin regimen.
752
753
Any change in insulin should be made cautiously and only under medical
754
supervision.
755
Corrections on this
756
35
757
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 42
758
WHAT TO DO IF…
759
760
The dose indicator window does not show zero after the injection:
761
762
1. You did not receive your full dose.
763
1 Follow the steps on page 23 to get the remaining part of your dose.
764
765
2. Your NovoPen Junior is malfunctioning.
766
Do not use your NovoPen Junior. Contact Novo Nordisk Pharmaceuticals,
767
Inc. at our toll free number (1-800-727-6500).
768
769
No insulin appears when you do the air shot:
770
771
1. The piston rod is not far enough down the cartridge holder to reach
772
the rear rubber stopper.
773
Repeat the air shot (see pages 16-19).
774
775
2. The NovoFine needle may not be securely attached.
776
a. Put the plastic outer cap back on the NovoFine needle.
777
b. Turn the plastic outer cap in a clockwise direction to tighten the
778
NovoFine needle.
779
780
3. The NovoFine needle may be blocked.
781
Change the NovoFine needle (see pages 14-15) and do an air shot (see
782
pages 16-19).
783
784
The piston rod is sticking out too far to attach the cartridge holder to the
785
barrel:
786
787
You must screw the piston rod back into the barrel (see page 7). Never try to
788
push it in or you can damage the mechanism.
789
1
790
The push button will not return to zero or the piston rod will not turn back
791
into the reset mechanism:
792
793
The return mechanism may be locked. This is usually due to improper
794
technique. Gently turn the mechanism side to side until it unlocks and then
795
call our toll free number (1-800-727-6500) so that we may go over your
796
technique with you.
797
798
36
799
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 43
WARRANTY
800
801
Should your NovoPen® Junior device be defective in materials or
802
workmanship within two (2) years of purchase, Novo Nordisk
803
Pharmaceuticals, Inc. will replace it at no charge if you mail the defective unit
804
along with a description of the problem and the sales receipt or other proof of
805
purchase to:
806
807
Novo Nordisk Pharmaceuticals, Inc.
808
Product Safety
809
100 College Road West
810
Princeton, NJ 08540
811
812
Protected by U.S. Patent Nos. 5,693,027; 5,626,566; 6,126,646 and Des.
813
347,894 (cartridge) restricted to use with Novo Nordisk insulin cartridges and
814
Novo Nordisk pen needles.
815
816
No other warranty is made with respect to NovoPen® Junior. This warranty
817
will be invalid and Novo Nordisk A/S, Novo Nordisk Pharmaceuticals, Inc.,
818
Bristol-Myers Squibb Co., Nipro Medical Industries Ltd., and Bang & Olufsen
819
A/S cannot be held responsible in the case of defects or damages arising
820
from:
821
822
! The use of the NovoPen® Junior with products other than PenFill 3 mL
823
cartridges and NovoFine single-use disposable needles.
824
825
! The use of the NovoPen® Junior not in accordance with the instructions in
826
this booklet.
827
828
! Physical damage to the NovoPen® Junior caused by neglect, misuse,
829
unauthorized repair, accident, or other breakage.
830
831
37
832
833
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDAs 19-938, 19-959, 19-991, & 20-986
NovoPen Junior Final revision
Page 44
834
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
4/11/02 07:24:52 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:23.669322
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19938s32lbl.pdf', 'application_number': 19959, 'submission_type': 'SUPPL ', 'submission_number': 34}
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12,099
|
NDA 19-957/S-007
NDA 19-957/S-009
Page 3
PRODUCT INFORMATION
CUTIVATE®
(fluticasone propionate ointment)
Ointment, 0.005%
For Dermatologic Use Only—
Not for Ophthalmic Use.
DESCRIPTION: CUTIVATE (fluticasone propionate ointment) Ointment, 0.005% contains
fluticasone propionate [(6α,11β,16α,17α)-6,9,-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-
oxopropoxy)androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester], a synthetic
fluorinated corticosteroid, for topical dermatologic use. The topical corticosteroids constitute a
class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.
Chemically, fluticasone propionate is C25H31F3O5S. It has the following structural formula:
Fluticasone propionate has a molecular weight of 500.6. It is a white to off-white powder
and is insoluble in water.
Each gram of CUTIVATE Ointment contains fluticasone propionate 0.05 mg in a base of
liquid paraffin, microcrystalline wax, propylene glycol, and sorbitan sesquioleate.
CLINICAL PHARMACOLOGY: Like other topical corticosteroids, fluticasone propionate has
anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the
anti-inflammatory activity of the topical steroids, in general, is unclear. However,
corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins,
collectively called lipocortins. It is postulated that these proteins control the biosynthesis of
potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the
release of their common precursor, arachidonic acid. Arachidonic acid is released from
membrane phospholipids by phospholipase A2.
Fluticasone propionate is lipophilic and has a strong affinity for the glucocorticoid receptor.
It has weak affinity for the progesterone receptor, and virtually no affinity for the
mineralocorticoid, estrogen, or androgen receptors. The therapeutic potency of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-007
NDA 19-957/S-009
Page 4
glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. The half-life of
the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours.
Studies performed with CUTIVATE Ointment indicate that it is in the medium range of
potency as compared with other topical corticosteroids.
Pharmacokinetics: Absorption: The activity of CUTIVATE is due to the parent drug,
fluticasone propionate. The extent of percutaneous absorption of topical corticosteroids is
determined by many factors, including the vehicle and the integrity of the epidermal barrier.
Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from
normal intact skin. Inflammation and/or other disease processes in the skin increase
percutaneous absorption.
In a study of 6 healthy volunteers applying 25 g of fluticasone propionate ointment 0.005%
twice daily to the trunk and legs for up to 5 days under occlusion, plasma levels of fluticasone
ranged from 0.08 to 0.22 ng/mL.
In an animal study using radiolabeled 0.05% fluticasone propionate cream and ointment
preparations, rats received a topical dose of 1 g/kg for a 24-hour period. Total recovery of
radioactivity was approximately 80% at the end of 7 days. The majority of the dose (73%)
was recovered from the surface of the application site. Less than 1% of the dose was
recovered in the skin at the application site. Approximately 5% of the dose was absorbed
systemically through the skin. Absorption from the skin continued for the duration of the study
(7 days), indicating a long retention time at the application site.
Distribution: Following intravenous administration of 1 mg of fluticasone propionate in
healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and
consistent with its high lipid solubility and tissue binding. The apparent volume of distribution
averaged 4.2 L/kg (range, 2.3-16.7 L/kg). The percentage of fluticasone propionate bound to
human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly
bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.
Metabolism: No metabolites of fluticasone propionate were detected in an in vitro study of
radiolabeled fluticasone propionate incubated in a human skin homogenate. The total blood
clearance of systemically absorbed fluticasone propionate averages 1093 mL/min (range,
618-1702 mL/min) after a 1-mg intravenous dose, with renal clearance accounting for less
than 0.02% of the total. Fluticasone propionate is metabolized in the liver by cytochrome
P450 3A4-mediated hydrolysis of the 5-fluoromethyl carbothioate grouping. This
transformation occurs in 1 metabolic step to produce the inactive 17-β-carboxylic acid
metabolite, the only known metabolite detected in man. This metabolite has approximately
2000 times less affinity than the parent drug for the glucocorticoid receptor of human lung
cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites
detected in vitro using cultured human hepatoma cells have not been detected in man.
Excretion: Following an intravenous dose of 1 mg in healthy volunteers, fluticasone
propionate showed polyexponential kinetics and had an average terminal half-life of 7.2
hours (range, 3.2-11.2 hours).
INDICATIONS AND USAGE: CUTIVATE Ointment is a medium potency corticosteroid
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-007
NDA 19-957/S-009
Page 5
indicated for the relief of the inflammatory and pruritic manifestations of
corticosteroid-responsive dermatoses.
CONTRAINDICATIONS: CUTIVATE Ointment is contraindicated in those patients with a
history of hypersensitivity to any of the components in the preparation.
PRECAUTIONS:
General: Systemic absorption of topical corticosteroids can produce reversible
hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for
glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing's
syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic
absorption of topical corticosteroids while on treatment.
Patients applying a topical steroid to a large surface area or to areas under occlusion
should be evaluated periodically for evidence of HPA axis suppression. This may be done by
using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests.
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to
reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of
HPA axis function is generally prompt upon discontinuation of topical corticosteroids.
Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring
supplemental systemic corticosteroids. For information on systemic supplementation, see
prescribing information for those products.
A concentrated fluticasone propionate ointment, 0.05% (10 times that of the marketed
fluticasone propionate ointment, 0.005%) suppressed 24-hour urinary free cortisol levels in 2
of 6 patients when used at a dose of 30 g/day for a week in patients with psoriasis or atopic
eczema. No suppression of A.M. plasma cortisol was observed. In a second study of the
same concentrated formulation of fluticasone propionate ointment, 0.05%, depression of A.M.
plasma cortisol levels was noted in 2 of 8 normal volunteers when applied at doses of 50
g/day for 21 days. Morning plasma levels returned to normal levels within 4 days upon
discontinuation of fluticasone propionate. In this study there was no corresponding decrease
in 24-hour urinary free cortisol levels.
Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due
to their larger skin surface to body mass ratios (see PRECAUTIONS: Pediatric Use).
Fluticasone propionate ointment, 0.005% may cause local cutaneous adverse reactions
(see ADVERSE REACTIONS).
If irritation develops, CUTIVATE Ointment should be discontinued and appropriate therapy
instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing
failure to heal rather than noting a clinical exacerbation as with most topical products not
containing corticosteroids. Such an observation should be corroborated with appropriate
diagnostic patch testing.
If concomitant skin infections are present or develop, an appropriate antifungal or
antibacterial agent should be used. If a favorable response does not occur promptly, use of
CUTIVATE Ointment should be discontinued until the infection has been adequately
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-007
NDA 19-957/S-009
Page 6
controlled.
CUTIVATE Ointment should not be used in the presence of preexisting skin atrophy and
should not be used where infection is present at the treatment site. CUTIVATE Ointment
should not be used in the treatment of rosacea and perioral dermatitis.
Information for Patients: Patients using topical corticosteroids should receive the following
information and instructions:
1. This medication is to be used as directed by the physician. It is for external use only. Avoid
contact with the eyes.
2. This medication should not be used for any disorder other than that for which it was
prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped so as to
be occlusive unless directed by the physician.
4. Patients should report to their physician any signs of local adverse reactions.
5. This medication should not be used on the face, underarms, or groin areas unless directed
by a physician.
6. As with other corticosteroids, therapy should be discontinued when control is achieved. If
no improvement is seen within 2 weeks, contact the physician.
Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis
suppression:
ACTH stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Two 18-month studies were
performed in mice to evaluate the carcinogenic potential of fluticasone propionate when given
topically (as an 0.05% ointment) and orally. No evidence of carcinogenicity was found in
either study.
Fluticasone propionate was not mutagenic in the standard Ames test, E. coli fluctuation
test, S. cerevisiae gene conversion test, or Chinese Hamster ovarian cell assay. It was not
clastogenic in mouse micronucleus or cultured human lymphocyte tests.
In a fertility and general reproductive performance study in rats, fluticasone propionate
administered subcutaneously to females at up to 50 mcg/kg per day and to males at up to
100 mcg/kg per day (later reduced to 50 mcg/kg per day) had no effect upon mating
performance or fertility. These doses are approximately 150 and 300 times, respectively, the
human systemic exposure following use of the recommended human topical dose of
fluticasone propionate ointment, 0.005%, assuming human percutaneous absorption of
approximately 3% and the use in a 70-kg person of 15 g/day.
Pregnancy: Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown
to be teratogenic in laboratory animals when administered systemically at relatively low
dosage levels. Some corticosteroids have been shown to be teratogenic after dermal
application in laboratory animals. Teratology studies in the mouse demonstrated fluticasone
propionate to be teratogenic (cleft palate) when administered subcutaneously in doses of 45
mcg/kg per day and 150 mcg/kg per day. This dose is approximately 140 and 450 times,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-007
NDA 19-957/S-009
Page 7
respectively, the human topical dose of fluticasone propionate ointment, 0.005%. There are
no adequate and well-controlled studies in pregnant women. CUTIVATE Ointment should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Systemically administered corticosteroids appear in human milk and could
suppress growth, interfere with endogenous corticosteroid production, or cause other
untoward effects. It is not known whether topical administration of corticosteroids could result
in sufficient systemic absorption to produce detectable quantities in human milk. Because
many drugs are excreted in human milk, caution should be exercised when CUTIVATE
Ointment is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Because of a
higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA
axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are
therefore also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse
effects including striae have been reported with inappropriate use of topical corticosteroids in pediatric
patients.
HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight
gain, and intracranial hypertension have been reported in pediatric patients receiving topical
corticosteroids. Manifestations of adrenal suppression in pediatric patients include low
plasma cortisol levels and an absence of response to ACTH stimulation.
Manifestations of intracranial hypertension include bulging fontanelles, headaches, and
bilateral papilledema.
Geriatric Use: A limited number of patients above 65 years of age (n=203) have been
treated with CUTIVATE Ointment in US and non-US clinical trials. While the number of
patients is too small to permit separate analysis of efficacy and safety, the adverse reactions
reported in this population were similar to those reported by younger patients. Based on
available data, no adjustment of dosage of CUTIVATE in geriatric patients is warranted.
ADVERSE REACTIONS: In controlled clinical trials, the total incidence of adverse reactions
associated with the use of CUTIVATE Ointment was approximately 4%. These adverse
reactions were usually mild, self-limiting, and consisted primarily of pruritus, burning,
hypertrichosis, increased erythema, hives, irritation, and lightheadedness. Each of these
events occurred individually in less than 1% of patients.
The following additional local adverse reactions have been reported infrequently with
topical corticosteroids, including fluticasone propionate, and they may occur more frequently
with the use of occlusive dressings and higher potency corticosteroids. These reactions are
listed in an approximately decreasing order of occurrence: dryness, folliculitis, acneiform
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary
infection, skin atrophy, striae, and miliaria. Also, there are reports of the development of
pustular psoriasis from chronic plaque psoriasis following reduction or discontinuation of
potent topical corticosteroid products.
OVERDOSAGE: Topically applied CUTIVATE Ointment can be absorbed in sufficient
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-007
NDA 19-957/S-009
Page 8
amounts to produce systemic effects (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION: Apply a thin film of CUTIVATE Ointment to the affected
skin areas twice daily. Rub in gently.
Geriatric Use: In studies where geriatric patients (65 years of age or older, see
PRECAUTIONS) have been treated with CUTIVATE Ointment, safety did not differ from that
in younger patients; therefore, no dosage adjustment is recommended.
HOW SUPPLIED: CUTIVATE Ointment, 0.005% is supplied in:
15-g tubes (NDC 0173-0431-00)
30-g tubes (NDC 0173-0431-01)
60-g tubes (NDC 0173-0431-02)
Store between 2°°°° and 30°°°°C (36°°°° and 86°°°°F).
Glaxo Wellcome Inc.
Research Triangle Park, NC 27709
RL-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Jonathan Wilkin
12/9/01 03:06:38 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19957s9lbl.pdf', 'application_number': 19957, 'submission_type': 'SUPPL ', 'submission_number': 7}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
----------------------- WARNINGS AND PRECAUTIONS ----------------------
These highlights do not include all the information needed to use
HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION safely
and effectively. See full prescribing information for HEPARIN
SODIUM IN 0.9% SODIUM CHLORIDE INJECTION.
HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION, for
intravenous use
Initial U.S. Approval: 1992
--------------------------- INDICATIONS AND USAGE --------------------------
HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION at the
concentration of 2 USP units/mL is an anticoagulant indicated for:
•
Maintenance of catheter patency (1)
----------------------- DOSAGE AND ADMINISTRATION ---------------------
Although the rate of infusion of the 2 USP units/mL formulation is
dependent upon the age, weight, clinical condition of the patient, and
the procedure being employed, an infusion rate of 3 mL/hour has been
found to be satisfactory. (2.2)
--------------------- DOSAGE FORMS AND STRENGTHS -------------------
Heparin Sodium 1,000 USP units per 500 mL (2 USP units per mL)
in 0.9% Sodium Chloride Injection (3)
----------------------------- CONTRAINDICATIONS ------------------------------
•
History of Heparin-induced Thrombocytopenia (HIT) (With or
Without Thrombosis) (4)
•
Known hypersensitivity to heparin or pork products (4)
FULL PRESCRIBING INFORMATION: CONTENTS *
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
2.2 Maintenance of Catheter Patency
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Fatal Medication Errors
5.2 Hemorrhage
5.3 Heparin-induced Thrombocytopenia (HIT) (With or
Without Thrombosis)
5.4 Thrombocytopenia
5.5 Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Platelet Inhibitors
•
Fatal Medication Errors: Confirm choice of correct strength prior
to administration. (5.1)
•
Hemorrhage: Fatal cases have occurred. Use caution in
conditions with increased risk of hemorrhage. (5.2)
•
HIT (With or Without Thrombosis): Monitor for signs and
symptoms and discontinue if indicative of HIT (With or Without
Thrombosis). (5.3)
---------------------------- ADVERSE REACTIONS -----------------------------
Most common adverse reactions are: hemorrhage,
thrombocytopenia, HIT (with or without thrombosis),
hypersensitivity reactions, and elevations of aminotransferase
levels. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact B. Braun
Medical Inc. at 1-800-227-2862 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------- DRUG INTERACTIONS --------------------------
•
Drugs that interfere with platelet aggregation may induce
bleeding. (7)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 05/2016
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Heparin Sodium Injection in 0.9% Sodium Chloride at the concentration of 2 USP units/mL is indicated as
an anticoagulant to maintain catheter patency.
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
Confirm the selection of the correct formulation and strength prior to administration of the drug.
This product should be administered by intravenous infusion.
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not use Heparin Sodium in 0.9% Sodium Chloride Injection as a “catheter lock flush” product.
Do not admix with other drugs.
Do not use plastic containers in series connection.
This product should not be infused under pressure.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
2.2 Maintenance of Catheter Patency
Although the rate of infusion of the 2 USP units/mL formulation is dependent upon the age, weight, clinical
condition of the patient, and the procedure being employed, an infusion rate of 3 mL/hour has been found
to be satisfactory.
3 DOSAGE FORMS AND STRENGTHS
• Heparin Sodium 1,000 USP units per 500 mL (2 USP units per mL) in 0.9% Sodium Chloride
Injection.
4 CONTRAINDICATIONS
The use of HEPARIN SODIUM is contraindicated in patients:
• With history of heparin-induced thrombocytopenia (HIT) (With or Without Thrombosis) [see Warnings
and Precautions (5.3)]
• With a known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse
Reactions (6.1)]
5 WARNINGS AND PRECAUTIONS
5.1 Fatal Medication Errors
Do not use this product as a “catheter lock flush” product. Heparin is supplied in various strengths. Fatal
hemorrhages have occurred due to medication errors. Carefully examine all heparin products to confirm
the correct container choice prior to administration of the drug.
5.2 Hemorrhage
Hemorrhage, including fatal events, has occurred in patients receiving HEPARIN SODIUM. Avoid using
heparin in the presence of major bleeding, except when the benefits of heparin therapy outweigh the
potential risks.
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hemorrhage can occur at virtually any site in patients receiving heparin. Adrenal hemorrhage (with
resultant acute adrenal insufficiency), ovarian hemorrhage, and retroperitoneal hemorrhage have
occurred during anticoagulant therapy with heparin [see Adverse Reactions (6.1]). A higher incidence of
bleeding has been reported in patients, particularly women, over 60 years of age [see Clinical
Pharmacology (12.3)]. An unexplained fall in hematocrit or fall in blood pressure should lead to serious
consideration of a hemorrhagic event.
Use heparin sodium with caution in disease states in which there is increased risk of hemorrhage,
including:
•
Cardiovascular — Subacute bacterial endocarditis. Severe hypertension.
•
Surgical — During and immediately following (a) spinal tap or spinal anesthesia or (b) major surgery,
especially involving the brain, spinal cord or eye.
•
Hematologic — Conditions associated with increased bleeding tendencies, such as hemophilia,
thrombocytopenia and some vascular purpuras.
•
Patients with hereditary antithrombin III deficiency receiving concurrent antithrombin III therapy – The
anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in
patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, reduce the heparin
dose during concomitant treatment with antithrombin III (human).
•
Gastrointestinal — Ulcerative lesions and continuous tube drainage of the stomach or small intestine.
Other — Menstruation, liver disease with impaired hemostasis.
5.3 Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis)
HIT is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may
progress to the development of venous and arterial thromboses, a condition known as HIT with
thrombosis. Thrombotic events may also be the initial presentation for HIT. These serious
thromboembolic events include deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis,
limb ischemia, stroke, myocardial infarction, thrombus formation on a prosthetic cardiac valve, mesenteric
thrombosis, renal arterial thrombosis, skin necrosis, gangrene of the extremities that may lead to
amputation, and possibly death. Monitor thrombocytopenia of any degree closely. If the platelet count falls
below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT,
and, if necessary, administer an alternative anticoagulant.
HIT can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with
thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT.
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.4 Thrombocytopenia
Thrombocytopenia has been reported to occur in patients receiving heparin with a reported incidence of
up to 30%. It can occur 2 to 20 days (average 5 to 9) following the onset of heparin therapy. Obtain
platelet counts before and periodically during heparin therapy. Monitor thrombocytopenia of any degree
closely. If the count falls below 100,000/mm3 or if recurrent thrombosis develops, promptly discontinue
heparin, evaluate for HIT, and, if necessary, administer an alternative anticoagulant [see Warnings and
Precautions (5.3)].
5.5 Hypersensitivity Reactions
Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-
threatening situations. [see Adverse Reactions (6.1)].
Because Heparin Sodium in 0.9% Sodium Chloride Injection is derived from animal tissue, monitor for
signs and symptoms of hypersensitivity when it is used in patients with a history of allergy.
6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling:
•
Fatal Medication Errors [see Warnings and Precautions (5.1)]
•
Hemorrhage [see Warnings and Precautions (5.2)]
•
Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) [see Warnings and
Precautions (5.3)]
•
Thrombocytopenia [see Warnings and Precautions (5.4)]
•
Hypersensitivity [see Warnings and Precautions (5.5)]
6.1 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of heparin sodium.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency.
•
Hemorrhage - Hemorrhage is the chief complication that may result from heparin therapy [see
Warnings and Precautions (5.2)]. Gastrointestinal or urinary tract bleeding during anticoagulant
therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at any site but
certain specific hemorrhagic complications may be difficult to detect:
-
Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred with heparin
therapy, including fatal cases. Ovarian (corpus luteum) hemorrhage developed in a number of
women of reproductive age receiving short- or long-term anticoagulant therapy.
-
Retroperitoneal hemorrhage.
•
Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and
Thrombocytopenia: [see Warnings and Precautions (5.3 and 5.4)]
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Hypersensitivity - Generalized hypersensitivity reactions have been reported with chills, fever, and
urticaria as the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and
vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching and burning,
especially on the plantar site of the feet, may occur [see Warnings and Precautions (5.5)].
•
Elevations of serum aminotransferases –Significant elevations of aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) levels have occurred in patients who have received
heparin.
•
Others - Osteoporosis following long-term administration of high-doses of heparin, cutaneous
necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient
alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin sodium have also been
reported.
7 DRUG INTERACTIONS
7.1 Platelet Inhibitors
Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole,
hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic
defense of heparinized patients) may induce bleeding and should be used with caution in patients
receiving heparin sodium.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of
adverse maternal or fetal outcomes in humans. No teratogenicity was observed in animal reproduction
studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses,
approximately 2777 times the recommended human dose (MRHD) for maintenance of catheter patency of
heparin [see Data]. In pregnant animals, doses up to 2777 times higher than the human daily dose of
heparin resulted in increased resorptions. Consider the benefits and risks of HEPARIN SODIUM IN 0.9%
SODIUM CHLORIDE INJECTION to a pregnant woman and possible risks to the fetus when prescribing
HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE INJECTION.
The estimated background risk of major birth defects and miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Data
Human Data
The maternal and fetal outcomes associated with uses of heparin via various dosing methods and
administration routes during pregnancy have been investigated in numerous studies. These
studies generally reported normal deliveries with no maternal or fetal bleeding and no other
complications.
Animal Data
In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously
during organogenesis at a dose of 10,000 USP units/kg/day, approximately 2777 times the human daily
dose. The number of early resorptions increased in both species. There was no evidence of teratogenic
effects.
8.2 Lactation
Risk Summary
There is no information regarding the presence of HEPARIN SODIUM IN 0.9% SODIUM CHLORIDE
INJECTION in human milk, the effects on the breastfed infant, or the effects on milk production. Due to
its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk
would not be orally absorbed by a nursing infant. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for HEPARIN SODIUM IN 0.9% SODIUM
CHLORIDE INJECTION and any potential adverse effects on the breastfed infant from HEPARIN
SODIUM IN 0.9% SODIUM CHLORIDE INJECTION or from the underlying maternal condition [see Use
in Specific Populations (8.4)].
8.4 Pediatric Use
There are no adequate and well controlled studies on heparin use in pediatric patients.
8.5 Geriatric Use
There are limited adequate and well-controlled studies in patients 65 years and older. However, a higher
incidence of bleeding has been reported in patients over 60 years of age, especially women [see Warnings
and Precautions (5.2)].
10 OVERDOSAGE
Bleeding is the chief sign of heparin overdosage.
Neutralization of heparin effect:
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
When clinical circumstances (bleeding) require reversal of heparinization, protamine sulfate (1% solution)
by slow infusion will neutralize heparin sodium. No more than 50 mg should be administered, very
slowly, in any 10 minute period. Each mg of protamine sulfate neutralizes approximately 100 USP Heparin
Units. The amount of protamine required decreases over time as heparin is metabolized. Although the
metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to
have a half-life of about 1/2 hour after intravenous injection.
Because fatal reactions often resembling anaphylaxis have been reported, protamine sulfate should be
given only when resuscitation techniques and treatment of anaphylactoid shock are readily available.
For additional information, consult the prescribing information for Protamine Sulfate Injection, USP.
11 DESCRIPTION
Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called
glycosaminoglycans having anticoagulant properties. It is composed of polymers of alternating derivations
of alpha-L-iduronic acid 2-sulfate (1), 2-deoxy-2-sulfamino-alpha-D-glucose 6-sulfate (2), beta-D
glucuronic acid (3), 2-acetamido-2-deoxy-alpha-D-glucose (4), and alpha-L-iduronic acid (5).
Structure of Heparin Sodium (representative subunits):
Heparin Sodium 1,000 USP units per 500 mL (2 USP units per mL) in 0.9% Sodium Chloride Injection is a
sterile, nonpyrogenic solution prepared from Heparin Sodium USP (derived from porcine intestinal mucosa
and standardized for use as an anticoagulant) in 0.9% Sodium Chloride Injection. It is to be administered
by intravenous injection. The potency is determined by a biological assay using a USP reference standard
based on units of heparin activity per milligram.
Each 100 mL contains 0.43 g Dibasic Sodium Phosphate•7H2O USP and 0.037 g Citric Acid Anhydrous
USP as a buffer system, 0.9 g Sodium Chloride USP, and Water for Injection USP qs.
pH: 7.0 (6.8-7.2); Calculated Osmolarity: 360 mOsmol/liter
Concentration of Electrolytes (mEq/liter): Sodium 186; Chloride 154; Phosphate (HPO= 4) 32; Citrate 6
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The plastic container is made from a multilayered film specifically developed for parenteral drugs. It
contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized
copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-
solution unit is a closed system and is not dependent upon entry of external air during administration. The
container is overwrapped to provide protection from the physical environment and to provide an additional
moisture barrier when necessary.
The plastic container is not made with natural rubber latex, PVC or DEHP.
The closure system has two ports; the one for the administration set has a tamper evident plastic
protector.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and
in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in
combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor
X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed, larger
amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion
of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation
of the fibrin stabilizing factor.
12.2 Pharmacodynamics
Bleeding time is usually unaffected by heparin.
12.3 Pharmacokinetics
Loglinear plots of heparin plasma concentrations with time for a wide range of dose levels are linear which
suggests the absence of zero order processes. Liver and the reticuloendothelial system are the sites of
biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (t½ = 10 minutes) and
after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship
between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of
heparin.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term studies in animals to evaluate the carcinogenic potential, reproduction studies in animals to
determine effects on fertility of males and females, and studies to determine mutagenic potential have not
been conducted.
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
Heparin Sodium in 0.9% Sodium Chloride Injection is supplied sterile and nonpyrogenic in Full Fill 500 mL
EXCEL® Containers packaged 24 per case.
NDC
REF
Concentration
Size
0264-9872-10
P8721
Heparin Sodium 1,000
USP units per 500 mL
(2 USP units per mL) in
0.9% Sodium Chloride
Injection
500 mL
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from
freezing. It is recommended that the product be stored at room temperature (25°C); however, brief
exposure up to 40°C does not adversely affect the product.
Storage in automated dispensing machines: Brief exposure up to 2 weeks to ultraviolet or fluorescent light
does not adversely affect the product labeling legibility; prolonged exposure can cause fading of the red
label. Rotate stock frequently.
17 PATIENT COUNSELING INFORMATION
Hemorrhage
Inform patients that it may take them longer than usual to stop bleeding, that they may bruise and/or
bleed more easily when they are treated with heparin, and that they should report any unusual bleeding
or bruising to their physician. Hemorrhage can occur at virtually any site in patients receiving heparin.
Fatal hemorrhages have occurred [see Warnings and Precautions (5.2)].
Prior to Surgery
Advise patients to inform physicians and dentists that they are receiving heparin before any surgery is
scheduled [see Warnings and Precautions (5.2)].
Heparin-Induced Thrombocytopenia
Inform patients of the risk of heparin-induced thrombocytopenia (HIT). HIT may progress to the
development of venous and arterial thromboses, a condition known as heparin-induced thrombocytopenia
and thrombosis (HITT). HIT (With or Without Thrombosis) can occur up to several weeks after the
discontinuation of heparin therapy [see Warnings and Precautions (5.3 and 5.4)].
Hypersensitivity
Inform patients that generalized hypersensitivity reactions have been reported.
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other Medications
Because of the risk of hemorrhage, advise patients to inform their physicians and dentists of all
medications they are taking, including non-prescription medications, and before starting any new
medication [see Drug Interactions (7.1)].
EXCEL is a registered trademark of B. Braun Medical Inc.
B. Braun Medical Inc.
Bethlehem, PA 18018-3524 USA
1-800-227-2862
Y36-002-901 LD-240-6
Reference ID: 3930402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019953s032lbl.pdf', 'application_number': 19953, 'submission_type': 'SUPPL ', 'submission_number': 32}
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NDA 19-957/S-011
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PRODUCT INFORMATION
CUTIVATE®
(fluticasone propionate ointment)
Ointment, 0.005%
For Dermatologic Use Only—
Not for Ophthalmic Use.
DESCRIPTION: CUTIVATE (fluticasone propionate ointment) Ointment, 0.005% contains fluticasone propionate [(6α,11
β,16α,17α)-6,9,-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid, S-
fluoromethyl ester], a synthetic fluorinated corticosteroid, for topical dermatologic use. The topical corticosteroids
constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.
Chemically, fluticasone propionate is C25H31F3O5S. It has the following structural formula:
Fluticasone propionate has a molecular weight of 500.6. It is a white to off-white powder and is insoluble in water.
Each gram of CUTIVATE Ointment contains fluticasone propionate 0.05 mg in a base of liquid paraffin,
microcrystalline wax, propylene glycol, and sorbitan sesquioleate.
CLINICAL PHARMACOLOGY: Like other topical corticosteroids, fluticasone propionate has anti-inflammatory,
antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in
general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins,
collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of
inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid.
Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Fluticasone propionate is lipophilic and has a strong affinity for the glucocorticoid receptor. It has weak affinity for the
progesterone receptor, and virtually no affinity for the mineralocorticoid, estrogen, or androgen receptors. The therapeutic
potency of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. The half-life of the fluticasone
propionate-glucocorticoid receptor complex is approximately 10 hours.
Studies performed with CUTIVATE Ointment indicate that it is in the medium range of potency as compared with other
topical corticosteroids.
Pharmacokinetics: Absorption: The activity of CUTIVATE is due to the parent drug, fluticasone propionate. The extent of
percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-011
Page 2
the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact
skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.
In a study of 6 healthy volunteers applying 25 g of fluticasone propionate ointment 0.005% twice daily to the trunk and
legs for up to 5 days under occlusion, plasma levels of fluticasone ranged from 0.08 to 0.22 ng/mL.
In an animal study using radiolabeled 0.05% fluticasone propionate cream and ointment preparations, rats received a
topical dose of 1 g/kg for a 24-hour period. Total recovery of radioactivity was approximately 80% at the end of 7 days.
The majority of the dose (73%) was recovered from the surface of the application site. Less than 1% of the dose was
recovered in the skin at the application site. Approximately 5% of the dose was absorbed systemically through the skin.
Absorption from the skin continued for the duration of the study (7 days), indicating a long retention time at the application
site.
Distribution: Following intravenous administration of 1 mg of fluticasone propionate in healthy volunteers, the initial
disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The
apparent volume of distribution averaged 4.2 L/kg (range, 2.3-16.7 L/kg). The percentage of fluticasone propionate bound
to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes.
Fluticasone propionate is not significantly bound to human transcortin.
Metabolism: No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone
propionate incubated in a human skin homogenate. The total blood clearance of systemically absorbed fluticasone
propionate averages 1093 mL/min (range, 618-1702 mL/min) after a 1-mg intravenous dose, with renal clearance
accounting for less than 0.02% of the total. Fluticasone propionate is metabolized in the liver by cytochrome P450
3A4-mediated hydrolysis of the 5-fluoromethyl carbothioate grouping. This transformation occurs in 1 metabolic step to
produce the inactive 17-β-carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has
approximately 2000 times less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro
and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human
hepatoma cells have not been detected in man.
Excretion: Following an intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed
polyexponential kinetics and had an average terminal half-life of 7.2 hours (range, 3.2-11.2 hours).
INDICATIONS AND USAGE: CUTIVATE Ointment is a medium potency corticosteroid indicated
for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses
in adult patients.
CONTRAINDICATIONS: CUTIVATE Ointment is contraindicated in those patients with a history of hypersensitivity to
any of the components in the preparation
PRECAUTIONS:
General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis
suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of
Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical
corticosteroids while on treatment.
Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for
evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary
free cortisol tests.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-011
Page 3
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of
application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon
discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur,
requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information
for those products.
Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to
body mass ratios (see PRECAUTIONS: Pediatric Use).
Fluticasone propionate ointment, 0.005% may cause local cutaneous adverse reactions (see ADVERSE REACTIONS).
If irritation develops, CUTIVATE Ointment should be discontinued and appropriate therapy instituted. Allergic contact
dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as
with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate
diagnostic patch testing.
If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a
favorable response does not occur promptly, use of CUTIVATE Ointment should be discontinued until the infection has
been adequately controlled.
CUTIVATE Ointment should not be used in the presence of preexisting skin atrophy and should not be used where
infection is present at the treatment site. CUTIVATE Ointment should not be used in the treatment of rosacea and perioral
dermatitis.
Information for Patients: Patients using topical corticosteroids should receive the following information and instructions:
1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped so as to be occlusive unless directed by
the physician.
4. Patients should report to their physician any signs of local adverse reactions.
5. This medication should not be used on the face, underarms, or groin areas unless directed by a physician.
6. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within
2 weeks, contact the physician.
Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression:
ACTH stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
A concentrated fluticasone propionate ointment, 0.05% (10 times that of the marketed fluticasone propionate ointment,
0.005%) suppressed 24-hour urinary free cortisol levels in 2 of 6 patients when used at a dose of 30 g/day for a week in
patients with psoriasis or atopic eczema. No suppression of A.M. plasma cortisol was observed. In a second study of the
same concentrated formulation of fluticasone propionate ointment, 0.05%, depression of A.M. plasma cortisol levels was
noted in 2 of 8 normal volunteers when applied at doses of 50 g/day for 21 days. Morning plasma levels returned to normal
levels within 4 days upon discontinuation of fluticasone propionate. In this study there was no corresponding decrease in
24-hour urinary free cortisol levels.
In a study of 35 pediatric patients treated with fluticasone propionate ointment 0.005% for atopic
dermatitis over at least 35% of body surface area, subnormal adrenal function was observed with
cosyntropin stimulation testing at the end of 3 to 4 weeks of treatment in 4 patients who had normal
testing prior to treatment. It is not known if these patients had recovery of adrenal function because
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-011
Page 4
follow-up testing was not performed (see PRECAUTIONS:Pediatric Use, and ADVERSE
REACTIONS). Adrenal suppression was indicated by either a ≤ 5 mcg/dL pre-stimulation cortisol, or
a cosyntropin post-stimulation cortisol ≤ 18 mcg/dL, and/or an increase of < 7 mcg/dL from the
baseline cortisol level.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Two 18-month studies were performed in mice to evaluate
the carcinogenic potential of fluticasone propionate when given topically (as an 0.05% ointment) and orally. No evidence of
carcinogenicity was found in either study.
Fluticasone propionate was not mutagenic in the standard Ames test, E. coli fluctuation test, S. cerevisiae gene
conversion test, or Chinese Hamster ovarian cell assay. It was not clastogenic in mouse micronucleus or cultured human
lymphocyte tests.
In a fertility and general reproductive performance study in rats, fluticasone propionate administered subcutaneously to
females at up to 50 mcg/kg per day and to males at up to 100 mcg/kg per day (later reduced to 50 mcg/kg per day) had no
effect upon mating performance or fertility. These doses are approximately 150 and 300 times, respectively, the human
systemic exposure following use of the recommended human topical dose of fluticasone propionate ointment, 0.005%,
assuming human percutaneous absorption of approximately 3% and the use in a 70-kg person of 15 g/day.
Pregnancy: Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory
animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be
teratogenic after dermal application in laboratory animals. Teratology studies in the mouse demonstrated fluticasone
propionate to be teratogenic (cleft palate) when administered subcutaneously in doses of 45 mcg/kg per day and 150 mcg/kg
per day. This dose is approximately 140 and 450 times, respectively, the human topical dose of fluticasone propionate
ointment, 0.005%. There are no adequate and well-controlled studies in pregnant women. CUTIVATE Ointment should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Systemically administered corticosteroids appear in human milk and could suppress growth, interfere
with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration
of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because
many drugs are excreted in human milk, caution should be exercised when CUTIVATE Ointment is administered to a
nursing woman.
Pediatric Use: Use of CUTIVATE Ointment in pediatric patients is not recommended.
In a study of 35 pediatric patients treated with fluticasone propionate ointment 0.005% for atopic
dermatitis over at least 35% of body surface area, subnormal adrenal function was observed with
cosyntropin stimulation testing at the end of 3 to 4 weeks of treatment in 4 patients who had normal
testing prior to treatment. It is not known if these patients had recovery of adrenal function because
follow-up testing was not performed (see PRECAUTIONS:Pediatric Use, and ADVERSE
REACTIONS). The decreased responsiveness to cosyntropin testing was not correlated to age of
patient, amount of fluticasone propionate ointment used, or serum levels of fluticasone propionate.
Plasma fluticasone propionate were not performed in a six-month old patient who demonstrated an
abnormal response to cosyntropin stimulation testing.
Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis
suppression and Cushing’s syndrome than mature patients because of a larger skin surface to body
weight ratio.
HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial
hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal
suppression in pediatric patients include low plasma cortisol levels and an absence of response to ACTH stimulation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-011
Page 5
Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
Geriatric Use: A limited number of patients above 65 years of age (n = 203) have been treated with CUTIVATE Ointment
in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety,
the adverse reactions reported in this population were similar to those reported by younger patients. Based on available data,
no adjustment of dosage of CUTIVATE in geriatric patients is warranted.
ADVERSE REACTIONS: In controlled clinical trials, the total incidence of adverse reactions associated with the use of
CUTIVATE Ointment was approximately 4%. These adverse reactions were usually mild, self-limiting, and consisted
primarily of pruritus, burning, hypertrichosis, increased erythema, hives, irritation, and lightheadedness. Each of these
events occurred individually in less than 1% of patients.
In a study of 35 pediatric patients treated with fluticasone propionate ointment 0.005% for atopic dermatitis over at least
35% of body surface area, subnormal adrenal function was observed with cosyntropin stimulation testing at the end of 3 to 4
weeks of treatment in 4 patients who had normal testing prior to treatment. It is not known if these patients had recovery of
adrenal function because follow-up testing was not performed (see PRECAUTIONS:Pediatric Use, and ADVERSE
REACTIONS). Telangiectasia on the face was noted in one patient on the eighth day of a four week treatment period.
Facial use was discontinued and the telangiectasia resolved.
The following additional local adverse reactions have been reported infrequently with topical corticosteroids, including
fluticasone propionate, and they may occur more frequently with the use of occlusive dressings and higher potency
corticosteroids. These reactions are listed in an approximately decreasing order of occurrence: dryness, folliculitis,
acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy,
striae, and miliaria. Also, there are reports of the development of pustular psoriasis from chronic plaque psoriasis following
reduction or discontinuation of potent topical corticosteroid products.
OVERDOSAGE: Topically applied CUTIVATE Ointment can be absorbed in sufficient amounts to produce systemic
effects (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION: Apply a thin film of CUTIVATE Ointment to the affected skin areas twice daily.
Rub in gently.
CUTIVATE Ointment should not be used with occlusive dressings.
Geriatric Use: In studies where geriatric patients (65 years of age or older, see PRECAUTIONS) have been treated with
CUTIVATE Ointment, safety did not differ from that in younger patients; therefore, no dosage adjustment is recommended.
HOW SUPPLIED: CUTIVATE Ointment, 0.005% is supplied in:
15-g tubes (NDC 0173-0431-00)
30-g tubes (NDC 0173-0431-01)
60-g tubes (NDC 0173-0431-02)
Store between 2°°°° and 30°°°°C (36°°°° and 86°°°°F).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-957/S-011
Page 6
GlaxoSmithKline
Research Triangle Park, NC 27709
December 2001
RL-
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Jonathan Wilkin
1/18/02 04:31:20 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19957s11lbl.pdf', 'application_number': 19957, 'submission_type': 'SUPPL ', 'submission_number': 11}
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/N-19-962S013_Toprol_prntlbl.pdf', 'application_number': 19962, 'submission_type': 'SUPPL ', 'submission_number': 13}
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______________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TOPROL
XL safely and effectively. See full prescribing information for TOPROL-XL.
TOPROL-XL (metoprolol succinate) Tablet, Extended Release for Oral
Use
INITIAL US APPROVAL: 1992
WARNING: ISCHEMIC HEART DISEASE
(See Full Prescribing Information for complete boxed warning)
Following abrupt cessation of therapy with beta-blocking agents,
exacerbations of angina pectoris and myocardial infarction have
occurred. Warn patients against interruption or discontinuation of
therapy without the physician’s advice. (5.1)
-----------INDICATIONS AND USAGE-------------
TOPROL-XL, metoprolol succinate, is a beta1-selective adrenoceptor
blocking agent.
TOPROL-XL is indicated for the treatment of:
•
Hypertension (1.1)
•
Angina Pectoris (1.2)
•
Heart Failure - for the treatment of stable, symptomatic (NYHA Class II
or III) heart failure of ischemic, hypertensive, or cardiomyopathic
origin.(1.3)
--------DOSAGE AND ADMINISTRATION-------
● Administer once daily. Dosing of TOPROL-XL should be
individualized. (2)
● Heart Failure: Recommended starting dose is 12.5 mg or 25 mg doubled
every two weeks to the highest dose tolerated or up to 200 mg. (2.3)
•
Hypertension: Usual initial dosage is 25 to 100 mg once daily. The
dosage may be increased at weekly (or longer) intervals until optimum
blood pressure reduction is achieved. Dosages above 400 mg per day
have not been studied. (2.1)
•
Angina Pectoris: Usual initial dosage is 100 mg once daily. Gradually
increase the dosage at weekly intervals until optimum clinical response
has been obtained or there is an unacceptable bradycardia. Dosages
above 400 mg per day have not been studied. (2.2)
• Switching from immediate release metoprolol to TOPROL-XL: use the
same total daily dose of TOPROL-XL. (2)
------DOSAGE FORMS AND STRENGTHS------
●
TOPROL-XL Extended Release Tablets (metoprolol succinate):
25mg, 50 mg, 100 mg and 200 mg. (3)
-------------CONTRAINDICATIONS----------------
● Known hypersensitivity to product components. (4)
● Severe bradycardia. (4)
● Heart block greater than first degree. (4)
● Cardiogenic shock. (4)
● Decompensated cardiac failure. (4)
● Sick sinus syndrome without a pacemaker. (4)
---------WARNINGS AND PRECAUTIONS-------
•
Heart Failure: Worsening cardiac failure may occur. (5.2)
•
Bronchospastic Disease: Avoid beta blockers. (5.3)
•
Pheochromocytoma: If required, first initiate therapy with an alpha
blocker. (5.4)
•
Major Surgery: Avoid initiation of high-dose extended release
metoprolol in patients undergoing non-cardiac surgery because it has
been associated with bradycardia, hypotension, stroke and death. Do not
routinely withdraw chronic beta blocker therapy prior to surgery. (5.5)
•
Diabetes and Hypoglycemia: May mask tachycardia occurring with
hypoglycemia (5.6)
•
Patients with Hepatic Impairment: (5.7)
•
Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might
precipitate a thyroid storm (5.8)
•
Anaphylactic Reactions: Patients may be unresponsive to the usual doses
of epinephrine used to treat allergic reaction (5.9)
•
Peripheral Vascular Disease: Can aggravate symptoms of arterial
insufficiency (5.10)
•
Calcium Channel Blockers: Because of significant inotropic and
chronotropic effects in patients treated with beta-blockers and calcium
channel blockers of the verapamil and diltiazem type, caution should be
exercised in patients treated with these agents concomitantly (5.11).
----------------ADVERSE REACTIONS--------------
•
Most common adverse reactions: tiredness, dizziness, depression,
shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash
(6.1)
To
report
SUSPECTED
ADVERSE
REACTIONS,
contact
AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------DRUG INTERACTIONS-----------
•
Catecholamine-depleting drugs may have an additive effect when given
with beta-blocking agents (7.1)
•
CYP2D6 Inhibitors are likely to increase metoprolol concentration (7.2)
•
Concomitant use of glycosides, clonidine, and diltiazem and verapamil
with beta-blockers can increase the risk of bradycardia (7.3)
•
Beta-blockers including metoprolol, may exacerbate the rebound
hypertension that can follow the withdrawal of clonidine (7.3)
--------USE IN SPECIFIC POPULATIONS-------
•
Pregnancy: There are no adequate and well-controlled studies in
pregnant women. Use this drug during pregnancy only if clearly needed.
(8.1)
•
Nursing Mothers: Consider possible infant exposure. (8.3)
•
Pediatrics: Safety and effectiveness have not been established in patients
< 6 years of age. (8.4)
•
Geriatrics: No notable difference in efficacy or safety vs. younger
patients. (8.5)
•
Hepatic Impairment: Consider initiating TOPROL-XL therapy at low
doses and gradually increase dosage to optimize therapy, while
monitoring closely for adverse events. (8.6)
--------SEE 17 FOR PATIENT COUNSELING INFORMATION---------
JUNE 2009
Full Prescribing Information: Contents*
1
INDICATIONS AND USAGE................................................ 3
1.1
Hypertension....................................................................... 3
1.2
Angina Pectoris .................................................................. 3
1.3
Heart Failure........................................................................ 3
2
DOSAGE AND ADMINISTRATION ..................................... 3
2.1
Hypertension....................................................................... 3
2.2
Angina Pectoris .................................................................. 3
2.3
Heart Failure........................................................................ 4
3
DOSAGE FORMS AND STRENGTHS ................................ 4
4
CONTRAINDICATIONS ....................................................... 4
5
WARNINGS AND PRECAUTIONS...................................... 4
5.1
Ischemic Heart Disease...................................................... 4
5.2
Heart Failure........................................................................ 4
5.3
Bronchospastic Disease .................................................... 4
5.4
Pheochromocytoma ........................................................... 4
5.5
Major Surgery...................................................................... 4
5.6
Diabetes and Hypoglycemia...............................................5
5.7
Hepatic Impairment .............................................................5
5.8
Thyrotoxicosis .....................................................................5
5.9
Anaphylactic Reaction ........................................................5
5.10
Peripheral Vascular Disease ..............................................5
5.11
Calcium Channel Blockers .................................................5
6
ADVERSE REACTIONS .......................................................5
6.1
Clinical Trials Experience ...................................................5
6.2
Post-Marketing Experience.................................................6
6.3
Laboratory Test Findings....................................................6
7
DRUG INTERACTIONS ........................................................6
7.1
Catecholamine Depleting Drugs ........................................6
7.2
CYP2D6 Inhibitors ...............................................................6
7.3
Digitalis, Clonidine, and Calcium Channel Blockers .......6
8
USE IN SPECIFIC POPULATIONS ......................................6
8.1
Pregnancy ............................................................................6
8.3
Nursing Mothers ..................................................................7
8.4
Pediatric Use........................................................................7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.5
Geriatric Use ....................................................................... 7
8.6
Hepatic Impairment ............................................................ 7
8.7
Renal Impairment................................................................ 7
10
OVERDOSAGE .................................................................... 7
11
DESCRIPTION ..................................................................... 8
12
CLINICAL PHARMACOLOGY............................................. 8
12.1
Mechanism of Action.......................................................... 8
12.2
Pharmacodynamics............................................................ 9
12.3
Pharmacokinetics ............................................................... 9
13
NONCLINICAL TOXICOLOGY .......................................... 10
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility . 10
14
CLINICAL STUDIES .......................................................... 10
14.1
Angina Pectoris ................................................................ 11
14.2
Heart Failure...................................................................... 11
15.
REFERENCES ................................................................... 12
16.
HOW SUPPLIED/STORAGE AND HANDLING ................ 12
17.
PATIENT COUNSELING INFORMATION ......................... 12
*Sections or subsections omitted from the full prescribing information are
not listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: ISCHEMIC HEART DISEASE:
Following abrupt cessation of therapy with certain beta-blocking agents,
exacerbations of angina pectoris and, in some cases, myocardial infarction have
occurred. When discontinuing chronically administered TOPROL-XL, particularly
in patients with ischemic heart disease, the dosage should be gradually reduced over
a period of 1 - 2 weeks and the patient should be carefully monitored. If angina
markedly worsens or acute coronary insufficiency develops, TOPROL-XL
administration should be reinstated promptly, at least temporarily, and other
measures appropriate for the management of unstable angina should be taken.
Warn patients against interruption or discontinuation of therapy without the
physician’s advice. Because coronary artery disease is common and may be
unrecognized, it may be prudent not to discontinue TOPROL-XL therapy abruptly
even in patients treated only for hypertension (5.1).
1
INDICATIONS AND USAGE
1.1
Hypertension
TOPROL-XL is indicated for the treatment of hypertension. It may be used alone or in
combination with other antihypertensive agents [see Dosage and Administration (2)].
1.2
Angina Pectoris
TOPROL-XL is indicated in the long-term treatment of angina pectoris, to reduce angina
attacks and to improve exercise tolerance.
1.3
Heart Failure
TOPROL-XL is indicated for the treatment of stable, symptomatic (NYHA Class II or III)
heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients
already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this
population, TOPROL-XL decreased the rate of mortality plus hospitalization, largely through
a reduction in cardiovascular mortality and hospitalizations for heart failure.
2
DOSAGE AND ADMINISTRATION
TOPROL-XL is an extended release tablet intended for once daily administration. For
treatment of hypertension and angina, when switching from immediate release metoprolol to
TOPROL-XL, use the same total daily dose of TOPROL-XL. Individualize the dosage of
TOPROL-XL. Titration may be needed in some patients.
TOPROL-XL tablets are scored and can be divided; however, do not crush or chew the whole
or half tablet.
2.1
Hypertension
Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be
increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved.
In general, the maximum effect of any given dosage level will be apparent after 1 week of
therapy. Dosages above 400 mg per day have not been studied.
Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in
patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in
SBP); however some other endpoints demonstrated effectiveness [see Use in Specific
Populations (8.4)]. If selected for treatment, the recommended starting dose of TOPROL-XL
is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily.
Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or
in excess of 200 mg) once daily have not been studied in pediatric patients [see Clinical
Pharmacology (12.3)].
TOPROL-XL is not recommended in pediatric patients < 6 years of age [see Use in Specific
Populations (8.4)].
2.2
Angina Pectoris
Individualize the dosage of TOPROL-XL. The usual initial dosage is 100 mg daily, given in a
single dose. Gradually increase the dosage at weekly intervals until optimum clinical response
has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg
per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually
over a period of 1 - 2 weeks [see Warnings and Precautions (5)].
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.3
Heart Failure
Dosage must be individualized and closely monitored during up-titration. Prior to initiation of
TOPROL-XL, stabilize the dose of other heart failure drug therapy. The recommended
starting dose of TOPROL-XL is 25 mg once daily for two weeks in patients with NYHA
Class II heart failure and 12.5 mg once daily in patients with more severe heart failure.
Double the dose every two weeks to the highest dosage level tolerated by the patient or up to
200 mg of TOPROL- XL. Initial difficulty with titration should not preclude later attempts to
introduce TOPROL-XL. If patients experience symptomatic bradycardia, reduce the dose of
TOPROL-XL. If transient worsening of heart failure occurs, consider treating with increased
doses of diuretics, lowering the dose of TOPROL-XL or temporarily discontinuing it. The
dose of TOPROL-XL should not be increased until symptoms of worsening heart failure have
been stabilized.
3
DOSAGE FORMS AND STRENGTHS
25 mg tablets White, oval, biconvex, film-coated scored tablet engraved with “A/β”.
50 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/mo”.
100 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/ms”.
200 mg tablets: White, oval, biconvex, film-coated scored tablet engraved with “A/my”.
4
CONTRAINDICATIONS
TOPROL-XL is contraindicated in severe bradycardia, second or third degree heart block,
cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent
pacemaker is in place), and in patients who are hypersensitive to any component of this
product.
5
WARNINGS AND PRECAUTIONS
5.1
Ischemic Heart Disease
Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of
angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing
chronically administered TOPROL-XL, particularly in patients with ischemic heart disease
gradually reduce the dosage over a period of 1 - 2 weeks and monitor the patient. If angina
markedly worsens or acute coronary ischemia develops, promptly reinstate TOPROL-XL, and
take measures appropriate for the management of unstable angina. Warn patients not to
interrupt therapy without their physician’s advice. Because coronary artery disease is
common and may be unrecognized, avoid abruptly discontinuing TOPROL-XL in patients
treated only for hypertension.
5.2
Heart Failure
Worsening cardiac failure may occur during up-titration of TOPROL-XL. If such symptoms
occur, increase diuretics and restore clinical stability before advancing the dose of TOPROL
XL [see Dosage and Administration (2)]. It may be necessary to lower the dose of TOPROL
XL or temporarily discontinue it. Such episodes do not preclude subsequent successful
titration of TOPROL-XL.
5.3
Bronchospastic Disease
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT
RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however,
TOPROL-XL may be used in patients with bronchospastic disease who do not respond to, or
cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute,
use the lowest possible dose of TOPROL-XL. Bronchodilators, including beta2-agonists,
should be readily available or administered concomitantly [see Dosage and Administration
(2)].
5.4
Pheochromocytoma
If TOPROL-XL is used in the setting of pheochromocytoma, it should be given in
combination with an alpha blocker, and only after the alpha blocker has been initiated.
Administration of beta-blockers alone in the setting of pheochromocytoma has been
associated with a paradoxical increase in blood pressure due to the attenuation of beta-
mediated vasodilatation in skeletal muscle.
5.5
Major Surgery
Avoid initiation of a high-dose regimen of extended release metoprolol in patients undergoing
non-cardiac surgery, since such use in patients with cardiovascular risk factors has been
associated with bradycardia, hypotension, stroke and death.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to
major surgery; however, the impaired ability of the heart to respond to reflex adrenergic
stimuli may augment the risks of general anesthesia and surgical procedures.
5.6
Diabetes and Hypoglycemia
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations
such as dizziness and sweating may not be significantly affected.
5.7
Hepatic Impairment
Consider initiating TOPROL-XL therapy at doses lower than those recommended for a given
indication; gradually increase dosage to optimize therapy, while monitoring closely for
adverse events.
5.8
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as
tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
5.9
Anaphylactic Reaction
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a
variety of allergens may be more reactive to repeated challenge and may be unresponsive to
the usual doses of epinephrine used to treat an allergic reaction.
5.10 Peripheral Vascular Disease
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with
peripheral vascular disease.
5.11 Calcium Channel Blockers
Because of significant inotropic and chronotropic effects in patients treated with beta-
blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be
exercised in patients treated with these agents concomitantly.
6
ADVERSE REACTIONS
The following adverse reactions are described elsewhere in labeling:
•
Worsening angina or myocardial infarction. [see Warnings and Precautions (5)]
•
Worsening heart failure. [see Warnings and Precautions (5)]
•
Worsening AV block. [see Contraindications (4)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in practice. The adverse reaction
information from clinical trials does, however, provide a basis for identifying the adverse
events that appear to be related to drug use and for approximating rates.
Most adverse reactions have been mild and transient. The most common (>2%) adverse
reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and
rash.
Heart Failure: In the MERIT-HF study comparing TOPROL-XL in daily doses up to 200
mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of TOPROL-XL
patients discontinued for adverse reactions vs. 12.2% of placebo patients.
The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence
of ≥ 1% in the TOPROL-XL group and greater than placebo by more than 0.5%, regardless
of the assessment of causality.
Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥ 1 % in the
TOPROL-XL Group and Greater Than Placebo by More Than 0.5 %
TOPROL-XL
n=1990 % of patients
Placebo
n=2001 % of patients
Dizziness/vertigo
1.8
1.0
Bradycardia
1.5
0.4
Accident and/or injury
1.4
0.8
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of TOPROL
XL or immediate-release metoprolol. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type),
palpitations, peripheral edema, syncope, chest pain and hypotension.
Respiratory: Wheezing (bronchospasm), dyspnea.
Central Nervous System: Confusion, short-term memory loss, headache, somnolence,
nightmares, insomnia. anxiety/nervousness, hallucinations, paresthesia.
Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.
Hypersensitive Reactions: Pruritus.
Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male
impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis,
Peyronie’s disease, sweating, photosensitivity, taste disturbance
Potential Adverse Reactions: In addition, there are adverse reactions not listed above that
have been reported with other beta-adrenergic blocking agents and should be considered
potential adverse reactions to TOPROL-XL.
Central Nervous System: Reversible mental depression progressing to catatonia; an acute
reversible syndrome characterized by disorientation for time and place, short-term memory
loss,
emotional
lability,
clouded
sensorium,
and
decreased
performance
on
neuropsychometrics.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Laryngospasm, respiratory distress.
6.3
Laboratory Test Findings
Clinical laboratory findings may include elevated levels of serum transaminase, alkaline
phosphatase, and lactate dehydrogenase.
7
DRUG INTERACTIONS
7.1
Catecholamine Depleting Drugs
Catecholamine-depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may
have an additive effect when given with beta-blocking agents. Observe patients treated with
TOPROL-XL plus a catecholamine depletory for evidence of hypotension or marked
bradycardia, which may produce vertigo, syncope, or postural hypotension.
7.2
CYP2D6 Inhibitors
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are
likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive
metabolizer phenotype, coadministration of quinidine 100 mg and immediate release
metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol
elimination half-life. In four patients with cardiovascular disease, coadministration of
propafenone 150 mg t.i.d. with immediate release metoprolol 50 mg t.i.d. resulted in two- to
five-fold increases in the steady-state concentration of metoprolol. These increases in plasma
concentration would decrease the cardioselectivity of metoprolol.
7.3
Digitalis, Clonidine, and Calcium Channel Blockers
Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and
decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.
If clonidine and a beta blocker, such as metoprolol are co administered, withdraw the beta-
blocker several days before the gradual withdrawal of clonidine because beta-blockers may
exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing
clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days
after clonidine administration has stopped [see Warnings and Precautions (5.11)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal
survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg
patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is
administered to the pregnant animal. These studies have revealed no evidence of impaired
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human response,
use this drug during pregnancy only if clearly needed.
8.3
Nursing Mothers
Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of
breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant
exposure when TOPROL-XL is administered to a nursing woman.
8.4
Pediatric Use
One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to
placebo or to one of three dose levels of TOPROL-XL (0.2, 1.0 or 2.0 mg/kg once daily) and
followed for 4 weeks. The study did not meet its primary endpoint (dose response for
reduction in SBP).
Some pre-specified secondary endpoints demonstrated effectiveness
including:
● Dose-response for reduction in DBP,
● 1.0 mg/kg vs. placebo for change in SBP, and
● 2.0 mg/kg vs. placebo for change in SBP and DBP.
The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to
5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater
reductions were seen in some individuals [see Dosage and Administration (2.1)].
No clinically relevant differences in the adverse event profile were observed for pediatric
patients aged 6 to 16 years as compared with adult patients.
Safety and effectiveness of TOPROL-XL have not been established in patients < 6 years of
age.
8.5
Geriatric Use
Clinical studies of TOPROL-XL in hypertension did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience in hypertensive patients has not identified
differences in responses between elderly and younger patients.
Of the 1,990 patients with heart failure randomized to TOPROL-XL in the MERIT-HF trial,
50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older.
There were no notable differences in efficacy or the rate of adverse reactions between older
and younger patients.
In general, use a low initial starting dose in elderly patients given their greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
8.6
Hepatic Impairment
No studies have been performed with TOPROL-XL in patients with hepatic impairment.
Because TOPROL-XL is metabolized by the liver, metoprolol blood levels are likely to
increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower
than those recommended for a given indication; and increase doses gradually in patients with
impaired hepatic function.
8.7
Renal Impairment
The systemic availability and half-life of metoprolol in patients with renal failure do not differ
to a clinically significant degree from those in normal subjects. No reduction in dosage is
needed in patients with chronic renal failure [see Clinical Pharmacology (12.3)].
.
10
OVERDOSAGE
Signs and Symptoms - Overdosage of TOPROL-XL may lead to severe bradycardia,
hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular
block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and
vomiting.
Treatment – Consider treating the patient with intensive care. Patients with myocardial
infarction or heart failure may be prone to significant hemodynamic instability. Seek
consultation with a regional poison control center and a medical toxicologist as needed. Beta-
blocker overdose may result in significant resistance to resuscitation with adrenergic agents,
including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the
following measures.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
There is very limited experience with the use of hemodialysis to remove metoprolol;
however, metoprolol is not highly protein bound
Bradycardia: Administer intravenous atropine; repeat to effect. If the response is inadequate,
consider intravenous isoproterenol or other positive chronotropic agents. Evaluate the need
for transvenous pacemaker insertion.
Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such
as dopamine or norepinephrine.
Bronchospasm: Administer a beta2-agonist, including albuterol inhalation, or an oral
theophylline derivative.
Cardiac Failure: Administer diuretics or digoxin for congestive heart failure. For cardiogenic
shock, consider IV dobutamine, isoproterenol, or glucagon.
DESCRIPTION
TOPROL-XL, metoprolol succinate, is a beta1-selective (cardioselective) adrenoceptor
blocking agent, for oral administration, available as extended release tablets. TOPROL-XL
has been formulated to provide a controlled and predictable release of metoprolol for once-
daily administration. The tablets comprise a multiple unit system containing metoprolol
succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug
delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The
tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100
and 200 mg of metoprolol tartrate, USP, respectively. Its chemical name is (±)1
(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its
structural formula is: Structural Formula
Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. It is
freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in
dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether
and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl
fumarate, polyethylene glycol, titanium dioxide, paraffin.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not
been elucidated. However, several possible mechanisms have been proposed: (1) competitive
antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites,
leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic
outflow to the periphery; and (3) suppression of renin activity.
Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart
failure has not been elucidated.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12.2
Pharmacodynamics
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in
man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2)
reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced
tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This
preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol
also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is
detectable only at plasma concentrations much greater than required for beta-blockade.
Animal and human experiments indicate that metoprolol slows the sinus rate and decreases
AV nodal conduction.
The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In
normal subjects, metoprolol is unable to reverse the beta2-mediated vasodilating effects of
epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely
reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces
FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent
beta1-receptor blocking doses.
The relationship between plasma metoprolol levels and reduction in exercise heart rate is
independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a
30% reduction in exercise heart rate, which is attributed to beta1-blockade. Beta1-blocking
effects in the range of 30-80% of the maximal effect (approximately 8-23% reduction in
exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The
relative beta1-selectivity of metoprolol diminishes and blockade or beta2-adrenoceptors
increases at plasma concentration above 300 nmol/L.
Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension,
and heart failure there are situations in which sympathetic stimulation is vital. In patients with
severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In
the presence of AV block, beta-blockade may prevent the necessary facilitating effect of
sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial
constriction by interfering with endogenous adrenergic bronchodilator activity in patients
subject to bronchospasm and may also interfere with exogenous bronchodilators in such
patients.
In other studies, treatment with TOPROL-XL produced an improvement in left ventricular
ejection fraction. TOPROL-XL was also shown to delay the increase in left ventricular end-
systolic and end-diastolic volumes after 6 months of treatment.
12.3
Pharmacokinetics
Adults: In man, absorption of metoprolol is rapid and complete. Plasma levels following oral
administration of conventional metoprolol tablets, however, approximate 50% of levels
following intravenous administration, indicating about 50% first-pass metabolism.
Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a
concentration 78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of
the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of
R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally,
it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination
is mainly by biotransformation in the liver, and the plasma half-life ranges from
approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered
unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have
no beta-blocking activity.
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug
is approximately 10%. The systemic availability and half-life of metoprolol in patients with
renal failure do not differ to a clinically significant degree from those in normal subjects.
Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with
chronic renal failure.
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8%
of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be
inhibited by a number of drugs. Poor metabolizers and extensive metabolizers who
concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol
blood levels, decreasing metoprolol's cardioselectivity [see Drug Interactions (7.2)].
In comparison to conventional metoprolol, the plasma metoprolol levels following
administration of TOPROL-XL are characterized by lower peaks, longer time to peak and
significantly lower peak to trough variation. The peak plasma levels following once-daily
administration of TOPROL-XL average one-fourth to one-half the peak plasma levels
obtained following a corresponding dose of conventional metoprolol, administered once daily
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
or in divided doses. At steady state the average bioavailability of metoprolol following
administration of TOPROL-XL, across the dosage range of 50 to 400 mg once daily, was
77% relative to the corresponding single or divided doses of conventional metoprolol.
Nevertheless, over the 24-hour dosing interval, β1-blockade is comparable and dose-related
[see Clinical Pharmacology (12)]. The bioavailability of metoprolol shows a dose-related,
although not directly proportional, increase with dose and is not significantly affected by food
following TOPROL-XL administration.
Pediatrics: The pharmacokinetic profile of TOPROL-XL was studied in 120 pediatric
hypertensive patients (6-17 years of age) receiving doses ranging from 12.5 to 200 mg once
daily. The pharmacokinetics of metoprolol were similar to those described previously in
adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol
pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body
weight. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of
metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day
(41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no
increase in the development of spontaneously occurring benign or malignant neoplasms of
any type. The only histologic changes that appeared to be drug related were an increased
incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli
and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three
oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200
mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in
female mice receiving the highest dose than in untreated control animals. There was no
increase in malignant or total (benign plus malignant) lung tumors, nor in the overall
incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice,
and no statistically or biologically significant differences were observed between treated and
control mice of either sex for any type of tumor.
All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice,
chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test,
and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a
Salmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a study
performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60
kg patient.
14
CLINICAL STUDIES
In five controlled studies in normal healthy subjects, the same daily doses of TOPROL-XL
and immediate release metoprolol were compared in terms of the extent and duration of beta1
blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg
of immediate release metoprolol per day. In these studies, TOPROL-XL was administered
once a day and immediate release metoprolol was administered once to four times a day. A
sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the two
formulations. In each study, beta1-blockade was expressed as the percent change from
baseline in exercise heart rate following standardized submaximal exercise tolerance tests at
steady state. TOPROL-XL administered once a day, and immediate release metoprolol
administered once to four times a day, provided comparable total beta1-blockade over 24
hours (area under the beta1-blockade versus time curve) in the dose range 100-400 mg. At a
dosage of 50 mg once daily, TOPROL-XL produced significantly higher total beta1-blockade
over 24 hours than immediate release metoprolol. For TOPROL-XL, the percent reduction in
exercise heart rate was relatively stable throughout the entire dosage interval and the level of
beta1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at
peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20%
reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg TOPROL-XL once
a day, respectively. In contrast to TOPROL-XL, immediate release metoprolol given at a dose
of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia,
but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with
TOPROL-XL over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen
was required for immediate release metoprolol. A controlled cross-over study in heart failure
patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate
release metoprolol administered t.i.d., 100 mg and 200 mg TOPROL-XL once daily. A 50
mg dose of immediate release metoprolol t.i.d. produced a peak plasma level of metoprolol
similar to the peak level observed with 200 mg of TOPROL-XL. A 200 mg dose of
TOPROL-XL produced a larger effect on suppression of exercise-induced and Holter
monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate release metoprolol.
In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized
to once daily TOPROL-XL (25, 100, or 400 mg), PLENDIL® (felodipine extended release
tablets), the combination, or placebo. After 9 weeks, TOPROL-XL alone decreased sitting
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-
dose. The combination of TOPROL-XL with PLENDIL has greater effects on blood pressure.
In controlled clinical studies, an immediate release dosage form of metoprolol was an
effective antihypertensive agent when used alone or as concomitant therapy with thiazide-
type diuretics at dosages of 100-450 mg daily. TOPROL-XL, in dosages of 100 to 400 mg
once daily, produces similar β1-blockade as conventional metoprolol tablets administered two
to four times daily. In addition, TOPROL-XL administered at a dose of 50 mg once daily
lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled,
comparative, clinical studies, immediate release metoprolol appeared comparable as an
antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected
both supine and standing blood pressure. Because of variable plasma levels attained with a
given dose and lack of a consistent relationship of antihypertensive activity to drug plasma
concentration, selection of proper dosage requires individual titration.
14.1
Angina Pectoris
By blocking catecholamine-induced increases in heart rate, in velocity and extent of
myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements
of the heart at any given level of effort, thus making it useful in the long-term management of
angina pectoris.
In controlled clinical trials, an immediate release formulation of metoprolol has been shown
to be an effective antianginal agent, reducing the number of angina attacks and increasing
exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily.
TOPROL-XL, in dosages of 100 to 400 mg once daily, has been shown to possess beta-
blockade similar to conventional metoprolol tablets administered two to four times daily.
14.2
Heart Failure
MERIT-HF was a double-blind, placebo-controlled study of TOPROL-XL conducted in 14
countries including the US. It randomized 3991 patients (1990 to TOPROL-XL) with
ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia,
hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to
beta-blocker use, those expected to undergo heart surgery, and those within 28 days of
myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-
cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality.
Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics,
ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were
NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to
ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48%
had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics,
89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent,
37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean
duration of follow-up was one year. At the end of the study, the mean daily dose of
TOPROL-XL was 159 mg.
The trial was terminated early for a statistically significant reduction in all-cause mortality
(34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was
reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related
mortality and heart failure-related hospitalizations, and NYHA functional class.
The table below shows the principal results for the overall study population. The figure
below illustrates principal results for a wide variety of subgroup comparisons, including US
vs. non-US populations (the latter of which was not pre-specified). The combined endpoints
of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure
hospitalization showed consistent effects in the overall study population and the subgroups,
including women and the US population. However, in the US subgroup (n=1071) and
women (n=898), overall mortality and cardiovascular mortality appeared less affected.
Analyses of female and US patients were carried out because they each represented about
25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret
and it is not known whether these represent true differences or chance effects.
Clinical Endpoints in the MERIT-HF Study
Clinical Endpoint
Number of Patients
Relative
Risk (95%
Cl)
Risk
Reduction
With
TOPROL-XL
Nominal P-
value
Placebo
n=2001
TOPROL
XL
n=1990
All-cause mortality
plus all-caused
hospitalization*
767
641
0.81(0.73
0.90)
19%
0.00012
All-cause mortality
217
145
0.66(0.53
0.81)
34%
0.00009
11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
All-cause mortality
plus heart failure
hospitalization*
439
311
0.69(0.60
0.80)
31%
0.0000008
Cardiovascular
mortality
203
128
0.62(0.50
0.78)
38%
0.000022
Sudden death
132
79
0.59(0.45
0.78)
41%
0.0002
Death due to
worsening heart
failure
58
30
0.51(0.33
0.79)
49%
0.0023
Hospitalizations due
to worsening heart
failure†
451
317
N/A
N/A
0.0000076
Cardiovascular
hospitalization†
773
649
N/A
N/A
0.00028
*Time to first event
†Comparison of treatment groups examines the number of hospitalizations (Wilcoxon test);
relative risk and risk reduction are not applicable. Results for Subgroups in MERIT-HF
15.
REFERENCES:
1. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC et al. Effects of extended-
release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a
randomised controlled trial. Lancet. 2008; 371:1839-47.
16.
HOW SUPPLIED/STORAGE AND HANDLING
Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol
tartrate, USP, are white, biconvex, film-coated, and scored.
Tablet,
Shape
, Engravin
g, Bottle of 1
00, Unit Dose
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC
0186
Packages of 100
NDC 0186
25 mg
Oval
A/
β
1088-05
1088-39
50 mg
Round
A/
mo
1090-05
1090-39
100 mg
Round
A/
ms
1092-05
1092-39
200 mg
Oval
A/
my
1094-05
N/A
Store at 25°C (77°F). Excursions permitted To 15-30°C (59- 86°F). (See USP Controlled Room
Temperature.)
17.
PATIENT COUNSELING INFORMATION
Advise patients to take TOPROL-XL regularly and continuously, as directed, preferably with
or immediately following meals. If a dose is missed, the patient should take only the next
scheduled dose (without doubling it). Patients should not interrupt or discontinue TOPROL
XL without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks
requiring alertness until the patient’s response to therapy with TOPROL-XL has been
determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the
physician or dentist before any type of surgery that he or she is taking TOPROL-XL.
Heart failure patients should be advised to consult their physician if they experience signs or
symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
TOPROL-XL and PLENDIL are trademarks of the AstraZeneca group of companies.
© AstraZeneca 2009
Manufactured for: AstraZeneca LP
Wilmington, DE 19850
By: AstraZeneca AB
S-151 85 Södertälje, Sweden
Made in Sweden
Rev. 1/2010
13
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
2025-02-12T13:46:24.535601
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______________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TOPROL
XL safely and effectively. See full prescribing information for TOPROL-XL.
TOPROL-XL (metoprolol succinate)Tablet, Extended Release for Oral
Use
INITIAL US APPROVAL: 1992
WARNING: ISCHEMIC HEART DISEASE
(See Full Prescribing Information for complete boxed warning)
Following abrupt cessation of therapy with beta-blocking agents,
exacerbations of angina pectoris and myocardial infarction have
occurred. Warn patients against interruption or discontinuation of
therapy without the physician’s advice. (5.1)
-----------INDICATIONS AND USAGE-------------
TOPROL-XL, metoprolol succinate, is a beta1-selective adrenoceptor
blocking agent.
TOPROL-XL is indicated for the treatment of:
•
Hypertension (1.1)
•
Angina Pectoris (1.2)
•
Heart Failure - for the treatment of stable, symptomatic (NYHA Class II
or III) heart failure of ischemic, hypertensive, or cardiomyopathic
origin.(1.3)
--------DOSAGE AND ADMINISTRATION-------
● Administer once daily. Dosing of TOPROL-XL should be
individualized. (2)
● Heart Failure: Recommended starting dose is 12.5 mg or 25 mg doubled
every two weeks to the highest dose tolerated or up to 200 mg. (2.3)
•
Hypertension: Usual initial dosage is 25 to 100 mg once daily. The
dosage may be increased at weekly (or longer) intervals until optimum
blood pressure reduction is achieved. Dosages above 400 mg per day
have not been studied. (2.1)
•
Angina Pectoris: Usual initial dosage is 100 mg once daily. Gradually
increase the dosage at weekly intervals until optimum clinical response
has been obtained or there is an unacceptable bradycardia. Dosages
above 400 mg per day have not been studied. (2.2)
• Switching from immediate release metoprolol to TOPROL-XL: use the
same total daily dose of TOPROL-XL. (2)
------DOSAGE FORMS AND STRENGTHS------
●
TOPROL-XL Extended Release Tablets (metoprolol succinate):
25mg, 50 mg, 100 mg and 200 mg. (3)
-------------CONTRAINDICATIONS----------------
● Known hypersensitivity to product components. (4)
● Severe bradycardia. (4)
● Heart block greater than first degree. (4)
● Cardiogenic shock. (4)
● Decompensated cardiac failure. (4)
● Sick sinus syndrome without a pacemaker. (4)
---------WARNINGS AND PRECAUTIONS-------
•
Heart Failure: Worsening cardiac failure may occur. (5.2)
•
Bronchospastic Disease: Avoid beta blockers. (5.3)
•
Pheochromocytoma: If required, first initiate therapy with an alpha
blocker. (5.4)
•
Major Surgery: Avoid initiation of high-dose extended release
metoprolol in patients undergoing non-cardiac surgery because it has
been associated with bradycardia, hypotension, stroke and death. Do not
routinely withdraw chronic beta blocker therapy prior to surgery. (5.5,
6.1)
•
Diabetes and Hypoglycemia: May mask tachycardia occurring with
hypoglycemia (5.6)
•
Patients with Hepatic Impairment: (5.7)
•
Thyrotoxicosis: Abrupt withdrawal in patients with thyrotoxicosis might
precipitate a thyroid storm (5.8)
•
Anaphylactic Reactions: Patients may be unresponsive to the usual doses
of epinephrine used to treat allergic reaction (5.9)
•
Peripheral Vascular Disease: Can aggravate symptoms of arterial
insufficiency (5.10)
• Calcium Channel Blockers: Because of significant inotropic and
chronotropic effects in patients treated with beta-blockers and calcium
channel blockers of the verapamil and diltiazem type, caution should be
exercised in patients treated with these agents concomitantly (5.11).
----------------ADVERSE REACTIONS--------------
•
Most common adverse reactions: tiredness, dizziness, depression,
shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash
(6.1)
To
report
SUSPECTED
ADVERSE
REACTIONS,
contact
AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------DRUG INTERACTIONS-----------
•
Catecholamine-depleting drugs may have an additive effect when given
with beta-blocking agents (7.1)
•
CYP2D6 Inhibitors are likely to increase metoprolol concentration (7.2)
•
Concomitant use of glycosides, clonidine, and diltiazem and verapamil
with beta-blockers can increase the risk of bradycardia (7.3)
•
Beta-blockers including metoprolol, may exacerbate the rebound
hypertension that can follow the withdrawal of clonidine (7.3)
--------USE IN SPECIFIC POPULATIONS-------
•
Pregnancy: There are no adequate and well-controlled studies in
pregnant women. Use this drug during pregnancy only if clearly needed.
(8.1)
•
Nursing Mothers: Consider possible infant exposure. (8.3)
•
Pediatrics: Safety and effectiveness have not been established in patients
< 6 years of age. (8.4)
•
Geriatrics: No notable difference in efficacy or safety vs. younger
patients. (8.5)
•
Hepatic Impairment: Consider initiating TOPROL-XL therapy at low
doses and gradually increase dosage to optimize therapy, while
monitoring closely for adverse events. (8.6)
--------SEE 17 FOR PATIENT COUNSELING INFORMATION---------
XX/2010
Full Prescribing Information: Contents*
1
INDICATIONS AND USAGE................................................ 3
1.1
Hypertension....................................................................... 3
1.2
Angina Pectoris .................................................................. 3
1.3
Heart Failure........................................................................ 3
2
DOSAGE AND ADMINISTRATION ..................................... 3
2.1
Hypertension....................................................................... 3
2.2
Angina Pectoris .................................................................. 3
2.3
Heart Failure........................................................................ 4
3
DOSAGE FORMS AND STRENGTHS ................................ 4
4
CONTRAINDICATIONS ....................................................... 4
5
WARNINGS AND PRECAUTIONS...................................... 4
5.1
Ischemic Heart Disease...................................................... 4
5.2
Heart Failure........................................................................ 4
5.3
Bronchospastic Disease .................................................... 4
5.4
Pheochromocytoma ........................................................... 4
5.5
Major Surgery...................................................................... 4
5.6
Diabetes and Hypoglycemia...............................................5
5.7
Hepatic Impairment .............................................................5
5.8
Thyrotoxicosis .....................................................................5
5.9
Anaphylactic Reaction ........................................................5
5.10
Peripheral Vascular Disease ..............................................5
5.11
Calcium Channel Blockers .................................................5
6
ADVERSE REACTIONS .......................................................5
6.1
Clinical Trials Experience ...................................................5
6.2
Post-Marketing Experience.................................................6
6.3
Laboratory Test Findings....................................................6
7
DRUG INTERACTIONS ........................................................6
7.1
Catecholamine Depleting Drugs ........................................6
7.2
CYP2D6 Inhibitors ...............................................................6
7.3
Digitalis, Clonidine, and Calcium Channel Blockers .......6
8
USE IN SPECIFIC POPULATIONS ......................................7
8.1
Pregnancy ............................................................................7
8.3
Nursing Mothers ..................................................................7
8.4
Pediatric Use........................................................................7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.5
Geriatric Use ....................................................................... 7
8.6
Hepatic Impairment ............................................................ 7
8.7
Renal Impairment................................................................ 7
10
OVERDOSAGE .................................................................... 7
11
DESCRIPTION ..................................................................... 8
12
CLINICAL PHARMACOLOGY............................................. 9
12.1
Mechanism of Action.......................................................... 9
12.2
Pharmacodynamics............................................................ 9
12.3
Pharmacokinetics ............................................................... 9
13
NONCLINICAL TOXICOLOGY .......................................... 10
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility . 10
14
CLINICAL STUDIES .......................................................... 10
14.1
Angina Pectoris ................................................................ 11
14.2
Heart Failure...................................................................... 11
15.
REFERENCES ......... ERROR! BOOKMARK NOT DEFINED.
16.
HOW SUPPLIED/STORAGE AND HANDLING ................ 13
17.
PATIENT COUNSELING INFORMATION ......................... 13
*Sections or subsections omitted from the full prescribing information are
not listed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: ISCHEMIC HEART DISEASE:
Following abrupt cessation of therapy with certain beta-blocking agents,
exacerbations of angina pectoris and, in some cases, myocardial infarction have
occurred. When discontinuing chronically administered TOPROL-XL, particularly
in patients with ischemic heart disease, the dosage should be gradually reduced over
a period of 1 - 2 weeks and the patient should be carefully monitored. If angina
markedly worsens or acute coronary insufficiency develops, TOPROL-XL
administration should be reinstated promptly, at least temporarily, and other
measures appropriate for the management of unstable angina should be taken.
Warn patients against interruption or discontinuation of therapy without the
physician’s advice. Because coronary artery disease is common and may be
unrecognized, it may be prudent not to discontinue TOPROL-XL therapy abruptly
even in patients treated only for hypertension (5.1).
1
INDICATIONS AND USAGE
1.1
Hypertension
TOPROL-XL is indicated for the treatment of hypertension. It may be used alone or in
combination with other antihypertensive agents [see Dosage and Administration (2)].
1.2
Angina Pectoris
TOPROL-XL is indicated in the long-term treatment of angina pectoris, to reduce angina
attacks and to improve exercise tolerance.
1.3
Heart Failure
TOPROL-XL is indicated for the treatment of stable, symptomatic (NYHA Class II or III)
heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients
already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this
population, TOPROL-XL decreased the rate of mortality plus hospitalization, largely through
a reduction in cardiovascular mortality and hospitalizations for heart failure.
2
DOSAGE AND ADMINISTRATION
TOPROL-XL is an extended release tablet intended for once daily administration. For
treatment of hypertension and angina, when switching from immediate release metoprolol to
TOPROL-XL, use the same total daily dose of TOPROL-XL. Individualize the dosage of
TOPROL-XL. Titration may be needed in some patients.
TOPROL-XL tablets are scored and can be divided; however, do not crush or chew the whole
or half tablet.
2.1
Hypertension
Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be
increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved.
In general, the maximum effect of any given dosage level will be apparent after 1 week of
therapy. Dosages above 400 mg per day have not been studied.
Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in
patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in
SBP); however some other endpoints demonstrated effectiveness [see Use in Specific
Populations (8.4)]. If selected for treatment, the recommended starting dose of TOPROL-XL
is 1.0 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily.
Dosage should be adjusted according to blood pressure response. Doses above 2.0 mg/kg (or
in excess of 200 mg) once daily have not been studied in pediatric patients [see Clinical
Pharmacology (12.3)].
TOPROL-XL is not recommended in pediatric patients < 6 years of age [see Use in Specific
Populations (8.4)].
2.2
Angina Pectoris
Individualize the dosage of TOPROL-XL. The usual initial dosage is 100 mg daily, given in a
single dose. Gradually increase the dosage at weekly intervals until optimum clinical response
has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg
per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually
over a period of 1 - 2 weeks [see Warnings and Precautions (5)].
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.3
Heart Failure
Dosage must be individualized and closely monitored during up-titration. Prior to initiation of
TOPROL-XL, stabilize the dose of other heart failure drug therapy. The recommended
starting dose of TOPROL-XL is 25 mg once daily for two weeks in patients with NYHA
Class II heart failure and 12.5 mg once daily in patients with more severe heart failure.
Double the dose every two weeks to the highest dosage level tolerated by the patient or up to
200 mg of TOPROL- XL. Initial difficulty with titration should not preclude later attempts to
introduce TOPROL-XL. If patients experience symptomatic bradycardia, reduce the dose of
TOPROL-XL. If transient worsening of heart failure occurs, consider treating with increased
doses of diuretics, lowering the dose of TOPROL-XL or temporarily discontinuing it. The
dose of TOPROL-XL should not be increased until symptoms of worsening heart failure have
been stabilized.
3
DOSAGE FORMS AND STRENGTHS
25 mg tablets White, oval, biconvex, film-coated scored tablet engraved with “A/β”.
50 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/mo”.
100 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/ms”.
200 mg tablets: White, oval, biconvex, film-coated scored tablet engraved with “A/my”.
4
CONTRAINDICATIONS
TOPROL-XL is contraindicated in severe bradycardia, second or third degree heart block,
cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent
pacemaker is in place), and in patients who are hypersensitive to any component of this
product.
5
WARNINGS AND PRECAUTIONS
5.1
Ischemic Heart Disease
Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of
angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing
chronically administered TOPROL-XL, particularly in patients with ischemic heart disease,
gradually reduce the dosage over a period of 1 - 2 weeks and monitor the patient. If angina
markedly worsens or acute coronary ischemia develops, promptly reinstate TOPROL-XL, and
take measures appropriate for the management of unstable angina. Warn patients not to
interrupt therapy without their physician’s advice. Because coronary artery disease is
common and may be unrecognized, avoid abruptly discontinuing TOPROL-XL in patients
treated only for hypertension.
5.2
Heart Failure
Worsening cardiac failure may occur during up-titration of TOPROL-XL. If such symptoms
occur, increase diuretics and restore clinical stability before advancing the dose of TOPROL
XL [see Dosage and Administration (2)]. It may be necessary to lower the dose of TOPROL
XL or temporarily discontinue it. Such episodes do not preclude subsequent successful
titration of TOPROL-XL.
5.3
Bronchospastic Disease
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT
RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however,
TOPROL-XL may be used in patients with bronchospastic disease who do not respond to, or
cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute,
use the lowest possible dose of TOPROL-XL. Bronchodilators, including beta2-agonists,
should be readily available or administered concomitantly, [see Dosage and Administration
(2)].
5.4
Pheochromocytoma
If TOPROL-XL is used in the setting of pheochromocytoma, it should be given in
combination with an alpha blocker, and only after the alpha blocker has been initiated.
Administration of beta-blockers alone in the setting of pheochromocytoma has been
associated with a paradoxical increase in blood pressure due to the attenuation of beta-
mediated vasodilatation in skeletal muscle.
5.5
Major Surgery
Avoid initiation of a high-dose regimen of extended release metoprolol in patients undergoing
non-cardiac surgery, since such use in patients with cardiovascular risk factors has been
associated with bradycardia, hypotension, stroke and death.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to
major surgery, however, the impaired ability of the heart to respond to reflex adrenergic
stimuli may augment the risks of general anesthesia and surgical procedures.
5.6
Diabetes and Hypoglycemia
Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations
such as dizziness and sweating may not be significantly affected.
5.7
Hepatic Impairment
Consider initiating TOPROL-XL therapy at doses lower than those recommended for a given
indication; gradually increase dosage to optimize therapy, while monitoring closely for
adverse events.
5.8
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as
tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
5.9
Anaphylactic Reaction
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a
variety of allergens may be more reactive to repeated challenge and may be unresponsive to
the usual doses of epinephrine used to treat an allergic reaction.
5.10 Peripheral Vascular Disease
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with
peripheral vascular disease.
5.11 Calcium Channel Blockers
Because of significant inotropic and chronotropic effects in patients treated with beta-
blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be
exercised in patients treated with these agents concomitantly.
6
ADVERSE REACTIONS
The following adverse reactions are described elsewhere in labeling:
•
Worsening angina or myocardial infarction. [see Warnings and Precautions (5)]
•
Worsening heart failure. [see Warnings and Precautions (5)]
•
Worsening AV block. [see Contraindications (4)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in practice. The adverse reaction
information from clinical trials does, however, provide a basis for identifying the adverse
events that appear to be related to drug use and for approximating rates.
Most adverse reactions have been mild and transient. The most common (>2%) adverse
reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and
rash.
Heart Failure: In the MERIT-HF study comparing TOPROL-XL in daily doses up to 200
mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of TOPROL-XL
patients discontinued for adverse reactions vs. 12.2% of placebo patients.
The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence
of ≥ 1% in the TOPROL-XL group and greater than placebo by more than 0.5%, regardless
of the assessment of causality.
Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥ 1 % in the
TOPROL-XL Group and Greater Than Placebo by More Than 0.5 %
TOPROL-XL
n=1990 % of patients
Placebo
n=2001 % of patients
Dizziness/vertigo
1.8
1.0
Bradycardia
1.5
0.4
Accident and/or injury
1.4
0.8
Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of
8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and
who were not taking beta–blocker therapy, TOPROL-XL 100 mg was started 2 to 4 hours
prior to surgery then continued for 30 days at 200 mg per day. TOPROL-XL use was
associated with a higher incidence of bradycardia (6.6% vs. 2.4% ; HR 2.74; 95% CI
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.19,3.43), hypotension (15% vs. 9.7%; HR 1.55 95% CI 1.37,1.74), stroke (1.0% vs 0.5%;
HR 2.17; 95% CI 1.26,3.74) and death (3.1% vs 2.3%; HR 1.33; 95% CI 1.03, 1.74)
compared to placebo.
6.2
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of TOPROL
XL or immediate-release metoprolol. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type),
palpitations, peripheral edema, syncope, chest pain and hypotension.
Respiratory: Wheezing (bronchospasm), dyspnea.
Central Nervous System: Confusion, short-term memory loss, headache, somnolence,
nightmares, insomnia. anxiety/nervousness, hallucinations, paresthesia.
Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.
Hypersensitive Reactions: Pruritus.
Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male
impotence, tinnitus, reversible alopecia, agranulocytosis, dry eyes, worsening of psoriasis,
Peyronie’s disease, sweating, photosensitivity, taste disturbance
Potential Adverse Reactions: In addition, there are adverse reactions not listed above that
have been reported with other beta-adrenergic blocking agents and should be considered
potential adverse reactions to TOPROL-XL.
Central Nervous System: Reversible mental depression progressing to catatonia; an acute
reversible syndrome characterized by disorientation for time and place, short-term memory
loss,
emotional
lability,
clouded
sensorium,
and
decreased
performance
on
neuropsychometrics.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Laryngospasm, respiratory distress.
6.3
Laboratory Test Findings
Clinical laboratory findings may include elevated levels of serum transaminase, alkaline
phosphatase, and lactate dehydrogenase.
7
DRUG INTERACTIONS
7.1
Catecholamine Depleting Drugs
Catecholamine-depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may
have an additive effect when given with beta-blocking agents. Observe patients treated with
TOPROL-XL plus a catecholamine depletor for evidence of hypotension or marked
bradycardia, which may produce vertigo, syncope, or postural hypotension.
7.2
CYP2D6 Inhibitors
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are
likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive
metabolizer phenotype, coadministration of quinidine 100 mg and immediate release
metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol
elimination half-life. In four patients with cardiovascular disease, coadministration of
propafenone 150 mg t.i.d. with immediate release metoprolol 50 mg t.i.d. resulted in two- to
five-fold increases in the steady-state concentration of metoprolol. These increases in plasma
concentration would decrease the cardioselectivity of metoprolol.
7.3
Digitalis, Clonidine, and Calcium Channel Blockers
Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and
decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.
If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-
blocker several days before the gradual withdrawal of clonidine because beta-blockers may
exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing
clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days
after clonidine administration has stopped [see WARNINGS AND PRECAUTIONS (5.11)].
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal
survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg
patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is
administered to the pregnant animal. These studies have revealed no evidence of impaired
fertility or teratogenicity. There are no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human response,
use this drug during pregnancy only if clearly needed.
8.3
Nursing Mothers
Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of
breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant
exposure when TOPROL-XL is administered to a nursing woman.
8.4
Pediatric Use
One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to
placebo or to one of three dose levels of TOPROL-XL (0.2, 1.0 or 2.0 mg/kg once daily) and
followed for 4 weeks. The study did not meet its primary endpoint (dose response for
reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness
including:
● Dose-response for reduction in DBP,
● 1.0 mg/kg vs. placebo for change in SBP, and
● 2.0 mg/kg vs. placebo for change in SBP and DBP.
The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to
5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater
reductions were seen in some individuals [see Dosage and Administration (2.1)].
No clinically relevant differences in the adverse event profile were observed for pediatric
patients aged 6 to 16 years as compared with adult patients.
Safety and effectiveness of TOPROL-XL have not been established in patients < 6 years of
age.
8.5
Geriatric Use
Clinical studies of TOPROL-XL in hypertension did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience in hypertensive patients has not identified
differences in responses between elderly and younger patients.
Of the 1,990 patients with heart failure randomized to TOPROL-XL in the MERIT-HF trial,
50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older.
There were no notable differences in efficacy or the rate of adverse reactions between older
and younger patients.
In general, use a low initial starting dose in elderly patients given their greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
8.6
Hepatic Impairment
No studies have been performed with TOPROL-XL in patients with hepatic impairment.
Because TOPROL-XL is metabolized by the liver, metoprolol blood levels are likely to
increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower
than those recommended for a given indication; and increase doses gradually in patients with
impaired hepatic function.
8.7
Renal Impairment
The systemic availability and half-life of metoprolol in patients with renal failure do not differ
to a clinically significant degree from those in normal subjects. No reduction in dosage is
needed in patients with chronic renal failure [see Clinical Pharmacology (12.3)].
.
10
OVERDOSAGE
Signs and Symptoms - Overdosage of TOPROL-XL may lead to severe bradycardia,
hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular
block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and
vomiting.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Treatment – Consider treating the patient with intensive care. Patients with myocardial
infarction or heart failure may be prone to significant hemodynamic instability. Seek
consultation with a regional poison control center and a medical toxicologist as needed. Beta-
blocker overdose may result in significant resistance to resuscitation with adrenergic agents,
including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the
following measures.
There is very limited experience with the use of hemodialysis to remove metoprolol, however
metoprolol is not highly protein bound.
Bradycardia: Administer intravenous atropine; repeat to effect . If the response is inadequate,
consider intravenous isoproterenol or other positive chronotropic agents. Evaluate the need
for transvenous pacemaker insertion.
Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such
as dopamine or norepinephrine.
Bronchospasm: Administer a beta2-agonist, including albuterol inhalation, or an oral
theophylline derivative.
Cardiac Failure: Administer diuretics or digoxin for congestive heart failure. For cardiogenic
shock, consider IV dobutamine, isoproterenol, or glucagon.
DESCRIPTION
TOPROL-XL, metoprolol succinate, is a beta1-selective (cardioselective) adrenoceptor
blocking agent, for oral administration, available as extended release tablets. TOPROL-XL
has been formulated to provide a controlled and predictable release of metoprolol for once-
daily administration. The tablets comprise a multiple unit system containing metoprolol
succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug
delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The
tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100
and 200 mg of metoprolol tartrate, USP, respectively. Its chemical name is (±)1
(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its
structural formula is: Strucrtural Formula
Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. It is
freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in
dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether
and heptane. Inactive ingredients: silicon dioxide, cellulose compounds, sodium stearyl
fumarate, polyethylene glycol, titanium dioxide, paraffin.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not
been elucidated. However, several possible mechanisms have been proposed: (1) competitive
antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites,
leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic
outflow to the periphery; and (3) suppression of renin activity.
Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart
failure has not been elucidated.
12.2
Pharmacodynamics
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in
man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2)
reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced
tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This
preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol
also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is
detectable only at plasma concentrations much greater than required for beta-blockade.
Animal and human experiments indicate that metoprolol slows the sinus rate and decreases
AV nodal conduction.
The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In
normal subjects, metoprolol is unable to reverse the beta2-mediated vasodilating effects of
epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely
reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces
FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent
beta1-receptor blocking doses.
The relationship between plasma metoprolol levels and reduction in exercise heart rate is
independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a
30% reduction in exercise heart rate, which is attributed to beta1-blockade. Beta1-blocking
effects in the range of 30-80% of the maximal effect (approximately 8-23% reduction in
exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The
relative beta1-selectivity of metoprolol diminishes and blockade or beta2-adrenoceptors
increases at plasma concentration above 300 nmol/L.
Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension,
and heart failure there are situations in which sympathetic stimulation is vital. In patients with
severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In
the presence of AV block, beta-blockade may prevent the necessary facilitating effect of
sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial
constriction by interfering with endogenous adrenergic bronchodilator activity in patients
subject to bronchospasm and may also interfere with exogenous bronchodilators in such
patients.
In other studies, treatment with TOPROL-XL produced an improvement in left ventricular
ejection fraction. TOPROL-XL was also shown to delay the increase in left ventricular end-
systolic and end-diastolic volumes after 6 months of treatment.
12.3
Pharmacokinetics
Adults: In man, absorption of metoprolol is rapid and complete. Plasma levels following oral
administration of conventional metoprolol tablets, however, approximate 50% of levels
following intravenous administration, indicating about 50% first-pass metabolism.
Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a
concentration 78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of
the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of
R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally,
it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination
is mainly by biotransformation in the liver, and the plasma half-life ranges from
approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered
unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have
no beta-blocking activity.
Following intravenous administration of metoprolol, the urinary recovery of unchanged drug
is approximately 10%. The systemic availability and half-life of metoprolol in patients with
renal failure do not differ to a clinically significant degree from those in normal subjects.
Consequently, no reduction in metoprolol succinate dosage is usually needed in patients with
chronic renal failure.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8%
of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be
inhibited by a number of drugs. Poor metabolizers and extensive metabolizers who
concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol
blood levels, decreasing metoprolol's cardioselectivity [see Drug Interactions (7.2)].
In comparison to conventional metoprolol, the plasma metoprolol levels following
administration of TOPROL-XL are characterized by lower peaks, longer time to peak and
significantly lower peak to trough variation. The peak plasma levels following once-daily
administration of TOPROL-XL average one-fourth to one-half the peak plasma levels
obtained following a corresponding dose of conventional metoprolol, administered once daily
or in divided doses. At steady state the average bioavailability of metoprolol following
administration of TOPROL-XL, across the dosage range of 50 to 400 mg once daily, was
77% relative to the corresponding single or divided doses of conventional metoprolol.
Nevertheless, over the 24-hour dosing interval, β1-blockade is comparable and dose-related
[see Clinical Pharmacology (12)]. The bioavailability of metoprolol shows a dose-related,
although not directly proportional, increase with dose and is not significantly affected by food
following TOPROL-XL administration.
Pediatrics: The pharmacokinetic profile of TOPROL-XL was studied in 120 pediatric
hypertensive patients (6-17 years of age) receiving doses ranging from 12.5 to 200 mg once
daily. The pharmacokinetics of metoprolol were similar to those described previously in
adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol
pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body
weight. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of
metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day
(41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no
increase in the development of spontaneously occurring benign or malignant neoplasms of
any type. The only histologic changes that appeared to be drug related were an increased
incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli
and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three
oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200
mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in
female mice receiving the highest dose than in untreated control animals. There was no
increase in malignant or total (benign plus malignant) lung tumors, nor in the overall
incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice,
and no statistically or biologically significant differences were observed between treated and
control mice of either sex for any type of tumor.
All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice,
chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test,
and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a
Salmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility due to metoprolol tartrate was observed in a study
performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60
kg patient.
14
CLINICAL STUDIES
In five controlled studies in normal healthy subjects, the same daily doses of TOPROL-XL
and immediate release metoprolol were compared in terms of the extent and duration of beta1
blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg
of immediate release metoprolol per day. In these studies, TOPROL-XL was administered
once a day and immediate release metoprolol was administered once to four times a day. A
sixth controlled study compared the beta1-blocking effects of a 50 mg daily dose of the two
formulations. In each study, beta1-blockade was expressed as the percent change from
baseline in exercise heart rate following standardized submaximal exercise tolerance tests at
steady state. TOPROL-XL administered once a day, and immediate release metoprolol
administered once to four times a day, provided comparable total beta1-blockade over 24
hours (area under the beta1-blockade versus time curve) in the dose range 100-400 mg. At a
dosage of 50 mg once daily, TOPROL-XL produced significantly higher total beta1-blockade
over 24 hours than immediate release metoprolol. For TOPROL-XL, the percent reduction in
exercise heart rate was relatively stable throughout the entire dosage interval and the level of
beta1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at
peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20%
reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg TOPROL-XL once
a day, respectively. In contrast to TOPROL-XL, immediate release metoprolol given at a dose
of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia,
but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with
TOPROL-XL over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
was required for immediate release metoprolol. A controlled cross-over study in heart failure
patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate
release metoprolol administered t.i.d., 100 mg and 200 mg TOPROL-XL once daily. A 50
mg dose of immediate release metoprolol t.i.d. produced a peak plasma level of metoprolol
similar to the peak level observed with 200 mg of TOPROL-XL. A 200 mg dose of
TOPROL-XL produced a larger effect on suppression of exercise-induced and Holter
monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate release metoprolol.
In a double-blind study, 1092 patients with mild-to-moderate hypertension were randomized
to once daily TOPROL-XL (25, 100, or 400 mg), PLENDIL® (felodipine extended release
tablets), the combination, or placebo. After 9 weeks, TOPROL-XL alone decreased sitting
blood pressure by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-
dose. The combination of TOPROL-XL with PLENDIL has greater effects on blood pressure.
In controlled clinical studies, an immediate release dosage form of metoprolol was an
effective antihypertensive agent when used alone or as concomitant therapy with thiazide-
type diuretics at dosages of 100-450 mg daily. TOPROL-XL, in dosages of 100 to 400 mg
once daily, produces similar β1-blockade as conventional metoprolol tablets administered two
to four times daily. In addition, TOPROL-XL administered at a dose of 50 mg once daily
lowered blood pressure 24-hours post-dosing in placebo-controlled studies. In controlled,
comparative, clinical studies, immediate release metoprolol appeared comparable as an
antihypertensive agent to propranolol, methyldopa, and thiazide-type diuretics, and affected
both supine and standing blood pressure. Because of variable plasma levels attained with a
given dose and lack of a consistent relationship of antihypertensive activity to drug plasma
concentration, selection of proper dosage requires individual titration.
14.1
Angina Pectoris
By blocking catecholamine-induced increases in heart rate, in velocity and extent of
myocardial contraction, and in blood pressure, metoprolol reduces the oxygen requirements
of the heart at any given level of effort, thus making it useful in the long-term management of
angina pectoris.
In controlled clinical trials, an immediate release formulation of metoprolol has been shown
to be an effective antianginal agent, reducing the number of angina attacks and increasing
exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily.
TOPROL-XL, in dosages of 100 to 400 mg once daily, has been shown to possess beta-
blockade similar to conventional metoprolol tablets administered two to four times daily.
14.2
Heart Failure
MERIT-HF was a double-blind, placebo-controlled study of TOPROL-XL conducted in 14
countries including the US. It randomized 3991 patients (1990 to TOPROL-XL) with
ejection fraction ≤0.40 and NYHA Class II-IV heart failure attributable to ischemia,
hypertension, or cardiomyopathy. The protocol excluded patients with contraindications to
beta-blocker use, those expected to undergo heart surgery, and those within 28 days of
myocardial infarction or unstable angina. The primary endpoints of the trial were (1) all-
cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality.
Patients were stabilized on optimal concomitant therapy for heart failure, including diuretics,
ACE inhibitors, cardiac glycosides, and nitrates. At randomization, 41% of patients were
NYHA Class II; 55% NYHA Class III; 65% of patients had heart failure attributed to
ischemic heart disease; 44% had a history of hypertension; 25% had diabetes mellitus; 48%
had a history of myocardial infarction. Among patients in the trial, 90% were on diuretics,
89% were on ACE inhibitors, 64% were on digitalis, 27% were on a lipid-lowering agent,
37% were on an oral anticoagulant, and the mean ejection fraction was 0.28. The mean
duration of follow-up was one year. At the end of the study, the mean daily dose of
TOPROL-XL was 159 mg.
The trial was terminated early for a statistically significant reduction in all-cause mortality
(34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was
reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related
mortality and heart failure-related hospitalizations, and NYHA functional class.
The table below shows the principal results for the overall study population. The figure
below illustrates principal results for a wide variety of subgroup comparisons, including US
vs. non-US populations (the latter of which was not pre-specified). The combined endpoints
of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure
hospitalization showed consistent effects in the overall study population and the subgroups,
including women and the US population. However, in the US subgroup (n=1071) and
women (n=898), overall mortality and cardiovascular mortality appeared less affected.
Analyses of female and US patients were carried out because they each represented about
25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret
and it is not known whether these represent true differences or chance effects.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical Endpoints in the MERIT-HF Study
Clinical Endpoint
Number of Patients
Relative
Risk (95%
Cl)
Risk
Reduction
With
TOPROL-XL
Nominal P-
value
Placebo
n=2001
TOPROL
XL
n=1990
All-cause mortality
plus all-caused
hospitalization*
767
641
0.81(0.73
0.90)
19%
0.00012
All-cause mortality
217
145
0.66(0.53
0.81)
34%
0.00009
All-cause mortality
plus heart failure
hospitalization*
439
311
0.69(0.60
0.80)
31%
0.0000008
Cardiovascular
mortality
203
128
0.62(0.50
0.78)
38%
0.000022
Sudden death
132
79
0.59(0.45
0.78)
41%
0.0002
Death due to
worsening heart
failure
58
30
0.51(0.33
0.79)
49%
0.0023
Hospitalizations due
to worsening heart
failure†
451
317
N/A
N/A
0.0000076
Cardiovascular
hospitalization†
773
649
N/A
N/A
0.00028
*Time to first event
†Comparison of treatment groups examines the number of hospitalizations (Wilcoxon test);
relative risk and risk reduction are not applicable. Graph
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
16.
HOW SUPPLIED/STORAGE AND HANDLING
Tablets containing metoprolol succinate equivalent to the indicated weight of metoprolol
tartrate, USP, are white, biconvex, film-coated, and scored.
Tablet
Shape
Engraving
Bottle of 100
NDC
0186
Unit Dose
Packages of 100
NDC 0186
25 mg
Oval
A/
β
1088-05
1088-39
50 mg
Round
A/
mo
1090-05
1090-39
100 mg
Round
A/
ms
1092-05
1092-39
200 mg
Oval
A/
my
1094-05
N/A
Store at 25°C (77°F). Excursions permitted To 15-30°C (59- 86°F). (See USP Controlled Room
Temperature.)
17.
PATIENT COUNSELING INFORMATION
Advise patients to take TOPROL-XL regularly and continuously, as directed, preferably with
or immediately following meals. If a dose is missed, the patient should take only the next
scheduled dose (without doubling it). Patients should not interrupt or discontinue TOPROL
XL without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks
requiring alertness until the patient’s response to therapy with TOPROL-XL has been
determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the
physician or dentist before any type of surgery that he or she is taking TOPROL-XL.
Heart failure patients should be advised to consult their physician if they experience signs or
symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
TOPROL-XL and PLENDIL are trademarks of the AstraZeneca group of companies.
© AstraZeneca 2010
Manufactured for: AstraZeneca LP
Wilmington, DE 19850
By: AstraZeneca AB
S-151 85 Södertälje, Sweden
Made in Sweden
Rev. XX/2010
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:24.604891
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019962s041lbl.pdf', 'application_number': 19962, 'submission_type': 'SUPPL ', 'submission_number': 41}
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12,107
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1
METOPROLOL SUCCINATE
Extended-release Tablets
DESCRIPTION
Metoprolol succinate, is a beta1-selective (cardioselective)
adrenoceptor blocking agent, for oral administration, available
as extended-release tablets. Metoprolol succinate extended-
release tablet has been formulated to provide a controlled and
predictable release of metoprolol for once-daily administration.
The tablets comprise a multiple unit system containing
metoprolol succinate in a multitude of controlled release pellets.
Each pellet acts as a separate drug delivery unit and is designed
to deliver metoprolol continuously over the dosage interval. The
tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol
succinate equivalent to 25, 50, 100 and 200 mg of metoprolol
tartrate, USP, respectively. Its chemical name is (±)1-
(isopropylamino)-3-[p-(2-methoxyethyl)
phenoxy]-2-propanol
succinate (2:1) (salt). Its structural formula is:
Metoprolol succinate is a white crystalline powder with a
molecular weight of 652.8. It is freely soluble in water; soluble
in methanol; sparingly soluble in ethanol; slightly soluble in
dichloromethane and 2-propanol; practically insoluble in ethyl-
acetate, acetone, diethylether and heptane. Inactive ingredients:
silicon dioxide, cellulose compounds, sodium stearyl fumarate,
polyethylene glycol, titanium dioxide, paraffin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
CLINICAL PHARMACOLOGY
General
Metoprolol is a beta1-selective (cardioselective) adrenergic
receptor blocking agent. This preferential effect is not absolute,
however, and at higher plasma concentrations, metoprolol also
inhibits beta2-adrenoreceptors, chiefly located in the bronchial
and vascular musculature. Metoprolol has no intrinsic
sympathomimetic activity, and membrane-stabilizing activity is
detectable only at plasma concentrations much greater than
required for beta-blockade. Animal and human experiments
indicate that metoprolol slows the sinus rate and decreases AV
nodal conduction.
Clinical pharmacology studies have confirmed the beta-blocking
activity of metoprolol in man, as shown by (1) reduction in heart
rate and cardiac output at rest and upon exercise, (2) reduction
of systolic blood pressure upon exercise, (3) inhibition of
isoproterenol-induced tachycardia, and (4) reduction of reflex
orthostatic tachycardia.
The relative beta1-selectivity of metoprolol has been confirmed
by the following: (1) In normal subjects, metoprolol is unable to
reverse the beta2-mediated vasodilating effects of epinephrine.
This contrasts with the effect of nonselective beta-blockers,
which
completely
reverse
the
vasodilating
effects
of
epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1
and FVC significantly less than a nonselective beta-blocker,
propranolol, at equivalent beta1-receptor blocking doses.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
In five controlled studies in normal healthy subjects, the same
daily doses of metoprolol succinate extended-release tablets and
immediate release metoprolol were compared in terms of the
extent and duration of beta1-blockade produced. Both
formulations were given in a dose range equivalent to 100-400
mg of immediate release metoprolol per day. In these studies,
metoprolol succinate extended-release tablet was administered
once a day and immediate release metoprolol was administered
once to four times a day. A sixth controlled study compared the
beta1-blocking effects of a 50 mg daily dose of the two
formulations. In each study, beta1-blockade was expressed as the
percent change from baseline in exercise heart rate following
standardized submaximal exercise tolerance tests at steady state.
Metoprolol succinate extended- release tablet administered once
a day, and immediate release metoprolol administered once to
four times a day, provided comparable total beta1-blockade over
24 hours (area under the beta1-blockade versus time curve) in
the dose range 100–400 mg. At a dosage of 50 mg once daily,
metoprolol
succinate
extended-release
tablet
produced
significantly higher total beta1-blockade over 24 hours than
immediate release metoprolol. For metoprolol succinate
extended-release tablet, the percent reduction in exercise heart
rate was relatively stable throughout the entire dosage interval
and the level of beta1-blockade increased with increasing doses
from 50 to 300 mg daily. The effects at peak/trough (ie, at 24-
hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20%
reduction in exercise heart rate for doses of 50, 100, 200, 300
and 400 mg metoprolol succinate extended-release tablets once a
day, respectively. In contrast to metoprolol succinate extended-
release tablet, immediate release metoprolol given at a dose of
50–100 mg once a day produced a significantly larger peak
effect on exercise tachycardia, but the effect was not evident at
24 hours. To match the peak to trough ratio obtained with
metoprolol succinate extended-release tablet over the dosing
range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen
was required for immediate release metoprolol. A controlled
cross-over study in heart failure patients compared the plasma
concentrations and beta1-blocking effects of 50 mg immediate
release metoprolol administered t.i.d., 100 mg and 200 mg
metoprolol succinate extended-release tablets once daily. A 50
mg dose of immediate release metoprolol t.i.d. produced a peak
plasma level of metoprolol similar to the peak level observed
with 200 mg of metoprolol succinate extended-release tablet. A
200 mg dose of metoprolol succinate extended- release tablet
produced a larger effect on suppression of exercise-induced and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Holter-monitored heart rate over 24 hours compared to 50 mg
t.i.d. of immediate release metoprolol.
The relationship between plasma metoprolol levels and
reduction in exercise heart rate is independent of the
pharmaceutical formulation. Using an Emax model, the maximum
effect is a 30% reduction in exercise heart rate, which is
attributed to beta1-blockade. Beta1-blocking effects in the range
of 30–80% of the maximal effect (approximately 8–23%
reduction in exercise heart rate) correspond to metoprolol
plasma concentrations from 30-540 nmol/L. The relative beta1-
selectivity of metoprolol diminishes and blockade of beta2-
adrenoceptors increases at plasma concentrations above 300
nmol/L.
Although beta-adrenergic receptor blockade is useful in the
treatment of angina, hypertension, and heart failure there are
situations in which sympathetic stimulation is vital. In patients
with severely damaged hearts, adequate ventricular function
may depend on sympathetic drive. In the presence of AV block,
beta-blockade may prevent the necessary facilitating effect of
sympathetic activity on conduction. Beta2-adrenergic blockade
results in passive bronchial constriction by interfering with
endogenous adrenergic bronchodilator activity in patients
subject to bronchospasm and may also interfere with exogenous
bronchodilators in such patients.
In other studies, treatment with metoprolol succinate extended-
release tablet produced an improvement in left ventricular
ejection fraction. Metoprolol succinate extended-release tablet
was also shown to delay the increase in left ventricular end-
systolic and end-diastolic volumes after 6 months of treatment.
Pharmacokinetics
Adults
In man, absorption of metoprolol is rapid and complete. Plasma
levels following oral administration of conventional metoprolol
tablets, however, approximate 50% of levels following
intravenous administration, indicating about 50% first-pass
metabolism. Metoprolol crosses the blood-brain barrier and has
been reported in the CSF in a concentration 78% of the
simultaneous plasma concentration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Plasma levels achieved are highly variable after oral
administration. Only a small fraction of the drug (about 12%) is
bound to human serum albumin. Metoprolol is a racemic
mixture of R- and S- enantiomers, and is primarily metabolized
by CYP2D6. When administered orally, it exhibits
stereoselective metabolism that is dependent on oxidation
phenotype. Elimination is mainly by biotransformation in the
liver, and the plasma half-life ranges from approximately 3 to 7
hours. Less than 5% of an oral dose of metoprolol is recovered
unchanged in the urine; the rest is excreted by the kidneys as
metabolites that appear to have no beta-blocking activity.
Following intravenous administration of metoprolol, the urinary
recovery of unchanged drug is approximately 10%. The
systemic availability and half-life of metoprolol in patients with
renal failure do not differ to a clinically significant degree from
those in normal subjects. Consequently, no reduction in dosage
is usually needed in patients with chronic renal failure.
Metoprolol is metabolized predominantly by CYP2D6, an
enzyme that is absent in about 8% of Caucasians (poor
metabolizers) and about 2% of most other populations.
CYP2D6 can be inhibited by a number of drugs. Concomitant
use of inhibiting drugs in poor metabolizers will increase blood
levels of metoprolol several-fold, decreasing metoprolol's
cardioselectivity. (See PRECAUTIONS, Drug Interactions.)
In comparison to conventional metoprolol, the plasma
metoprolol levels following administration of metoprolol
succinate extended-release tablet are characterized by lower
peaks, longer time to peak and significantly lower peak to
trough variation. The peak plasma levels following once-daily
administration of metoprolol succinate extended-release tablet
average one-fourth to one-half the peak plasma levels obtained
following a corresponding dose of conventional metoprolol,
administered once daily or in divided doses. At steady state the
average bioavailability of metoprolol following administration
of metoprolol succinate extended-release tablet, across the
dosage range of 50 to 400 mg once daily, was 77% relative to
the corresponding single or divided doses of conventional
metoprolol. Nevertheless, over the 24-hour dosing interval, ß1-
blockade is comparable and dose-related (see CLINICAL
PHARMACOLOGY). The bioavailability of metoprolol shows
a dose-related, although not directly proportional, increase with
dose and is not significantly affected by food following
metoprolol succinate extended-release tablet administration.
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Pediatrics
The pharmacokinetic profile of metoprolol succinate extended-
release tablet was studied in 120 pediatric hypertensive patients
(6-17 years of age) receiving doses ranging from 12.5 to 200 mg
once daily. The pharmacokinetics of metoprolol were similar to
those described previously in adults. Age, gender, race, and
ideal body weight had no significant effects on metoprolol
pharmacokinetics. Metoprolol apparent oral clearance (CL/F)
increased
linearly
with
body
weight.
Metoprolol
pharmacokinetics have not been investigated in patients < 6
years of age.
Hypertension
The mechanism of the antihypertensive effects of beta-blocking
agents has not been elucidated. However, several possible
mechanisms have been proposed: (1) competitive antagonism of
catecholamines at peripheral (especially cardiac) adrenergic
neuron sites, leading to decreased cardiac output; (2) a central
effect leading to reduced sympathetic outflow to the periphery;
and (3) suppression of renin activity.
Clinical Trials
In a double-blind study, 1092 patients with mild-to-moderate
hypertension were randomized to once daily metoprolol
succinate extended-release tablets (25, 100, or 400 mg),
PLENDIL®
(felodipine
extended-release
tablets),
the
combination, or placebo. After 9 weeks, metoprolol succinate
extended-release tablet alone decreased sitting blood pressure by
6-8/4-7 mmHg (placebo-corrected change from baseline) at 24
hours post-dose. The combination of metoprolol succinate
extended-release tablet with PLENDIL has greater effects on
blood pressure.
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In controlled clinical studies, an immediate release dosage form
of metoprolol was an effective antihypertensive agent when used
alone or as concomitant therapy with thiazide-type diuretics at
dosages of 100-450 mg daily. Metoprolol succinate extended-
release tablet, in dosages of 100 to 400 mg once daily, produces
similar
ß1-blockade
as
conventional
metoprolol
tablets
administered two to four times daily. In addition, metoprolol
succinate extended-release tablet administered at a dose of 50
mg once daily lowered blood pressure 24-hours post-dosing in
placebo-controlled studies. In controlled, comparative, clinical
studies, immediate release metoprolol appeared comparable as
an antihypertensive agent to propranolol, methyldopa, and
thiazide-type diuretics, and affected both supine and standing
blood pressure. Because of variable plasma levels attained with
a given dose and lack of a consistent relationship of
antihypertensive activity to drug plasma concentration, selection
of proper dosage requires individual titration.
Angina Pectoris
By blocking catecholamine-induced increases in heart rate, in
velocity and extent of myocardial contraction, and in blood
pressure, metoprolol reduces the oxygen requirements of the
heart at any given level of effort, thus making it useful in the
long-term management of angina pectoris.
Clinical Trials
In controlled clinical trials, an immediate release formulation of
metoprolol has been shown to be an effective antianginal agent,
reducing the number of angina attacks and increasing exercise
tolerance. The dosage used in these studies ranged from 100 to
400 mg daily. Metoprolol succinate extended-release tablets, in
dosages of 100 to 400 mg once daily, has been shown to possess
beta-blockade similar to conventional metoprolol tablets
administered two to four times daily.
Heart Failure
The precise mechanism for the beneficial effects of
beta-blockers in heart failure has not been elucidated.
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Clinical Trials
MERIT-HF was a double-blind, placebo-controlled study of
metoprolol succinate extended- release tablet conducted in 14
countries including the US. It randomized 3991 patients (1990
to metoprolol succinate extended-release tablets) with ejection
fraction ≤ 0.40 and NYHA Class II-IV heart failure attributable
to ischemia, hypertension, or cardiomyopathy. The protocol
excluded patients with contraindications to beta-blocker use,
those expected to undergo heart surgery, and those within 28
days of myocardial infarction or unstable angina. The primary
endpoints of the trial were (1) all-cause mortality plus all-cause
hospitalization (time to first event) and (2) all-cause mortality.
Patients were stabilized on optimal concomitant therapy for
heart failure, including diuretics, ACE inhibitors, cardiac
glycosides, and nitrates. At randomization, 41% of patients
were NYHA Class II, 55% NYHA Class III; 65% of patients
had heart failure attributed to ischemic heart disease; 44% had a
history of hypertension; 25% had diabetes mellitus; 48% had a
history of myocardial infarction. Among patients in the trial,
90% were on diuretics, 89% were on ACE inhibitors, 64% were
on digitalis, 27% were on a lipid-lowering agent, 37% were on
an oral anticoagulant, and the mean ejection fraction was 0.28.
The mean duration of follow-up was one year. At the end of the
study, the mean daily dose of metoprolol succinate extended-
release tablet was 159 mg.
The trial was terminated early for a statistically significant
reduction in all-cause mortality (34%, nominal p= 0.00009).
The risk of all-cause mortality plus all-cause hospitalization was
reduced by 19% (p= 0.00012). The trial also showed
improvements in heart failure-related mortality and heart failure-
related hospitalizations, and NYHA functional class.
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The table below shows the principal results for the overall study
population. The figure below illustrates principal results for a
wide variety of subgroup comparisons, including US vs. non-US
populations (the latter of which was not pre-specified). The
combined endpoints of all-cause mortality plus all-cause
hospitalization and of mortality plus heart failure hospitalization
showed consistent effects in the overall study population and the
subgroups, including women and the US population. However,
in the US subgroup (n=1071) and women (n=898), overall
mortality and cardiovascular mortality appeared less affected.
Analyses of female and US patients were carried out because
they each represented about 25% of the overall population.
Nonetheless, subgroup analyses can be difficult to interpret and
it is not known whether these represent true differences or
chance effects.
Clinical Endpoints in the MERRIT-HF
Study
Number of Patients
Risk
Reduction
Metoprolol
Relative
With
Clinical
Placebo
Succinate
Extended-
Release
Tablets
Risk
Metoprolol
Succinate
Extended-
Release
Tablets
Nominal
Endpoint
n=2001
n=1990
(95% CI)
P-value
All-cause
mortality plus
all-cause
hospitalization*
767
641
0.81
(0.73-0.90)
19%
0.00012
All-cause
mortality
217
145
0.66
(0.53-0.81)
34%
0.00009
All-cause
mortality plus
heart failure
hospitalization*
439
311
0.69
(0.60-0.80)
31%
0.0000008
Cardiovascular
mortality
203
128
0.62
(0.50-0.78)
38%
0.000022
Sudden death
132
79
0.59
(0.45-0.78)
41%
0.0002
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Number of Patients
Risk
Reduction
Metoprolol
Relative
With
Clinical
Placebo
Succinate
Extended-
Release
Tablets
Risk
Metoprolol
Succinate
Extended-
Release
Tablets
Nominal
Endpoint
n=2001
n=1990
(95% CI)
P-value
Death due to
worsening heart
failure
58
30
0.51
(0.33-0.79)
49%
0.0023
Hospitalizations
due to
worsening heart
failure†
451
317
N/A
N/A
0.0000076
Cardiovascular
hospitalization†
773
649
N/A
N/A
0.00028
*Time to first event
† Comparison of treatment groups examines the number of hospitalizations
(Wilcoxon test); relative risk and risk reduction are not applicable.
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INDICATIONS AND USAGE
Hypertension
Metoprolol succinate extended-release tablet is indicated for the
treatment of hypertension. It may be used alone or in
combination with other antihypertensive agents.
Angina Pectoris
Metoprolol succinate extended-release tablet is indicated in the
long-term treatment of angina pectoris.
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Heart Failure
Metoprolol succinate extended-release tablet is indicated for the
treatment of stable, symptomatic (NYHA Class II or III) heart
failure of ischemic, hypertensive, or cardiomyopathic origin. It
was studied in patients already receiving ACE inhibitors,
diuretics, and, in the majority of cases, digitalis. In this
population,
metoprolol
succinate
extended-release
tablet
decreased the rate of mortality plus hospitalization, largely
through
a
reduction
in
cardiovascular
mortality
and
hospitalizations for heart failure.
CONTRAINDICATIONS
Metoprolol succinate extended-release tablet is contraindicated
in severe bradycardia, heart block greater than first degree,
cardiogenic shock, decompensated cardiac failure, sick sinus
syndrome (unless a permanent pacemaker is in place) (see
WARNINGS) and in patients who are hypersensitive to any
component of this product.
WARNINGS
Ischemic Heart Disease: Following abrupt cessation of therapy
with certain beta-blocking agents, exacerbations of angina
pectoris and, in some cases, myocardial infarction have
occurred.
When
discontinuing
chronically
administered
metoprolol succinate extended-release tablets, particularly in
patients with ischemic heart disease, the dosage should be
gradually reduced over a period of 1–2 weeks and the patient
should be carefully monitored. If angina markedly worsens or
acute coronary insufficiency develops, metoprolol succinate
extended-release tablet administration should be reinstated
promptly, at least temporarily, and other measures appropriate
for the management of unstable angina should be taken. Patients
should be warned against interruption or discontinuation of
therapy without the physician’s advice. Because coronary artery
disease is common and may be unrecognized, it may be prudent
not to discontinue metoprolol succinate extended-release tablet
therapy abruptly even in patients treated only for hypertension.
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Bronchospastic
Diseases:
PATIENTS
WITH
BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL,
NOT RECEIVE BETA-BLOCKERS. Because of its relative
beta1-selectivity, however, metoprolol succinate extended-
release tablet may be used with caution in patients with
bronchospastic disease who do not respond to, or cannot
tolerate, other antihypertensive treatment. Since beta1-selectivity
is not absolute, a beta2-stimulating agent should be administered
concomitantly, and the lowest possible dose of metoprolol
succinate extended- release tablets should be used (see
DOSAGE AND ADMINISTRATION).
Major Surgery: The necessity or desirability of withdrawing
beta-blocking therapy prior to major surgery is controversial; the
impaired ability of the heart to respond to reflex adrenergic
stimuli may augment the risks of general anesthesia and surgical
procedures.
Metoprolol succinate extended-release tablet, like other beta-
blockers, is a competitive inhibitor of beta-receptor agonists, and
its effects can be reversed by administration of such agents, eg,
dobutamine or isoproterenol. However, such patients may be
subject to protracted severe hypotension. Difficulty in restarting
and maintaining the heart beat has also been reported with
beta-blockers.
Diabetes and Hypoglycemia: Metoprolol succinate extended-
release tablets should be used with caution in diabetic patients if
a beta-blocking agent is required. Beta-blockers may mask
tachycardia
occurring
with
hypoglycemia,
but
other
manifestations such as dizziness and sweating may not be
significantly affected.
Thyrotoxicosis: Beta-adrenergic blockade may mask certain
clinical signs (eg, tachycardia) of hyperthyroidism. Patients
suspected of developing thyrotoxicosis should be managed
carefully to avoid abrupt withdrawal of beta-blockade, which
might precipitate a thyroid storm.
Peripheral Vascular Disease: Beta-blockers can precipitate or
aggravate symptoms of arterial insufficiency in patients with
peripheral vascular disease. Caution should be exercised in such
individuals.
Calcium Channel Blockers: Because of significant inotropic
and chronotropic effects in patients treated with beta-blockers
and calcium channel blockers of the verapamil and diltiazem
type, caution should be exercised in patients treated with these
agents concomitantly.
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PRECAUTIONS
General
Metoprolol succinate extended-release tablets should be used
with caution in patients with impaired hepatic function. In
patients with pheochromocytoma, an alpha-blocking agent
should be initiated prior to the use of any beta-blocking agent.
Worsening cardiac failure may occur during up-titration of
metoprolol succinate extended- release tablets. If such
symptoms occur, diuretics should be increased and the dose of
metoprolol succinate extended-release tablets should not be
advanced until clinical stability is restored (see DOSAGE AND
ADMINISTRATION). It may be necessary to lower the dose of
metoprolol succinate extended-release tablet or temporarily
discontinue it. Such episodes do not preclude subsequent
successful titration of metoprolol succinate extended-release
tablets.
Information for Patients
Patients should be advised to take metoprolol succinate
extended-release tablets regularly and continuously, as directed,
preferably with or immediately following meals. If a dose
should be missed, the patient should take only the next
scheduled dose (without doubling it). Patients should not
interrupt or discontinue metoprolol succinate extended-release
tablets without consulting the physician.
Patients should be advised (1) to avoid operating automobiles
and machinery or engaging in other tasks requiring alertness
until the patient’s response to therapy with metoprolol succinate
extended-release tablets has been determined; (2) to contact the
physician if any difficulty in breathing occurs; (3) to inform the
physician or dentist before any type of surgery that he or she is
taking metoprolol succinate extended-release tablets.
Heart failure patients should be advised to consult their
physician if they experience signs or symptoms of worsening
heart failure such as weight gain or increasing shortness of
breath.
Laboratory Tests
Clinical laboratory findings may include elevated levels of
serum
transaminase,
alkaline
phosphatase,
and
lactate
dehydrogenase.
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Drug Interactions
Catecholamine-depleting drugs (eg, reserpine, mono amine
oxidase (MAO) inhibitors) may have an additive effect when
given with beta-blocking agents. Patients treated with
metoprolol
succinate
extended-release
tablets
plus
a
catecholamine depletor should therefore be closely observed for
evidence of hypotension or marked bradycardia, which may
produce vertigo, syncope, or postural hypotension.
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine,
paroxetine, and propafenone are likely to increase metoprolol
concentration. In healthy subjects with CYP2D6 extensive
metabolizer phenotype, coadministration of quinidine 100 mg
and immediate release metoprolol 200 mg tripled the
concentration of S-metoprolol and doubled the metoprolol
elimination half-life. In four patients with cardiovascular
disease, coadministration of propafenone 150 mg t.i.d. with
immediate release metoprolol 50 mg t.i.d. resulted in
two- to five-fold increases in the steady-state concentration of
metoprolol. These increases in plasma concentration would
decrease the cardioselectivity of metoprolol.
Both digitalis glycosides and beta-blockers slow atrioventricular
conduction and decrease heart rate. Concomitant use can
increase the risk of bradycardia.
Beta-blockers may exacerbate the rebound hypertension which
can follow the withdrawal of clonidine. If the two drugs are
coadministered, the beta blocker should be withdrawn several
days before the gradual withdrawal of clonidine. If replacing
clonidine by beta-blocker therapy, the introduction of beta-
blockers should be delayed for several days after clonidine
administration has stopped.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have been conducted to evaluate
the carcinogenic potential of metoprolol tartrate. In 2-year
studies in rats at three oral dosage levels of up to 800 mg/kg/day
(41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-
kg patient), there was no increase in the development of
spontaneously occurring benign or malignant neoplasms of any
type. The only histologic changes that appeared to be drug
related were an increased incidence of generally mild focal
accumulation of foamy macrophages in pulmonary alveoli and a
slight increase in biliary hyperplasia. In a 21-month study in
Swiss albino mice at three oral dosage levels of up to 750
mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200
mg for a 60-kg patient), benign lung tumors (small adenomas)
occurred more frequently in female mice receiving the highest
dose than in untreated control animals. There was no increase in
malignant or total (benign plus malignant) lung tumors, nor in
the overall incidence of tumors or malignant tumors. This 21-
month study was repeated in CD-1 mice, and no statistically or
biologically significant differences were observed between
treated and control mice of either sex for any type of tumor.
All genotoxicity tests performed on metoprolol tartrate (a
dominant lethal study in mice, chromosome studies in somatic
cells, a Salmonella/mammalian-microsome mutagenicity test,
and a nucleus anomaly test in somatic interphase nuclei) and
metoprolol succinate (a Salmonella/mammalian-microsome
mutagenicity test) were negative.
No evidence of impaired fertility due to metoprolol tartrate was
observed in a study performed in rats at doses up to 22 times, on
a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient.
Pregnancy Category C
Metoprolol
tartrate
has
been
shown
to
increase
post-implantation loss and decrease neonatal survival in rats at
doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg
in a 60-kg patient. Distribution studies in mice confirm
exposure of the fetus when metoprolol tartrate is administered to
the pregnant animal. These studies have revealed no evidence of
impaired fertility or teratogenicity. There are no adequate and
well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if
clearly needed.
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Nursing Mothers
Metoprolol is excreted in breast milk in very small quantities.
An infant consuming 1 liter of breast milk daily would receive a
dose of less than 1 mg of the drug. Caution should be exercised
when
metoprolol
succinate
extended-release
tablet
is
administered to a nursing woman.
Pediatric Use
One hundred forty-four hypertensive pediatric patients aged 6 to
16 years were randomized to placebo or to one of three dose
levels of metoprolol succinate extended-release tablets (0.2, 1.0
or 2.0 mg/kg once daily) and followed for 4 weeks. The study
did not meet its primary end point (dose response for reduction
in SBP). Some pre-specified secondary end points
demonstrated effectiveness including:
● Dose-response for reduction in DBP,
● 1.0 mg/kg vs. placebo for change in SBP, and
● 2.0 mg/kg vs. placebo for change in SBP and DBP.
The mean placebo corrected reductions in SBP ranged from 3 to
6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart
rate ranged from 5 to 7 bpm but considerable greater reductions
were seen in some individuals. (See DOSAGE and
ADMINISTRATION, Pediatric Hypertensive Patients > 6 years
of age).
No clinically relevant differences in the adverse event profile
were observed for pediatric patients aged 6 to 16 years as
compared with adult patients.
Safety and effectiveness of metoprolol succinate extended-
release tablets have not been established in patients < 6 years of
age.
Geriatric Use
Clinical studies of metoprolol succinate extended-release tablets
in hypertension did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience in
hypertensive patients has not identified differences in responses
between elderly and younger patients.
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Of the 1,990 patients with heart failure randomized to
metoprolol succinate extended-release tablets in the MERIT-HF
trial, 50% (990) were 65 years of age and older and 12% (238)
were 75 years of age and older. There were no notable
differences in efficacy or the rate of adverse events between
older and younger patients.
In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range,
reflecting greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug
therapy.
Risk of Anaphylactic Reactions
While taking beta-blockers, patients with a history of severe
anaphylactic reactions to a variety of allergens may be more
reactive to repeated challenge, either accidental, diagnostic, or
therapeutic. Such patients may be unresponsive to the usual
doses of epinephrine used to treat allergic reaction.
ADVERSE REACTIONS
Hypertension and Angina
Most adverse effects have been mild and transient. The
following adverse reactions have been reported for immediate
release metoprolol tartrate.
Central Nervous System: Tiredness and dizziness have occurred
in about 10 of 100 patients. Depression has been reported in
about 5 of 100 patients. Mental confusion and short-term
memory loss have been reported. Headache, somnolence,
nightmares, and insomnia have also been reported.
Cardiovascular: Shortness of breath and bradycardia have
occurred in approximately 3 of 100 patients. Cold extremities;
arterial insufficiency, usually of the Raynaud type; palpitations;
congestive heart failure; peripheral edema; syncope; chest pain;
and hypotension have been reported in about 1 of 100 patients
(see
CONTRAINDICATIONS,
WARNINGS,
and
PRECAUTIONS).
Respiratory: Wheezing (bronchospasm) and dyspnea have been
reported in about 1 of 100 patients (see WARNINGS).
Gastrointestinal: Diarrhea has occurred in about 5 of
100 patients. Nausea, dry mouth, gastric pain, constipation,
flatulence, digestive tract disorders, and heartburn have been
reported in about 1 of 100 patients.
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Hypersensitive Reactions: Pruritus or rash have occurred in
about 5 of 100 patients. Worsening of psoriasis has also been
reported.
Miscellaneous: Peyronie’s disease has been reported in fewer
than 1 of 100,000 patients. Musculoskeletal pain, blurred vision,
decreased libido, and tinnitus have also been reported.
There have been rare reports of reversible alopecia,
agranulocytosis, and dry eyes. Discontinuation of the drug
should be considered if any such reaction is not otherwise
explicable. The oculomucocutaneous syndrome associated with
the beta-blocker practolol has not been reported with
metoprolol.
Potential Adverse Reactions
In addition, there are a variety of adverse reactions not listed
above, which have been reported with other beta-adrenergic
blocking agents and should be considered potential adverse
reactions to metoprolol succinate extended-release tablets.
Central
Nervous
System: Reversible mental
depression
progressing to catatonia; an acute reversible syndrome
characterized by disorientation for time and place, short-term
memory loss, emotional lability, slightly clouded sensorium, and
decreased performance on neuropsychometrics.
Cardiovascular:
Intensification
of
AV
block
(see
CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura,
thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore
throat, laryngospasm, and respiratory distress.
Heart Failure
In the MERIT-HF study, serious adverse events and adverse
events leading to discontinuation of study medication were
systematically collected. In the MERIT-HF study comparing
metoprolol succinate extended-release tablets in daily doses up
to 200 mg (mean dose 159 mg once-daily) (n=1990) to placebo
(n=2001), 10.3% of metoprolol succinate extended-release tablet
patients discontinued for adverse events vs. 12.2% of placebo
patients.
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The table below lists adverse events in the MERIT-HF study
that occurred at an incidence of equal to or greater than 1% in
the metoprolol succinate extended-release tablet group and
greater than placebo by more than 0.5%, regardless of the
assessment of causality.
Adverse Events Occurring in the MERIT-
HF Study at an Indicence ≥1% in the
Metoprolol Succinate Extended-Release
Tablet Group and Greater Than Placebo
by More Than 0.5%
Metoprolol Succinate
Extended-Release Tablets
n=1990
% of patients
Placebo
n=2001
% of patients
Dizziness/vertigo
1.8
1.0
Bradycardia
1.5
0.4
Accident and/or injury
1.4
0.8
Other adverse events with an incidence of > 1% on metoprolol
succinate extended-release tablets and as common on placebo
(within 0.5%) included myocardial infarction, pneumonia,
cerebrovascular
disorder,
chest
pain,
dyspnea/dyspnea
aggravated, syncope, coronary artery disorder, ventricular
tachycardia/arrhythmia
aggravated,
hypotension,
diabetes mellitus/diabetes mellitus aggravated, abdominal pain,
and fatigue.
Post-Marketing Experience
The following adverse reactions have been reported with
metoprolol succinate extended-release tablets in worldwide post-
marketing use, regardless of causality:
Cardiovascular: 2nd and 3rd degree heart block, cardiogenic
shock in patients with acute myocardial infarction
Gastrointestinal: hepatitis, vomiting.
Hematologic: thrombocytopenia.
Musculoskeletal: arthralgia.
Nervous System/Psychiatric: anxiety/nervousness,
hallucinations, paresthesia.
Reproductive, male: impotence.
Skin: increased sweating, photosensitivity, urticaria.
Special Sense Organs: taste disturbances.
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OVERDOSAGE
Acute Toxicity
There have been a few reports of overdosage with metoprolol
succinate extended-release tablets and no specific overdosage
information was obtained with this drug, with the exception of
animal toxicology data. However, since metoprolol succinate
extended-release tablet (metoprolol succinate salt) contains the
same active moiety, metoprolol, as conventional metoprolol
tablets (metoprolol tartrate salt), the recommendations on
overdosage for metoprolol conventional tablets are applicable to
metoprolol succinate extended-release tablets.
Signs and Symptoms
Overdosage of metoprolol succinate extended-release tablets
may
lead
to
severe
hypotension,
sinus
bradycardia,
atrioventricular block, heart failure, cardiogenic shock, cardiac
arrest, bronchospasm, impairment of consciousness/coma,
nausea, vomiting, and cyanosis.
Treatment
In general, patients with acute or recent myocardial infarction or
congestive heart failure may be more hemodynamically unstable
than other patients and should be treated accordingly. When
possible the patient should be treated under intensive care
conditions. On the basis of the pharmacologic actions of
metoprolol, the following general measures should be employed:
Elimination of the Drug: Gastric lavage should be performed.
Bradycardia: Atropine should be administered. If there is no
response
to
vagal
blockade,
isoproterenol
should
be
administered cautiously.
Hypotension: A vasopressor should be administered, eg,
levarterenol or dopamine.
Bronchospasm: A beta2-stimulating agent and/or a theophylline
derivative should be administered.
Cardiac Failure: A digitalis glycoside and diuretics should be
administered. In shock resulting from inadequate cardiac
contractility, administration of dobutamine, isoproterenol, or
glucagon may be considered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
DOSAGE AND ADMINISTRATION
Metoprolol succinate extended-release tablets are intended for
once daily administration. For treatment of hypertension and
angina, when switching from immediate release metoprolol to
metoprolol succinate extended-release tablet, the same total
daily dose of metoprolol succinate extended-release tablet
should be used. Dosages of metoprolol succinate extended-
release tablets should be individualized and titration may be
needed in some patients.
Metoprolol succinate extended-release tablets are scored and can
be divided; however, the whole or half tablet should be
swallowed whole and not chewed or crushed.
Hypertension
The usual initial dosage is 25 to 100 mg daily in a single dose,
whether used alone or added to a diuretic. The dosage may be
increased at weekly (or longer) intervals until optimum blood
pressure reduction is achieved. In general, the maximum effect
of any given dosage level will be apparent after 1 week of
therapy. Dosages above 400 mg per day have not been studied.
Pediatric Hypertensive Patients ≥ 6 Years of age
A pediatric clinical hypertension study in patients 6 to 16 years
of age did not meet its primary endpoint (dose response for
reduction in SBP), however some other endpoints demonstrated
effectiveness (see PRECAUTIONS, Pediatric Use).
If selected for treatment, the recommended starting dose of
metoprolol succinate extended-release tablet is 1.0 mg/kg once
daily however, the maximum initial dose should not exceed 50
mg once daily. The minimum available dose is one half of the
25 mg metoprolol succinate extended-release tablet. Dosage
should be adjusted according to blood pressure response. Doses
above 2.0 mg/kg (or in excess of 200 mg) once daily have not
been studied in pediatric patients. (See CLINICAL
PHARMACOLOGY, Pharmacokinetics.)
Metoprolol
succinate
extended-release
tablet
is
not
recommended in pediatric patients < 6 years of age (see
CLINICAL
PHARMACOLOGY,
Pharmacokinetics
and
PRECAUTIONS, Pediatric Use.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Angina Pectoris
The dosage of metoprolol succinate extended-release tablets
should be individualized. The usual initial dosage is 100 mg
daily, given in a single dose. The dosage may be gradually
increased at weekly intervals until optimum clinical response
has been obtained or there is a pronounced slowing of the heart
rate. Dosages above 400 mg per day have not been studied. If
treatment is to be discontinued, the dosage should be reduced
gradually over a period of 1–2 weeks (see WARNINGS).
Heart Failure
Dosage must be individualized and closely monitored during up-
titration. Prior to initiation of metoprolol succinate extended-
release tablet, the dosing of diuretics, ACE inhibitors, and
digitalis (if used) should be stabilized. The recommended
starting dose of metoprolol succinate extended-release tablet is
25 mg once daily for two weeks in patients with NYHA Class II
heart failure and 12.5 mg once daily in patients with more severe
heart failure. The dose should then be doubled every two weeks
to the highest dosage level tolerated by the patient or up to 200
mg of metoprolol succinate extended-release tablet. If transient
worsening of heart failure occurs, it may be treated with
increased doses of diuretics, and it may also be necessary to
lower the dose of metoprolol succinate extended-release tablet
or temporarily discontinue it. The dose of metoprolol succinate
extended-release tablet should not be increased until symptoms
of worsening heart failure have been stabilized. Initial difficulty
with titration should not preclude later attempts to introduce
metoprolol succinate extended-release tablets. If heart failure
patients experience symptomatic bradycardia, the dose of
metoprolol succinate extended-release tablet should be reduced.
HOW SUPPLIED
Tablets containing metoprolol succinate equivalent to the
indicated weight of metoprolol tartrate, USP, are white,
biconvex, film-coated and scored.
Tablet
Shape
Engraving
Bottle of 100
NDC 49884
25 mg*
Oval
m
β
404-01
50 mg
Round
m
50
405-01
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Tablet
Shape
Engraving
Bottle of 100
NDC 49884
100 mg
Round
m
100
406-01
200 mg
Oval
m
200
407-01
*The 25mg tablet is scored on both sides.
Store at 25°C (77°F). Excursions permitted to 15-30°C
(59-86°F). (See USP Controlled Room Temperature.)
©AstraZeneca 2007
Manufactured for:
Par Pharmaceutical Companies, Inc
Spring Valley, NY 10977 U.S.A.
By: AstraZeneca AB
S-151 85 Södertälje, Sweden
Made in Sweden
30410-03
Rev 12/07
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019962s036lbl.pdf', 'application_number': 19962, 'submission_type': 'SUPPL ', 'submission_number': 36}
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TERAZOL 7(terconazole) Vaginal Cream 0.4%
TERAZOL 3(terconazole) Vaginal Cream 0.8%
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg
DESCRIPTION
TERAZOL® 7(terconazole) Vaginal Cream 0.4% is a white to off-white, water washable
cream for intravaginal administration containing 0.4% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable
cream for intravaginal administration containing 0.8% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white suppositories
for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-
1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or
palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole.
The structural formula of terconazole is as follows:
TERCONAZOLE
C26H31Cl2N5O3
[INSERT STRUCTURE HERE]
Terconazole, a triazole derivative, is a white to almost white powder with a molecular
weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in
butanol.
CLINICAL PHARMACOLOGY
Following intravaginal administration of terconazole in humans, absorption ranged from
5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects
with tubal ligations.
Following daily intravaginal administration of 0.8% terconazole 40 mg
(0.8% cream x 5 g) for seven days to normal humans, plasma concentrations were low
and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours.
Results from similar studies in patients with vulvovaginal candidiasis indicate that the
slow rate of absorption, the lack of accumulation, and the mean peak plasma
concentration of terconazole was not different from that observed in healthy women. The
absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with
vulvovaginal candidiasis were also similar to those found in normal volunteers.
Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life
of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3).
Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the
AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood
with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both
by renal (32-56%) and fecal (47-52%) routes.
In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is
independent of drug concentration.
Photosensitivity reactions were observed in some normal volunteers following repeated
dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered
artificial ultraviolet light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in
patients who were treated with terconazole suppositories or vaginal cream (0.4% and
0.8%).
Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida
albicans. Antifungal activity has also been demonstrated against other fungi. The MIC
values of terconazole against most Lactobacillus spp. typically found in the human
vagina were ≥128 mcg/mL; therefore these beneficial bacteria were not affected by drug
treatment.
The exact pharmacologic mode of action of terconazole is uncertain; however, it may
exert its antifungal activity by the disruption of normal fungal cell membrane
permeability. No resistance to terconazole has developed during successive passages of
C. albicans.
INDICATIONS AND USAGE
TERAZOL 7 Vaginal Cream 0.4%, TERAZOL 3 Vaginal Cream 0.8% and TERAZOL 3
Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal
candidiasis (moniliasis). As these products are effective only for vulvovaginitis caused by
the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of the
cream or suppositories.
WARNINGS
None.
PRECAUTIONS
General: Discontinue use and do not retreat with terconazole if sensitization, irritation,
fever, chills or flu-like symptoms are reported during use.
The base contained in the suppository formulation may interact with certain rubber or
latex products, such as those used in vaginal contraceptive diaphragms, therefore
concurrent use is not recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic
studies (standard KOH smear and/or cultures) should be repeated to confirm the
diagnosis and rule out other pathogens.
Drug Interactions:
TERAZOL 7 Vaginal Cream 0.4% and TERAZOL 3 Vaginal Suppositories 80mg:
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL 3 Vaginal Cream 0.8%:
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8%
terconazole vaginal cream was administered to healthy female volunteers established on a
low dose oral contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not
been performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of
microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo
for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ
cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up to
40 mg/kg/day (25x the recommended intravaginal human dose of the suppository
formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream
formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream
formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in
rats.
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a
delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of
embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease
in litter size and number of viable young and reduced fetal weight. There was also delay
in ossification and an increased incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole
in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level
(0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole
0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in
normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and
by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after
intravaginal administration of terconazole 80 mg vaginal suppository. This safety
assessment does not account for possible exposure of the fetus through direct transfer to
terconazole from the irritated vagina by diffusion across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the first
trimester of pregnancy unless the physician considers it essential to the welfare of the
patient.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have shown
that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed
decreased survival during the first few post-partum days, but overall pup weight and
weight gain were comparable to or greater than controls throughout lactation. Because
many drugs are excreted in human milk, and because of the potential for adverse reaction
in nursing infants from terconazole, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use:
Safety and efficacy in children have not been established.
Geriatric Use:
Clinical studies of TERAZOL did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients.
ADVERSE REACTIONS
TERAZOL 7 Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with
vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on
comparative analyses with placebo, the adverse experiences considered most likely
related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo)
and body pain (2.1% vs. 0% with placebo). Vulvovaginal burning (5.2%), itching (2.3%)
or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than
with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0%
with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The
adverse drug experience on terconazole most frequently causing discontinuation was
vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%).
TERAZOL 3 Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with
vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three
days. Based on comparative analyses with placebo and a standard agent, the adverse
experiences considered most likely related to terconazole 0.8% vaginal cream were
headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
Genital complaints in general, and burning and itching in particular, occurred less
frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% with
placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were
abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The
therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. The
adverse drug experience most frequently causing discontinuation of therapy was
vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3%
with the placebo group.
TERAZOL 3 Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with
vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories.
Based on comparative analyses with placebo (295 patients), the adverse experiences
considered adverse reactions most likely related to terconazole 80 mg vaginal
suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female
genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that were reported but were
not statistically significantly different from placebo were burning (15.2% vs. 11.2% with
placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% v. 1.4% with placebo)
and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related
dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The
adverse drug experience on terconazole most frequently causing discontinuation was
burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs. 1.4% with placebo).
OVERDOSAGE
Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD
50 values were found to be 1741 and 849 mg/kg for the male and female, respectively.
The oral LD 50 values for the male and female dog were ~1280 and ≥640 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
TERAZOL 7 Vaginal Cream 0.4%:
One full applicator (5 g) of TERAZOL 7 Vaginal Cream (20 mg terconazole) should be
administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL 3 Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL 3 Vaginal Cream (40 mg terconazole) should be
administered intravaginally once daily at bedtime for three consecutive days.
TERAZOL 3 Vaginal Suppositories 80 mg
One TERAZOL 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Before prescribing another course of therapy, the diagnosis should be reconfirmed by
smears and/or cultures and other pathogens commonly associated with vulvovaginitis
ruled out. The therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45 g
(NDC 0062-5350-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20 g
(NDC 0062-5356-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g,
elliptically shaped white to off-white suppositories in packages of three
(NDC 0062-5351-01) with a vaginal applicator. Store at controlled room temperature 15 -
30° C (59 - 86° F).
Rx only *Trademark
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
TERAZOL 7 (terconazole) Vaginal Cream 0.4%
TERAZOL 3 (terconazole) Vaginal Cream 0.8%
PATIENT INSTRUCTIONS
Filling the applicator:
1. Remove the cap from the tube.
2. Use the pointed tip on the top of the cap to puncture the seal on the tube.
3. Screw the applicator onto the tube.
4. Squeeze the tube from the bottom and fill the applicator until the plunger stops.
5. Unscrew the applicator from the tube.
Illustration of cap puncturing tube
Illustration of applicator screwed onto tube
Using the applicator:
1. Lie on your back with your knees drawn up toward your chest.
Illustration of lower extremities.
2. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into
the vagina as far as it will comfortably go.
3. Slowly press the plunger of the applicator to release the cream into the vagina.
4. Remove the applicator from the vagina.
5. Apply one applicatorful each night for as many days at bedtime, as directed by your
doctor.
Cleaning the applicator: (Does not apply to sample applicators, which are for one
time use only)
After each use, you should thoroughly clean the applicator by following the procedure
below:
1. Pull the plunger out of the barrel.
2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
3. Put the applicator back together by gently pushing the plunger into the barrel as far as
it will go.
Illustration – separate plunger from barrel
NOTE: Store the cream at Controlled Room Temperature 15-30oC (59-86oF). See end
flap for lot number and expiration date.
U.S. Patent No. D-279,504
TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by
your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or
without the applicator.
A. Insertion with the applicator
1. Filling the applicator
• Break off suppository from the plastic strip.
• Pull the plastic completely apart at the notched end.
• Place the flat end of the suppository into the open end of the applicator
as shown. You are now ready to insert the suppository into the vagina.
Illustration 1
Illustration 2
2. Using the applicator
• Lie on your back with your knees drawn up toward your chest.
• Holding the applicator by the ribbed end of the barrel, gently insert it
into the vagina as far as it will comfortably go.
• Press the plunger to release the suppository into the vagina.
• Remove the applicator from the vagina.
Illustration of lower extremities
3. Cleaning the applicator (Does not apply to sample applicators, which
are for one time use only)
After each use, you should thoroughly clean the applicator by following
the procedure below:
• Pull the plunger out of the barrel.
• Wash both pieces with lukewarm, soapy water, and dry them
thoroughly.
• Put the applicator back together by gently pushing the plunger into the
barrel as far as it will go.
B. Insertion without the applicator
• Lie on your back with your knees drawn up toward your chest.
• Place the suppository on the tip of your finger as shown.
• Insert the suppository gently into the vagina as far as it will comfortably go.
NOTE: Store the suppositories at Controlled Room Temperature 15-30°C (59-86°F). See
end flap for lot number and expiration date.
U.S. Patent No. D-279,504
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be
present in small and harmless amounts in the mouth, digestive tract, and vagina.
Sometimes the natural balance of the vagina becomes upset. This may lead to rapid
growth of Candida, which results in a yeast infection. Symptoms of a yeast infection
include itching, burning, redness, and an abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms
and looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These factors
don’t actually cause the problem, but they may create a situation that allows the yeast to
grow rapidly.
• Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in
heat and moisture (two conditions in which yeast organisms thrive). Looser pants or
skirts, 100% cotton underwear, and stockings may help avoid this problem.
• Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce
the risk of yeast infections.
• Antibiotics: Antibiotics work by eliminating disease-causing organisms. While
they are helpful in curing other problems, antibiotics may lead to an overgrowth of
Candida in the vagina.
• Pregnancy: Hormonal changes in the body during pregnancy encourage the growth
of yeast. This is a very common time for an infection to occur. Until the baby is
born, it may be hard to completely eliminate yeast infections. If you believe you are
pregnant, tell your doctor.
• Menstruation: Sometimes monthly changes in hormone levels may lead to yeast
infections.
• Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics
often have sugar in their urine, their vaginas are rich in this substance. Careful
control of diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them from
coming back.
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor, even if
you feel better quickly.
2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository
formulation (not the cream) may damage the diaphragm. Therefore, use of the
diaphragm during therapy with the suppository is not recommended. Consult your
physician.
3. If your partner has any penile itching, redness, or discomfort, he should consult his
physician and mention that you are being treated for a yeast infection.
4. You can use the medication even if you are having your menstrual period. However,
you should not use tampons because they may absorb the medication. Instead, use
external pads or napkins until you have finished your medication. You may also wish
to wear a sanitary napkin if the vaginal medication leaks.
5. Dry the genital area thoroughly after showering, bathing, or swimming. Change out
of a wet bathing suit or damp exercise clothes as soon as possible. A dry
environment is less likely to encourage the growth of yeast.
6. Wipe from front to rear (away from the vagina) after a bowel movement.
7. Don’t douche unless your doctor specifically tells you to do so. Douching may
disturb the vaginal balance.
8. Don’t scratch if you can help it. Scratching can cause more irritation and spread the
infection.
9. Discuss with your physician any medication you are already taking. Certain types of
medication can make your vagina more susceptible to infection.
10. Eat nutritious meals to promote your general health.
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
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TERAZOL
7(terconazole) Vaginal Cream 0.4%
TERAZOL
3(terconazole) Vaginal Cream 0.8%
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg
DESCRIPTION
TERAZOL® 7(terconazole) Vaginal Cream 0.4% is a white to off-white, water washable
cream for intravaginal administration containing 0.4% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable
cream for intravaginal administration containing 0.8% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white suppositories
for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-
1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or
palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole.
The structural formula of terconazole is as follows:
TERCONAZOLE
C26H31Cl2N5O3
[INSERT STRUCTURE HERE]
Terconazole, a triazole derivative, is a white to almost white powder with a molecular
weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in
butanol.
CLINICAL PHARMACOLOGY
Following intravaginal administration of terconazole in humans, absorption ranged from
5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects
with tubal ligations.
Following daily intravaginal administration of 0.8% terconazole 40 mg
(0.8% cream x 5 g) for seven days to normal humans, plasma concentrations were low
and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Results from similar studies in patients with vulvovaginal candidiasis indicate that the
slow rate of absorption, the lack of accumulation, and the mean peak plasma
concentration of terconazole was not different from that observed in healthy women. The
absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with
vulvovaginal candidiasis were also similar to those found in normal volunteers.
Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life
of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3).
Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the
AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood
with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both
by renal (32-56%) and fecal (47-52%) routes.
In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is
independent of drug concentration.
Photosensitivity reactions were observed in some normal volunteers following repeated
dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered
artificial ultraviolet light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in
patients who were treated with terconazole suppositories or vaginal cream (0.4% and
0.8%).
Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida
albicans. Antifungal activity has also been demonstrated against other fungi. The MIC
values of terconazole against most Lactobacillus spp. typically found in the human
vagina were ≥128 mcg/mL; therefore these beneficial bacteria were not affected by drug
treatment.
The exact pharmacologic mode of action of terconazole is uncertain; however, it may
exert its antifungal activity by the disruption of normal fungal cell membrane
permeability. No resistance to terconazole has developed during successive passages of
C. albicans.
INDICATIONS AND USAGE
TERAZOL 7 Vaginal Cream 0.4%, TERAZOL 3 Vaginal Cream 0.8% and TERAZOL 3
Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal
candidiasis (moniliasis). As these products are effective only for vulvovaginitis caused by
the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of the
cream or suppositories.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
None.
PRECAUTIONS
General: Discontinue use and do not retreat with terconazole if sensitization, irritation,
fever, chills or flu-like symptoms are reported during use.
The base contained in the suppository formulation may interact with certain rubber or
latex products, such as those used in vaginal contraceptive diaphragms, therefore
concurrent use is not recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic
studies (standard KOH smear and/or cultures) should be repeated to confirm the
diagnosis and rule out other pathogens.
Drug Interactions:
TERAZOL 7 Vaginal Cream 0.4% and TERAZOL 3 Vaginal Suppositories80mg:
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL 3 Vaginal Cream 0.8%:
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8%
terconazole vaginal cream was administered to healthy female volunteers established on a
low dose oral contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not
been performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of
microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo
for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ
cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up to
40 mg/kg/day (25x the recommended intravaginal human dose of the suppository
formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream
formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream
formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in
rats.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a
delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of
embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease
in litter size and number of viable young and reduced fetal weight. There was also delay
in ossification and an increased incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole
in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level
(0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole
0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in
normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and
by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after
intravaginal administration of terconazole 80 mg vaginal suppository. This safety
assessment does not account for possible exposure of the fetus through direct transfer to
terconazole from the irritated vagina by diffusion across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the first
trimester of pregnancy unless the physician considers it essential to the welfare of the
patient.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have shown
that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed
decreased survival during the first few post-partum days, but overall pup weight and
weight gain were comparable to or greater than controls throughout lactation. Because
many drugs are excreted in human milk, and because of the potential for adverse reaction
in nursing infants from terconazole, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use:
Safety and efficacy in children have not been established.
Geriatric Use:
Clinical studies of TERAZOL did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients.
ADVERSE REACTIONS
TERAZOL 7 Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with
vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on
comparative analyses with placebo, the adverse experiences considered most likely
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo)
and body pain (2.1% vs. 0% with placebo). Vulvovaginal burning (5.2%), itching (2.3%)
or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than
with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0%
with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The
adverse drug experience on terconazole most frequently causing discontinuation was
vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%).
TERAZOL 3 Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with
vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three
days. Based on comparative analyses with placebo and a standard agent, the adverse
experiences considered most likely related to terconazole 0.8% vaginal cream were
headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
Genital complaints in general, and burning and itching in particular, occurred less
frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% with
placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were
abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The
therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. The
adverse drug experience most frequently causing discontinuation of therapy was
vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3%
with the placebo group.
TERAZOL 3 Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with
vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories.
Based on comparative analyses with placebo (295 patients), the adverse experiences
considered adverse reactions most likely related to terconazole 80 mg vaginal
suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female
genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that were reported but were
not statistically significantly different from placebo were burning (15.2% vs. 11.2% with
placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% v. 1.4% with placebo)
and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related
dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The
adverse drug experience on terconazole most frequently causing discontinuation was
burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs. 1.4% with placebo).
OVERDOSAGE
Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD
50 values were found to be 1741 and 849 mg/kg for the male and female, respectively.
The oral LD 50 values for the male and female dog were ~1280 and ≥640 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
TERAZOL 7 Vaginal Cream 0.4%:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
One full applicator (5 g) of TERAZOL 7 Vaginal Cream (20 mg terconazole) should be
administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL 3 Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL 3 Vaginal Cream (40 mg terconazole) should be
administered intravaginally once daily at bedtime for three consecutive days.
TERAZOL 3 Vaginal Suppositories 80 mg
One TERAZOL 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Before prescribing another course of therapy, the diagnosis should be reconfirmed by
smears and/or cultures and other pathogens commonly associated with vulvovaginitis
ruled out. The therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45 g
(NDC 0062-5350-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20 g
(NDC 0062-5356-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g,
elliptically shaped white to off-white suppositories in packages of three
(NDC 0062-5351-01) with a vaginal applicator. Store at controlled room temperature 15 -
30° C (59 - 86° F).
Rx only *Trademark
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TERAZOL
7 (terconazole) Vaginal Cream 0.4%
TERAZOL
3 (terconazole) Vaginal Cream 0.8%
PATIENT INSTRUCTIONS
Filling the applicator:
1. Remove the cap from the tube.
2. Use the pointed tip on the top of the cap to puncture the seal on the tube.
3. Screw the applicator onto the tube.
4. Squeeze the tube from the bottom and fill the applicator until the plunger stops.
5. Unscrew the applicator from the tube.
Illustration of cap puncturing tube
Illustration of applicator screwed onto tube
Using the applicator:
1. Lie on your back with your knees drawn up toward your chest.
Illustration of lower extremities.
2. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into
the vagina as far as it will comfortably go.
3. Slowly press the plunger of the applicator to release the cream into the vagina.
4. Remove the applicator from the vagina.
5. Apply one applicatorful each night for as many days at bedtime, as directed by your
doctor.
Cleaning the applicator: (Does not apply to sample applicators, which are for one
time use only)
After each use, you should thoroughly clean the applicator by following the procedure
below:
1. Pull the plunger out of the barrel.
2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
3. Put the applicator back together by gently pushing the plunger into the barrel as far as
it will go.
Illustration – separate plunger from barrel
NOTE: Store the cream at Controlled Room Temperature 15-30oC (59-86oF). See end
flap for lot number and expiration date.
U.S. Patent No. D-279,504
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TERAZOL
3 (terconazole) Vaginal Suppositories 80 mg
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by
your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or
without the applicator.
A. Insertion with the applicator
1. Filling the applicator
• Break off suppository from the plastic strip.
• Pull the plastic completely apart at the notched end.
• Place the flat end of the suppository into the open end of the applicator
as shown. You are now ready to insert the suppository into the vagina.
Illustration 1
Illustration 2
2. Using the applicator
• Lie on your back with your knees drawn up toward your chest.
• Holding the applicator by the ribbed end of the barrel, gently insert it
into the vagina as far as it will comfortably go.
• Press the plunger to release the suppository into the vagina.
• Remove the applicator from the vagina.
Illustration of lower extremities
3. Cleaning the applicator (Does not apply to sample applicators, which
are for one time use only)
After each use, you should thoroughly clean the applicator by following
the procedure below:
• Pull the plunger out of the barrel.
• Wash both pieces with lukewarm, soapy water, and dry them
thoroughly.
• Put the applicator back together by gently pushing the plunger into the
barrel as far as it will go.
B. Insertion without the applicator
• Lie on your back with your knees drawn up toward your chest.
• Place the suppository on the tip of your finger as shown.
• Insert the suppository gently into the vagina as far as it will comfortably go.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOTE: Store the suppositories at Controlled Room Temperature 15-30°C (59-86°F). See
end flap for lot number and expiration date.
U.S. Patent No. D-279,504
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be
present in small and harmless amounts in the mouth, digestive tract, and vagina.
Sometimes the natural balance of the vagina becomes upset. This may lead to rapid
growth of Candida, which results in a yeast infection. Symptoms of a yeast infection
include itching, burning, redness, and an abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms
and looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These factors
don’t actually cause the problem, but they may create a situation that allows the yeast to
grow rapidly.
• Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in
heat and moisture (two conditions in which yeast organisms thrive). Looser pants or
skirts, 100% cotton underwear, and stockings may help avoid this problem.
• Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce
the risk of yeast infections.
• Antibiotics: Antibiotics work by eliminating disease-causing organisms. While
they are helpful in curing other problems, antibiotics may lead to an overgrowth of
Candida in the vagina.
• Pregnancy: Hormonal changes in the body during pregnancy encourage the growth
of yeast. This is a very common time for an infection to occur. Until the baby is
born, it may be hard to completely eliminate yeast infections. If you believe you are
pregnant, tell your doctor.
• Menstruation: Sometimes monthly changes in hormone levels may lead to yeast
infections.
• Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics
often have sugar in their urine, their vaginas are rich in this substance. Careful
control of diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them from
coming back.
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor, even if
you feel better quickly.
2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
formulation (not the cream) may damage the diaphragm. Therefore, use of the
diaphragm during therapy with the suppository is not recommended. Consult your
physician.
3. If your partner has any penile itching, redness, or discomfort, he should consult his
physician and mention that you are being treated for a yeast infection.
4. You can use the medication even if you are having your menstrual period. However,
you should not use tampons because they may absorb the medication. Instead, use
external pads or napkins until you have finished your medication. You may also wish
to wear a sanitary napkin if the vaginal medication leaks.
5. Dry the genital area thoroughly after showering, bathing, or swimming. Change out
of a wet bathing suit or damp exercise clothes as soon as possible. A dry
environment is less likely to encourage the growth of yeast.
6. Wipe from front to rear (away from the vagina) after a bowel movement.
7. Don’t douche unless your doctor specifically tells you to do so. Douching may
disturb the vaginal balance.
8. Don’t scratch if you can help it. Scratching can cause more irritation and spread the
infection.
9. Discuss with your physician any medication you are already taking. Certain types of
medication can make your vagina more susceptible to infection.
10. Eat nutritious meals to promote your general health.
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:24.785383
|
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Ultravate®
(halobetasol propionate ointment) Ointment, 0.05%
For Dermatological Use Only. Not for Ophthalmic Use.
DESCRIPTION
Ultravate® (halobetasol propionate ointment) Ointment, 0.05% contains halobetasol propionate, a synthetic corticosteroid for top-
ical dermatological use. The corticosteroids constitute a class of primarily synthetic steroids used topically as an anti-inflamma-
tory and antipruritic agent.
Chemically halobetasol propionate is 21-chloro-6α, 9-difluoro-11β, 17-dihydroxy-16β-methylpregna-1, 4-diene-3-20-dione,
17-propionate, C25H31ClF2O5. It has the following structural formula:
Halobetasol propionate has the molecular weight of 485. It is a white crystalline powder insoluble in water.
Each gram of Ultravate Ointment contains 0.5 mg/g of halobetasol propionate in a base of aluminum stearate, beeswax, pen-
taerythritol cocoate, petrolatum, propylene glycol, sorbitan sesquioleate, and stearyl citrate.
CLINICAL PHARMACOLOGY
Like other topical corticosteroids, halobetasol propionate has anti-inflammatory, antipruritic and vasoconstrictive actions.The mech-
anism of the anti-inflammatory activity of the topical corticosteroids, in general, is unclear. However, corticosteroids are thought to
act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins con-
trol the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their
common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Pharmacokinetics
The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity
of the epidermal barrier. Occlusive dressings with hydrocortisone for up to 24 hours have not been demonstrated to increase pen-
etration; however, occlusion of hydrocortisone for 96 hours markedly enhances penetration.Topical corticosteroids can be absorbed
from normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.
Human and animal studies indicate that less than 6% of the applied dose of halobetasol propionate enters the circulation within
96 hours following topical administration of the ointment.
Studies performed with Ultravate Ointment indicate that it is in the super-high range of potency as compared with other topi-
cal corticosteroids.
INDICATIONS AND USAGE
Ultravate Ointment 0.05% is a super-high potency corticosteroid indicated for the relief of the inflammatory and pruritic mani-
festations of corticosteroid-responsive dermatoses.Treatment beyond two consecutive weeks is not recommended, and the total
dosage should not exceed 50 g/week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA)
axis. Use in children under 12 years of age is not recommended.
As with other highly active corticosteroids, therapy should be discontinued when control has been achieved. If no improvement
is seen within 2 weeks, reassessment of the diagnosis may be necessary.
CONTRAINDICATIONS
Ultravate Ointment is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
PRECAUTIONS
General
Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the
potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia,
and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.
Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evi-
dence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free-cortisol
tests. Patients receiving super potent corticosteroids should not be treated for more than 2 weeks at a time and only small areas
should be treated at any one time due to the increased risk of HPA suppression.
Ultravate Ointment produced HPA axis suppression when used in divided doses at 7 grams per day for one week in patients
with psoriasis. These effects were reversible upon discontinuation of treatment.
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or
to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corti-
costeroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic cor-
ticosteroids. For information on systemic supplementation, see prescribing information for those products.
Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body
mass ratios (see PRECAUTIONS: Pediatric Use).
If irritation develops, Ultravate Ointment should be discontinued and appropriate therapy instituted. Allergic contact dermatitis
with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topi-
cal products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing.
If concomitant skin infections are present or develop, an appropriate antifungal or anti-bacterial agent should be used. If a favorable
response does not occur promptly,use of Ultravate Ointment should be discontinued until the infection has been adequately controlled.
Ultravate Ointment should not be used in the treatment of rosacea or perioral dermatitis, and it should not be used on the face,
groin, or in the axillae.
Information for Patients
Patients using topical corticosteroids should receive the following information and instructions:
1) The medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
O
O
CH2Cl
CH3
HO
CH3
F
F
CH3
OCOC2H5
Z2
Z2
F.P.O.
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2) The medication should not be used for any disorder other than that for which it was prescribed.
3) The treated skin area should not be bandaged, otherwise covered or wrapped, so as to be occlusive unless directed by the physician.
4) Patients should report to their physician any signs of local adverse reactions.
Laboratory Tests
The following tests may be helpful in evaluating patients for HPA axis suppression: ACTH-stimulation test; A.M. plasma cortisol
test; Urinary free-cortisol test.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of halobetasol propionate.
Positive mutagenicity effects were observed in two genotoxicity assays. Halobetasol propionate was positive in a Chinese ham-
ster micronucleus test, and in a mouse lymphoma gene mutation assay in vitro.
Studies in the rat following oral administration at dose levels up to 50 µg/kg/day indicated no impairment of fertility or gen-
eral reproductive performance.
In other genotoxicity testing, halobetasol propionate was not found to be genotoxic in the Ames/Salmonella assay, in the sis-
ter chromatid exchange test in somatic cells of the Chinese hamster, in chromosome aberration studies of germinal and somatic
cells of rodents, and in a mammalian spot test to determine point mutations.
Pregnancy
Teratogenic effects: Pregnancy Category C
Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage
levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.
Halobetasol propionate has been shown to be teratogenic in SPF rats and chinchilla-type rabbits when given systemically dur-
ing gestation at doses of 0.04 to 0.1 mg/kg in rats and 0.01 mg/kg in rabbits.These doses are approximately 13, 33 and 3 times,
respectively, the human topical dose of Ultravate Ointment. Halobetasol propionate was embryotoxic in rabbits but not in rats.
Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats, but not in rabbits.
There are no adequate and well-controlled studies of the teratogenic potential of halobetasol propionate in pregnant women.
Ultravate Ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corti-
costeroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could
result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in
human milk, caution should be exercised when Ultravate Ointment is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Ultravate Ointment in pediatric patients have not been established and use in pediatric patients under
12 is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than
adults of HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore
also at greater risk of adrenal insufficiency during or after withdrawal of treatment. Adverse effects including striae have been
reported with inappropriate use of topical corticosteroids in infants and children.
HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain and intracranial hypertension have
been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma
cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging
fontanelles, headaches, and bilateral papilledema.
Geriatric Use
Of approximately 850 patients treated with Ultravate® Ointment in clinical studies, 21% were 61 years and over and 6% were
71 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients;
and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS
In controlled clinical trials, the most frequent adverse events reported for Ultravate Ointment included stinging or burning in 1.6%
of the patients. Less frequently reported adverse reactions were pustulation, erythema, skin atrophy, leukoderma, acne, itching,
secondary infection, telangiectasia, urticaria, dry skin, miliaria, paresthesia, and rash.
The following additional local adverse reactions are reported infrequently with topical corticosteroids, and they may occur more
frequently with high potency corticosteroids, such as Ultravate Ointment. These reactions are listed in an approximate decreas-
ing order of occurrence: folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact
dermatitis, secondary infection, striae and miliaria.
OVERDOSAGE
Topically applied Ultravate Ointment can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION
Apply a thin layer of Ultravate Ointment to the affected skin once or twice daily, as directed by your physician, and rub in gently
and completely.
Ultravate (halobetasol propionate ointment) Ointment is a super-high potency topical corticosteroid; therefore, treatment should
be limited to two weeks, and amounts greater than 50 g/wk should not be used. As with other corticosteroids, therapy should be
discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary.
Ultravate Ointment should not be used with occlusive dressings.
HOW SUPPLIED
Ultravate® (halobetasol propionate ointment) Ointment, 0.05% is supplied in the following tube sizes:
15 g (NDC 0072-1450-15)
50 g (NDC 0072-1450-50)
STORAGE
Store between 15°C and 30°C (59°F and 86°F).
U.S. Patent No. 4,619,921
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
51-022864-00
Revised April 2003
Z2
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019966s008lbl.pdf', 'application_number': 19966, 'submission_type': 'SUPPL ', 'submission_number': 8}
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Zebeta®
(Bisoprolol Fumarate) Tablets
November 2010
799-33-100004
Rx only
DESCRIPTION
Zebeta (bisoprolol fumarate) is a synthetic, beta1-selective (cardioselective) adrenoceptor blocking agent.
The chemical name for bisoprolol fumarate is (±)-1-[4-[[2-(1-Methylethoxy)ethoxy]methyl]phenoxy]-3
[(1-methylethyl)amino]-2-propanol(E)-2-butenedioate (2:1) (salt). It possesses an asymmetric carbon
atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of
the beta-blocking activity. Its empirical formula is (C18H31NO4)2•C4H4O4 and its structure is: structural formula
Bisoprolol fumarate has a molecular weight of 766.97. It is a white crystalline powder which is
approximately equally hydrophilic and lipophilic, and is readily soluble in water, methanol, ethanol, and
chloroform.
Zebeta is available as 5 and 10 mg tablets for oral administration.
Inactive ingredients include Colloidal Silicon Dioxide, Corn Starch, Crospovidone, Dibasic Calcium
Phosphate, Hypromellose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol,
Polysorbate 80, and Titanium Dioxide. The 5 mg tablets also contain Red and Yellow Iron Oxide.
CLINICAL PHARMACOLOGY
Zebeta is a beta1-selective (cardioselective) adrenoceptor blocking agent without significant membrane
stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage range.
Cardioselectivity is not absolute, however, and at higher doses (≥ 20 mg) bisoprolol fumarate also inhibits
beta2-adrenoceptors, chiefly located in the bronchial and vascular musculature; to retain selectivity it is
therefore important to use the lowest effective dose.
Pharmacokinetics and Metabolism
The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. Absorption is
not affected by the presence of food. The first pass metabolism of bisoprolol fumarate is about 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2-4 hours of
dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once
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daily dosing with bisoprolol fumarate results in less than twofold intersubject variation in peak plasma
levels. The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients, in part
because of decreased renal function in that population. Steady state is attained within 5 days of once
daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor
ranges from 1.1 to 1.3, and is what would be expected from the first order kinetics and once daily dosing.
Plasma concentrations are proportional to the administered dose in the range of 5 to 20 mg.
Pharmacokinetic characteristics of the two enantiomers are similar.
Bisoprolol fumarate is eliminated equally by renal and non-renal pathways with about 50% of the dose
appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. In
humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the
dose is excreted in the feces. Bisoprolol fumarate is not metabolized by cytochrome P450 II D6
(debrisoquin hydroxylase).
In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately
threefold compared to healthy subjects.
In patients with cirrhosis of the liver, the elimination of Zebeta (bisoprolol fumarate) is more variable in
rate and significantly slower than that in healthy subjects, with plasma half-life ranging from 8.3 to 21.7
hours.
Pharmacodynamics
The most prominent effect of Zebeta is the negative chronotropic effect, resulting in a reduction in resting
and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in
stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at
rest or during exercise.
Findings in short-term clinical hemodynamics studies with Zebeta are similar to those observed with
other beta-blocking agents.
The mechanism of action of its antihypertensive effects has not been completely established. Factors
which may be involved include:
1) Decreased cardiac output,
2) Inhibition of renin release by the kidneys,
3) Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.
In normal volunteers, Zebeta therapy resulted in a reduction of exercise- and isoproterenol-induced
tachycardia. The maximal effect occurred within 1-4 hours post-dosing. Effects persisted for 24 hours at
doses equal to or greater than 5 mg.
Electrophysiology studies in man have demonstrated that Zebeta significantly decreases heart rate,
increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial
stimulation, prolongs AV nodal conduction.
Beta1-selectivity of Zebeta has been demonstrated in both animal and human studies. No effects at
therapeutic doses on beta2-adrenoceptor density have been observed. Pulmonary function studies have
been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary
disease (COPD). Doses of Zebeta ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from
100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in
airways resistance (AWR) and decreases in forced expiratory volume (FEV1) were observed with doses of
bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR also noted with the other
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cardioselective beta-blockers. The changes induced by beta-blockade with all agents were reversed by
bronchodilator therapy.
Zebeta had minimal effect on serum lipids during antihypertensive studies. In U.S. placebo-controlled
trials, changes in total cholesterol averaged +0.8% for bisoprolol fumarate-treated patients, and +0.7% for
placebo. Changes in triglycerides averaged +19% for bisoprolol fumarate-treated patients, and +17% for
placebo.
Zebeta (bisoprolol fumarate) has also been given concomitantly with thiazide diuretics. Even very low
doses of hydrochlorothiazide (6.25 mg) were found to be additive with bisoprolol fumarate in lowering
blood pressure in patients with mild-to-moderate hypertension.
CLINICAL STUDIES
In two randomized double-blind placebo-controlled trials conducted in the U.S., reductions in systolic and
diastolic blood pressure and heart rate 24 hours after dosing in patients with mild-to-moderate
hypertension are shown below. In both studies, mean systolic/diastolic blood pressures at baseline were
approximately 150/100 mm Hg, and mean heart rate was 76 bpm. Drug effect is calculated by subtracting
the placebo effect from the overall change in blood pressure and heart rate.
Sitting Systolic/Diastolic Pressure (BP) and Heart Rate (HR)
Mean Decrease (D) After 3 to 4 Weeks
Study A
Bisoprolol Fumarate
Placebo
5 mg
10 mg
20 mg
n=
61
61
61
61
Total ΔBP (mm Hg)
5.4/3.2
10.4/8.0
11.2/10.9
12.8/11.9
Drug Effecta
-
5.0/4.8
5.8/7.7
7.4/8.7
Total ΔHR (bpm)
0.5
7.2
8.7
11.3
Drug Effecta
-
6.7
8.2
10.8
Study B
Bisoprolol
Fumarate
Placebo
2.5 mg
10 mg
n=
56
59
62
Total ΔBP (mm Hg)
3.0/3.7
7.6/8.1
13.5/11.2
Drug Effecta
-
4.6/4.4
10.5/7.5
Total ΔHR (bpm)
1.6
3.8
10.7
Drug Effecta
-
2.2
9.1
a Observed total change from baseline minus placebo.
Blood pressure responses were seen within one week of treatment and changed little thereafter. They
were sustained for 12 weeks and for over a year in studies of longer duration. Blood pressure returned to
baseline when bisoprolol fumarate was tapered over two weeks in a long-term study.
Overall, significantly greater blood pressure reductions were observed on bisoprolol fumarate than on
placebo regardless of race, age, or gender. There were no significant differences in response between
black and nonblack patients.
INDICATIONS AND USAGE
Zebeta is indicated in the management of hypertension. It may be used alone or in combination with
other antihypertensive agents.
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CONTRAINDICATIONS
Zebeta is contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree
AV block, and marked sinus bradycardia.
WARNINGS
Cardiac Failure
Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive
heart failure, and beta-blockade may result in further depression of myocardial contractility and
precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt
congestive failure. However, in some patients with compensated cardiac failure it may be necessary to
utilize them. In such a situation, they must be used cautiously.
In Patients Without a History of Cardiac Failure
Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac
failure. At the first signs or symptoms of heart failure, discontinuation of Zebeta should be considered.
In some cases, beta-blocker therapy can be continued while heart failure is treated with other drugs.
Abrupt Cessation of Therapy
Exacerbation of angina pectoris, and, in some instances, myocardial infarction or ventricular arrhythmia,
have been observed in patients with coronary artery disease following abrupt cessation of therapy with
beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of
therapy without the physician’s advice. Even in patients without overt coronary artery disease, it may be
advisable to taper therapy with Zebeta over approximately one week with the patient under careful
observation. If withdrawal symptoms occur, Zebeta therapy should be reinstituted, at least temporarily.
Peripheral Vascular Disease
Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral
vascular disease. Caution should be exercised in such individuals.
Bronchospastic Disease
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE
BETA-BLOCKERS. Because of its relative beta1-selectivity, however, Zebeta may be used with
caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other
antihypertensive treatment. Since beta1-selectivity is not absolute, the lowest possible dose of
Zebeta should be used, with therapy starting at 2.5 mg. A beta2 agonist (bronchodilator) should be
made available.
Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery;
however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of
general anesthesia and surgical procedures.
Diabetes and Hypoglycemia
Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.
Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum
glucose levels. Because of its beta1-selectivity, this is less likely with Zebeta. However, patients subject
to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should
be cautioned about these possibilities and bisoprolol fumarate should be used with caution.
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Thyrotoxicosis
Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt
withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or
may precipitate thyroid storm.
PRECAUTIONS
Impaired Renal or Hepatic Function
Use caution in adjusting the dose of Zebeta in patients with renal or hepatic impairment (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Drug Interactions
Zebeta should not be combined with other beta-blocking agents. Patients receiving catecholamine-
depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added beta-
adrenergic blocking action of Zebeta may produce excessive reduction of sympathetic activity. In patients
receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that Zebeta be
discontinued for several days before the withdrawal of clonidine.
Zebeta should be used with care when myocardial depressants or inhibitors of AV conduction, such as
certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine
[diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate.
Concomitant use can increase the risk of bradycardia.
Concurrent use of rifampin increases the metabolic clearance of Zebeta, resulting in a shortened
elimination half-life of Zebeta. However, initial dose modification is generally not necessary.
Pharmacokinetic studies document no clinically relevant interactions with other agents given
concomitantly, including thiazide diuretics and cimetidine. There was no effect of Zebeta on prothrombin
time in patients on stable doses of warfarin.
Risk of Anaphylactic Reaction:
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens
may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients
may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.
Information for Patients
Patients, especially those with coronary artery disease, should be warned about discontinuing use of
Zebeta without a physician’s supervision. Patients should also be advised to consult a physician if any
difficulty in breathing occurs, or if they develop signs or symptoms of congestive heart failure or
excessive bradycardia.
Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic
agents, should be cautioned that beta-blockers may mask some of the manifestations of hypoglycemia,
particularly tachycardia, and bisoprolol fumarate should be used with caution.
Patients should know how they react to this medicine before they operate automobiles and machinery or
engage in other tasks requiring alertness.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and
24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to
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250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body weight basis, these doses are 625 and 312
times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based
on a 50 kg individual); on a body surface area basis, these doses are 59 times (mice) and 64 times (rats)
the MRHD. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity
(Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the
unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There
was no evidence of mutagenic potential in these in vitro and in vivo assays.
Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of
bisoprolol fumarate, or 375 and 77 times the MRHD on the basis of body weight and body surface area,
respectively.
Pregnancy Category C
In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 375 and 77 times
the MRHD on the basis of body weight and body surface area, respectively. Bisoprolol fumarate was
fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body
weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body
weight basis and 26 times the MRHD on the basis of body surface area. The maternotoxicity occurred at
375 times the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area.
In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12
times the MRHD based on body weight and body surface area, respectively, but was embryolethal
(increased early resorptions) at 12.5 mg/kg/day.
There are no adequate and well-controlled studies in pregnant women. Zebeta (bisoprolol fumarate)
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Small amounts of bisoprolol fumarate (< 2% of the dose) have been detected in the milk of lactating rats.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk caution should be exercised when bisoprolol fumarate is administered to nursing women.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Zebeta has been used in elderly patients with hypertension. Response rates and mean decreases in
systolic and diastolic blood pressure were similar to the decreases in younger patients in the U.S. clinical
studies. Although no dose response study was conducted in elderly patients, there was a tendency for
older patients to be maintained on higher doses of bisoprolol fumarate.
Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to
increase with increasing dose. In general, no disparity in adverse experience reports or dropouts for
safety reasons was observed between older and younger patients. Dose adjustment based on age is not
necessary.
ADVERSE REACTIONS
Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of
withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies.
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In Study A, doses of 5, 10, and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B,
doses of 2.5, 10, and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273
patients were treated with 5-20 mg of bisoprolol fumarate; 132 received placebo.
Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8%
for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy.
The following table presents adverse experiences, whether or not considered drug related, reported in at
least 1% of patients in these studies, for all patients studied in placebo-controlled clinical trials (2.5-40
mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5-20
mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear
to be dose related.
Body System/Adverse Experience
All Adverse Experiences (%a)
Bisoprolol Fumarate
Placebo
5-20 mg
2.5-40 mg
(n=132)
(n=273)
(n=404)
%
%
%
Skin
increased sweating
1.5
0.7
1.0
Musculoskeletal
arthralgia
2.3
2.2
2.7
Central Nervous System
dizziness
3.8
2.9
3.5
headache
11.4
8.8
10.9
hypoaesthesia
0.8
1.1
1.5
Autonomic Nervous System
dry mouth
1.5
0.7
1.3
Heart Rate/Rhythm
bradycardia
0
0.4
0.5
Psychiatric
vivid dreams
0
0
0
insomnia
2.3
1.5
2.5
depression
0.8
0
0.2
Gastrointestinal
diarrhea
1.5
2.6
3.5
nausea
1.5
1.5
2.2
vomiting
0
1.1
1.5
Respiratory
bronchospasm
0
0
0
cough
4.5
2.6
2.5
dyspnea
0.8
1.1
1.5
pharyngitis
2.3
2.2
2.2
rhinitis
3.0
2.9
4.0
sinusitis
1.5
2.2
2.2
URI
3.8
4.8
5.0
Body as a Whole
asthenia
0
0.4
1.5
chest pain
0.8
1.1
1.5
fatigue
1.5
6.6
8.2
edema (peripheral)
3.8
3.7
3.0
a percentage of patients with event
Reference ID: 2900034
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The following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in
worldwide studies, or in postmarketing experience (in italics):
Central Nervous System
Dizziness, unsteadiness, vertigo, syncope, headache, paresthesia, hypoesthesia, hyperesthesia,
somnolence, sleep disturbances, anxiety/restlessness, decreased concentration/memory.
Autonomic Nervous System
Dry mouth.
Cardiovascular
Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension,
orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.
Psychiatric
Vivid dreams, insomnia, depression.
Gastrointestinal
Gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic
ulcer.
Musculoskeletal
Muscle/joint pain, arthralgia, back/neck pain, muscle cramps, twitching/tremor.
Skin
Rash, acne, eczema, psoriasis, skin irritation, pruritus, flushing, sweating, alopecia, dermatitis,
angioedema, exfoliative dermatitis, cutaneous vasculitis.
Special Senses
Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache,
taste abnormalities.
Metabolic
Gout.
Respiratory
Asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, URI.
Genitourinary
Decreased libido/impotence, Peyronie’s disease, cystitis, renal colic, polyuria.
Hematologic
Purpura.
General
Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.
In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and
should be considered potential adverse effects of ZEBETA:
Reference ID: 2900034
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Central Nervous System
Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome
characterized by disorientation to time and place, emotional lability, slightly clouded sensorium.
Allergic
Fever, combined with aching and sore throat, laryngospasm, respiratory distress.
Hematologic
Agranulocytosis, thrombocytopenia, thrombocytopenic purpura.
Gastrointestinal
Mesenteric arterial thrombosis, ischemic colitis.
Miscellaneous
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with
Zebeta (bisoprolol fumarate) during investigational use or extensive foreign marketing experience.
LABORATORY ABNORMALITIES
In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides,
but this was not a consistent finding.
Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with
bisoprolol fumarate treatment for 4-12 weeks, the incidence of concomitant elevations in SGOT and
SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant
elevations greater than twice normal.
In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6-18 months, the
incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%.
The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of
greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In
many cases these elevations were attributed to underlying disorders, or resolved during continued
treatment with bisoprolol fumarate.
Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium,
glucose, and phosphorus and decreases in WBC and platelets. These were generally not of clinical
importance and rarely resulted in discontinuation of bisoprolol fumarate.
As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About
15% of patients in long-term studies converted to a positive titer, although about one-third of these
patients subsequently reconverted to a negative titer while on continued therapy.
OVERDOSAGE
The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension,
congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum:
2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted.
Sympathomimetic agents were given in some cases, and all patients recovered.
In general, if overdose occurs, Zebeta therapy should be stopped and supportive and symptomatic
treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable. Based on
Reference ID: 2900034
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the expected pharmacologic actions and recommendations for other beta-blockers, the following general
measures should be considered when clinically warranted:
Bradycardia
Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive
chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker
insertion may be necessary.
Hypotension
IV fluids and vasopressors should be administered. Intravenous glucagon may be useful.
Heart Block (second or third degree)
Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac
pacemaker insertion, as appropriate.
Congestive Heart Failure
Initiate conventional therapy (ie, digitalis, diuretics, inotropic agents, vasodilating agents).
Bronchospasm
Administer bronchodilator therapy such as isoproterenol and/or aminophylline.
Hypoglycemia
Administer IV glucose.
DOSAGE AND ADMINISTRATION
The dose of Zebeta must be individualized to the needs of the patient. The usual starting dose is 5 mg
once daily. In some patients, 2.5 mg may be an appropriate starting dose (see Bronchospastic Disease in
WARNINGS). If the antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg
and then, if necessary, to 20 mg once daily.
Patients with Renal or Hepatic Impairment
In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less
than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration.
Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in
patients undergoing dialysis.
Geriatric Patients
It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic
dysfunction (see above and Geriatric Use in PRECAUTIONS).
Pediatric Patients
There is no pediatric experience with Zebeta.
HOW SUPPLIED
Zebeta® (bisoprolol fumarate) is supplied as 5 mg and 10 mg tablets.
The 5 mg tablet is pink, heart-shaped, biconvex, film-coated, vertically scored in half on both sides, with
an engraved stylized b/stylized b on one side and 6/0 on the reverse side, supplied as follows:
30
Unit-of-use
NDC 51285-060-01
Reference ID: 2900034
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The 10 mg tablet is white, heart-shaped, biconvex, film-coated, with an engraved stylized b on one side
and 61 on the reverse side, supplied as follows:
30
Unit-of-use
NDC 51285-061-01
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from moisture.
Dispense in tight containers.
DURAMED PHARMACEUTICALS, INC.
Subsidiary of Barr Pharmaceuticals, Inc.
Pomona, New York 10970
Revised November 2010
BR-60, 61
Reference ID: 2900034
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------
----------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
MARY R SOUTHWORTH
02/03/2011
Reference ID: 2900034
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019982s016lbl.pdf', 'application_number': 19982, 'submission_type': 'SUPPL ', 'submission_number': 16}
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Linda Katz
1/18/02 03:30:33 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19983s16lbl.pdf', 'application_number': 19983, 'submission_type': 'SUPPL ', 'submission_number': 16}
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NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 1
Novo Nordisk
Insulin Information For The Patient Using
Novolin® 70/30 FlexPen
70% NPH, Human Insulin Isophane (recombinant DNA origin)
Suspension & and 30% Regular, Human Insulin (recombinant DNA origin)
Injection (recombinant DNA origin)
in a 3 mL disposable Prefilled Insulin Syringe
100 units/mL (U-100)
Please read both sides of this leaflet carefully before using this product.
Novolin® 70/30 FlexPen
prefilled insulin syringe is for single-person use only.
See Important Notes section.
WARNING
ANY CHANGE OF INSULIN SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER
MEDICAL SUPERVISION. CHANGES IN PURITY, STRENGTH, BRAND
(MANUFACTURER), TYPE (REGULAR, NPH, LENTE®, ETC.), SPECIES (BEEF, PORK,
BEEF-PORK, HUMAN), AND/OR METHOD OF MANUFACTURE (RECOMBINANT
DNA VERSUS ANIMAL-SOURCE INSULIN) MAY RESULT IN THE NEED FOR A
CHANGE IN DOSAGE.
SPECIAL CARE SHOULD BE TAKEN WHEN THE TRANSFER IS FROM A
STANDARD BEEF OR MIXED SPECIES INSULIN TO A PURIFIED PORK OR HUMAN
INSULIN. IF A DOSAGE ADJUSTMENT IS NEEDED, IT WILL USUALLY BECOME
APPARENT EITHER IN THE FIRST FEW DAYS OR OVER A PERIOD OF SEVERAL
WEEKS. ANY CHANGE IN TREATMENT SHOULD BE CAREFULLY MONITORED.
PLEASE READ THE SECTIONS “INSULIN REACTION AND SHOCK” AND
“DIABETIC KETOACIDOSIS AND COMA” FOR SYMPTOMS OF HYPOGLYCEMIA
(LOW BLOOD GLUCOSE) AND HYPERGLYCEMIA (HIGH BLOOD GLUCOSE).
INSULIN USE IN DIABETES
Your physician has explained that you have diabetes and that your treatment involves injections of insulin
or insulin therapy combined with an oral antidiabetic medicine. Insulin is normally produced by the
pancreas, a gland that lies behind the stomach. Without insulin, glucose (a simple sugar made from
digested food) is trapped in the bloodstream and cannot enter the cells of the body. Some patients who
don’t make enough of their own insulin, or who cannot use the insulin they do make properly, must take
insulin by injection in order to control their blood glucose levels.
Each case of diabetes is different and requires direct and continued medical supervision. Your physician
has told you the type, strength and amount of insulin you should use and the time(s) at which you should
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 2
inject it, and has also discussed with you a diet and exercise schedule. You should contact your
physician if you experience any difficulties or if you have questions.
TYPES OF INSULINS
Standard and purified animal insulins as well as human insulins are available. Standard and purified
insulins differ in their degree of purification and content of noninsulin material. Standard and purified
insulins also vary in species source; they may be of beef, pork, or mixed beef and pork origin. Human
insulin is identical in structure to the insulin produced by the human pancreas, and thus differs from
animal insulins. Insulins vary in time of action; see PRODUCT DESCRIPTION for additional
information.
Your physician has prescribed the insulin that is right for you; be sure you have purchased the correct
insulin and check it carefully before you use it.
PRODUCT DESCRIPTION
This package contains five (5) Novolin® 70/30 FlexPen prefilled insulin syringes. Novolin® 70/30 is a
mixture of 70% NPH, Human Insulin Isophane (recombinant DNA origin) Suspension (recombinant
DNA origin) and 30% Regular Human Insulin (recombinant DNA origin) Injection (recombinant DNA
origin). The concentration of this product is 100 units of insulin per milliliter. It is a cloudy or milky
suspension of human insulin with protamine and zinc. The insulin substance (the cloudy material) settles
at the bottom of the insulin reservoir, therefore, the syringe Novolin 70/30 FlexPen must be rotated up
and down so that the contents are uniformly mixed before a dose is given. Novolin® 70/30 has an
intermediate duration of action. The effect of Novolin® 70/30 begins approximately 1/2 hour after
injection. The effect is maximal between 2 and approximately12 hours. The full duration of action may
last up to 24 hours after injection.
The time course of action of any insulin may vary considerably in different individuals, or at different
times in the same individual. Because of this variation, the time periods listed here should be considered
as general guidelines only.
This human insulin (recombinant DNA origin) is structurally identical to the insulin produced by the
human pancreas. This human insulin is produced by recombinant DNA technology utilizing
Saccharomyces cerevisiae (bakers’ yeast) as the production organism.
STORAGE
Novolin® 70/30 FlexPen prefilled insulin syringes should be stored in a cold (2° - 8°C [36° - 46°F])
place, preferably in a refrigerator, but not in the freezer. Do not let it freeze. Keep Novolin® 70/30
FlexPen prefilled insulin syringes in the carton so that they will stay clean and protected from light.
The Novolin® 70/30 FlexPen prefilled insulin syringe that you are currently using can be kept
unrefrigerated for 10 days, as long as it is kept as cool as possible (below 86°F [30°C]).
Unrefrigerated Novolin® 70/30 FlexPen prefilled insulin syringes must be used within this time
period or discarded after 10 days even if it still contains Novolin 70/30. Be sure to protect Novolin®
70/30 FlexPen prefilled insulin syringes from sunlight and extreme heat or cold. Never use insulin
after the expiration date printed on the label and carton.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 3
Never use any Novolin® 70/30 FlexPen prefilled insulin syringes if the precipitate (the white deposit)
has become lumpy or granular in appearance or has formed a deposit of solid particles on the wall of
the insulin reservoir. This insulin should not be used if the liquid in the insulin reservoir remains clear
after it has been mixed.
Never use insulin after the expiration date printed on the label and carton.
IMPORTANT
Failure to comply with the following antiseptic measures may lead to infections at the injection site.
- Disposable needles are not to be re-used; they should be used only once and destroyed.
- Clean your hands and the injection site with soap and water or with alcohol.
- Wipe the rubber stopper on the insulin cartridge with an alcohol swab.
PREPARING THE INJECTION
Never place a single-use disposable needle on your Novolin® 70/30 FlexPen prefilled insulin syringe
until you are ready to give an injection, and remove the needle immediately after each injection. If the
needle is not removed some liquid may be expelled from the cartridge causing a change in the insulin
concentration (strength). The cloudy material in an insulin suspension will settle to the bottom of the
insulin reservoir, so the contents must be mixed before injection. FlexPen prefilled insulin syringes
contain a glass ball to aid mixing. Rotate the FlexPen prefilled insulin syringe up and down so that the
contents are uniformly mixed before the dose is given. Follow the directions for use of this syringe on
the reverse side of this insert.
Insulin prefilled syringes Novolin 70/30 FlexPenTMmay contain a small amount of air. To prevent an
injection of air and make certain insulin is delivered, an air shot must be done before each injection.
Directions for performing an air shot are provided on the reverse side of this insert.
GIVING THE INJECTION
1. The following areas are suitable for subcutaneous insulin injection: thighs, upper arms, buttocks,
abdomen. Do not change areas without consulting your physician. The actual point of injection
should be changed each time; injection sites should be about an inch apart.
2. The injection site should be clean and dry. Pinch up skin area to be injected and hold it firmly.
3. Hold the device upright and push the needle quickly and firmly into the pinched-up area. Release the
skin and push the push-button all the way in to inject insulin beneath the skin. To ensure that all the
insulin is injected keep the needle in the skin for several seconds after injection with your thumb on
the push-button.
4. Do not inject into a muscle unless your physician has advised it. You should never inject insulin into
a vein.
5. Remove the needle. If slight bleeding occurs, press lightly with a dry cotton swab for a few seconds
– do not rub.
For additional information see GIVING THE INJECTION on the reverse side of this insert.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 4
USAGE IN PREGNANCY
It is particularly important to maintain good control of your diabetes during pregnancy and special
attention must be paid to your diet, exercise and insulin regimens. If you are pregnant or nursing a baby,
consult your physician or nurse educator.
INSULIN REACTION AND SHOCK
Insulin reaction (hypoglycemia) occurs when the blood glucose falls very low. This can happen if you
take too much insulin, miss or delay a meal, exercise more than usual or work too hard without eating,
or become ill (especially with vomiting or fever). Hypoglycemia can also happen if you combine insulin
therapy and other medications that lower blood glucose, such as oral antidiabetic agents or other
prescription and over-the-counter drugs. The first symptoms of an insulin reaction usually come on
suddenly. They may include a cold sweat, fatigue, nervousness or shakiness, rapid heartbeat, or
nausea. Personality change or confusion may also occur. If you drink or eat something right away (a
glass of milk or orange juice, or several sugar candies), you can often stop the progression of
symptoms. If symptoms persist, call your physician - an insulin reaction can lead to unconsciousness. If
a reaction results in loss of consciousness, emergency medical care should be obtained immediately. If
you have had repeated reactions or if an insulin reaction has led to a loss of consciousness, contact your
physician. Severe hypoglycemia can result in temporary or permanent impairment of brain function and
death.
In certain cases, the nature and intensity of the warning symptoms of hypoglycemia may
change. A few patients have reported that after being transferred to human insulin, the early
warning symptoms of hypoglycemia were less pronounced than they had been with animal-
source insulin.
DIABETIC KETOACIDOSIS AND COMA
Diabetic ketoacidosis may develop if your body has too little insulin. The most common causes are
acute illness or infection or failure to take enough insulin by injection. If you are ill you should check
your urine for ketones. The symptoms of diabetic ketoacidosis usually come on gradually, over a
period of hours or days, and include a drowsy feeling, flushed face, thirst and loss of appetite. Notify
your physician right away if the urine test is positive for ketones (acetone) or if you have any of these
symptoms. Fast, heavy breathing and rapid pulse are more severe symptoms and you should have
medical attention right away. Severe, sustained hyperglycemia may result in diabetic coma and death.
ADVERSE REACTIONS
A few people with diabetes develop red, swollen and itchy skin where the insulin has been injected.
This is called a “local reaction” and it may occur if the injection is not properly made, if the skin is
sensitive to the cleansing solution, or if you are allergic to the insulin being used. If you have a local
reaction, tell your physician.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 5
Generalized insulin allergy occurs rarely, but when it does it may cause a serious reaction, including skin
rash over the body, shortness of breath, fast pulse, sweating, and a drop in blood pressure. If any of
these symptoms develop, you should seek emergency medical care.
If severe allergic reactions to insulin have occurred (i.e., generalized rash, swelling or breathing
difficulties) you should be skin-tested with each new insulin preparation before it is used.
IMPORTANT NOTES
1. A change in the type, strength, species or purity of insulin could require a dosage adjustment. Any
change in insulin should be made under medical supervision.
2. To avoid possible transmission of disease, Novolin® 70/30 FlexPen prefilled insulin syringe is for
single-person use only.
3. You may have learned how to test your urine or your blood for glucose. It is important to do these
tests regularly and to record the results for review with your physician or nurse educator.
4. If you have an acute illness, especially with vomiting or fever, continue taking your insulin. If
possible, stay on your regular diet. If you have trouble eating, drink fruit juices, regular soft drinks,
or clear soups; if you can, eat small amounts of bland foods. Test your urine for glucose and
ketones and, if possible, test your blood glucose. Note the results and contact your physician for
possible insulin dose adjustment. If you have severe and prolonged vomiting, seek emergency
medical care.
5. You should always carry identification which states that you have diabetes.
6. Always ask your physician or pharmacist before taking any drug.
Always consult your physician if you have any questions about your condition or the use of
insulin.
Helpful information for people with diabetes is published by American Diabetes Association, 1660
Duke Street, Alexandria, VA 22314
Novo Nordisk Pharmaceuticals, Inc.
Princeton, NJ 08540
Manufactured by
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark and
Novo Nordisk Pharmaceuticals Industries, Inc.
3612 Powhatan Road
Clayton, NC 27520
www.novonordisk-us.com
Novo Nordisk, Novolin®, Lente®, NovoFine® and FlexPenare trademarks owned by Novo
Nordisk A/S
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 6
Printed in Denmark
Date of issue: August 2001
© 2001 Novo Nordisk
FlexPen
prefilled insulin syringe directions for use
Novolin® 70/30 FlexPen prefilled insulin syringe is a disposable dial-a-dose insulin delivery system
able to deliver 1 to a maximum of 60 units. The dose can be adjusted in increments of 1 unit.
Novolin 70/30 FlexPen prefilled insulin syringe is designed for use with NovoFine® single use needles
or other products specifically recommended by Novo Nordisk. Novolin 70/30 FlexPen prefilled
insulin syringe is not recommended for the blind or severely visually impaired without the assistance of a
sighted individual trained in the proper use of the product.
Please read these instructions completely before using this device.
Residual
scale
window
Cap
Residual scale
Dosage
indicator
window
Push button
12
units
Dose
selector
Inner needle cap
Outer
needle cap
Needle
Protective
tab
NovoFine®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 7
1. PREPARING THE FLEXPEN: PREFILLED INSULIN SYRINGE
a Pull off the cap.
b Wipe the rubber stopper with an alcohol swab.
c A. Remove the protective tab from the disposable needle and screw the needle onto the FlexPen.
Never place a disposable needle on your FlexPen until you are ready to give an injection. Remove
the needle right after use. If the needle is not removed, some liquid may leak from the FlexPen.
d B. Pull off the outer and inner needle caps. Do not discard the outer needle cap.
Giving the airshot before each injection:
Small amounts of air may collect in the needle and insulin reservoir during normal use.
To avoid injecting air and to ensure proper dosing, hold the syringe with the needle pointing up and
tap the syringe gently with your finger so any air bubbles collect in the top of the reservoir. Remove
both the plastic outer cap and the needle cap.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 9
e C. Dial 2 units.
f
D. Holding the syringe with the needle pointing up, tap the reservoir gently with your finger a few
times. Still with the needle pointing up, press the push button as far as it will go and see if a drop of
insulin appears at the needle tip. If not, repeat the procedure until insulin appears. Before the first
use of each Novolin® 70/30 FlexPen prefilled insulin syringe you may need to perform up to 6
airshots to get a droplet of insulin at the needle tip. If you need to make more than 6 airshots, do
not use the syringe, and return the product to Novo Nordisk. A small air bubble may remain but it
will not be injected because the operating mechanism prevents the reservoir from being completely
emptied.
2. SETTING THE DOSE
g E. Check that the dose selector is set at 0. Dial the number of units you need to inject. The dose
can be corrected either up or down by turning the dose selector in either direction. When dialing
back be careful not to push the push button as insulin will come out. You cannot set a dose larger
than the number of units left in the reservoir.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 10
3. GIVING THE INJECTION
Use the injection technique recommended by your doctor.
h F. Deliver the dose by pressing the push button all the way in. Be careful only to push the push
button when injecting.
i
G. After the injection the needle should remain under the skin for several seconds. Keep the push
button fully depressed until the needle is withdrawn from the skin. This will ensure that the full dose
has been delivered.
j
H. Replace the outer needle cap, unscrew the needle, and throw it away appropriately.
It is important that you use a new needle for each injection. Health care professionals,
relatives and other care givers should follow general precautionary measures for removal and
disposal of needles to eliminate the risk of unintended needle penetration.
For more information see Giving The Injection on the reverse side of this insert.
4. SUBSEQUENT INJECTIONS
It is important that you use a new needle for each injection. Follow the directions in steps 1 – 3.
The numbers on the insulin reservoir can be used to estimate the amount of insulin left in the syringe. Do
not use these numbers to measure the insulin dose.
You cannot set a dose greater than the number of units remaining in the reservoir.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 11
5. FUNCTION CHECK
If your Novolin® 70/30 FlexPen prefilled insulin syringe is not working properly, follow this procedure:
- Screw on a new NovoFine needle
- Give an airshot as described in sections C to D e to f.
- Put the outer needle cap onto the needle
- Dispense 20 units into the outer needle cap, holding the pen with the needle pointing downwards.
The insulin should fill the lower part of the cap (as shown in figure I). If Novolin® 70/30 FlexPen
prefilled insulin syringe has released too much or too little insulin, repeat the test. If it happens again,
contact Novo Nordisk and do not use your Novolin® 70/30 FlexPen prefilled insulin syringe.
Dispose of the used Novolin® 70/30 FlexPen prefilled insulin syringe carefully without the needle
attached.
6. IMPORTANT NOTES
• If you need to perform more than 6 airshots before the first use of Novolin® 70/30 FlexPen prefilled
insulin syringe to get a droplet of insulin at the needle tip, do not use the FlexPen.
• Remember to perform an air shot before each injection. See figures C and D e and f.
• Take care not to drop the FlexPen.
• Remember to keep the Novolin® 70/30 FlexPen prefilled insulin syringe with you; don’t leave it in a
car or other location where extremes of temperature can occur.
• Novolin® 70/30 FlexPen prefilled insulin syringe is designed for use with NovoFine disposable
needles or other products specifically recommended by Novo Nordisk.
• Never place a disposable needle on this syringe until you are ready to use it. Remove the needle
immediately after use.
• Throw away used needles in a responsible manner, so others will not be harmed.
• Throw away the used syringe, without the needle attached.
I
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 12
• Always carry a spare Novolin® 70/30 FlexPen prefilled insulin syringe with you in case your
FlexPen is damaged or lost.
• Novo Nordisk cannot be held responsible for adverse reactions occurring as a consequence of
using this insulin delivery system with products that are not recommended by Novo Nordisk.
• Keep this syringe out of the reach of children.
Call 800-727-6500 for additional information.
Novo Nordisk Pharmaceuticals Inc.
Princeton, New Jersey 08540
Manufactured by
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark and
Novo Nordisk Pharmaceuticals Industries, Inc.
3612 Powhatan Road
Clayton, NC 27520
www.novonordisk-us.com
Novo Nordisk, Novolin, FlexPen, and NovoFineare trademarks owned by Novo Nordisk A/S
Licensed under U.S. Patent No. XXXXXXX
Date of Issue: August 2001
© 2001 Novo Nordisk
Printed in Denmark
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-991/S-037 (document submission date 8/14/01)
FDA revision date 8/21/01
Page 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
David Orloff
12/19/01 04:59:15 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19991s37lbl.pdf', 'application_number': 19991, 'submission_type': 'SUPPL ', 'submission_number': 37}
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PRESCRIBING INFORMATION
1
ZOFRAN®
2
(ondansetron hydrochloride)
3
Injection
4
5
ZOFRAN®
6
(ondansetron hydrochloride)
7
Injection Premixed
8
DESCRIPTION
9
The active ingredient in ZOFRAN Injection and ZOFRAN Injection Premixed is ondansetron
10
hydrochloride (HCl), the racemic form of ondansetron and a selective blocking agent of the
11
serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-
12
1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the
13
following structural formula:
14
15
16
17
The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9.
18
Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.
19
Sterile Injection for Intravenous (I.V.) or Intramuscular (I.M.) Administration: Each
20
1 mL of aqueous solution in the 2-mL single-dose vial contains 2 mg of ondansetron as the
21
hydrochloride dihydrate; 9.0 mg of sodium chloride, USP; and 0.5 mg of citric acid
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monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for
23
Injection, USP.
24
Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as
25
the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate,
26
USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF
27
and 0.15 mg of propylparaben, NF as preservatives in Water for Injection, USP.
28
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution. The pH of the injection
29
solution is 3.3 to 4.0.
30
Sterile, Premixed Solution for Intravenous Administration in Single-Dose, Flexible
31
Plastic Containers: Each 50 mL contains ondansetron 32 mg (as the hydrochloride dihydrate);
32
dextrose 2,500 mg; and citric acid 26 mg and sodium citrate 11.5 mg as buffers in Water for
33
Injection, USP. It contains no preservatives. The osmolarity of this solution is 270 mOsm/L
34
(approx.), and the pH is 3.0 to 4.0.
35
This label may not be the latest approved by FDA.
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The flexible plastic container is fabricated from a specially formulated, nonplasticized,
36
thermoplastic co-polyester (CR3). Water can permeate from inside the container into the
37
overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the
38
plastic container also can leach out certain of the chemical components in very small amounts
39
before the expiration period is attained. However, the safety of the plastic has been confirmed by
40
tests in animals according to USP biological standards for plastic containers.
41
CLINICAL PHARMACOLOGY
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Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While
43
ondansetron's mechanism of action has not been fully characterized, it is not a dopamine-receptor
44
antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve
45
terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain
46
whether ondansetron's antiemetic action in chemotherapy-induced emesis is mediated centrally,
47
peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with
48
release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary
49
5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel
50
with the onset of emesis. The released serotonin may stimulate the vagal afferents through the
51
5-HT3 receptors and initiate the vomiting reflex.
52
In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor
53
of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or
54
pretreatment with a serotonin 5-HT3 receptor antagonist.
55
In normal volunteers, single I.V. doses of 0.15 mg/kg of ondansetron had no effect on
56
esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal
57
transit time. In another study in six normal male volunteers, a 16-mg dose infused over 5 minutes
58
showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or
59
electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow
60
colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin
61
concentrations.
62
In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered
63
intravenously or intramuscularly was dynamically similar in the prevention of emesis and nausea
64
using the ipecacuanha model of emesis. Both treatments were well tolerated.
65
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the
66
degree of neuromuscular blockade produced by atracurium. Interactions with general or local
67
anesthetics have not been studied.
68
Pharmacokinetics: Ondansetron is extensively metabolized in humans, with approximately
69
5% of a radiolabeled dose recovered as the parent compound from the urine. The primary
70
metabolic pathway is hydroxylation on the indole ring followed by glucuronide or sulfate
71
conjugation.
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Although some nonconjugated metabolites have pharmacologic activity, these are not found
73
in plasma at concentrations likely to significantly contribute to the biological activity of
74
ondansetron.
75
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic
76
cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall
77
ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of
78
metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one
79
enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little
80
change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by
81
cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained
82
chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½
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of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on
84
the basis of available data, no dosage adjustment for ondansetron is recommended (see
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PRECAUTIONS: Drug Interactions).
86
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of
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ondansetron.
88
In normal volunteers, the following mean pharmacokinetic data have been determined
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following a single 0.15-mg/kg I.V. dose.
90
91
Table 1. Pharmacokinetics in Normal Volunteers
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Age-group
n
Peak Plasma
Concentration
(ng/mL)
Mean Elimination
Half-life (h)
Plasma Clearance
(L/h/kg)
19-40
11
102
3.5
0.381
61-74
12
106
4.7
0.319
≥75
11
170
5.5
0.262
93
A reduction in clearance and increase in elimination half-life are seen in patients over 75 years
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of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65
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years of age and those under 65 years of age; there was an insufficient number of patients over
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75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended
97
in the elderly.
98
In patients with mild-to-moderate hepatic impairment, clearance is reduced twofold and mean
99
half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe
100
hepatic impairment (Child-Pugh score2 of 10 or greater), clearance is reduced twofold to threefold
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and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours.
102
In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.
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Due to the very small contribution (5%) of renal clearance to the overall clearance, renal
104
impairment was not expected to significantly influence the total clearance of ondansetron.
105
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However, ondansetron mean plasma clearance was reduced by about 41% in patients with severe
106
renal impairment (creatinine clearance <30 mL/min). This reduction in clearance is variable and
107
was not consistent with an increase in half-life. No reduction in dose or dosing frequency in
108
these patients is warranted.
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In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no
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difference in the multidose pharmacokinetics over a 4-day period. In a study of 21 pediatric
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cancer patients (aged 4 to 18 years) who received three I.V. doses of 0.15 mg/kg of ondansetron
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at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic
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parameters similar to those of adults. Patients aged 4 to 12 years generally showed higher
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clearance and somewhat larger volume of distribution than adults. Most pediatric patients
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younger than 15 years of age with cancer had a shorter (2.4 hours) ondansetron plasma half-life
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than patients older than 15 years of age. It is not known whether these differences in ondansetron
117
plasma half-life may result in differences in efficacy between adults and some young pediatric
118
patients (see CLINICAL TRIALS: Pediatric Studies).
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In a study of 21 pediatric patients (aged 3 to 12 years) who were undergoing surgery requiring
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anesthesia for a duration of 45 minutes to 2 hours, a single I.V. dose of ondansetron, 2 mg (3 to
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7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia induction.
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Mean weight-normalized clearance and volume of distribution values in these pediatric surgical
123
patients were similar to those previously reported for young adults. Mean terminal half-life was
124
slightly reduced in pediatric patients (range, 2.5 to 3 hours) in comparison with adults (range, 3 to
125
3.5 hours).
126
In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was
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264 ng/mL following a single 32-mg dose administered as a 15-minute I.V. infusion. The mean
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elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not
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proportional to dose as measured by comparing dose-normalized AUC values to an 8-mg dose.
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This is consistent with a small decrease in systemic clearance with increasing plasma
131
concentrations.
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A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a
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single 4-mg dose administered as a 5-minute infusion compared to a single intramuscular
134
injection. Systemic exposure as measured by mean AUC was equivalent, with values of 156
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[95% CI 136, 180] and 161 [95% CI 137, 190] ng•h/mL for I.V. and I.M. groups, respectively.
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Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V.
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infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean
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elimination half-life was not affected by route of administration.
139
Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with binding
140
constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also
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distributes into erythrocytes.
142
A positive lymphoblast transformation test to ondansetron has been reported, which suggests
143
immunologic sensitivity to ondansetron.
144
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CLINICAL TRIALS
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Chemotherapy-Induced Nausea and Vomiting: In a double-blind study of three different
146
dosing regimens of ZOFRAN Injection, 0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given
147
three times during the course of cancer chemotherapy, the 0.15-mg/kg dosing regimen was more
148
effective than the 0.015-mg/kg dosing regimen. The 0.30-mg/kg dosing regimen was not shown
149
to be more effective than the 0.15-mg/kg dosing regimen.
150
Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, ZOFRAN
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Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing
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nausea and vomiting induced by cisplatin-based chemotherapy. Treatment response was as
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shown in Table 2.
154
155
Table 2. Prevention of Chemotherapy-Induced Nausea and Emesis in Single-Day Cisplatin
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Therapy*
157
ZOFRAN
Injection
Placebo
P Value†
Number of patients
14
14
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
2 (14%)
8 (57%)
2 (14%)
2 (14%)
0 (0%)
0 (0%)
1 (7%)
13 (93%)
0.001
Median number of emetic episodes
1.5
Undefined‡
Median time to first emetic episode (h)
11.6
2.8
0.001
Median nausea scores (0-100)§
3
59
0.034
Global satisfaction with control of
nausea and vomiting (0-100)
II
96
10.5
0.009
* Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5)
158
or moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other
159
chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There
160
was no difference between treatments in the types of chemotherapy that would account for
161
differences in response.
162
† Efficacy based on "all patients treated" analysis.
163
‡
Median undefined since at least 50% of the patients were rescued or had more than five
164
emetic episodes.
165
§ Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
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II Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
167
168
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Ondansetron was compared with metoclopramide in a single-blind trial in 307 patients
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receiving cisplatin >100 mg/m2 with or without other chemotherapeutic agents. Patients received
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the first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional
171
ondansetron doses were administered 4 and 8 hours later, or five additional metoclopramide
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doses were administered 2, 4, 7, 10, and 13 hours later. Cisplatin was administered over a period
173
of 3 hours or less. Episodes of vomiting and retching were tabulated over the period of 24 hours
174
after cisplatin. The results of this study are summarized in Table 3.
175
176
Table 3. Prevention of Emesis Induced by Cisplatin (≥100 mg/m2) Single-Day Therapy*
177
ZOFRAN
Injection
Metoclopramide
P Value
Dose
0.15 mg/kg x 3
2 mg/kg x 6
Number of patients in efficacy population
136
138
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
54 (40%)
34 (25%)
19 (14%)
29 (21%)
41 (30%)
30 (22%)
18 (13%)
49 (36%)
Comparison of treatments with respect to
0 Emetic episodes
More than 5 emetic episodes/rescued
54/136
29/136
41/138
49/138
0.083
0.009
Median number of emetic episodes
1
2
0.005
Median time to first emetic episode (h)
20.5
4.3
<0.001
Global satisfaction with control of nausea
and vomiting (0-100)†
85
63
0.001
Acute dystonic reactions
0
8
0.005
Akathisia
0
10
0.002
* In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including
178
cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments
179
in the types of chemotherapy that would account for differences in response.
180
†
Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
181
182
In a stratified, randomized, double-blind, parallel-group, multicenter study, a single 32-mg
183
dose of ondansetron was compared with three 0.15-mg/kg doses in patients receiving cisplatin
184
doses of either 50 to 70 mg/m2 or ≥100 mg/m2. Patients received the first ondansetron dose
185
30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours
186
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later to the group receiving three 0.15-mg/kg doses. In both strata, significantly fewer patients on
187
the single 32-mg dose than those receiving the three-dose regimen failed.
188
189
Table 4. Prevention of Chemotherapy-Induced Nausea and Emesis in Single-Dose Therapy
190
Ondansetron
Dose
0.15 mg/kg x 3
32 mg x 1
P Value
High-dose cisplatin (≥100 mg/m2)
Number of patients
100
102
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
41 (41%)
19 (19%)
4 (4%)
36 (36%)
49 (48%)
25 (25%)
8 (8%)
20 (20%)
0.315
0.009
Median time to first emetic episode (h)
21.7
23
0.173
Median nausea scores (0-100)*
28
13
0.004
Medium-dose cisplatin (50-70 mg/m2)
Number of patients
101
93
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
62 (61%)
11 (11%)
6 (6%)
22 (22%)
68 (73%)
14 (15%)
3 (3%)
8 (9%)
0.083
0.011
Median time to first emetic episode (h)
Undefined†
Undefined
Median nausea scores (0-100)*
9
3
0.131
* Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
191
† Median undefined since at least 50% of patients did not have any emetic episodes.
192
193
Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled study
194
of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500
195
to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than placebo
196
in preventing nausea and vomiting. The results are summarized in Table 5.
197
198
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Table 5. Prevention of Chemotherapy-Induced Nausea and Emesis in Single-Day
199
Cyclophosphamide Therapy*
200
ZOFRAN
Injection
Placebo
P Value†
Number of patients
10
10
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
7 (70%)
0 (0%)
2 (20%)
1 (10%)
0 (0%)
2 (20%)
4 (40%)
4 (40%)
0.001
0.131
Median number of emetic episodes
0
4
0.008
Median time to first emetic episode (h)
Undefined‡
8.79
Median nausea scores (0-100)§
0
60
0.001
Global satisfaction with control of
nausea and vomiting (0-100)II
100
52
0.008
* Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including
201
fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between
202
treatments in the type of chemotherapy that would account for differences in response.
203
† Efficacy based on "all patients treated" analysis.
204
‡ Median undefined since at least 50% of patients did not have any emetic episodes.
205
§ Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
206
II Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
207
208
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose,
209
100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with
210
ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median,
211
2; range, 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes
212
occurred in 217 (81%) re-treatment courses.
213
Pediatric Studies: Four open-label, noncomparative (one US, three foreign) trials have
214
been performed with 209 pediatric cancer patients aged 4 to 18 years given a variety of cisplatin
215
or noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged
216
from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral
217
administration of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial,
218
ZOFRAN was administered intravenously (only) in three doses of 0.15 mg/kg each for a total
219
daily dose of 7.2 to 39 mg. In these studies, 58% of the 196 evaluable patients had a complete
220
response (no emetic episodes) on day 1. Thus, prevention of emesis in these pediatric patients
221
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was essentially the same as for patients older than 18 years of age. Overall, ZOFRAN Injection
222
was well tolerated in these pediatric patients.
223
Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and
224
Vomiting: Adult surgical patients who received ondansetron immediately before the induction
225
of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid:
226
alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or
227
vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double-blind US
228
studies involving 554 patients. ZOFRAN Injection (4 mg) I.V. given over 2 to 5 minutes was
229
significantly more effective than placebo. The results of these studies are summarized in Table 6.
230
231
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Table 6. Prevention of Postoperative Nausea and Vomiting in Adult Patients
232
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
103 (76%)
13 (10%)
20 (15%)
139
64 (46%)
17 (12%)
58 (42%)
<0.001
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
134
56 (42%)
136
39 (29%)
Study 2
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
85 (63%)
16 (12%)
35 (26%)
143
63 (44%)
29 (20%)
51 (36%)
0.002
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
125
48 (38%)
133
42 (32%)
233
The study populations in Table 6 consisted mainly of females undergoing laparoscopic
234
procedures.
235
In a placebo-controlled study conducted in 468 males undergoing outpatient procedures, a
236
single 4 mg I.V. ondansetron dose prevented postoperative vomiting over a 24-hour study period
237
in 79% of males receiving drug compared to 63% of males receiving placebo (P<0.001).
238
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major
239
abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg I.V. ondansetron dose
240
for prevention of postoperative nausea and vomiting over a 24-hour study period. At the 4-mg
241
dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the first study
242
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(P<0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the second
243
study (P=0.001) experienced no emetic episodes. No additional benefit was observed in patients
244
who received I.V. ondansetron 8 mg compared to patients who received I.V. ondansetron 4 mg.
245
Pediatric Studies: Three double-blind, placebo-controlled studies have been performed
246
(one US, two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing
247
general anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or
248
without adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were
249
randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing
250
40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was
251
administered over at least 30 seconds, immediately prior to or following anesthesia induction.
252
Ondansetron was significantly more effective than placebo in preventing nausea and vomiting.
253
The results of these studies are summarized in Table 7.
254
255
Table 7. Prevention of Postoperative Nausea and Vomiting in Pediatric Patients
256
Treatment Response Over
24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Study 1
Number of patients
0 Emetic episodes
Failure*
205
140 (68%)
65 (32%)
210
82 (39%)
128 (61%)
≤0.001
Study 2
Number of patients
0 Emetic episodes
Failure*
112
68 (61%)
44 (39%)
110
38 (35%)
72 (65%)
≤0.001
Study 3
Number of patients
0 Emetic episodes
Failure*
206
123 (60%)
83 (40%)
206
96 (47%)
110 (53%)
≤0.01
Nausea assessments†:
Number of patients
None
185
119 (64%)
191
99 (52%)
≤0.01
* Failure was one or more emetic episodes, rescued, or withdrawn.
257
† Nausea measured as none, mild, or severe.
258
259
Prevention of Further Postoperative Nausea and Vomiting: Adult surgical patients
260
receiving general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid:
261
alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or
262
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vecuronium or atracurium; and supplemental isoflurane) who received no prophylactic
263
antiemetics and who experienced nausea and/or vomiting within 2 hours postoperatively were
264
evaluated in two double-blind US studies involving 441 patients. Patients who experienced an
265
episode of postoperative nausea and/or vomiting were given ZOFRAN Injection (4 mg) I.V. over
266
2 to 5 minutes, and this was significantly more effective than placebo. The results of these studies
267
are summarized in Table 8.
268
269
Table 8. Prevention of Further Postoperative Nausea and Vomiting in Adult Patients
270
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
Median time to first emetic episode (min)*
104
49 (47%)
12 (12%)
43 (41%)
55.0
117
19 (16%)
9 (8%)
89 (76%)
43.0
<0.001
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
period†
98
1.7
102
3.1
Study 2
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
Median time to first emetic episode (min)*
112
49 (44%)
14 (13%)
49 (44%)
60.5
108
28 (26%)
3 (3%)
77 (71%)
34.0
0.006
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
period†
105
1.9
85
2.9
* After administration of study drug.
271
† Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
272
273
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The study populations in Table 8 consisted mainly of women undergoing laparoscopic
274
procedures.
275
Pediatric Studies: One double-blind, placebo-controlled, US study was performed in 351
276
male and female outpatients (2 to 12 years of age) who received general anesthesia with nitrous
277
oxide and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who
278
experienced two or more emetic episodes within 2 hours following discontinuation of nitrous
279
oxide were randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric
280
patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo
281
administered over at least 30 seconds. Ondansetron was significantly more effective than placebo
282
in preventing further episodes of nausea and vomiting. The results of the study are summarized
283
in Table 9.
284
285
Table 9. Prevention of Further Postoperative Nausea and Vomiting in Pediatric Patients
286
Treatment Response
Over 24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Number of patients
0 Emetic episodes
Failure*
180
96 (53%)
84 (47%)
171
29 (17%)
142 (83%)
≤0.001
* Failure was one or more emetic episodes, rescued, or withdrawn.
287
288
Repeat Dosing in Adults: In patients who do not achieve adequate control of postoperative
289
nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron
290
4 mg, administration of a second I.V. dose of ondansetron 4 mg postoperatively does not provide
291
additional control of nausea and vomiting.
292
INDICATIONS AND USAGE
293
1. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic
294
cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose
295
beyond 24 hours in these patients has not been established.
296
2. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine
297
prophylaxis is not recommended for patients in whom there is little expectation that nausea
298
and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be
299
avoided postoperatively, ZOFRAN Injection is recommended even where the incidence of
300
postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic
301
ZOFRAN Injection and experience nausea and/or vomiting postoperatively, ZOFRAN
302
Injection may be given to prevent further episodes (see CLINICAL TRIALS).
303
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
304
ZOFRAN Injection and ZOFRAN Injection Premixed are contraindicated for patients known
305
to have hypersensitivity to the drug.
306
WARNINGS
307
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity
308
to other selective 5-HT3 receptor antagonists.
309
PRECAUTIONS
310
Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used
311
instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or
312
in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or
313
gastric distention.
314
Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome
315
P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY,
316
Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450
317
drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these
318
enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of
319
limited available data, no dosage adjustment is recommended for patients on these drugs.
320
Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of
321
CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was
322
significantly increased and ondansetron blood concentrations were decreased. However, on the
323
basis of available data, no dosage adjustment for ondansetron is recommended for patients on
324
these drugs.1,3
325
Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol
326
has been observed, data from 2 small studies indicate that ondansetron may be associated with an
327
increase in patient controlled administration of tramadol.4,5
328
Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is
329
not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the
330
pharmacokinetics of ondansetron.
331
In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of
332
high-dose methotrexate.
333
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not
334
seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per
335
day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral
336
administration of ondansetron up to 15 mg/kg per day did not affect fertility or general
337
reproductive performance of male and female rats.
338
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
339
performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no
340
evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no
341
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
are not always predictive of human response, this drug should be used during pregnancy only if
343
clearly needed.
344
Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether
345
ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution
346
should be exercised when ondansetron is administered to a nursing woman.
347
Pediatric Use: Little information is available about dosage in pediatric patients under 2 years
348
of age (see DOSAGE AND ADMINISTRATION section for use in pediatric patients 4 to
349
18 years of age receiving cancer chemotherapy or for use in pediatric patients 2 to 12 years of age
350
receiving general anesthesia).
351
Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and
352
postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65
353
years of age and over. No overall differences in safety or effectiveness were observed between
354
these subjects and younger subjects, and other reported clinical experience has not identified
355
differences in responses between the elderly and younger patients, but greater sensitivity of some
356
older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of
357
65 (see CLINICAL PHARMACOLOGY).
358
ADVERSE REACTIONS
359
Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 10 have been
360
reported in individuals receiving ondansetron at a dosage of three 0.15-mg/kg doses or as a single
361
32-mg dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily
362
cisplatin, and I.V. fluids. Most were receiving a diuretic.
363
364
Table 10. Principal Adverse Events in Comparative Trials
365
Number of Patients With Event
ZOFRAN
Injection
0.15 mg/kg x 3
n = 419
ZOFRAN
Injection
32 mg x 1
n = 220
Metoclopramide
n = 156
Placebo
n = 34
Diarrhea
16%
8%
44%
18%
Headache
17%
25%
7%
15%
Fever
8%
7%
5%
3%
Akathisia
0%
0%
6%
0%
Acute dystonic reactions*
0%
0%
5%
0%
* See Neurological.
366
367
The following have been reported during controlled clinical trials:
368
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations,
369
hypotension, and tachycardia have been reported. In many cases, the relationship to ZOFRAN
370
Injection was unclear.
371
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients
372
receiving multiday ondansetron.
373
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values
374
of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been
375
reported to exceed twice the upper limit of normal in approximately 5% of patients. The
376
increases were transient and did not appear to be related to dose or duration of therapy. On repeat
377
exposure, similar transient elevations in transaminase values occurred in some courses, but
378
symptomatic hepatic disease did not occur.
379
Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.
380
Neurological: There have been rare reports consistent with, but not diagnostic of,
381
extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal
382
seizure. The relationship to ZOFRAN was unclear.
383
Other: Rare cases of hypokalemia have been reported. The relationship to ZOFRAN Injection
384
was unclear.
385
Postoperative Nausea and Vomiting: The adverse events in Table 11 have been reported in
386
≥2% of adults receiving ondansetron at a dosage of 4 mg I.V. over 2 to 5 minutes in clinical
387
trials. Rates of these events were not significantly different in the ondansetron and placebo
388
groups. These patients were receiving multiple concomitant perioperative and postoperative
389
medications.
390
391
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 11. Adverse Events in ≥2% of Adults Receiving Ondansetron at a Dosage of 4 mg I.V.
392
over 2 to 5 Minutes in Clinical Trials
393
ZOFRAN Injection
4 mg I.V.
n = 547 patients
Placebo
n = 547 patients
Headache
92 (17%)
77 (14%)
Dizziness
67 (12%)
88 (16%)
Musculoskeletal pain
57 (10%)
59 (11%)
Drowsiness/sedation
44 (8%)
37 (7%)
Shivers
38 (7%)
39 (7%)
Malaise/fatigue
25 (5%)
30 (5%)
Injection site reaction
21 (4%)
18 (3%)
Urinary retention
17 (3%)
15 (3%)
Postoperative CO2-related pain*
12 (2%)
16 (3%)
Chest pain (unspecified)
12 (2%)
15 (3%)
Anxiety/agitation
11 (2%)
16 (3%)
Dysuria
11 (2%)
9 (2%)
Hypotension
10 (2%)
12 (2%)
Fever
10 (2%)
6 (1%)
Cold sensation
9 (2%)
8 (1%)
Pruritus
9 (2%)
3 (<1%)
Paresthesia
9 (2%)
2 (<1%)
* Sites of pain included abdomen, stomach, joints, rib cage, shoulder.
394
395
Pediatric Use: The adverse events in Table 12 were the most commonly reported adverse
396
events in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric patients
397
weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered
398
intravenously over at least 30 seconds. Rates of these events were not significantly different in
399
the ondansetron and placebo groups. These patients were receiving multiple concomitant
400
perioperative and postoperative medications.
401
402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 12. Frequency of Adverse Events From Controlled Studies in Pediatric Patients
403
Adverse Event
Ondansetron
n = 755 Patients
Placebo
n = 731 Patients
Wound problem
80 (11%)
86 (12%)
Anxiety/agitation
49 (6%)
47 (6%)
Headache
44 (6%)
43 (6%)
Drowsiness/sedation
41 (5%)
56 (8%)
Pyrexia
32 (4%)
41 (6%)
404
Observed During Clinical Practice: In addition to adverse events reported from clinical
405
trials, the following events have been identified during post-approval use of intravenous
406
formulations of ZOFRAN. Because they are reported voluntarily from a population of unknown
407
size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a
408
combination of their seriousness, frequency of reporting, or potential causal connection to
409
ZOFRAN.
410
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia,
411
premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic
412
alterations (including second-degree heart block and ST segment depression), palpitations, and
413
syncope.
414
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g.,
415
anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest,
416
hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been
417
reported.
418
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death have
419
been reported in patients with cancer receiving concurrent medications including potentially
420
hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
421
Local Reactions: Pain, redness, and burning at site of injection.
422
Lower Respiratory: Hiccups
423
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic reactions.
424
Skin: Urticaria
425
Special Senses: Transient blurred vision, in some cases associated with abnormalities of
426
accommodation, and transient dizziness during or shortly after I.V. infusion.
427
DRUG ABUSE AND DEPENDENCE
428
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor
429
does it substitute for benzodiazepines in direct addiction studies.
430
OVERDOSAGE
431
There is no specific antidote for ondansetron overdose. Patients should be managed with
432
appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages
433
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(three doses) as large as 252 mg have been administered intravenously without significant
434
adverse events. These doses are more than 10 times the recommended daily dose.
435
In addition to the adverse events listed above, the following events have been described in the
436
setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus
437
severe constipation occurred in one patient that was administered 72 mg of ondansetron
438
intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took
439
48 mg of oral ondansetron. Following infusion of 32 mg over only a 4-minute period, a
440
vasovagal episode with transient second-degree heart block was observed. In all instances, the
441
events resolved completely.
442
DOSAGE AND ADMINISTRATION
443
Prevention of Chemotherapy-Induced Nausea and Vomiting: The recommended I.V.
444
dosage of ZOFRAN is a single 32-mg dose or three 0.15-mg/kg doses. A single 32-mg dose is
445
infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. The
446
recommended infusion rate should not be exceeded (see OVERDOSAGE). With the three-dose
447
(0.15-mg/kg) regimen, the first dose is infused over 15 minutes beginning 30 minutes before the
448
start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and
449
8 hours after the first dose of ZOFRAN.
450
ZOFRAN Injection should not be mixed with solutions for which physical and chemical
451
compatibility have not been established. In particular, this applies to alkaline solutions as a
452
precipitate may form.
453
Vial: DILUTE BEFORE USE. ZOFRAN Injection should be diluted in 50 mL of 5%
454
Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
455
Flexible Plastic Container: ZOFRAN Injection Premixed, 32 mg in 5% Dextrose, 50 mL,
456
REQUIRES NO DILUTION.
457
Pediatric Use: On the basis of the limited available information (see CLINICAL TRIALS:
458
Pediatric Studies and CLINICAL PHARMACOLOGY: Pharmacokinetics), the dosage in
459
pediatric patients 4 to 18 years of age should be three 0.15-mg/kg doses (see above). Little
460
information is available about dosage in pediatric patients 3 years of age and younger.
461
Geriatric Use: The dosage recommendation is the same as for the general population.
462
Prevention of Postoperative Nausea and Vomiting: The recommended I.V. dosage of
463
ZOFRAN for adults is 4 mg undiluted administered intravenously in not less than 30 seconds,
464
preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if
465
the patient experiences nausea and/or vomiting occurring shortly after surgery. Alternatively,
466
4 mg undiluted may be administered intramuscularly as a single injection for adults. While
467
recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg
468
have been studied. In patients who do not achieve adequate control of postoperative nausea and
469
vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron 4 mg,
470
administration of a second I.V. dose of 4 mg ondansetron postoperatively does not provide
471
additional control of nausea and vomiting.
472
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Vial: ZOFRAN Injection REQUIRES NO DILUTION FOR ADMINISTRATION FOR
473
POSTOPERATIVE NAUSEA AND VOMITING.
474
Pediatric Use: The recommended I.V. dosage of ZOFRAN for pediatric patients (2 to
475
12 years of age) is a single 0.1-mg/kg dose for pediatric patients weighing 40 kg or less, or a
476
single 4-mg dose for pediatric patients weighing more than 40 kg. The rate of administration
477
should not be less than 30 seconds, preferably over 2 to 5 minutes. Little information is available
478
about dosage in pediatric patients younger than 2 years of age.
479
Geriatric Use: The dosage recommendation is the same as for the general population.
480
Dosage Adjustment for Patients With Impaired Renal Function: The dosage
481
recommendation is the same as for the general population. There is no experience beyond
482
first-day administration of ondansetron.
483
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with
484
severe hepatic impairment (Child-Pugh2 score of 10 or greater), a single maximal daily dose of
485
8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic
486
chemotherapy is recommended. There is no experience beyond first-day administration of
487
ondansetron.
488
ZOFRAN Injection Premixed in Flexible Plastic Containers: Instructions for Use:
489
To Open: Tear outer wrap at notch and remove solution container. Check for minute leaks by
490
squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
491
Preparation for Administration: Use aseptic technique.
492
1. Close flow control clamp of administration set.
493
2. Remove cover from outlet port at bottom of container.
494
3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly
495
seated. NOTE: See full directions on administration set carton.
496
4. Suspend container from hanger.
497
5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion
498
of ZOFRAN Injection Premixed.
499
6. Open flow control clamp to expel air from set. Close clamp.
500
7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
501
8. Perform venipuncture.
502
9. Regulate rate of administration with flow control clamp.
503
Caution: ZOFRAN Injection Premixed in flexible plastic containers is to be administered by
504
I.V. drip infusion only. ZOFRAN Injection Premixed should not be mixed with solutions for
505
which physical and chemical compatibility have not been established. In particular, this applies
506
to alkaline solutions as a precipitate may form. If used with a primary I.V. fluid system, the
507
primary solution should be discontinued during ZOFRAN Injection Premixed infusion.
508
Do not administer unless solution is clear and container is undamaged.
509
Warning: Do not use flexible plastic container in series connections.
510
Stability: ZOFRAN Injection is stable at room temperature under normal lighting conditions for
511
48 hours after dilution with the following I.V. fluids: 0.9% Sodium Chloride Injection, 5%
512
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45%
513
Sodium Chloride Injection, and 3% Sodium Chloride Injection.
514
Although ZOFRAN Injection is chemically and physically stable when diluted as
515
recommended, sterile precautions should be observed because diluents generally do not contain
516
preservative. After dilution, do not use beyond 24 hours.
517
Note: Parenteral drug products should be inspected visually for particulate matter and
518
discoloration before administration whenever solution and container permit.
519
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored
520
upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking
521
the vial vigorously.
522
HOW SUPPLIED
523
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
524
NDC 0173-0442-02 2-mL single-dose vials (Carton of 5)
525
NDC 0173-0442-00 20-mL multidose vials (Singles)
526
Store between 2° and 30°C (36° and 86°F). Protect from light.
527
ZOFRAN Injection Premixed, 32 mg/50 mL, in 5% Dextrose, contains no preservatives and
528
is supplied as a sterile, premixed solution for I.V. administration in single-dose, flexible plastic
529
containers (NDC 0173-0461-00) (case of 6).
530
Store between 2° and 30°C (36° and 86°F). Protect from light. Avoid excessive heat.
531
Protect from freezing.
532
REFERENCE
533
1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND)
534
metabolism in humans. Clin Pharmacol Ther 1997;61:228.
535
2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the
536
oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649.
537
3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral
538
and intravenous ondansetron. Clin Pharmacol Ther 1999;65:377-381.
539
4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg 2001;92:1319-1321.
540
5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg 2002;94:1553-1557.
541
542
543
GlaxoSmithKline
544
Research Triangle Park, NC 27709
545
546
ZOFRAN® Injection Premixed:
547
Manufactured for GlaxoSmithKline
548
Research Triangle Park, NC 27709
549
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
by Abbott Laboratories, North Chicago, IL 60064
550
551
©2004, GlaxoSmithKline. All rights reserved.
552
553
May 2004
RL-2083
554
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:25.433680
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20007s034,20403s013lbl.pdf', 'application_number': 20007, 'submission_type': 'SUPPL ', 'submission_number': 34}
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12,123
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NDA 19-992/S-020
Page 3
CILOXAN®
(ciprofloxacin HCL ophthalmic solution)
0.3% as Base
Sterile
DESCRIPTION:
CILOXAN® (ciprofloxacin HCL ophthalmic solution) is a synthetic, sterile, multiple dose,
antimicrobial for topical use. Ciprofloxacin is a fluoroquinolone antibacterial active against a broad
spectrum of gram positive and gram-negative ocular pathogens. It is available as the
monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-
3-quinoline-carboxylic acid. It is a faint to light yellow crystalline powder with a molecular weight of
385.8. Its empirical formula is C17H18FN3O3•HCl•H2O and its chemical structure is as follows:
[Structure]
Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-position, a piperazine
moiety at the 7-position, and a cyclopropyl ring at the 1-position.
Each mL of CILOXAN Ophthalmic Solution contains: Active: ciprofloxacin HCl 3.5 mg equivalent to
3 mg base. Preservative: benzalkonium chloride 0.006%. Inactives: sodium acetate, acetic acid,
mannitol 4.6%, edetate disodium 0.05%, hydrochloric acid and/or sodium hydroxide (to adjust pH) and
Purified Water. The pH is approximately 4.5 and the osmolality is approximately 300 mOsm.
CLINICAL PHARMACOLOGY:
Systemic Absorption: A systemic absorption study was performed in which CILOXAN Ophthalmic
Solution was administered in each eye every two hours while awake for two days followed by every
four hours while awake for an additional 5 days. The maximum reported plasma concentration of
ciprofloxacin was less than 5 ng/mL. The mean concentration was usually less than 2.5 ng/mL.
Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-negative and
gram-positive organisms. The bactericidal action of ciprofloxacin results from interference with the
enzyme DNA gyrase which is needed for the synthesis of bacterial DNA.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms both
in vitro and in clinical infections (SEE INDICATIONS AND USAGE section):
Gram-Positive:
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus (Viridans Group)
Gram-Negative:
Haemophilus influenzae
Pseudomonas aeruginosa
Serratia marcescens
Ciprofloxacin has been shown to be active in vitro against most strains of the following organisms,
however, the clinical significance of these data is unknown:
NDA 19-992/S-020
Page 4
Gram-Positive:
Enterococcus faecalis (Many strains are only moderately susceptible)
Staphylococcus haemolyticus
Staphylococcus hominis
Staphylococcus saprophyticus
Streptococcus pyogenes
Gram-Negative
Acinetobacter calcoaceticus
Escherichia coli
Proteus mirabilis
subsp. anitratus
Haemophilus ducreyi
Proteus vulgaris
Aeromonas caviae
Haemophilus parainfluenzae
Providencia rettgeri
Aeromonas hydrophila
Kiebsiella pneumoniae
Providencia stuartii
Brucella melitensis
Klebsiella oxytoca
Salmonella enteritidis
Campylobacter coli
Legionella pneumophila
Salmonella typhi
Campylobacter jejuni
Moraxella (Branhamella)
Shigella sonneii
Citrobacter diversus
catarrhalis
Shigella flexneri
Citrobacter freundii
Morganella morganii
Vibrio cholerae
Edwardsiella tarda
Neisseria gonorrhoeae
Vibrio parahaemolyticus
Enterobacter aerogenes
Neisseria meningitidis
Vibrio vulnificus
Enterobacter cloacae
Pasteurella multocida
Yersinia enterocolitica
Other Organisms: Chlamydia trachomatis (only moderately susceptible) and Mycobacterium
tuberculosis (only moderately susceptible).
Most strains of Pseudomonas cepacia and some strains of Pseudomonas maltophilia are resistant to
ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile .
The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory
concentration (MIC) by more than a factor of 2. Resistance to ciprofloxacin in vitro usually develops
slowly (multiple-step mutation).
Ciprofloxacin does not cross-react with other antimicrobial agents such as beta-lactams or
aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin.
Clinical Studies: Following therapy with CILOXAN Ophthalmic Solution, 76% of the patients with
corneal ulcers and positive bacterial cultures were clinically cured and complete re-epithelialization
occurred in about 92% of the ulcers.
In 3 and 7 day multicenter clinical trials, 52% of the patients with conjunctivitis and positive
conjunctival cultures were clinically cured and 70-80% had all causative pathogens eradicated by the
end of treatment.
INDICATIONS AND USAGE:
CILOXAN Ophthalmic Solution is indicated for the treatment of infections caused by susceptible
strains of the designated microorganisms in the conditions listed below:
NDA 19-992/S-020
Page 5
Corneal Ulcers:
Pseudomonas aeruginosa
Serratia marcescens *
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus (Viridans Group) *
Conjunctivitis:
Haemophilus influenzae
Staphylococcus aureus
Staphylococcus epidermidis
Streptococcus pneumoniae
*Efficacy for this organism was studied in fewer than 10 infections.
CONTRAINDICATIONS:
A history of hypersensitivity to ciprofloxacin or any other component of the medication is a
contraindication to its use. A history of hypersensitivity to other quinolones may also contraindicate
the use of ciprofloxacin.
WARNINGS:
NOT FOR INJECTION INTO THE EYE.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose,
have been reported in patients receiving systemic quinolone therapy. Some reactions were
accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema,
dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious
anaphylactic reactions require immediate emergency treatment with epinephrine and other
resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines,
corticosteroids, pressor amines and airway management, as clinically indicated.
Remove contact lenses before using.
PRECAUTIONS:
General: As with other antibacterial preparations, prolonged use of ciprofloxacin may result in
overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate
therapy should be initiated. Whenever clinical judgment dictates, the patient should be examined with
the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of
hypersensitivity reaction.
In clinical studies of patients with bacterial corneal ulcer, a white crystalline precipitate located in the
superficial portion of the corneal defect was observed in 35 (16.6%) of 210 patients. The onset of the
precipitate was within 24 hours to 7 days after starting therapy. In one patient, the precipitate was
immediately irrigated out upon its appearance. In 17 patients, resolution of the precipitate was seen in
1 to 8 days (seven within the first 24-72 hours), in five patients, resolution was noted in 10-13 days. In
nine patients, exact resolution days were unavailable; however, at follow-up examinations, 18-44 days
after onset of the event, complete resolution of the precipitate was noted. In three patients, outcome
NDA 19-992/S-020
Page 6
information was unavailable. The precipitate did not preclude continued use of ciprofloxacin, nor did
it adversely affect the clinical course of the ulcer or visual outcome. (SEE ADVERSE REACTIONS ).
Information for patients: Do not touch dropper tip to any surface, as this may contaminate the
solution.
Drug Interactions: Specific drug interaction studies have not been conducted with ophthalmic
ciprofloxacin. However, the systemic administration of some quinolones has been shown to elevate
plasma concentrations of theophylline, interfere with the metabolism of caffeine, enhance the effects of
the oral anticoagulant, warfarin, and its derivatives, and has been associated with transient elevations
in serum creatinine in patients receiving cyclosporine concomitantly.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Eight in vitro mutagenicity tests have been conducted with ciprofloxacin and the test results are listed
below:
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay
(Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but the results of the following three in vivo test systems
gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice).
Long term carcinogenicity studies in mice and rats have been completed. After daily oral dosing for
up to two years, there is no evidence that ciprofloxacin had any carcinogenic or tumorigenic effects in
these species.
Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rats and mice at
doses up to six times the usual daily human oral dose and have revealed no evidence of impaired
fertility or harm to the fetus due to ciprofloxacin. In rabbits, as with most antimicrobial agents,
ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal
weight loss and an increased incidence of abortion. No teratogenicity was observed at either dose.
After intravenous administration, at doses up to 20 mg/kg, no maternal toxicity was produced and no
embryotoxicity or teratogenicity was observed. There are no adequate and well controlled studies in
pregnant women. CILOXAN Ophthalmic Solution should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether topically applied ciprofloxacin is excreted in human milk.
However, it is known that orally administered ciprofloxacin is excreted in the milk of lactating rats and
oral ciprofloxacin has been reported in human breast milk after a single 500 mg dose. Caution should
be exercised when CILOXAN Ophthalmic Solution is administered to a nursing mother.
NDA 19-992/S-020
Page 7
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 1 year have not been
established. Although ciprofloxacin and other quinolones cause arthropathy in immature animals after
oral administration, topical ocular administration of ciprofloxacin to immature animals did not cause
any arthropathy and there is no evidence that the ophthalmic dosage form has any effect on the weight
bearing joints.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly
and younger patients.
ADVERSE REACTIONS:
The most frequently reported drug related adverse reaction was local burning or discomfort. In corneal
ulcer studies with frequent administration of the drug, white crystalline precipitates were seen in
approximately 17% of patients (SEE PRECAUTIONS ). Other reactions occurring in less than 10% of
patients included lid margin crusting, crystals/scales, foreign body sensation, itching, conjunctival
hyperemia and a bad taste following instillation. Additional events occurring in less than 1% of
patients included corneal staining, keratopathy/keratitis, allergic reactions, lid edema, tearing,
photophobia, corneal infiltrates, nausea and decreased vision.
OVERDOSAGE:
A topical overdose of CILOXAN Ophthalmic Solution may be flushed from the eye(s) with warm tap
water.
DOSAGE AND ADMINISTRATION:
Corneal Ulcers: The recommended dosage regimen for the treatment of corneal ulcers is two drops
into the affected eye every 15 minutes for the first six hours and then two drops into the affected eye
every 30 minutes for the remainder of the first day. On the second day, instill two drops in the affected
eye hourly. On the third through the fourteenth day, place two drops in the affected eye every four
hours. Treatment may be continued after 14 days if corneal re-epithelialization has not occurred.
Bacterial Conjunctivitis: The recommended dosage regimen for the treatment of bacterial
conjunctivitis is one or two drops instilled into the conjunctival sac(s) every two hours while awake
for two days and one or two drops every four hours while awake for the next five days.
How Supplied: As a sterile ophthalmic solution in Alcon’s DROP-TAINER® dispensing system
consisting of a natural low density polyethylene bottle and dispensing plug and tan polypropylene
closure. Tamper evidence is provided with a shrink band around the closure and neck area of the
package.
2.5 mL in 8 mL bottle - NDC 0065-0656-25
5 mL in 8 mL bottle - NDC 0065-0656-05
10 mL in 10 mL bottle - NDC 0065-0656-10
STORAGE: Store at 2° - 25°C (36° - 77°F). Protect from light.
ANIMAL PHARMACOLOGY:
Ciprofloxacin and related drugs have been shown to cause arthropathy in immature animals of most
species tested following oral administration. However, a one-month topical ocular study using
immature Beagle dogs did not demonstrate any articular lesions.
NDA 19-992/S-020
Page 8
Rx only
U.S. Patent No. 4,670,444
Alcon® Pharmaceuticals
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
Revised: September 2004
©2003 Alcon, Inc
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Janice Soreth
2/7/2006 02:59:33 PM
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custom-source
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2025-02-12T13:46:25.441065
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019992s020lbl.pdf', 'application_number': 19992, 'submission_type': 'SUPPL ', 'submission_number': 20}
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NDA 20-007/S-035
Page 3
PRESCRIBING INFORMATION
ZOFRAN®
(ondansetron hydrochloride)
Injection
ZOFRAN®
(ondansetron hydrochloride)
Injection Premixed
DESCRIPTION
The active ingredient in ZOFRAN Injection and ZOFRAN Injection Premixed is
ondansetron hydrochloride (HCl), the racemic form of ondansetron and a selective blocking agent of
the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-
imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following
structural formula:
The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of
365.9.
Ondansetron HCl is a white to off-white powder that is soluble in water and normal
saline.
Sterile Injection for Intravenous (I.V.) or Intramuscular (I.M.) Administration: Each 1 mL
of aqueous solution in the 2-mL single-dose vial contains 2 mg of ondansetron as the hydrochloride
dihydrate; 9.0 mg of sodium chloride, USP; and 0.5 mg of citric acid monohydrate, USP and 0.25 mg
of sodium citrate dihydrate, USP as buffers in Water for Injection, USP.
Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as the
hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and
0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of
propylparaben, NF as preservatives in Water for Injection, USP.
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution. The pH of the injection solution
is 3.3 to 4.0.
Sterile, Premixed Solution for Intravenous Administration in Single-Dose, Flexible
Plastic Containers: Each 50 mL contains ondansetron 32 mg (as the hydrochloride dihydrate);
dextrose 2,500 mg; and citric acid 26 mg and sodium citrate 11.5 mg as buffers in Water for Injection,
USP. It contains no preservatives. The osmolarity of this solution is 270 mOsm/L (approx.), and the pH
is 3.0 to 4.0.
The flexible plastic container is fabricated from a specially formulated, nonplasticized, thermoplastic
co-polyester (CR3). Water can permeate from inside the container into the overwrap but not in amounts
sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-035
Page 4
certain of the chemical components in very small amounts before the expiration period is attained.
However, the safety of the plastic has been confirmed by tests in animals according to USP biological
standards for plastic containers.
CLINICAL PHARMACOLOGY
Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron's
mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist.
Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and
centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron's
antiemetic action in chemotherapy-induced nausea and vomiting is mediated centrally, peripherally, or
in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from
the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic
acid) excretion increases after cisplatin administration in parallel with the onset of vomiting. The
released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the
vomiting reflex.
In animals, the emetic response to cisplatin can be prevented by pretreatment with an
inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or
pretreatment with a serotonin 5-HT3 receptor antagonist.
In normal volunteers, single I.V. doses of 0.15 mg/kg of ondansetron had no effect on
esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit
time. In another study in six normal male volunteers, a 16-mg dose infused over 5 minutes showed no
effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram
(ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal
volunteers. Ondansetron has no effect on plasma prolactin concentrations.
In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered
intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting
using the ipecacuanha model of emesis.
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or
the degree of neuromuscular blockade produced by atracurium. Interactions with general or local
anesthetics have not been studied.
Pharmacokinetics: Ondansetron is extensively metabolized in humans, with approximately 5% of a
radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is
hydroxylation on the indole ring followed by glucuronide or sulfate conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not found in
plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic
cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall
ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic
enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g.,
CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall
rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450
inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4
inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ of ondansetron was observed.1
This resulted in a significant increase in clearance. However, on the basis of available data, no dosage
adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions).
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-035
Page 5
In normal adult volunteers, the following mean pharmacokinetic data have been
determined following a single 0.15-mg/kg I.V. dose.
Table 1. Pharmacokinetics in Normal Adult Volunteers
Age-group
(years)
n
Peak Plasma
Concentration
(ng/mL)
Mean Elimination
Half-life (h)
Plasma Clearance
(L/h/kg)
19-40
11
102
3.5
0.381
61-74
12
106
4.7
0.319
≥75
11
170
5.5
0.262
A reduction in clearance and increase in elimination half-life are seen in patients over
75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over
65 years of age and those under 65 years of age; there was an insufficient number of patients over
75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the
elderly.
In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and
mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe
hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and
apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients
with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.
Due to the very small contribution (5%) of renal clearance to the overall clearance, renal
impairment was not expected to significantly influence the total clearance of ondansetron. However,
ondansetron mean plasma clearance was reduced by about 41% in patients with severe renal
impairment (creatinine clearance <30 mL/min). This reduction in clearance is variable and was not
consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is
warranted.
In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no
difference in the multidose pharmacokinetics over a 4-day period. In a study of 21 pediatric cancer
patients (4 to 18 years of age) who received three I.V. doses of 0.15 mg/kg of ondansetron at 4-hour
intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar
to those of adults. Patients 4 to 12 years of age generally showed higher clearance and somewhat larger
volume of distribution than adults. Most pediatric patients younger than 15 years of age with cancer
had a shorter (2.4 hours) ondansetron plasma half-life than patients older than 15 years of age. It is not
known whether these differences in ondansetron plasma half-life may result in differences in efficacy
between adults and some young pediatric patients (see CLINICAL TRIALS: Pediatric Studies).
Pharmacokinetic samples were collected from 74 cancer patients 6 to 48 months of age,
who received a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses during a safety and
efficacy trial. These data were combined with sequential pharmacokinetics data from 41 surgery
patients 1 month to 24 months of age, who received a single dose of 0.1 mg/kg of I.V. ondansetron
prior to surgery with general anesthesia, and a population pharmacokinetic analysis was performed on
the combined data set. The results of this analysis are included in Table 2 and are compared to the
pharmacokinetic results in cancer patients 4 to 18 years of age.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-035
Page 6
Table 2. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Cancer Patients
4 to 18 years of Age
N = 21
0.599
1.9
2.8
Population PK Patients*
1 month to 48 months of Age
N = 115
0.582
3.65
4.9
* Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age
who receive a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses would be expected to
achieve a systemic exposure (AUC) consistent with the exposure achieved in previous pediatric studies
in cancer patients (4 to 18 years of age) at similar doses.
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery
requiring anesthesia for a duration of 45 minutes to 2 hours, a single I.V. dose of ondansetron, 2 mg (3
to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean
weight-normalized clearance and volume of distribution values in these pediatric surgical patients were
similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in
pediatric patients (range, 2.5 to 3 hours) in comparison with adults (range, 3 to 3.5 hours).
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing
surgery requiring general anesthesia, a single I.V. dose of ondansetron, 0.1 or 0.2 mg/kg, was
administered prior to surgery. As shown in Table 3, the 41 patients with pharmacokinetic data were
divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months of age, and are
compared to pediatric patients 3 to 12 years of age.
Table 3. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Surgery Patients
3 to 12 years of Age
N = 21
0.439
1.65
2.9
Pediatric Surgery Patients
5 to 24 months of Age
N = 22
0.581
2.3
2.9
Pediatric Surgery Patients
1 month to 4 months of Age
N = 19
0.401
3.5
6.7
In general, surgical and cancer pediatric patients younger than 18 years tend to have a
higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric
patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher
volume of distribution in this age group.
In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was
264 ng/mL following a single 32-mg dose administered as a 15-minute I.V. infusion. The mean
elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to
dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with
a small decrease in systemic clearance with increasing plasma concentrations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-035
Page 7
A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a
single 4-mg dose administered as a 5-minute infusion compared to a single intramuscular injection.
Systemic exposure as measured by mean AUC was equivalent, with values of 156 [95% CI 136, 180]
and 161 [95% CI 137, 190] ng•h/mL for I.V. and I.M. groups, respectively. Mean peak plasma
concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V. infusion and 31.9 [95%
CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean elimination half-life was not
affected by route of administration.
Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with
binding constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also
distributes into erythrocytes.
A positive lymphoblast transformation test to ondansetron has been reported, which
suggests immunologic sensitivity to ondansetron.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting:
Adult Studies: In a double-blind study of three different dosing regimens of ZOFRAN Injection,
0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer
chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing
regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the 0.15-mg/kg
dosing regimen.
Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, ZOFRAN
Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing nausea
and vomiting induced by cisplatin-based chemotherapy. Treatment response was as shown in Table 4.
Table 4. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cisplatin
Therapy* in Adults
ZOFRAN
Injection
Placebo
P Value†
Number of patients
14
14
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
2 (14%)
8 (57%)
2 (14%)
2 (14%)
0 (0%)
0 (0%)
1 (7%)
13 (93%)
0.001
Median number of emetic episodes
1.5
Undefined‡
Median time to first emetic episode (h)
11.6
2.8
0.001
Median nausea scores (0-100)§
3
59
0.034
Global satisfaction with control of
nausea and vomiting (0-100)
II
96
10.5
0.009
* Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5) or
moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other
chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There was no
difference between treatments in the types of chemotherapy that would account for differences in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-035
Page 8
response.
† Efficacy based on "all patients treated" analysis.
‡
Median undefined since at least 50% of the patients were rescued or had more than five emetic
episodes.
§ Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
II Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Ondansetron was compared with metoclopramide in a single-blind trial in 307 patients
receiving cisplatin ≥100 mg/m2 with or without other chemotherapeutic agents. Patients received the
first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional ondansetron
doses were administered 4 and 8 hours later, or five additional metoclopramide doses were
administered 2, 4, 7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less.
Episodes of vomiting and retching were tabulated over the period of 24 hours after cisplatin. The
results of this study are summarized in Table 5.
Table 5. Prevention of Vomiting Induced by Cisplatin (≥100 mg/m2) Single-Day Therapy* in
Adults
ZOFRAN Injection
Metoclopramide
P Value
Dose
0.15 mg/kg x 3
2 mg/kg x 6
Number of patients in efficacy population
136
138
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
54 (40%)
34 (25%)
19 (14%)
29 (21%)
41 (30%)
30 (22%)
18 (13%)
49 (36%)
Comparison of treatments with respect to
0 Emetic episodes
More than 5 emetic episodes/rescued
54/136
29/136
41/138
49/138
0.083
0.009
Median number of emetic episodes
1
2
0.005
Median time to first emetic episode (h)
20.5
4.3
<0.001
Global satisfaction with control of nausea
and vomiting (0-100)†
85
63
0.001
Acute dystonic reactions
0
8
0.005
Akathisia
0
10
0.002
* In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including
cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the
types of chemotherapy that would account for differences in response.
†
Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
In a stratified, randomized, double-blind, parallel-group, multicenter study, a single
32-mg dose of ondansetron was compared with three 0.15-mg/kg doses in patients receiving cisplatin
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doses of either 50 to 70 mg/m2 or ≥100 mg/m2. Patients received the first ondansetron dose 30 minutes
before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later to the group
receiving three 0.15-mg/kg doses. In both strata, significantly fewer patients on the single 32-mg dose
than those receiving the three-dose regimen failed.
Table 6. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Dose Therapy in
Adults
Ondansetron
Dose
0.15 mg/kg x 3
32 mg x 1
P Value
High-dose cisplatin (≥100 mg/m2)
Number of patients
100
102
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
41 (41%)
19 (19%)
4 (4%)
36 (36%)
49 (48%)
25 (25%)
8 (8%)
20 (20%)
0.315
0.009
Median time to first emetic episode (h)
21.7
23
0.173
Median nausea scores (0-100)*
28
13
0.004
Medium-dose cisplatin (50-70 mg/m2)
Number of patients
101
93
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
62 (61%)
11 (11%)
6 (6%)
22 (22%)
68 (73%)
14 (15%)
3 (3%)
8 (9%)
0.083
0.011
Median time to first emetic episode (h)
Undefined†
Undefined
Median nausea scores (0-100)*
9
3
0.131
*
Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
†
Median undefined since at least 50% of patients did not have any emetic episodes.
Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled
study of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500
to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than placebo in
preventing nausea and vomiting. The results are summarized in Table 7.
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Table 7. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day
Cyclophosphamide Therapy* in Adults
ZOFRAN
Injection
Placebo
P Value†
Number of patients
10
10
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
7 (70%)
0 (0%)
2 (20%)
1 (10%)
0 (0%)
2 (20%)
4 (40%)
4 (40%)
0.001
0.131
Median number of emetic episodes
0
4
0.008
Median time to first emetic episode (h)
Undefined‡
8.79
Median nausea scores (0-100)§
0
60
0.001
Global satisfaction with control of
nausea and vomiting (0-100)II
100
52
0.008
* Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including
fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between
treatments in the type of chemotherapy that would account for differences in response.
†
Efficacy based on "all patients treated" analysis.
‡
Median undefined since at least 50% of patients did not have any emetic episodes.
§
Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
II
Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose,
100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with ondansetron
and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median, 2; range, 1 to 10).
No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes occurred in 217 (81%)
re-treatment courses.
Pediatric Studies: Four open-label, noncomparative (one US, three foreign) trials have been
performed with 209 pediatric cancer patients 4 to 18 years of age given a variety of cisplatin or
noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged from 0.04
to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration of
ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, ZOFRAN was administered
intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2 to 39 mg. In these
studies, 58% of the 196 evaluable patients had a complete response (no emetic episodes) on day 1.
Thus, prevention of vomiting in these pediatric patients was essentially the same as for patients older
than 18 years of age.
An open-label, multicenter, noncomparative trial has been performed in 75 pediatric
cancer patients 6 to 48 months of age receiving at least one moderately or highly emetogenic
chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were
American Hispanic, and 15% were black patients. ZOFRAN was administered intravenously over 15
minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before the start of
chemotherapy, the second and third doses were administered 4 and 8 hours after the first dose,
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respectively. Eighteen patients (25%) received routine prophylactic dexamethasone (i.e., not given as
rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic episodes) on day 1.
Thus, prevention of vomiting in these pediatric patients was comparable to the prevention of vomiting
in patients 4 years of age and older.
Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and
Vomiting:
Adult Studies: Adult surgical patients who received ondansetron immediately before the induction of
general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or
fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or
atracurium; and supplemental isoflurane) were evaluated in two double-blind US studies involving
554 patients. ZOFRAN Injection (4 mg) I.V. given over 2 to 5 minutes was significantly more effective
than placebo. The results of these studies are summarized in Table 8.
Table 8. Prevention of Postoperative Nausea and Vomiting in Adult Patients
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic
episode/rescued
136
103 (76%)
13 (10%)
20 (15%)
139
64 (46%)
17 (12%)
58 (42%)
<0.001
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
134
56 (42%)
136
39 (29%)
Study 2
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
85 (63%)
16 (12%)
35 (26%)
143
63 (44%)
29 (20%)
51 (36%)
0.002
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
125
48 (38%)
133
42 (32%)
The study populations in Table 8 consisted mainly of females undergoing laparoscopic
procedures.
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In a placebo-controlled study conducted in 468 males undergoing outpatient procedures,
a single 4-mg I.V. ondansetron dose prevented postoperative vomiting over a 24-hour study period in
79% of males receiving drug compared to 63% of males receiving placebo (P<0.001).
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major
abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg I.V. ondansetron dose for
prevention of postoperative nausea and vomiting over a 24-hour study period. At the 4-mg dosage,
59% of patients receiving ondansetron versus 45% receiving placebo in the first study (P<0.001) and
41% of patients receiving ondansetron versus 30% receiving placebo in the second study (P=0.001)
experienced no emetic episodes. No additional benefit was observed in patients who received I.V.
ondansetron 8 mg compared to patients who received I.V. ondansetron 4 mg.
Pediatric Studies: Three double-blind, placebo-controlled studies have been performed (one US,
two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing general anesthesia
with nitrous oxide. The surgical procedures included tonsillectomy with or without adenoidectomy,
strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized to either single I.V.
doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric
patients weighing more than 40 kg) or placebo. Study drug was administered over at least 30 seconds,
immediately prior to or following anesthesia induction. Ondansetron was significantly more effective
than placebo in preventing nausea and vomiting. The results of these studies are summarized in Table
9.
Table 9. Prevention of Postoperative Nausea and Vomiting in Pediatric Patients 2 to 12 Years of
Age
Treatment Response Over
24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Study 1
Number of patients
0 Emetic episodes
Failure*
205
140 (68%)
65 (32%)
210
82 (39%)
128 (61%)
≤0.001
Study 2
Number of patients
0 Emetic episodes
Failure*
112
68 (61%)
44 (39%)
110
38 (35%)
72 (65%)
≤0.001
Study 3
Number of patients
0 Emetic episodes
Failure*
206
123 (60%)
83 (40%)
206
96 (47%)
110 (53%)
≤0.01
Nausea assessments†:
Number of patients
None
185
119 (64%)
191
99 (52%)
≤0.01
*
Failure was one or more emetic episodes, rescued, or withdrawn.
†
Nausea measured as none, mild, or severe.
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A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric patients 1 month
to 24 months of age who were undergoing routine surgery under general anesthesia. Seventy-five
percent (75%) were males; 64% were white, 15% were black, 13% were American Hispanic, 2% were
Asian, and 6% were “other race” patients. A single 0.1-mg/kg I.V. dose of ondansetron was
administered within 5 minutes following induction of anesthesia was statistically significantly more
effective than placebo in preventing vomiting. In the placebo group, 28% of patients experienced
vomiting compared to 11% of subjects who received ondansetron (P<0. 01). Overall, 32 (10%) of
placebo patients and 18 (5%) of patients who received ondansetron received antiemetic rescue
medication(s) or prematurely withdrew from the study.
Prevention of Further Postoperative Nausea and Vomiting:
Adults Studies: Adult surgical patients receiving general balanced anesthesia (barbiturate:
thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular
blockade: succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) who
received no prophylactic antiemetics and who experienced nausea and/or vomiting within 2 hours
postoperatively were evaluated in two double-blind US studies involving 441 patients. Patients who
experienced an episode of postoperative nausea and/or vomiting were given ZOFRAN Injection (4 mg)
I.V. over 2 to 5 minutes, and this was significantly more effective than placebo. The results of these
studies are summarized in Table 10.
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Table 10. Prevention of Further Postoperative Nausea and Vomiting in Adult Patients
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
Median time to first emetic episode (min)*
104
49 (47%)
12 (12%)
43 (41%)
55.0
117
19 (16%)
9 (8%)
89 (76%)
43.0
<0.001
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
period†
98
1.7
102
3.1
Study 2
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
0 Emetic episodes
1 Emetic episode
More than 1 emetic
episode/rescued
Median time to first emetic episode (min)*
112
49 (44%)
14 (13%)
49 (44%)
60.5
108
28 (26%)
3 (3%)
77 (71%)
34.0
0.006
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
period†
105
1.9
85
2.9
*
After administration of study drug.
†
Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
The study populations in Table 10 consisted mainly of women undergoing laparoscopic
procedures.
Repeat Dosing in Adults: In patients who do not achieve adequate control of postoperative nausea
and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron 4 mg,
administration of a second I.V. dose of ondansetron 4 mg postoperatively does not provide additional
control of nausea and vomiting.
Pediatric Study: One double-blind, placebo-controlled, US study was performed in 351 male and
female outpatients (2 to 12 years of age) who received general anesthesia with nitrous oxide and no
prophylactic antiemetics. Surgical procedures were unrestricted. Patients who experienced two or more
emetic episodes within 2 hours following discontinuation of nitrous oxide were randomized to either
single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for
pediatric patients weighing more than 40 kg) or placebo administered over at least 30 seconds.
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Ondansetron was significantly more effective than placebo in preventing further episodes of nausea
and vomiting. The results of the study are summarized in Table 11.
Table 11. Prevention of Further Postoperative Nausea and Vomiting in Pediatric Patients 2 to
12 years of Age
Treatment Response
Over 24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Number of patients
0 Emetic episodes
Failure*
180
96 (53%)
84 (47%)
171
29 (17%)
142 (83%)
≤0.001
* Failure was one or more emetic episodes, rescued, or withdrawn.
INDICATIONS AND USAGE
1. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer
chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in
these patients has not been established.
2. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis
is not recommended for patients in whom there is little expectation that nausea and/or vomiting will
occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively,
ZOFRAN Injection is recommended even where the incidence of postoperative nausea and/or
vomiting is low. For patients who do not receive prophylactic ZOFRAN Injection and experience
nausea and/or vomiting postoperatively, ZOFRAN Injection may be given to prevent further
episodes (see CLINICAL TRIALS).
CONTRAINDICATIONS
ZOFRAN Injection and ZOFRAN Injection Premixed are contraindicated for patients
known to have hypersensitivity to the drug.
WARNINGS
Hypersensitivity reactions have been reported in patients who have exhibited
hypersensitivity to other selective 5-HT3 receptor antagonists.
PRECAUTIONS
Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be
used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or
in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or
gastric distention.
Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450
drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY,
Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450
drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes
may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available
data, no dosage adjustment is recommended for patients on these drugs.
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Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of
CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was
significantly increased and ondansetron blood concentrations were decreased. However, on the basis of
available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3
Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol
has been observed, data from 2 small studies indicate that ondansetron may be associated with an
increase in patient controlled administration of tramadol.4,5
Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model
is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the
pharmacokinetics of ondansetron.
In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood
levels of high-dose methotrexate.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in
2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day,
respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of
ondansetron up to 15 mg/kg per day did not affect fertility or general reproductive performance of male
and female rats.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no
evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate
and well-controlled studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether
ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution
should be exercised when ondansetron is administered to a nursing woman.
Pediatric Use: Little information is available about the use of ondansetron in pediatric surgical
patients younger than 1 month of age. (See CLINICAL TRIALS section for studies of ondansetron in
prevention of post-operative nausea and vomiting in patients 1 month of age and older.) Little
information is available about the use of ondansetron in pediatric cancer patients younger than
6 months of age. (See CLINICAL TRIALS section for studies of ondansetron in chemotherapy-induced
nausea and vomiting in pediatric patients 6 months of age and older.) (See DOSAGE AND
ADMINISTRATION.)
The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower
and the half-life is ~2.5 fold longer than patients who are >4 to 24 months of age. As a precaution, it is
recommended that patients less than 4 months of age receiving this drug be closely monitored. (See
CLINICAL PHARMACOLOGY: Pharmacokinetics).
The frequency and type of adverse events reported in pediatric patients receiving
ondansetron were similar to those in patients receiving placebo. (See ADVERSE EVENTS.)
Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and
postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65 years of
age and over. No overall differences in safety or effectiveness were observed between these subjects
and younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals cannot be
ruled out. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL
PHARMACOLOGY).
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ADVERSE REACTIONS
Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 12 have been
reported in adults receiving ondansetron at a dosage of three 0.15-mg/kg doses or as a single 32-mg
dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily cisplatin,
and I.V. fluids. Most were receiving a diuretic.
Table 12. Principal Adverse Events in Comparative Trials in Adults
Number of Adult Patients With Event
ZOFRAN
Injection
0.15 mg/kg x 3
n = 419
ZOFRAN
Injection
32 mg x 1
n = 220
Metoclopramide
n = 156
Placebo
n = 34
Diarrhea
16%
8%
44%
18%
Headache
17%
25%
7%
15%
Fever
8%
7%
5%
3%
Akathisia
0%
0%
6%
0%
Acute dystonic reactions*
0%
0%
5%
0%
*
See Neurological.
The following have been reported during controlled clinical trials:
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations,
hypotension, and tachycardia have been reported. In many cases, the relationship to ZOFRAN Injection
was unclear.
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients
receiving multiday ondansetron.
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline
values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been
reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were
transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar
transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease
did not occur.
Integumentary: Rash has occurred in approximately 1% of patients receiving
ondansetron.
Neurological: There have been rare reports consistent with, but not diagnostic of,
extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal seizure.
The relationship to ZOFRAN was unclear.
Other: Rare cases of hypokalemia have been reported. The relationship to ZOFRAN
Injection was unclear.
Postoperative Nausea and Vomiting: The adverse events in Table 13 have been reported in ≥2%
of adults receiving ondansetron at a dosage of 4 mg I.V. over 2 to 5 minutes in clinical trials. Rates of
these events were not significantly different in the ondansetron and placebo groups. These patients
were receiving multiple concomitant perioperative and postoperative medications.
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Table 13. Adverse Events in ≥2% of Adults Receiving Ondansetron at a Dosage of 4 mg I.V. over
2 to 5 Minutes in Clinical Trials
ZOFRAN Injection
4 mg I.V.
n = 547 patients
Placebo
n = 547 patients
Headache
92 (17%)
77 (14%)
Dizziness
67 (12%)
88 (16%)
Musculoskeletal pain
57 (10%)
59 (11%)
Drowsiness/sedation
44 (8%)
37 (7%)
Shivers
38 (7%)
39 (7%)
Malaise/fatigue
25 (5%)
30 (5%)
Injection site reaction
21 (4%)
18 (3%)
Urinary retention
17 (3%)
15 (3%)
Postoperative CO2-related pain*
12 (2%)
16 (3%)
Chest pain (unspecified)
12 (2%)
15 (3%)
Anxiety/agitation
11 (2%)
16 (3%)
Dysuria
11 (2%)
9 (2%)
Hypotension
10 (2%)
12 (2%)
Fever
10 (2%)
6 (1%)
Cold sensation
9 (2%)
8 (1%)
Pruritus
9 (2%)
3 (<1%)
Paresthesia
9 (2%)
2 (<1%)
*Sites of pain included abdomen, stomach, joints, rib cage, shoulder.
Pediatric Use: The adverse events in Table 14 were the most commonly reported
adverse events in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric
patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered
intravenously over at least 30 seconds. Rates of these events were not significantly different in the
ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and
postoperative medications.
Table 14. Frequency of Adverse Events From Controlled Studies in Pediatric Patients 2 to
12 years of Age
Adverse Event
Ondansetron
n = 755 Patients
Placebo
n = 731 Patients
Wound problem
80 (11%)
86 (12%)
Anxiety/agitation
49 (6%)
47 (6%)
Headache
44 (6%)
43 (6%)
Drowsiness/sedation
41 (5%)
56 (8%)
Pyrexia
32 (4%)
41 (6%)
The adverse events in Table 15 were the most commonly reported adverse events in
pediatric patients, 1 month to 24 months of age, receiving a single 0.1-mg/kg I.V. dose of ondansetron.
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The incidence and type of adverse events were similar in both the ondansetron and placebo groups.
These patients were receiving multiple concomitant perioperative and postoperative medications.
Table 15. Frequency of Adverse Events (Greater Than or Equal to 2% in Either Treatment
Group) in Pediatric Patients 1 Month to 24 Months of Age
Adverse Event
Ondansetron
n = 336 Patients
Placebo
n = 334 Patients
Pyrexia
14 (4%)
14 (4%)
Bronchospasm
2 (<1%)
6 (2%)
Post-procedural pain
4 (1%)
6 (2%)
Diarrhea
6 (2%)
3 (<1%)
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during post-approval use of intravenous formulations of
ZOFRAN. Because they are reported voluntarily from a population of unknown size, estimates of
frequency cannot be made. The events have been chosen for inclusion due to a combination of their
seriousness, frequency of reporting, or potential causal connection to ZOFRAN.
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia,
premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations
(including second-degree heart block and ST segment depression), palpitations, and syncope.
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g.,
anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest,
hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been
reported.
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death
have been reported in patients with cancer receiving concurrent medications including potentially
hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
Local Reactions: Pain, redness, and burning at site of injection.
Lower Respiratory: Hiccups
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic
reactions.
Skin: Urticaria
Special Senses: Transient blurred vision, in some cases associated with abnormalities
of accommodation, and transient dizziness during or shortly after I.V. infusion.
DRUG ABUSE AND DEPENDENCE
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine
nor does it substitute for benzodiazepines in direct addiction studies.
OVERDOSAGE
There is no specific antidote for ondansetron overdose. Patients should be managed with
appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages (three
doses) as large as 252 mg have been administered intravenously without significant adverse events.
These doses are more than 10 times the recommended daily dose.
In addition to the adverse events listed above, the following events have been described
in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus
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NDA 20-007/S-035
Page 20
severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously
as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral
ondansetron. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with
transient second-degree heart block was observed. In all instances, the events resolved completely.
DOSAGE AND ADMINISTRATION
Prevention of Chemotherapy-Induced Nausea and Vomiting:
Adult Dosing: The recommended I.V. dosage of ZOFRAN for adults is a single 32-mg dose or three
0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the
start of emetogenic chemotherapy. The recommended infusion rate should not be exceeded (see
OVERDOSAGE). With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes
beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are
administered 4 and 8 hours after the first dose of ZOFRAN.
ZOFRAN Injection should not be mixed with solutions for which physical and chemical
compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate
may form.
Vial: DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY-
INDUCED NAUSEA AND VOMITING. ZOFRAN Injection should be diluted in 50 mL of 5%
Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Flexible Plastic Container: REQUIRES NO DILUTION. ZOFRAN Injection
Premixed, 32 mg in 5% Dextrose, 50 mL.
Pediatric Dosing: On the basis of the available information (see CLINICAL TRIALS: Pediatric
Studies and CLINICAL PHARMACOLOGY: Pharmacokinetics), the dosage in pediatric cancer
patients 6 months to 18 years of age should be three 0.15-mg/kg doses. The first dose is to be
administered 30 minutes before the start of moderately to highly emetogenic chemotherapy,
subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN. The
drug should be infused intravenously over 15 minutes. Little information is available about dosage in
pediatric cancer patients younger than 6 months of age.
Vial: DILUTE BEFORE USE. ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose
Injection or 0.9% Sodium Chloride Injection before administration.
Flexible Plastic Container: REQUIRES NO DILUTION. ZOFRAN Injection Premixed, 32 mg
in 5% Dextrose, 50 mL.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Prevention of Postoperative Nausea and Vomiting:
Adult Dosing: The recommended I.V. dosage of ZOFRAN for adults is 4 mg undiluted
administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately
before induction of anesthesia, or postoperatively if the patient experiences nausea and/or vomiting
occurring shortly after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as
a single injection for adults. While recommended as a fixed dose for patients weighing more than
40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of
postoperative nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of
ondansetron 4 mg, administration of a second I.V. dose of 4 mg ondansetron postoperatively does not
provide additional control of nausea and vomiting.
Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR POSTOPERATIVE
NAUSEA AND VOMITING.
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NDA 20-007/S-035
Page 21
Pediatric Dosing: The recommended I.V. dosage of ZOFRAN for pediatric surgical patients
(1 month to 12 years of age) is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single
4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than
30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or
postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery.
Prevention of further nausea and vomiting was only studied in patients who had not received
prophylactic Zofran.
Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR
POSTOPERATIVE NAUSEA AND VOMITING.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Dosage Adjustment for Patients With Impaired Renal Function: The dosage
recommendation is the same as for the general population. There is no experience beyond first-day
administration of ondansetron.
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe
hepatic impairment (Child-Pugh2 score of 10 or greater), a single maximal daily dose of 8 mg to be
infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is
recommended. There is no experience beyond first-day administration of ondansetron.
ZOFRAN Injection Premixed in Flexible Plastic Containers: Instructions for Use: To
Open: Tear outer wrap at notch and remove solution container. Check for minute leaks by squeezing
container firmly. If leaks are found, discard unit as sterility may be impaired.
Preparation for Administration: Use aseptic technique.
1. Close flow control clamp of administration set.
2. Remove cover from outlet port at bottom of container.
3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly
seated. NOTE: See full directions on administration set carton.
4. Suspend container from hanger.
5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of
ZOFRAN Injection Premixed.
6. Open flow control clamp to expel air from set. Close clamp.
7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
8. Perform venipuncture.
9. Regulate rate of administration with flow control clamp.
Caution: ZOFRAN Injection Premixed in flexible plastic containers is to be administered by I.V. drip
infusion only. ZOFRAN Injection Premixed should not be mixed with solutions for which physical and
chemical compatibility have not been established. In particular, this applies to alkaline solutions as a
precipitate may form. If used with a primary I.V. fluid system, the primary solution should be
discontinued during ZOFRAN Injection Premixed infusion.
Do not administer unless solution is clear and container is undamaged.
Warning: Do not use flexible plastic container in series connections.
Stability: ZOFRAN Injection is stable at room temperature under normal lighting conditions for
48 hours after dilution with the following I.V. fluids: 0.9% Sodium Chloride Injection, 5% Dextrose
Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium
Chloride Injection, and 3% Sodium Chloride Injection.
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NDA 20-007/S-035
Page 22
Although ZOFRAN Injection is chemically and physically stable when diluted as
recommended, sterile precautions should be observed because diluents generally do not contain
preservative. After dilution, do not use beyond 24 hours.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration
before administration whenever solution and container permit.
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored
upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial
vigorously.
HOW SUPPLIED
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
NDC 0173-0442-02 2-mL single-dose vials (Carton of 5)
NDC 0173-0442-00 20-mL multidose vials (Singles)
Store between 2° and 30°C (36° and 86°F). Protect from light.
ZOFRAN Injection Premixed, 32 mg/50 mL, in 5% Dextrose, contains no
preservatives and is supplied as a sterile, premixed solution for I.V. administration in single-dose,
flexible plastic containers (NDC 0173-0461-00) (case of 6).
Store between 2° and 30°C (36° and 86°F). Protect from light. Avoid excessive heat.
Protect from freezing.
REFERENCES
1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND)
metabolism in humans. Clin Pharmacol Ther. 1997;61:228.
2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the
oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649.
3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and
intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381.
4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321.
5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557.
GlaxoSmithKline
Research Triangle Park, NC 27709
ZOFRAN® Injection Premixed:
Manufactured for GlaxoSmithKline
Research Triangle Park, NC 27709
by Abbott Laboratories, North Chicago, IL 60064
©YEAR, GlaxoSmithKline. All rights reserved.
Month YEAR
RL-XXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:25.641953
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20007s035lbl.pdf', 'application_number': 20007, 'submission_type': 'SUPPL ', 'submission_number': 35}
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DOCUMENT INFORMATION PAGE
This page is for FDA internal use only. Do NOT send this page with the letter.
Application #(s):
NDA 20-007/S-037
NDA 20-403/S-014
Document Type:
NDA Letters
Document Group:
NDA Supplement Approval Letters
Document Name:
Approval, effective on date of letter, based on enclosed labeling text or submitted
draft labeling (with or without minor editorial revisions included in the letter).
Shortcut ID Code:
SNDA-I1
COMIS Decision Code
AP
Drafted by:
BHS/12-27-2005
Revised by:
BHS/12-27-2005
Initialed by:
BKS/12-27-2005, LL/12-27-2005, EB/12-27-2005, BEH/12-27-2005
Finalized:
BHS/12-27-2005
Filename:
C:\data\My Documents\NDA\Zofran SLRs\AP LTR INJ w ATT LBL 12-27-2005
SNDA-I1.doc
DFS Key Words:
Notes:
Version: 11/18/05
END OF DOCUMENT INFORMATION PAGE
The letter begins on the next page.
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration
Rockville, MD 20857
NDA 20-007/S-037
NDA 20-403/S-014
GlaxoSmithKline
Attention: Ellen S. Cutler, Senior Director, Regulatory Affairs
2301 Renaissance Boulevard
Building 510, P.O. Box 61540
King of Prussia, PA 19406-2772
Dear Ms. Cutler:
Please refer to your supplemental new drug applications as follow:
NDA
Number
Name of Drug Product
Supplement
Number
Date
of Supplement
Date of Receipt
20-007
Zofran® (ondansetron hydrochloride)
Injection
037
June 29, 2005
June 30, 2005
20-403
Zofran® (ondansetron hydrochloride)
Injection Premixed
014
June 29, 2005
June 30, 2005
submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act.
We acknowledge receipt of your faxed submission dated December 22, 2005 agreeing to our labeling
revision.
These “Changes Being Effected” supplemental new drug applications provide to update the
ADVERSE REACTIONS section of each label, respectively, by adding a subsection Special Senses:
Eye Disorders.
We completed our review of these applications, as amended. These applications are approved,
effective on the date of this letter, for use as recommended in the agreed-upon labeling text.
The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert),
and submitted labeling (package insert submitted December 22, 2005).
Please submit an electronic version of the FPL according to the guidance for industry titled Providing
Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
of the copies on heavy-weight paper or similar material. For administrative purposes, designate these
submissions "FPL for approved supplement NDA 20-007/S-037 and NDA 20-403/S-014.”
Approval of these submissions by FDA are not required before the labeling is used.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-037
NDA 20-403/S-014
Page 2
We remind you that you must comply with reporting requirements for an approved NDA
(21 CFR 314.80 and 314.81).
If you have any questions, call Betsy Scroggs, Pharm.D, Regulatory Project Manager, at
(301) 796-0991.
Sincerely,
{See appended electronic signature page}
Brian E. Harvey, M.D., Ph.D.
Director
Division of Gastroenterology Products
Office of Drug Evaluation III
Center for Drug Evaluation and Research
Enclosure
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NDA 20-007/S-037
NDA 20-403/S-014
Page 3
PRESCRIBING INFORMATION
ZOFRAN®
(ondansetron hydrochloride)
Injection
ZOFRAN®
(ondansetron hydrochloride)
Injection Premixed
DESCRIPTION
The active ingredient in ZOFRAN Injection and ZOFRAN Injection Premixed is
ondansetron hydrochloride (HCl), the racemic form of ondansetron and a selective blocking agent of
the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-
imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following
structural formula:
The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of
365.9.
Ondansetron HCl is a white to off-white powder that is soluble in water and normal
saline.
Sterile Injection for Intravenous (I.V.) or Intramuscular (I.M.) Administration: Each 1 mL
of aqueous solution in the 2-mL single-dose vial contains 2 mg of ondansetron as the hydrochloride
dihydrate; 9.0 mg of sodium chloride, USP; and 0.5 mg of citric acid monohydrate, USP and 0.25 mg
of sodium citrate dihydrate, USP as buffers in Water for Injection, USP.
Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as the
hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and
0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of
propylparaben, NF as preservatives in Water for Injection, USP.
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution. The pH of the injection solution
is 3.3 to 4.0.
Sterile, Premixed Solution for Intravenous Administration in Single-Dose, Flexible
Plastic Containers: Each 50 mL contains ondansetron 32 mg (as the hydrochloride dihydrate);
dextrose 2,500 mg; and citric acid 26 mg and sodium citrate 11.5 mg as buffers in Water for Injection,
USP. It contains no preservatives. The osmolarity of this solution is 270 mOsm/L (approx.), and the pH
is 3.0 to 4.0.
The flexible plastic container is fabricated from a specially formulated, nonplasticized, thermoplastic
co-polyester (CR3). Water can permeate from inside the container into the overwrap but not in amounts
sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out
certain of the chemical components in very small amounts before the expiration period is attained.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-037
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Page 4
However, the safety of the plastic has been confirmed by tests in animals according to USP biological
standards for plastic containers.
CLINICAL PHARMACOLOGY
Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron's
mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist.
Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and
centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron's
antiemetic action in chemotherapy-induced nausea and vomiting is mediated centrally, peripherally, or
in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from
the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic
acid) excretion increases after cisplatin administration in parallel with the onset of vomiting. The
released serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the
vomiting reflex.
In animals, the emetic response to cisplatin can be prevented by pretreatment with an
inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or
pretreatment with a serotonin 5-HT3 receptor antagonist.
In normal volunteers, single I.V. doses of 0.15 mg/kg of ondansetron had no effect on
esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit
time. In another study in six normal male volunteers, a 16-mg dose infused over 5 minutes showed no
effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram
(ECG). Multiday administration of ondansetron has been shown to slow colonic transit in normal
volunteers. Ondansetron has no effect on plasma prolactin concentrations.
In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered
intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting
using the ipecacuanha model of emesis.
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or
the degree of neuromuscular blockade produced by atracurium. Interactions with general or local
anesthetics have not been studied.
Pharmacokinetics: Ondansetron is extensively metabolized in humans, with approximately 5% of a
radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is
hydroxylation on the indole ring followed by glucuronide or sulfate conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not found in
plasma at concentrations likely to significantly contribute to the biological activity of ondansetron.
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic
cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall
ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic
enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g.,
CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall
rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450
inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4
inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½ of ondansetron was observed.1
This resulted in a significant increase in clearance. However, on the basis of available data, no dosage
adjustment for ondansetron is recommended (see PRECAUTIONS: Drug Interactions).
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-037
NDA 20-403/S-014
Page 5
In normal adult volunteers, the following mean pharmacokinetic data have been
determined following a single 0.15-mg/kg I.V. dose.
Table 1. Pharmacokinetics in Normal Adult Volunteers
Age-group
(years)
n
Peak Plasma
Concentration
(ng/mL)
Mean Elimination
Half-life (h)
Plasma Clearance
(L/h/kg)
19-40
11
102
3.5
0.381
61-74
12
106
4.7
0.319
≥75
11
170
5.5
0.262
A reduction in clearance and increase in elimination half-life are seen in patients over
75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over
65 years of age and those under 65 years of age; there was an insufficient number of patients over
75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the
elderly.
In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and
mean half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe
hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and
apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients
with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.
DUE TO THE VERY SMALL CONTRIBUTION (5%) OF RENAL CLEARANCE TO THE OVERALL CLEARANCE,
RENAL IMPAIRMENT WAS NOT EXPECTED TO SIGNIFICANTLY INFLUENCE THE TOTAL CLEARANCE OF
ONDANSETRON. HOWEVER, ONDANSETRON MEAN PLASMA CLEARANCE WAS REDUCED BY ABOUT 41% IN
PATIENTS WITH SEVERE RENAL IMPAIRMENT (CREATININE CLEARANCE <30 ML/MIN). THIS REDUCTION IN
CLEARANCE IS VARIABLE AND WAS NOT CONSISTENT WITH AN INCREASE IN HALF-LIFE. NO REDUCTION IN
DOSE OR DOSING FREQUENCY IN THESE PATIENTS IS WARRANTED.
In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no
difference in the multidose pharmacokinetics over a 4-day period. In a study of 21 pediatric cancer
patients (4 to 18 years of age) who received three I.V. doses of 0.15 mg/kg of ondansetron at 4-hour
intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar
to those of adults. Patients 4 to 12 years of age generally showed higher clearance and somewhat larger
volume of distribution than adults. Most pediatric patients younger than 15 years of age with cancer
had a shorter (2.4 hours) ondansetron plasma half-life than patients older than 15 years of age. It is not
known whether these differences in ondansetron plasma half-life may result in differences in efficacy
between adults and some young pediatric patients (see CLINICAL TRIALS: Pediatric Studies).
Pharmacokinetic samples were collected from 74 cancer patients 6 to 48 months of age,
who received a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses during a safety and
efficacy trial. These data were combined with sequential pharmacokinetics data from 41 surgery
patients 1 month to 24 months of age, who received a single dose of 0.1 mg/kg of I.V. ondansetron
prior to surgery with general anesthesia, and a population pharmacokinetic analysis was performed on
the combined data set. The results of this analysis are included in Table 2 and are compared to the
pharmacokinetic results in cancer patients 4 to 18 years of age.
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NDA 20-403/S-014
Page 6
Table 2. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Cancer Patients
4 to 18 years of age
N = 21
0.599
1.9
2.8
Population PK Patients*
1 month to 48 months of age
N = 115
0.582
3.65
4.9
*
Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery
patients.
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age
who receive a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses would be expected to
achieve a systemic exposure (AUC) consistent with the exposure achieved in previous pediatric studies
in cancer patients (4 to 18 years of age) at similar doses.
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery
requiring anesthesia for a duration of 45 minutes to 2 hours, a single I.V. dose of ondansetron, 2 mg (3
to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean
weight-normalized clearance and volume of distribution values in these pediatric surgical patients were
similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in
pediatric patients (range, 2.5 to 3 hours) in comparison with adults (range, 3 to 3.5 hours).
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing
surgery requiring general anesthesia, a single I.V. dose of ondansetron, 0.1 or 0.2 mg/kg, was
administered prior to surgery. As shown in Table 3, the 41 patients with pharmacokinetic data were
divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months of age, and are
compared to pediatric patients 3 to 12 years of age.
Table 3. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Surgery Patients
3 to 12 years of age
N = 21
0.439
1.65
2.9
Pediatric Surgery Patients
5 to 24 months of age
N = 22
0.581
2.3
2.9
Pediatric Surgery Patients
1 month to 4 months of age
N = 19
0.401
3.5
6.7
In general, surgical and cancer pediatric patients younger than 18 years tend to have a
higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric
patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher
volume of distribution in this age group.
In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was
264 ng/mL following a single 32-mg dose administered as a 15-minute I.V. infusion. The mean
elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to
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NDA 20-403/S-014
Page 7
dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with
a small decrease in systemic clearance with increasing plasma concentrations.
A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a
single 4-mg dose administered as a 5-minute infusion compared to a single intramuscular injection.
Systemic exposure as measured by mean AUC was equivalent, with values of 156 [95% CI 136, 180]
and 161 [95% CI 137, 190] ng•h/mL for I.V. and I.M. groups, respectively. Mean peak plasma
concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V. infusion and 31.9 [95%
CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean elimination half-life was not
affected by route of administration.
Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with
binding constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also
distributes into erythrocytes.
A positive lymphoblast transformation test to ondansetron has been reported, which
suggests immunologic sensitivity to ondansetron.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting:
Adult Studies: In a double-blind study of three different dosing regimens of ZOFRAN Injection,
0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer
chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing
regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the 0.15-mg/kg
dosing regimen.
Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, ZOFRAN
Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing nausea
and vomiting induced by cisplatin-based chemotherapy. Treatment response was as shown in Table 4.
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Table 4. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cisplatin
Therapy* in Adults
ZOFRAN
Injection
Placebo
P Value†
Number of patients
14
14
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
2 (14%)
8 (57%)
2 (14%)
2 (14%)
0 (0%)
0 (0%)
1 (7%)
13 (93%)
0.001
Median number of emetic episodes
1.5
Undefined‡
Median time to first emetic episode (h)
11.6
2.8
0.001
Median nausea scores (0-100)§
3
59
0.034
Global satisfaction with control of
nausea and vomiting (0-100)
II
96
10.5
0.009
* Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5) or
moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other
chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There was no
difference between treatments in the types of chemotherapy that would account for differences in
response.
† Efficacy based on "all patients treated" analysis.
‡
Median undefined since at least 50% of the patients were rescued or had more than five emetic
episodes.
§ Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
II Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Ondansetron was compared with metoclopramide in a single-blind trial in 307 patients
receiving cisplatin ≥100 mg/m2 with or without other chemotherapeutic agents. Patients received the
first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional ondansetron
doses were administered 4 and 8 hours later, or five additional metoclopramide doses were
administered 2, 4, 7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less.
Episodes of vomiting and retching were tabulated over the period of 24 hours after cisplatin. The
results of this study are summarized in Table 5.
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Table 5. Prevention of Vomiting Induced by Cisplatin (≥100 mg/m2) Single-Day Therapy* in
Adults
ZOFRAN Injection
Metoclopramide
P Value
Dose
0.15 mg/kg x 3
2 mg/kg x 6
Number of patients in efficacy population
136
138
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
54 (40%)
34 (25%)
19 (14%)
29 (21%)
41 (30%)
30 (22%)
18 (13%)
49 (36%)
Comparison of treatments with respect to
0 Emetic episodes
More than 5 emetic episodes/rescued
54/136
29/136
41/138
49/138
0.083
0.009
Median number of emetic episodes
1
2
0.005
Median time to first emetic episode (h)
20.5
4.3
<0.001
Global satisfaction with control of nausea
and vomiting (0-100)†
85
63
0.001
Acute dystonic reactions
0
8
0.005
Akathisia
0
10
0.002
* In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including
cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the
types of chemotherapy that would account for differences in response.
†
Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
In a stratified, randomized, double-blind, parallel-group, multicenter study, a single
32-mg dose of ondansetron was compared with three 0.15-mg/kg doses in patients receiving cisplatin
doses of either 50 to 70 mg/m2 or ≥100 mg/m2. Patients received the first ondansetron dose 30 minutes
before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later to the group
receiving three 0.15-mg/kg doses. In both strata, significantly fewer patients on the single 32-mg dose
than those receiving the three-dose regimen failed.
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Table 6. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Dose Therapy in
Adults
Ondansetron
Dose
0.15 mg/kg x 3
32 mg x 1
P Value
High-dose cisplatin (≥100 mg/m2)
Number of patients
100
102
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
41 (41%)
19 (19%)
4 (4%)
36 (36%)
49 (48%)
25 (25%)
8 (8%)
20 (20%)
0.315
0.009
Median time to first emetic episode (h)
21.7
23
0.173
Median nausea scores (0-100)*
28
13
0.004
Medium-dose cisplatin (50-70 mg/m2)
Number of patients
101
93
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
62 (61%)
11 (11%)
6 (6%)
22 (22%)
68 (73%)
14 (15%)
3 (3%)
8 (9%)
0.083
0.011
Median time to first emetic episode (h)
Undefined†
Undefined
Median nausea scores (0-100)*
9
3
0.131
*
Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
†
Median undefined since at least 50% of patients did not have any emetic episodes.
Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled
study of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500
to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than placebo in
preventing nausea and vomiting. The results are summarized in Table 7.
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Table 7. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day
Cyclophosphamide Therapy* in Adults
ZOFRAN
Injection
Placebo
P Value†
Number of patients
10
10
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
7 (70%)
0 (0%)
2 (20%)
1 (10%)
0 (0%)
2 (20%)
4 (40%)
4 (40%)
0.001
0.131
Median number of emetic episodes
0
4
0.008
Median time to first emetic episode (h)
Undefined‡
8.79
Median nausea scores (0-100)§
0
60
0.001
Global satisfaction with control of
nausea and vomiting (0-100)II
100
52
0.008
* Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including
fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between
treatments in the type of chemotherapy that would account for differences in response.
†
Efficacy based on "all patients treated" analysis.
‡
Median undefined since at least 50% of patients did not have any emetic episodes.
§
Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
II
Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose,
100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with ondansetron
and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median, 2; range, 1 to 10).
No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes occurred in 217 (81%)
re-treatment courses.
Pediatric Studies: Four open-label, noncomparative (one US, three foreign) trials have been
performed with 209 pediatric cancer patients 4 to 18 years of age given a variety of cisplatin or
noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged from 0.04
to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration of
ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, ZOFRAN was administered
intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2 to 39 mg. In these
studies, 58% of the 196 evaluable patients had a complete response (no emetic episodes) on day 1.
Thus, prevention of vomiting in these pediatric patients was essentially the same as for patients older
than 18 years of age.
An open-label, multicenter, noncomparative trial has been performed in 75 pediatric
cancer patients 6 to 48 months of age receiving at least one moderately or highly emetogenic
chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were
American Hispanic, and 15% were black patients. ZOFRAN was administered intravenously over 15
minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before the start of
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chemotherapy, the second and third doses were administered 4 and 8 hours after the first dose,
respectively. Eighteen patients (25%) received routine prophylactic dexamethasone (i.e., not given as
rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic episodes) on day 1.
Thus, prevention of vomiting in these pediatric patients was comparable to the prevention of vomiting
in patients 4 years of age and older.
Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and
Vomiting:
Adult Studies: Adult surgical patients who received ondansetron immediately before the induction of
general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or
fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or
atracurium; and supplemental isoflurane) were evaluated in two double-blind US studies involving
554 patients. ZOFRAN Injection (4 mg) I.V. given over 2 to 5 minutes was significantly more effective
than placebo. The results of these studies are summarized in Table 8.
Table 8. Prevention of Postoperative Nausea and Vomiting in Adult Patients
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic
episode/rescued
136
103 (76%)
13 (10%)
20 (15%)
139
64 (46%)
17 (12%)
58 (42%)
<0.001
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
134
56 (42%)
136
39 (29%)
Study 2
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
85 (63%)
16 (12%)
35 (26%)
143
63 (44%)
29 (20%)
51 (36%)
0.002
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
125
48 (38%)
133
42 (32%)
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The study populations in Table 8 consisted mainly of females undergoing laparoscopic
procedures.
In a placebo-controlled study conducted in 468 males undergoing outpatient procedures,
a single 4-mg I.V. ondansetron dose prevented postoperative vomiting over a 24-hour study period in
79% of males receiving drug compared to 63% of males receiving placebo (P<0.001).
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major
abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg I.V. ondansetron dose for
prevention of postoperative nausea and vomiting over a 24-hour study period. At the 4-mg dosage,
59% of patients receiving ondansetron versus 45% receiving placebo in the first study (P<0.001) and
41% of patients receiving ondansetron versus 30% receiving placebo in the second study (P=0.001)
experienced no emetic episodes. No additional benefit was observed in patients who received I.V.
ondansetron 8 mg compared to patients who received I.V. ondansetron 4 mg.
Pediatric Studies: Three double-blind, placebo-controlled studies have been performed (one US,
two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing general anesthesia
with nitrous oxide. The surgical procedures included tonsillectomy with or without adenoidectomy,
strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized to either single I.V.
doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric
patients weighing more than 40 kg) or placebo. Study drug was administered over at least 30 seconds,
immediately prior to or following anesthesia induction. Ondansetron was significantly more effective
than placebo in preventing nausea and vomiting. The results of these studies are summarized in Table
9.
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Table 9. Prevention of Postoperative Nausea and Vomiting in Pediatric Patients 2 to 12 Years of
Age
Treatment Response Over
24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Study 1
Number of patients
0 Emetic episodes
Failure*
205
140 (68%)
65 (32%)
210
82 (39%)
128 (61%)
≤0.001
Study 2
Number of patients
0 Emetic episodes
Failure*
112
68 (61%)
44 (39%)
110
38 (35%)
72 (65%)
≤0.001
Study 3
Number of patients
0 Emetic episodes
Failure*
206
123 (60%)
83 (40%)
206
96 (47%)
110 (53%)
≤0.01
Nausea assessments†:
Number of patients
None
185
119 (64%)
191
99 (52%)
≤0.01
*
Failure was one or more emetic episodes, rescued, or withdrawn.
†
Nausea measured as none, mild, or severe.
A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric
patients 1 month to 24 months of age who were undergoing routine surgery under general anesthesia.
Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were American
Hispanic, 2% were Asian, and 6% were “other race” patients. A single 0.1-mg/kg I.V. dose of
ondansetron administered within 5 minutes following induction of anesthesia was statistically
significantly more effective than placebo in preventing vomiting. In the placebo group, 28% of patients
experienced vomiting compared to 11% of subjects who received ondansetron (P≤0.01). Overall, 32
(10%) of placebo patients and 18 (5%) of patients who received ondansetron received antiemetic rescue
medication(s) or prematurely withdrew from the study.
Prevention of Further Postoperative Nausea and Vomiting:
Adult Studies: Adult surgical patients receiving general balanced anesthesia (barbiturate: thiopental,
methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade:
succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) who received no
prophylactic antiemetics and who experienced nausea and/or vomiting within 2 hours postoperatively
were evaluated in two double-blind US studies involving 441 patients. Patients who experienced an
episode of postoperative nausea and/or vomiting were given ZOFRAN Injection (4 mg) I.V. over 2 to
5 minutes, and this was significantly more effective than placebo. The results of these studies are
summarized in Table 10.
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Table 10. Prevention of Further Postoperative Nausea and Vomiting in Adult Patients
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
Median time to first emetic episode (min)*
104
49 (47%)
12 (12%)
43 (41%)
55.0
117
19 (16%)
9 (8%)
89 (76%)
43.0
<0.001
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
period†
98
1.7
102
3.1
Study 2
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
0 Emetic episodes
1 Emetic episode
More than 1 emetic
episode/rescued
Median time to first emetic episode (min)*
112
49 (44%)
14 (13%)
49 (44%)
60.5
108
28 (26%)
3 (3%)
77 (71%)
34.0
0.006
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
period†
105
1.9
85
2.9
*
After administration of study drug.
†
Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
The study populations in Table 10 consisted mainly of women undergoing laparoscopic
procedures.
Repeat Dosing in Adults: In patients who do not achieve adequate control of postoperative nausea
and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron 4 mg,
administration of a second I.V. dose of ondansetron 4 mg postoperatively does not provide additional
control of nausea and vomiting.
Pediatric Study: One double-blind, placebo-controlled, US study was performed in 351 male and
female outpatients (2 to 12 years of age) who received general anesthesia with nitrous oxide and no
prophylactic antiemetics. Surgical procedures were unrestricted. Patients who experienced two or more
emetic episodes within 2 hours following discontinuation of nitrous oxide were randomized to either
single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for
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pediatric patients weighing more than 40 kg) or placebo administered over at least 30 seconds.
Ondansetron was significantly more effective than placebo in preventing further episodes of nausea
and vomiting. The results of the study are summarized in Table 11.
Table 11. Prevention of Further Postoperative Nausea and Vomiting in Pediatric Patients 2 to
12 Years of Age
Treatment Response
Over 24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Number of patients
0 Emetic episodes
Failure*
180
96 (53%)
84 (47%)
171
29 (17%)
142 (83%)
≤0.001
* Failure was one or more emetic episodes, rescued, or withdrawn.
INDICATIONS AND USAGE
1. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer
chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose beyond 24 hours in
these patients has not been established.
2. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis
is not recommended for patients in whom there is little expectation that nausea and/or vomiting will
occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively,
ZOFRAN Injection is recommended even where the incidence of postoperative nausea and/or
vomiting is low. For patients who do not receive prophylactic ZOFRAN Injection and experience
nausea and/or vomiting postoperatively, ZOFRAN Injection may be given to prevent further
episodes (see CLINICAL TRIALS).
CONTRAINDICATIONS
ZOFRAN Injection and ZOFRAN Injection Premixed are contraindicated for patients
known to have hypersensitivity to the drug.
WARNINGS
Hypersensitivity reactions have been reported in patients who have exhibited
hypersensitivity to other selective 5-HT3 receptor antagonists.
PRECAUTIONS
Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be
used instead of nasogastric suction. The use of ondansetron in patients following abdominal surgery or
in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or
gastric distention.
Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome P-450
drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY,
Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450
drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes
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may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available
data, no dosage adjustment is recommended for patients on these drugs.
Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of
CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was
significantly increased and ondansetron blood concentrations were decreased. However, on the basis of
available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3
Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol
has been observed, data from 2 small studies indicate that ondansetron may be associated with an
increase in patient controlled administration of tramadol.4,5
Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model
is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the
pharmacokinetics of ondansetron.
In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood
levels of high-dose methotrexate.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not seen in
2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day,
respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral administration of
ondansetron up to 15 mg/kg per day did not affect fertility or general reproductive performance of male
and female rats.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no
evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate
and well-controlled studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether
ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution
should be exercised when ondansetron is administered to a nursing woman.
Pediatric Use: Little information is available about the use of ondansetron in pediatric surgical
patients younger than 1 month of age. (See CLINICAL TRIALS section for studies of ondansetron in
prevention of postoperative nausea and vomiting in patients 1 month of age and older.) Little
information is available about the use of ondansetron in pediatric cancer patients younger than
6 months of age. (See CLINICAL TRIALS section for studies of ondansetron in chemotherapy-induced
nausea and vomiting in pediatric patients 6 months of age and older.) (See DOSAGE AND
ADMINISTRATION.)
The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower
and the half-life is ~2.5 fold longer than patients who are >4 to 24 months of age. As a precaution, it is
recommended that patients less than 4 months of age receiving this drug be closely monitored. (See
CLINICAL PHARMACOLOGY: Pharmacokinetics).
The frequency and type of adverse events reported in pediatric patients receiving
ondansetron were similar to those in patients receiving placebo. (See ADVERSE EVENTS.)
Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and
postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65 years of
age and over. No overall differences in safety or effectiveness were observed between these subjects
and younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals cannot be
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ruled out. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL
PHARMACOLOGY).
ADVERSE REACTIONS
Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 12 have been
reported in adults receiving ondansetron at a dosage of three 0.15-mg/kg doses or as a single 32-mg
dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily cisplatin,
and I.V. fluids. Most were receiving a diuretic.
Table 12. Principal Adverse Events in Comparative Trials in Adults
Number of Adult Patients With Event
ZOFRAN
Injection
0.15 mg/kg x 3
n = 419
ZOFRAN
Injection
32 mg x 1
n = 220
Metoclopramide
n = 156
Placebo
n = 34
Diarrhea
16%
8%
44%
18%
Headache
17%
25%
7%
15%
Fever
8%
7%
5%
3%
Akathisia
0%
0%
6%
0%
Acute dystonic reactions*
0%
0%
5%
0%
*
See Neurological.
THE FOLLOWING HAVE BEEN REPORTED DURING CONTROLLED CLINICAL TRIALS:
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations,
hypotension, and tachycardia have been reported. In many cases, the relationship to ZOFRAN Injection
was unclear.
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients
receiving multiday ondansetron.
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline
values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been
reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were
transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar
transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease
did not occur.
Integumentary: Rash has occurred in approximately 1% of patients receiving
ondansetron.
Neurological: There have been rare reports consistent with, but not diagnostic of,
extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal seizure.
The relationship to ZOFRAN was unclear.
Other: Rare cases of hypokalemia have been reported. The relationship to ZOFRAN
Injection was unclear.
Postoperative Nausea and Vomiting: The adverse events in Table 13 have been reported in ≥2%
of adults receiving ondansetron at a dosage of 4 mg I.V. over 2 to 5 minutes in clinical trials. Rates of
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these events were not significantly different in the ondansetron and placebo groups. These patients
were receiving multiple concomitant perioperative and postoperative medications.
Table 13. Adverse Events in ≥2% of Adults Receiving Ondansetron at a Dosage of 4 mg I.V. over
2 to 5 Minutes in Clinical Trials
ZOFRAN Injection
4 mg I.V.
n = 547 patients
Placebo
n = 547 patients
Headache
92 (17%)
77 (14%)
Dizziness
67 (12%)
88 (16%)
Musculoskeletal pain
57 (10%)
59 (11%)
Drowsiness/sedation
44 (8%)
37 (7%)
Shivers
38 (7%)
39 (7%)
Malaise/fatigue
25 (5%)
30 (5%)
Injection site reaction
21 (4%)
18 (3%)
Urinary retention
17 (3%)
15 (3%)
Postoperative CO2-related pain*
12 (2%)
16 (3%)
Chest pain (unspecified)
12 (2%)
15 (3%)
Anxiety/agitation
11 (2%)
16 (3%)
Dysuria
11 (2%)
9 (2%)
Hypotension
10 (2%)
12 (2%)
Fever
10 (2%)
6 (1%)
Cold sensation
9 (2%)
8 (1%)
Pruritus
9 (2%)
3 (<1%)
Paresthesia
9 (2%)
2 (<1%)
*Sites of pain included abdomen, stomach, joints, rib cage, shoulder.
Pediatric Use: The adverse events in Table 14 were the most commonly reported
adverse events in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric
patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered
intravenously over at least 30 seconds. Rates of these events were not significantly different in the
ondansetron and placebo groups. These patients were receiving multiple concomitant perioperative and
postoperative medications.
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Table 14. Frequency of Adverse Events From Controlled Studies in Pediatric Patients 2 to
12 Years of Age
Adverse Event
Ondansetron
n = 755 Patients
Placebo
n = 731 Patients
Wound problem
80 (11%)
86 (12%)
Anxiety/agitation
49 (6%)
47 (6%)
Headache
44 (6%)
43 (6%)
Drowsiness/sedation
41 (5%)
56 (8%)
Pyrexia
32 (4%)
41 (6%)
The adverse events in Table 15 were the most commonly reported adverse events in
pediatric patients, 1 month to 24 months of age, receiving a single 0.1-mg/kg I.V. dose of ondansetron.
The incidence and type of adverse events were similar in both the ondansetron and placebo groups.
These patients were receiving multiple concomitant perioperative and postoperative medications.
Table 15. Frequency of Adverse Events (Greater Than or Equal to 2% in Either Treatment
Group) in Pediatric Patients 1 Month to 24 Months of Age
Adverse Event
Ondansetron
n = 336 Patients
Placebo
n = 334 Patients
Pyrexia
14 (4%)
14 (4%)
Bronchospasm
2 (<1%)
6 (2%)
Post-procedural pain
4 (1%)
6 (2%)
Diarrhea
6 (2%)
3 (<1%)
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during post-approval use of intravenous formulations of
ZOFRAN. Because they are reported voluntarily from a population of unknown size, estimates of
frequency cannot be made. The events have been chosen for inclusion due to a combination of their
seriousness, frequency of reporting, or potential causal connection to ZOFRAN.
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia,
premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations
(including second-degree heart block and ST segment depression), palpitations, and syncope.
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g.,
anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest,
hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been
reported.
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death
have been reported in patients with cancer receiving concurrent medications including potentially
hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
Local Reactions: Pain, redness, and burning at site of injection.
Lower Respiratory: Hiccups
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic
reactions.
Skin: Urticaria
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Special Senses: Transient dizziness during or shortly after I.V. infusion.
Eye Disorders: Transient blurred vision, in some cases associated with abnormalities
of accommodation. Cases of transient blindness, predominantly during intravenous administration,
have been reported. These cases of transient blindness were reported to resolve within a few minutes
up to 48 hours.
DRUG ABUSE AND DEPENDENCE
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine
nor does it substitute for benzodiazepines in direct addiction studies.
OVERDOSAGE
There is no specific antidote for ondansetron overdose. Patients should be managed with
appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages (three
doses) as large as 252 mg have been administered intravenously without significant adverse events.
These doses are more than 10 times the recommended daily dose.
In addition to the adverse events listed above, the following events have been described
in the setting of ondansetron overdose: "Sudden blindness" (amaurosis) of 2 to 3 minutes' duration plus
severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously
as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of oral
ondansetron. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with
transient second-degree heart block was observed. In all instances, the events resolved completely.
DOSAGE AND ADMINISTRATION
Prevention of Chemotherapy-Induced Nausea and Vomiting:
Adult Dosing: The recommended I.V. dosage of ZOFRAN for adults is a single 32-mg dose or three
0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the
start of emetogenic chemotherapy. The recommended infusion rate should not be exceeded (see
OVERDOSAGE). With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes
beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are
administered 4 and 8 hours after the first dose of ZOFRAN.
ZOFRAN Injection should not be mixed with solutions for which physical and chemical
compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate
may form.
Vial: DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY-
INDUCED NAUSEA AND VOMITING. ZOFRAN Injection should be diluted in 50 mL of 5%
Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Flexible Plastic Container: REQUIRES NO DILUTION. ZOFRAN Injection
Premixed, 32 mg in 5% Dextrose, 50 mL.
Pediatric Dosing: On the basis of the available information (see CLINICAL TRIALS: Pediatric
Studies and CLINICAL PHARMACOLOGY: Pharmacokinetics), the dosage in pediatric cancer
patients 6 months to 18 years of age should be three 0.15-mg/kg doses. The first dose is to be
administered 30 minutes before the start of moderately to highly emetogenic chemotherapy,
subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN. The
drug should be infused intravenously over 15 minutes. Little information is available about dosage in
pediatric cancer patients younger than 6 months of age.
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Vial: DILUTE BEFORE USE. ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose
Injection or 0.9% Sodium Chloride Injection before administration.
Flexible Plastic Container: REQUIRES NO DILUTION. ZOFRAN Injection Premixed, 32 mg
in 5% Dextrose, 50 mL.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Prevention of Postoperative Nausea and Vomiting:
Adult Dosing: The recommended I.V. dosage of ZOFRAN for adults is 4 mg undiluted
administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately
before induction of anesthesia, or postoperatively if the patient experiences nausea and/or vomiting
occurring shortly after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as
a single injection for adults. While recommended as a fixed dose for patients weighing more than
40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of
postoperative nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of
ondansetron 4 mg, administration of a second I.V. dose of 4 mg ondansetron postoperatively does not
provide additional control of nausea and vomiting.
Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR POSTOPERATIVE
NAUSEA AND VOMITING.
Pediatric Dosing: The recommended I.V. dosage of ZOFRAN for pediatric surgical patients
(1 month to 12 years of age) is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single
4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than
30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or
postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery.
Prevention of further nausea and vomiting was only studied in patients who had not received
prophylactic Zofran.
Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR
POSTOPERATIVE NAUSEA AND VOMITING.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Dosage Adjustment for Patients With Impaired Renal Function: The dosage
recommendation is the same as for the general population. There is no experience beyond first-day
administration of ondansetron.
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with severe
hepatic impairment (Child-Pugh2 score of 10 or greater), a single maximal daily dose of 8 mg to be
infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is
recommended. There is no experience beyond first-day administration of ondansetron.
ZOFRAN Injection Premixed in Flexible Plastic Containers: Instructions for Use: To
Open: Tear outer wrap at notch and remove solution container. Check for minute leaks by squeezing
container firmly. If leaks are found, discard unit as sterility may be impaired.
Preparation for Administration: Use aseptic technique.
1. Close flow control clamp of administration set.
2. Remove cover from outlet port at bottom of container.
3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly
seated. NOTE: See full directions on administration set carton.
4. Suspend container from hanger.
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Page 23
5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of
ZOFRAN Injection Premixed.
6. Open flow control clamp to expel air from set. Close clamp.
7. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
8. Perform venipuncture.
9. Regulate rate of administration with flow control clamp.
Caution: ZOFRAN Injection Premixed in flexible plastic containers is to be administered by I.V. drip
infusion only. ZOFRAN Injection Premixed should not be mixed with solutions for which physical and
chemical compatibility have not been established. In particular, this applies to alkaline solutions as a
precipitate may form. If used with a primary I.V. fluid system, the primary solution should be
discontinued during ZOFRAN Injection Premixed infusion.
Do not administer unless solution is clear and container is undamaged.
Warning: Do not use flexible plastic container in series connections.
Stability: ZOFRAN Injection is stable at room temperature under normal lighting conditions for
48 hours after dilution with the following I.V. fluids: 0.9% Sodium Chloride Injection, 5% Dextrose
Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium
Chloride Injection, and 3% Sodium Chloride Injection.
Although ZOFRAN Injection is chemically and physically stable when diluted as
recommended, sterile precautions should be observed because diluents generally do not contain
preservative. After dilution, do not use beyond 24 hours.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration
before administration whenever solution and container permit.
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored
upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial
vigorously.
HOW SUPPLIED
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
NDC 0173-0442-02 2-mL single-dose vials (Carton of 5)
NDC 0173-0442-00 20-mL multidose vials (Singles)
Store between 2° and 30°C (36° and 86°F). Protect from light.
ZOFRAN Injection Premixed, 32 mg/50 mL, in 5% Dextrose, contains no
preservatives and is supplied as a sterile, premixed solution for I.V. administration in single-dose,
flexible plastic containers (NDC 0173-0461-00) (case of 6).
Store between 2° and 30°C (36° and 86°F). Protect from light. Avoid excessive heat.
Protect from freezing.
REFERENCES
1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND)
metabolism in humans. Clin Pharmacol Ther. 1997;61:228.
2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the
oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-007/S-037
NDA 20-403/S-014
Page 24
3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and
intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381.
4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321.
5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557.
GlaxoSmithKline
Research Triangle Park, NC 27709
ZOFRAN® Injection Premixed:
Manufactured for GlaxoSmithKline
Research Triangle Park, NC 27709
by Hospira, Inc., Lake Forest, IL 60045
©2005, GlaxoSmithKline. All rights reserved.
June 2005
RL-2197
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Brian Harvey
12/27/2005 01:55:30 PM
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:25.793456
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020007s037,020403s014lbl.pdf', 'application_number': 20007, 'submission_type': 'SUPPL ', 'submission_number': 37}
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PRESCRIBING INFORMATION
ZOFRAN®
(ondansetron hydrochloride)
Injection
DESCRIPTION
The active ingredient in ZOFRAN Injection is ondansetron hydrochloride (HCl), the racemic
form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type.
Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H
structural formula
The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9.
Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.
Sterile Injection for Intravenous (I.V.) or Intramuscular (I.M.) Administration: Each
1 mL of aqueous solution in the 2-mL single-dose vial contains 2 mg of ondansetron as the
hydrochloride dihydrate; 9.0 mg of sodium chloride, USP; and 0.5 mg of citric acid
monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for
Injection, USP.
Each 1 mL of aqueous solution in the 20-mL multidose vial contains 2 mg of ondansetron as
the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate,
USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF
and 0.15 mg of propylparaben, NF as preservatives in Water for Injection, USP.
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution. The pH of the injection
solution is 3.3 to 4.0.
CLINICAL PHARMACOLOGY
Pharmacodynamics: Ondansetron is a selective 5-HT3 receptor antagonist. While
ondansetron’s mechanism of action has not been fully characterized, it is not a
dopamine-receptor antagonist. Serotonin receptors of the 5-HT3 type are present both
peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area
postrema. It is not certain whether ondansetron's antiemetic action in chemotherapy-induced
nausea and vomiting is mediated centrally, peripherally, or in both sites. However, cytotoxic
chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells
of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion
increases after cisplatin administration in parallel with the onset of vomiting. The released
1
serotonin may stimulate the vagal afferents through the 5-HT3 receptors and initiate the vomiting
reflex.
In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor
of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or
pretreatment with a serotonin 5-HT3 receptor antagonist.
In normal volunteers, single I.V. doses of 0.15 mg/kg of ondansetron had no effect on
esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal
transit time. In another study in six normal male volunteers, a 16-mg dose infused over 5 minutes
showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or
electrocardiogram (ECG). Multiday administration of ondansetron has been shown to slow
colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin
concentrations.
In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered
intravenously or intramuscularly was dynamically similar in the prevention of nausea and
vomiting using the ipecacuanha model of emesis.
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the
degree of neuromuscular blockade produced by atracurium. Interactions with general or local
anesthetics have not been studied.
Pharmacokinetics: Ondansetron is extensively metabolized in humans, with approximately
5% of a radiolabeled dose recovered as the parent compound from the urine. The primary
metabolic pathway is hydroxylation on the indole ring followed by glucuronide or sulfate
conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not found
in plasma at concentrations likely to significantly contribute to the biological activity of
ondansetron.
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic
cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall
ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of
metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one
enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little
change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by
cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained
chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, Cmax, and T½
of ondansetron was observed.1 This resulted in a significant increase in clearance. However, on
the basis of available data, no dosage adjustment for ondansetron is recommended (see
PRECAUTIONS: Drug Interactions).
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of
ondansetron.
In normal adult volunteers, the following mean pharmacokinetic data have been determined
following a single 0.15-mg/kg I.V. dose.
2
Table 1. Pharmacokinetics in Normal Adult Volunteers
Age-group
(years)
n
Peak Plasma
Concentration
(ng/mL)
Mean Elimination
Half-life (h)
Plasma Clearance
(L/h/kg)
19-40
11
102
3.5
0.381
61-74
12
106
4.7
0.319
≥ 75
11
170
5.5
0.262
A reduction in clearance and increase in elimination half-life are seen in patients over 75 years
of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65
years of age and those under 65 years of age; there was an insufficient number of patients over
75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended
in the elderly.
In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean
half-life is increased to 11.6 hours compared to 5.7 hours in normals. In patients with severe
hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced 2-fold to 3-fold and
apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In
patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.
Due to the very small contribution (5%) of renal clearance to the overall clearance, renal
impairment was not expected to significantly influence the total clearance of ondansetron.
However, ondansetron mean plasma clearance was reduced by about 41% in patients with severe
renal impairment (creatinine clearance < 30 mL/min). This reduction in clearance is variable and
was not consistent with an increase in half-life. No reduction in dose or dosing frequency in
these patients is warranted.
In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no
difference in the multidose pharmacokinetics over a 4-day period. In a study of 21 pediatric
cancer patients (4 to 18 years of age) who received three I.V. doses of 0.15 mg/kg of ondansetron
at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic
parameters similar to those of adults. Patients 4 to 12 years of age generally showed higher
clearance and somewhat larger volume of distribution than adults. Most pediatric patients
younger than 15 years of age with cancer had a shorter (2.4 hours) ondansetron plasma half-life
than patients older than 15 years of age. It is not known whether these differences in ondansetron
plasma half-life may result in differences in efficacy between adults and some young pediatric
patients (see CLINICAL TRIALS: Pediatric Studies).
Pharmacokinetic samples were collected from 74 cancer patients 6 to 48 months of age, who
received a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses during a safety and
efficacy trial. These data were combined with sequential pharmacokinetics data from 41 surgery
patients 1 month to 24 months of age, who received a single dose of 0.1 mg/kg of I.V.
ondansetron prior to surgery with general anesthesia, and a population pharmacokinetic analysis
3
was performed on the combined data set. The results of this analysis are included in Table 2 and
are compared to the pharmacokinetic results in cancer patients 4 to 18 years of age.
Table 2. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Cancer Patients
4 to 18 years of age
N = 21
0.599
1.9
2.8
Population PK Patientsa
1 month to 48 months of age
N = 115
0.582
3.65
4.9
a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age who
receive a dose of 0.15 mg/kg of I.V. ondansetron every 4 hours for 3 doses would be expected to
achieve a systemic exposure (AUC) consistent with the exposure achieved in previous pediatric
studies in cancer patients (4 to 18 years of age) at similar doses.
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery
requiring anesthesia for a duration of 45 minutes to 2 hours, a single I.V. dose of ondansetron,
2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia
induction. Mean weight-normalized clearance and volume of distribution values in these
pediatric surgical patients were similar to those previously reported for young adults. Mean
terminal half-life was slightly reduced in pediatric patients (range, 2.5 to 3 hours) in comparison
with adults (range, 3 to 3.5 hours).
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing
surgery requiring general anesthesia, a single I.V. dose of ondansetron, 0.1 or 0.2 mg/kg, was
administered prior to surgery. As shown in Table 3, the 41 patients with pharmacokinetic data
were divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months of
age, and are compared to pediatric patients 3 to 12 years of age.
Table 3. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Surgery Patients
3 to 12 years of age
N = 21
0.439
1.65
2.9
Pediatric Surgery Patients
5 to 24 months of age
N = 22
0.581
2.3
2.9
Pediatric Surgery Patients
N = 19
0.401
3.5
6.7
4
table
In general, surgical and cancer pediatric patients younger than 18 years tend to have a higher
ondansetron clearance compared to adults leading to a shorter half-life in most pediatric patients.
In patients 1 month to 4 months of age, a longer half-life was observed due to the higher volume
of distribution in this age group.
In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was
264 ng/mL following a single 32-mg dose administered as a 15-minute I.V. infusion. The mean
elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not
proportional to dose as measured by comparing dose-normalized AUC values to an 8-mg dose.
This is consistent with a small decrease in systemic clearance with increasing plasma
concentrations.
A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a
single 4-mg dose administered as a 5-minute infusion compared to a single intramuscular
injection. Systemic exposure as measured by mean AUC was equivalent, with values of 156
[95% CI 136, 180] and 161 [95% CI 137, 190] ng•h/mL for I.V. and I.M. groups, respectively.
Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after I.V.
infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at 41 minutes after I.M. injection. The mean
elimination half-life was not affected by route of administration.
Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, with binding
constant over the pharmacologic concentration range (10 to 500 ng/mL). Circulating drug also
distributes into erythrocytes.
A positive lymphoblast transformation test to ondansetron has been reported, which suggests
immunologic sensitivity to ondansetron.
CLINICAL TRIALS
Chemotherapy-Induced Nausea and Vomiting: Adult Studies: In a double-blind study
of three different dosing regimens of ZOFRAN Injection, 0.015 mg/kg, 0.15 mg/kg, and
0.30 mg/kg, each given three times during the course of cancer chemotherapy, the 0.15-mg/kg
dosing regimen was more effective than the 0.015-mg/kg dosing regimen. The 0.30-mg/kg
dosing regimen was not shown to be more effective than the 0.15-mg/kg dosing regimen.
Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, ZOFRAN
Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing
nausea and vomiting induced by cisplatin-based chemotherapy. Treatment response was as
shown in Table 4.
5
c
Table 4. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day
Cisplatin Therapya in Adults
ZOFRAN
Injection
Placebo
P Valueb
Number of patients
14
14
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
2 (14%)
8 (57%)
2 (14%)
2 (14%)
0 (0%)
0 (0%)
1 (7%)
13 (93%)
0.001
Median number of emetic episodes
1.5
Undefinedc
Median time to first emetic episode (h)
11.6
2.8
0.001
Median nausea scores (0-100)d
3
59
0.034
Global satisfaction with control of
nausea and vomiting (0-100)
e
96
10.5
0.009
a Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5)
or moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other
chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There
was no difference between treatments in the types of chemotherapy that would account for
differences in response.
b Efficacy based on "all patients treated" analysis.
Median undefined since at least 50% of the patients were rescued or had more than five
emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Ondansetron was compared with metoclopramide in a single-blind trial in 307 patients
receiving cisplatin ≥ 100 mg/m2 with or without other chemotherapeutic agents. Patients received
the first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional
ondansetron doses were administered 4 and 8 hours later, or five additional metoclopramide
doses were administered 2, 4, 7, 10, and 13 hours later. Cisplatin was administered over a period
of 3 hours or less. Episodes of vomiting and retching were tabulated over the period of 24 hours
after cisplatin. The results of this study are summarized in Table 5.
6
Table 5. Prevention of Vomiting Induced by Cisplatin (≥ 100 mg/m2) Single-Day Therapya
in Adults
ZOFRAN Injection
Metoclopramide
P Value
Dose
0.15 mg/kg x 3
2 mg/kg x 6
Number of patients in efficacy population
136
138
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
54 (40%)
34 (25%)
19 (14%)
29 (21%)
41 (30%)
30 (22%)
18 (13%)
49 (36%)
Comparison of treatments with respect to
0 Emetic episodes
More than 5 emetic episodes/rescued
54/136
29/136
41/138
49/138
0.083
0.009
Median number of emetic episodes
1
2
0.005
Median time to first emetic episode (h)
20.5
4.3
< 0.001
Global satisfaction with control of nausea
and vomiting (0-100)b
85
63
0.001
Acute dystonic reactions
0
8
0.005
Akathisia
0
10
0.002
a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including
cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments
in the types of chemotherapy that would account for differences in response.
b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
In a stratified, randomized, double-blind, parallel-group, multicenter study, a single 32-mg
dose of ondansetron was compared with three 0.15-mg/kg doses in patients receiving cisplatin
doses of either 50 to 70 mg/m2 or ≥ 100 mg/m2. Patients received the first ondansetron dose
30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours
later to the group receiving three 0.15-mg/kg doses. In both strata, significantly fewer patients on
the single 32-mg dose than those receiving the three-dose regimen failed.
7
Table 6. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Dose
Therapy in Adults
0.15 mg/kg x 3
Ondansetron
Dose
32 mg x 1
P Value
High-dose cisplatin (≥ 100 mg/m2)
Number of patients
100
102
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
41 (41%)
19 (19%)
4 (4%)
36 (36%)
49 (48%)
25 (25%)
8 (8%)
20 (20%)
0.315
0.009
Median time to first emetic episode (h)
21.7
23
0.173
Median nausea scores (0-100)a
28
13
0.004
Medium-dose cisplatin (50-70 mg/m2)
Number of patients
101
93
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
62 (61%)
11 (11%)
6 (6%)
22 (22%)
68 (73%)
14 (15%)
3 (3%)
8 (9%)
0.083
0.011
Median time to first emetic episode (h)
Undefinedb
Undefined
Median nausea scores (0-100)a
9
3
0.131
a Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
b Median undefined since at least 50% of patients did not have any emetic episodes.
Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled
study of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide
(500 to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than
placebo in preventing nausea and vomiting. The results are summarized in Table 7.
8
c
Table 7. Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day
Cyclophosphamide Therapya in Adults
ZOFRAN
Injection
Placebo
P Valueb
Number of patients
10
10
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
7 (70%)
0 (0%)
2 (20%)
1 (10%)
0 (0%)
2 (20%)
4 (40%)
4 (40%)
0.001
0.131
Median number of emetic episodes
0
4
0.008
Median time to first emetic episode (h)
Undefinedc
8.79
Median nausea scores (0-100)d
0
60
0.001
Global satisfaction with control of
nausea and vomiting (0-100)e
100
52
0.008
a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including
fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between
treatments in the type of chemotherapy that would account for differences in response.
b Efficacy based on "all patients treated" analysis.
Median undefined since at least 50% of patients did not have any emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose,
100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with
ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median,
2; range, 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes
occurred in 217 (81%) re-treatment courses.
Pediatric Studies: Four open-label, noncomparative (one US, three foreign) trials have
been performed with 209 pediatric cancer patients 4 to 18 years of age given a variety of cisplatin
or noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged
from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral
administration of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial,
ZOFRAN was administered intravenously (only) in three doses of 0.15 mg/kg each for a total
daily dose of 7.2 to 39 mg. In these studies, 58% of the 196 evaluable patients had a complete
response (no emetic episodes) on day 1. Thus, prevention of vomiting in these pediatric patients
was essentially the same as for patients older than 18 years of age.
9
An open-label, multicenter, noncomparative trial has been performed in 75 pediatric cancer
patients 6 to 48 months of age receiving at least one moderately or highly emetogenic
chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were
American Hispanic, and 15% were black patients. ZOFRAN was administered intravenously
over 15 minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before
the start of chemotherapy, the second and third doses were administered 4 and 8 hours after the
first dose, respectively. Eighteen patients (25%) received routine prophylactic dexamethasone
(i.e., not given as rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic
episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was comparable to
the prevention of vomiting in patients 4 years of age and older.
Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and
Vomiting: Adult Studies: Adult surgical patients who received ondansetron immediately
before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or
thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade:
succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) were
evaluated in two double-blind US studies involving 554 patients. ZOFRAN Injection (4 mg) I.V.
given over 2 to 5 minutes was significantly more effective than placebo. The results of these
studies are summarized in Table 8.
10
Table 8. Prevention of Postoperative Nausea and Vomiting in Adult Patients
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
136
139
Treatment response over 24-h
postoperative period
0 Emetic episodes
103 (76%)
64 (46%)
< 0.001
1 Emetic episode
13 (10%)
17 (12%)
More than 1 emetic episode/rescued
20 (15%)
58 (42%)
Nausea assessments:
Number of patients
134
136
No nausea over 24-h postoperative
56 (42%)
39 (29%)
period
Study 2
Emetic episodes:
Number of patients
136
143
Treatment response over 24-h
postoperative period
0 Emetic episodes
85 (63%)
63 (44%)
0.002
1 Emetic episode
16 (12%)
29 (20%)
More than 1 emetic episode/rescued
35 (26%)
51 (36%)
Nausea assessments:
Number of patients
125
133
No nausea over 24-h postoperative
48 (38%)
42 (32%)
period
The study populations in Table 8 consisted mainly of females undergoing laparoscopic
procedures.
In a placebo-controlled study conducted in 468 males undergoing outpatient procedures, a
single 4-mg I.V. ondansetron dose prevented postoperative vomiting over a 24-hour study period
in 79% of males receiving drug compared to 63% of males receiving placebo (P < 0.001).
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major
abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg I.V. ondansetron dose
for prevention of postoperative nausea and vomiting over a 24-hour study period. At the 4-mg
dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the first study
(P < 0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the
11
second study (P = 0.001) experienced no emetic episodes. No additional benefit was observed in
patients who received I.V. ondansetron 8 mg compared to patients who received I.V. ondansetron
4 mg.
Pediatric Studies: Three double-blind, placebo-controlled studies have been performed
(one US, two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing
general anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or
without adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were
randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing
40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was
administered over at least 30 seconds, immediately prior to or following anesthesia induction.
Ondansetron was significantly more effective than placebo in preventing nausea and vomiting.
The results of these studies are summarized in Table 9.
Table 9. Prevention of Postoperative Nausea and Vomiting in Pediatric Patients 2 to
12 Years of Age
Treatment Response Over
24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Study 1
Number of patients
205
210
0 Emetic episodes
140 (68%)
82 (39%)
≤ 0.001
Failurea
65 (32%)
128 (61%)
Study 2
Number of patients
112
110
0 Emetic episodes
68 (61%)
38 (35%)
≤ 0.001
Failurea
44 (39%)
72 (65%)
Study 3
Number of patients
206
206
0 Emetic episodes
123 (60%)
96 (47%)
≤ 0.01
Failurea
Nausea assessmentsb:
83 (40%)
110 (53%)
Number of patients
185
191
None
119 (64%)
99 (52%)
≤ 0.01
a Failure was one or more emetic episodes, rescued, or withdrawn.
b Nausea measured as none, mild, or severe.
A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric patients
1 month to 24 months of age who were undergoing routine surgery under general anesthesia.
12
Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were American
Hispanic, 2% were Asian, and 6% were “other race” patients. A single 0.1-mg/kg I.V. dose of
ondansetron administered within 5 minutes following induction of anesthesia was statistically
significantly more effective than placebo in preventing vomiting. In the placebo group, 28% of
patients experienced vomiting compared to 11% of subjects who received ondansetron
(P ≤ 0.01). Overall, 32 (10%) of placebo patients and 18 (5%) of patients who received
ondansetron received antiemetic rescue medication(s) or prematurely withdrew from the study.
Prevention of Further Postoperative Nausea and Vomiting: Adult Studies: Adult
surgical patients receiving general balanced anesthesia (barbiturate: thiopental, methohexital, or
thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade:
succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) who
received no prophylactic antiemetics and who experienced nausea and/or vomiting within 2 hours
postoperatively were evaluated in two double-blind US studies involving 441 patients. Patients
who experienced an episode of postoperative nausea and/or vomiting were given ZOFRAN
Injection (4 mg) I.V. over 2 to 5 minutes, and this was significantly more effective than placebo.
The results of these studies are summarized in Table 10.
13
Table 10. Prevention of Further Postoperative Nausea and Vomiting in Adult Patients
Ondansetron
4 mg I.V.
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
104
117
0 Emetic episodes
49 (47%)
19 (16%)
< 0.001
1 Emetic episode
12 (12%)
9 (8%)
More than 1 emetic episode/rescued
43 (41%)
89 (76%)
Median time to first emetic episode (min)a
55.0
43.0
Nausea assessments:
Number of patients
98
102
Mean nausea score over 24-h postoperative
periodb
1.7
3.1
Study 2
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
112
108
0 Emetic episodes
49 (44%)
28 (26%)
0.006
1 Emetic episode
14 (13%)
3 (3%)
More than 1 emetic episode/rescued
49 (44%)
77 (71%)
Median time to first emetic episode (min)a
60.5
34.0
Nausea assessments:
Number of patients
105
85
Mean nausea score over 24-h postoperative
periodb
1.9
2.9
a After administration of study drug.
b Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
The study populations in Table 10 consisted mainly of women undergoing laparoscopic
procedures.
Repeat Dosing in Adults: In patients who do not achieve adequate control of postoperative
nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron
4 mg, administration of a second I.V. dose of ondansetron 4 mg postoperatively does not provide
additional control of nausea and vomiting.
14
Pediatric Study: One double-blind, placebo-controlled, US study was performed in 351
male and female outpatients (2 to 12 years of age) who received general anesthesia with nitrous
oxide and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who
experienced two or more emetic episodes within 2 hours following discontinuation of nitrous
oxide were randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric
patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo
administered over at least 30 seconds. Ondansetron was significantly more effective than placebo
in preventing further episodes of nausea and vomiting. The results of the study are summarized
in Table 11.
Table 11. Prevention of Further Postoperative Nausea and Vomiting in Pediatric Patients 2
to 12 Years of Age
Treatment Response
Ondansetron
Placebo
Over 24 Hours
n (%)
n (%)
P Value
Number of patients
180
171
0 Emetic episodes
96 (53%)
29 (17%)
≤ 0.001
Failurea
84 (47%)
142 (83%)
a Failure was one or more emetic episodes, rescued, or withdrawn.
INDICATIONS AND USAGE
1. Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic
cancer chemotherapy, including high-dose cisplatin. Efficacy of the 32-mg single dose
beyond 24 hours in these patients has not been established.
2. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine
prophylaxis is not recommended for patients in whom there is little expectation that nausea
and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must
be avoided postoperatively, ZOFRAN Injection is recommended even where the incidence of
postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic
ZOFRAN Injection and experience nausea and/or vomiting postoperatively, ZOFRAN
Injection may be given to prevent further episodes (see CLINICAL TRIALS).
CONTRAINDICATIONS
The concomitant use of apomorphine with ondansetron is contraindicated based on reports of
profound hypotension and loss of consciousness when apomorphine was administered with
ondansetron.
ZOFRAN Injection is contraindicated for patients known to have hypersensitivity to the drug.
WARNINGS
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity
to other selective 5-HT3 receptor antagonists.
15
PRECAUTIONS
General: Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not
be used instead of nasogastric suction. The use of ondansetron in patients following abdominal
surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive
ileus and/or gastric distention.
Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT
interval prolongation have been reported.
Drug Interactions: Ondansetron does not itself appear to induce or inhibit the cytochrome
P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY:
Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450
drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these
enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of
limited available data, no dosage adjustment is recommended for patients on these drugs.
Apomorphine: Based on reports of profound hypotension and loss of consciousness when
apomorphine was administered with ondansetron, concomitant use of apomorphine with
ondansetron is contraindicated (see CONTRAINDICATIONS).
Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of
CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was
significantly increased and ondansetron blood concentrations were decreased. However, on the
basis of available data, no dosage adjustment for ondansetron is recommended for patients on
these drugs.1,3
Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol
has been observed, data from 2 small studies indicate that ondansetron may be associated with an
increase in patient controlled administration of tramadol.4,5
Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is
not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the
pharmacokinetics of ondansetron.
In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of
high-dose methotrexate.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenic effects were not
seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per
day, respectively. Ondansetron was not mutagenic in standard tests for mutagenicity. Oral
administration of ondansetron up to 15 mg/kg per day did not affect fertility or general
reproductive performance of male and female rats.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no
evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
16
Nursing Mothers: Ondansetron is excreted in the breast milk of rats. It is not known whether
ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution
should be exercised when ondansetron is administered to a nursing woman.
Pediatric Use: Little information is available about the use of ondansetron in pediatric surgical
patients younger than 1 month of age. (See CLINICAL TRIALS section for studies of
ondansetron in prevention of postoperative nausea and vomiting in patients 1 month of age and
older.) Little information is available about the use of ondansetron in pediatric cancer patients
younger than 6 months of age. (See CLINICAL TRIALS section for studies of ondansetron in
chemotherapy-induced nausea and vomiting in pediatric patients 6 months of age and older.) (See
DOSAGE AND ADMINISTRATION.)
The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower and
the half-life is ~2.5 fold longer than patients who are > 4 to 24 months of age. As a precaution, it
is recommended that patients less than 4 months of age receiving this drug be closely monitored.
(See CLINICAL PHARMACOLOGY: Pharmacokinetics).
The frequency and type of adverse events reported in pediatric patients receiving ondansetron
were similar to those in patients receiving placebo. (See ADVERSE EVENTS.)
Geriatric Use: Of the total number of subjects enrolled in cancer chemotherapy-induced and
postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65
years of age and over. No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but greater sensitivity of some
older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of
65 (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
Chemotherapy-Induced Nausea and Vomiting: The adverse events in Table 12 have been
reported in adults receiving ondansetron at a dosage of three 0.15-mg/kg doses or as a single
32-mg dose in clinical trials. These patients were receiving concomitant chemotherapy, primarily
cisplatin, and I.V. fluids. Most were receiving a diuretic.
17
Table 12. Principal Adverse Events in Comparative Trials in Adults
Number of Adult Patients With Event
ZOFRAN
Injection
0.15 mg/kg x 3
n = 419
ZOFRAN
Injection
32 mg x 1
n = 220
Metoclopramide
n = 156
Placebo
n = 34
Diarrhea
16%
8%
44%
18%
Headache
17%
25%
7%
15%
Fever
8%
7%
5%
3%
Akathisia
0%
0%
6%
0%
Acute dystonic reactionsa
0%
0%
5%
0%
a See Neurological.
The following have been reported during controlled clinical trials:
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations,
hypotension, and tachycardia have been reported. In many cases, the relationship to ZOFRAN
Injection was unclear.
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients
receiving multiday ondansetron.
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline values
of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been
reported to exceed twice the upper limit of normal in approximately 5% of patients. The
increases were transient and did not appear to be related to dose or duration of therapy. On repeat
exposure, similar transient elevations in transaminase values occurred in some courses, but
symptomatic hepatic disease did not occur.
Integumentary: Rash has occurred in approximately 1% of patients receiving ondansetron.
Neurological: There have been rare reports consistent with, but not diagnostic of,
extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal
seizure. The relationship to ZOFRAN was unclear.
Other: Rare cases of hypokalemia have been reported. The relationship to ZOFRAN Injection
was unclear.
Postoperative Nausea and Vomiting: The adverse events in Table 13 have been reported in
≥ 2% of adults receiving ondansetron at a dosage of 4 mg I.V. over 2 to 5 minutes in clinical
trials. Rates of these events were not significantly different in the ondansetron and placebo
groups. These patients were receiving multiple concomitant perioperative and postoperative
medications.
18
Table 13. Adverse Events in ≥ 2% of Adults Receiving Ondansetron at a Dosage of 4 mg
I.V. over 2 to 5 Minutes in Clinical Trials
ZOFRAN Injection
4 mg I.V.
n = 547 patients
Placebo
n = 547 patients
Headache
92 (17%)
77 (14%)
Dizziness
67 (12%)
88 (16%)
Musculoskeletal pain
57 (10%)
59 (11%)
Drowsiness/sedation
44 (8%)
37 (7%)
Shivers
38 (7%)
39 (7%)
Malaise/fatigue
25 (5%)
30 (5%)
Injection site reaction
21 (4%)
18 (3%)
Urinary retention
17 (3%)
15 (3%)
Postoperative CO2-related paina
12 (2%)
16 (3%)
Chest pain (unspecified)
12 (2%)
15 (3%)
Anxiety/agitation
11 (2%)
16 (3%)
Dysuria
11 (2%)
9 (2%)
Hypotension
10 (2%)
12 (2%)
Fever
10 (2%)
6 (1%)
Cold sensation
9 (2%)
8 (1%)
Pruritus
9 (2%)
3 (< 1%)
Paresthesia
9 (2%)
2 (< 1%)
a Sites of pain included abdomen, stomach, joints, rib cage, shoulder.
Pediatric Use: The adverse events in Table 14 were the most commonly reported adverse
events in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric patients
weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered
intravenously over at least 30 seconds. Rates of these events were not significantly different in
the ondansetron and placebo groups. These patients were receiving multiple concomitant
perioperative and postoperative medications.
19
Table 14. Frequency of Adverse Events From Controlled Studies in Pediatric Patients 2 to
12 Years of Age
Adverse Event
Ondansetron
n = 755 Patients
Placebo
n = 731 Patients
Wound problem
80 (11%)
86 (12%)
Anxiety/agitation
49 (6%)
47 (6%)
Headache
44 (6%)
43 (6%)
Drowsiness/sedation
41 (5%)
56 (8%)
Pyrexia
32 (4%)
41 (6%)
The adverse events in Table 15 were the most commonly reported adverse events in pediatric
patients, 1 month to 24 months of age, receiving a single 0.1-mg/kg I.V. dose of ondansetron.
The incidence and type of adverse events were similar in both the ondansetron and placebo
groups. These patients were receiving multiple concomitant perioperative and postoperative
medications.
Table 15. Frequency of Adverse Events (Greater Than or Equal to 2% in Either Treatment
Group) in Pediatric Patients 1 Month to 24 Months of Age
Adverse Event
Ondansetron
n = 336 Patients
Placebo
n = 334 Patients
Pyrexia
14 (4%)
14 (4%)
Bronchospasm
2 (< 1%)
6 (2%)
Post-procedural pain
4 (1%)
6 (2%)
Diarrhea
6 (2%)
3 (< 1%)
Observed During Clinical Practice: In addition to adverse events reported from clinical
trials, the following events have been identified during post-approval use of intravenous
formulations of ZOFRAN. Because they are reported voluntarily from a population of unknown
size, estimates of frequency cannot be made. The events have been chosen for inclusion due to a
combination of their seriousness, frequency of reporting, or potential causal connection to
ZOFRAN.
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia,
premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic
alterations (including second-degree heart block, QT interval prolongation, and ST segment
depression), palpitations, and syncope.
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g.,
anaphylaxis/anaphylactoid reactions, angioedema, bronchospasm, cardiopulmonary arrest,
hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been
reported.
20
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death have
been reported in patients with cancer receiving concurrent medications including potentially
hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.
Local Reactions: Pain, redness, and burning at site of injection.
Lower Respiratory: Hiccups
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic reactions.
Skin: Urticaria
Special Senses: Transient dizziness during or shortly after I.V. infusion.
Eye Disorders: Transient blurred vision, in some cases associated with abnormalities of
accommodation. Cases of transient blindness, predominantly during intravenous administration,
have been reported. These cases of transient blindness were reported to resolve within a few
minutes up to 48 hours.
DRUG ABUSE AND DEPENDENCE
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor
does it substitute for benzodiazepines in direct addiction studies.
OVERDOSAGE
There is no specific antidote for ondansetron overdose. Patients should be managed with
appropriate supportive therapy. Individual doses as large as 150 mg and total daily dosages
(three doses) as large as 252 mg have been administered intravenously without significant
adverse events. These doses are more than 10 times the recommended daily dose.
In addition to the adverse events listed above, the following events have been described in the
setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration
plus severe constipation occurred in one patient that was administered 72 mg of ondansetron
intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took
48 mg of oral ondansetron. Following infusion of 32 mg over only a 4-minute period, a
vasovagal episode with transient second-degree heart block was observed. In all instances, the
events resolved completely.
DOSAGE AND ADMINISTRATION
Prevention of Chemotherapy-Induced Nausea and Vomiting: Adult Dosing: The
recommended I.V. dosage of ZOFRAN for adults is a single 32-mg dose or three 0.15-mg/kg
doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the start of
emetogenic chemotherapy. The recommended infusion rate should not be exceeded (see
OVERDOSAGE). With the three-dose (0.15-mg/kg) regimen, the first dose is infused over
15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent
doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN.
ZOFRAN Injection should not be mixed with solutions for which physical and chemical
compatibility have not been established. In particular, this applies to alkaline solutions as a
precipitate may form.
21
Vial: DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY
INDUCED NAUSEA AND VOMITING. ZOFRAN Injection should be diluted in 50 mL of
5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Pediatric Dosing: On the basis of the available information (see CLINICAL TRIALS:
Pediatric Studies and CLINICAL PHARMACOLOGY: Pharmacokinetics), the dosage in
pediatric cancer patients 6 months to 18 years of age should be three 0.15-mg/kg doses. The first
dose is to be administered 30 minutes before the start of moderately to highly emetogenic
chemotherapy, subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose
of ZOFRAN. The drug should be infused intravenously over 15 minutes. Little information is
available about dosage in pediatric cancer patients younger than 6 months of age.
Vial: DILUTE BEFORE USE FOR PREVENTION OF CHEMOTHERAPY
INDUCED NAUSEA AND VOMITING. ZOFRAN Injection should be diluted in 50 mL of
5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Prevention of Postoperative Nausea and Vomiting: Adult Dosing: The recommended
I.V. dosage of ZOFRAN for adults is 4 mg undiluted administered intravenously in not less than
30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or
postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery.
Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for
adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients
above 80 kg have been studied. In patients who do not achieve adequate control of postoperative
nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of ondansetron
4 mg, administration of a second I.V. dose of 4 mg ondansetron postoperatively does not provide
additional control of nausea and vomiting.
Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR
POSTOPERATIVE NAUSEA AND VOMITING.
Pediatric Dosing: The recommended I.V. dosage of ZOFRAN for pediatric surgical
patients (1 month to 12 years of age) is a single 0.1-mg/kg dose for patients weighing 40 kg or
less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration
should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or
following anesthesia induction, or postoperatively if the patient experiences nausea and/or
vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only
studied in patients who had not received prophylactic ZOFRAN.
Vial: REQUIRES NO DILUTION FOR ADMINISTRATION FOR
POSTOPERATIVE NAUSEA AND VOMITING.
Geriatric Dosing: The dosage recommendation is the same as for the general population.
Dosage Adjustment for Patients With Impaired Renal Function: The dosage
recommendation is the same as for the general population. There is no experience beyond
first-day administration of ondansetron.
22
company logo
Dosage Adjustment for Patients With Impaired Hepatic Function: In patients with
severe hepatic impairment (Child-Pugh2 score of 10 or greater), a single maximal daily dose of
8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic
chemotherapy is recommended. There is no experience beyond first-day administration of
ondansetron.
Stability: ZOFRAN Injection is stable at room temperature under normal lighting conditions for
48 hours after dilution with the following I.V. fluids: 0.9% Sodium Chloride Injection, 5%
Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45%
Sodium Chloride Injection, and 3% Sodium Chloride Injection.
Although ZOFRAN Injection is chemically and physically stable when diluted as
recommended, sterile precautions should be observed because diluents generally do not contain
preservative. After dilution, do not use beyond 24 hours.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored
upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking
the vial vigorously.
HOW SUPPLIED
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
NDC 0173-0442-02 2-mL single-dose vials (Carton of 5)
NDC 0173-0442-00 20-mL multidose vials (Singles)
Store between 2° and 30°C (36° and 86°F). Protect from light.
REFERENCES
1. Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on ondansetron (OND)
metabolism in humans. Clin Pharmacol Ther. 1997;61:228.
2. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the
oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649.
3. Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral
and intravenous ondansetron. Clin Pharmacol Ther. 1999;65:377-381.
4. De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321.
5. Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557.
GlaxoSmithKline
Research Triangle Park, NC 27709
23
©2010, GlaxoSmithKline. All rights reserved.
May 2010
ZFJ:2PI
24
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020007s040,020403s018lbl.pdf', 'application_number': 20007, 'submission_type': 'SUPPL ', 'submission_number': 40}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZOFRAN safely and effectively. See full prescribing information for
ZOFRAN.
ZOFRAN® (ondansetron hydrochloride) injection for intravenous use
Initial U.S. Approval: 1991
---------------------------RECENT MAJOR CHANGES -------------------
Warnings and Precautions, Electrocardiographic Changes
09/2011
(5.2)
----------------------------INDICATIONS AND USAGE--------------------
ZOFRAN Injection is a 5-HT3 receptor antagonist indicated:
• Prevention of nausea and vomiting associated with initial and repeat
courses of emetogenic cancer chemotherapy. (1.1)
• Prevention of postoperative nausea and/or vomiting. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
Prevention of nausea and vomiting associated with initial and repeat courses
of emetogenic cancer chemotherapy (2.1):
Population
Age
ZOFRAN
Injection Dosage
Intravenous
Infusion Rate
(30 min before
the start of
chemotherapy)
Adults
> 18 yrs
32 mg x 1 or
0.15 mg/kg x 3
over 15 min
Pediatrics
6 mos. – 18 yrs
0.15 mg/kg x 3
over 15 min
Prevention of Postoperative Nausea and/or Vomiting (2.2):
Population
Age
ZOFRAN
Injection Dosage
Intravenous
Infusion Rate
Adults
> 12 yrs
4 mg x 1
over 2 - 5 min
Pediatrics
(> 40 kg)
1 mo. – 12 yrs
4 mg x 1
over 2 - 5 min
Pediatrics
(≤ 40 kg)
1 mo. – 12 yrs
0.1 mg/kg x 1
over 2 - 5 min
• In patients with severe hepatic impairment, a total daily dose of 8 mg
should not be exceeded. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS -------------
ZOFRAN Injection (2 mg/mL): 2 mL single dose vial and 20 mL multidose
vials. (3)
-------------------------------CONTRAINDICATIONS-----------------------
• Patients known to have hypersensitivity (e.g., anaphylaxis) to this product
or any of its components. (4)
• Concomitant use of apomorphine. (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
• Hypersensitivity reactions including anaphylaxis and bronchospasm, have
been reported in patients who have exhibited hypersensitivity to other
selective 5-HT3 receptor antagonists. (5.1)
• Transient ECG changes including QT interval prolongation and Torsade
de Pointes have been reported. Avoid ZOFRAN in patients with
congenital long QT syndrome. (5.2)
• Use in patients following abdominal surgery or in patients with
chemotherapy-induced nausea and vomiting may mask a progressive ileus
and/or gastric distention. (5.3)(5.4)
------------------------------ ADVERSE REACTIONS ----------------------
Chemotherapy-Induced Nausea and Vomiting –
• The most common adverse reactions (≥ 7%) in adults are diarrhea,
headache, and fever. (6.1)
Postoperative Nausea and Vomiting –
• The most common adverse reaction (≥ 10%) which occurs at a higher
frequency compared to placebo in adults is headache. (6.1)
• The most common adverse reaction (≥ 2%) which occurs at a higher
frequency compared to placebo in pediatric patients 1 to 24 months of age
is diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS-----------------------
• Apomorphine – profound hypotension and loss of consciousness.
Concomitant use with ondansetron is contraindicated. (7.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: September 2011
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Prevention of Nausea and Vomiting Associated with
Initial and Repeat Courses of Emetogenic Cancer
Chemotherapy
1.2
Prevention of Postoperative Nausea and/or Vomiting
2 DOSAGE AND ADMINISTRATION
2.1
Prevention of Nausea and Vomiting Associated with
Initial and Repeat Courses of Emetogenic Chemotherapy
2.2
Prevention of Postoperative Nausea and Vomiting
2.3
Stability and Handling
2.4
Dosage Adjustment for Patients with Impaired Hepatic
Function
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
5.2
Electrocardiographic Changes
5.3
Masking of Progressive Ileus and Gastric Distension
5.4
Effect on Peristalsis
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Drugs Affecting Cytochrome P-450 Enzymes
7.2
Apomorphine
7.3
Phenytoin, Carbamazepine, and Rifampin
7.4
Tramadol
7.5
Chemotherapy
7.6
Temazepam
7.7
Alfentanil and Atracurium
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
9
DRUG ABUSE AND DEPENDENCE
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Chemotherapy-Induced Nausea and Vomiting
14.2 Prevention of Postoperative Nausea and/or Vomiting
14.3 Prevention of Further Postoperative Nausea and
Vomiting
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
Reference ID: 3014843
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Prevention of Nausea and Vomiting Associated with Initial and Repeat
Courses of Emetogenic Cancer Chemotherapy
ZOFRAN Injection is indicated for the prevention of nausea and vomiting associated
with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin
[see Clinical Studies (14.1)].
ZOFRAN is approved for patients aged 6 months and older.
1.2
Prevention of Postoperative Nausea and/or Vomiting
ZOFRAN Injection is indicated for the prevention of postoperative nausea and/or
vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in
whom there is little expectation that nausea and/or vomiting will occur postoperatively. In
patients in whom nausea and/or vomiting must be avoided postoperatively, ZOFRAN Injection is
recommended even when the incidence of postoperative nausea and/or vomiting is low. For
patients who do not receive prophylactic ZOFRAN Injection and experience nausea and/or
vomiting postoperatively, ZOFRAN Injection may be given to prevent further episodes [see
Clinical Studies (14.3)].
ZOFRAN is approved for patients aged 1 month and older.
2
DOSAGE AND ADMINISTRATION
2.1
Prevention of Nausea and Vomiting Associated with Initial and Repeat
Courses of Emetogenic Chemotherapy
ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium
Chloride Injection before administration.
Adults: The recommended adult intravenous dosage of ZOFRAN is a single 32-mg dose
or three 0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes
before the start of emetogenic chemotherapy. Efficacy of the 32-mg single dose beyond 24 hours
has not been established. The recommended infusion rate should not be exceeded [see
Overdosage(10)]. With the three-dose (0.15-mg/kg) regimen, the first dose is infused over
15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent
doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN.
Pediatrics: For pediatric patients 6 months through 18 years of age, the intravenous
dosage of ZOFRAN is three 0.15-mg/kg doses [see Clinical Studies (14.1) and Clinical
Pharmacology (12.3)]. The first dose is to be administered 30 minutes before the start of
moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are
administered 4 and 8 hours after the first dose of ZOFRAN. The drug should be infused
intravenously over 15 minutes.
Reference ID: 3014843
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2
Prevention of Postoperative Nausea and Vomiting
ZOFRAN Injection should not be mixed with solutions for which physical and chemical
compatibility have not been established. In particular, this applies to alkaline solutions as a
precipitate may form.
Adults: The recommended adult intravenous dosage of ZOFRAN is 4 mg undiluted
administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes,
immediately before induction of anesthesia, or postoperatively if the patient did not receive
prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after
surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection
for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few
patients above 80 kg have been studied. In patients who do not achieve adequate control of
postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous
dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron
postoperatively does not provide additional control of nausea and vomiting.
Pediatrics: For pediatric patients 1 month through 12 years of age, the dosage is a single
0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing
more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2
to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the
patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting
occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in
patients who had not received prophylactic ZOFRAN.
2.3
Stability and Handling
After dilution, do not use beyond 24 hours. Although ZOFRAN Injection is chemically
and physically stable when diluted as recommended, sterile precautions should be observed
because diluents generally do not contain preservative.
ZOFRAN Injection is stable at room temperature under normal lighting conditions for
48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection,
5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and
0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials
stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by
shaking the vial vigorously.
2.4
Dosage Adjustment for Patients with Impaired Hepatic Function
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single
maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the
emetogenic chemotherapy is recommended. There is no experience beyond first-day
administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].
Reference ID: 3014843
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
DOSAGE FORMS AND STRENGTHS
ZOFRAN Injection, 2 mg/mL is a clear, colorless, nonpyrogenic, sterile solution available
as a 2 mL single dose vial and 20 mL multidose vial.
4
CONTRAINDICATIONS
ZOFRAN Injection is contraindicated for patients known to have hypersensitivity (e.g.,
anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported
in patients taking ondansetron. [See Adverse Reactions (6.2)].
The concomitant use of apomorphine with ondansetron is contraindicated based on
reports of profound hypotension and loss of consciousness when apomorphine was administered
with ondansetron.
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported
in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
5.2
Electrocardiographic Changes
ECG changes including QT interval prolongation have been seen in patients receiving
ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in
patients using ondansetron. Avoid ZOFRAN in patients with congenital long QT syndrome. ECG
monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or
hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal
products that lead to QT prolongation.
5.3
Masking of Progressive Ileus and Gastric Distension
The use of ZOFRAN in patients following abdominal surgery or in patients with
chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distention.
5.4
Effect on Peristalsis
ZOFRAN is not a drug that stimulates gastric or intestinal peristalsis. It should not be
used instead of nasogastric suction.
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in clinical practice.
The following adverse reactions have been reported in clinical trials of adult patients
treated with ondansetron, the active ingredient of intravenous ZOFRAN at a dosage of three
0.15-mg/kg doses or as a single 32-mg dose. A causal relationship to therapy with ZOFRAN
(ondansetron) was unclear in many cases.
Reference ID: 3014843
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Chemotherapy-Induced Nausea and Vomiting:
Table 1. Adverse Reactions Reported in > 5% of Adult Patients Who Received
Ondansetron at a Dosage of Three 0.15-mg/kg Doses or as a Single 32-mg Dose
Adverse Reaction
Number of Adult Patients With Reaction
ZOFRAN
Injection
0.15 mg/kg x 3
n = 419
ZOFRAN
Injection
32 mg x 1
n = 220
Metoclopramide
n = 156
Placebo
n = 34
Diarrhea
16%
8%
44%
18%
Headache
17%
25%
7%
15%
Fever
8%
7%
5%
3%
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations,
hypotension, and tachycardia have been reported.
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients
receiving multiday ondansetron.
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline
values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have
been reported to exceed twice the upper limit of normal in approximately 5% of patients. The
increases were transient and did not appear to be related to dose or duration of therapy. On repeat
exposure, similar transient elevations in transaminase values occurred in some courses, but
symptomatic hepatic disease did not occur.
Integumentary: Rash has occurred in approximately 1% of patients receiving
ondansetron.
Neurological: There have been rare reports consistent with, but not diagnostic of,
extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal
seizure.
Other: Rare cases of hypokalemia have been reported.
Postoperative Nausea and Vomiting: The adverse reactions in Table 2 have been
reported in ≥ 2% of adults receiving ondansetron at a dosage of 4 mg intravenous over 2 to
5 minutes in clinical trials.
Reference ID: 3014843
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Adverse Reactions Reported in ≥ 2% (and With Greater Frequency than the
Placebo Group) of Adult Patients Receiving Ondansetron at a Dosage of 4 mg Intravenous
over 2 to 5 Minutes
Adverse Reactiona,b
ZOFRAN Injection
4 mg Intravenous
n = 547 patients
Placebo
n = 547 patients
Headache
92 (17%)
77 (14%)
Drowsiness/sedation
44 (8%)
37 (7%)
Injection site reaction
21 (4%)
18 (3%)
Fever
10 (2%)
6 (1%)
Cold sensation
9 (2%)
8 (1%)
Pruritus
9 (2%)
3 (< 1%)
Paresthesia
9 (2%)
2 (< 1%)
a Adverse Reactions: Rates of these reactions were not significantly different in the
ondansetron and placebo groups
b Patients were receiving multiple concomitant perioperative and postoperative medications
Pediatric Use: Rates of adverse reactions were similar in both the ondansetron and
placebo groups in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric
patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg)
administered intravenously over at least 30 seconds. Diarrhea was seen more frequently in
patients taking ZOFRAN (2%) compared to placebo (<1%) in the 1 month to 24 month age
group. These patients were receiving multiple concomitant perioperative and postoperative
medications.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
ondansetron. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure. The reactions have been chosen for inclusion due to a combination
of their seriousness, frequency of reporting, or potential causal connection to ondansetron.
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia,
premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic
alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment
depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron,
transient ECG changes including QT/QTc interval prolongation have been reported [see
Warnings and Precautions (5.2)].
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g.,
anaphylatic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension,
laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A
Reference ID: 3014843
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
positive lymphocyte transformation test to ondansetron has been reported, which suggests
immunologic sensitivity to ondansetron.
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death
have been reported in patients with cancer receiving concurrent medications including potentially
hepatotoxic cytotoxic chemotherapy and antibiotics.
Local Reactions: Pain, redness, and burning at site of injection.
Lower Respiratory: Hiccups
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic
reactions. Transient dizziness during or shortly after intravenous infusion.
Skin: Urticaria
Eye Disorders: Cases of transient blindness, predominantly during intravenous
administration, have been reported. These cases of transient blindness were reported to resolve
within a few minutes up to 48 hours. Transient blurred vision, in some cases associated with
abnormalities of accommodation, have also been reported.
7
DRUG INTERACTIONS
7.1
Drugs Affecting Cytochrome P-450 Enzymes
Ondansetron does not appear to induce or inhibit the cytochrome P-450
drug-metabolizing enzyme system of the liver . Because ondansetron is metabolized by hepatic
cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or
inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron
[see Clinical Pharmacology (12.3)]. On the basis of limited available data, no dosage adjustment
is recommended for patients on these drugs.
7.2
Apomorphine
Based on reports of profound hypotension and loss of consciousness when apomorphine
was administered with ondansetron, the concomitant use of apomorphine with ondansetron is
contradindicated [see Contraindications (4)].
7.3
Phenytoin, Carbamazepine, and Rifampin
In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and
rifampin), the clearance of ondansetron was significantly increased and ondansetron blood
concentrations were decreased. However, on the basis of available data, no dosage adjustment
for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3)].
7.4
Tramadol
Although there are no data on pharmacokinetic drug interactions between ondansetron
and tramadol, data from two small studies indicate that concomitant use of ondansetron may
result in reduced analgesic activity of tramadol. Patients on concomitant ondansetron self
administered tramadol more frequently in these studies, leading to an increased cumulative dose
in patient controlled administration (PCA) of tramadol.
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7.5
Chemotherapy
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of
ondansetron.
In a crossover study in 76 pediatric patients, intravenous ondansetron did not increase
blood levels of high-dose methotrexate.
7.6
Temazepam
The coadministration of ondansetron had no effect on the pharmacokinetics and
pharmacodynamics of temazepam.
7.7
Alfentanil and Atracurium
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the
degree of neuromuscular blockade produced by atracurium. Interactions with general or local
anesthetics have not been studied.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. Reproduction studies have been performed in pregnant rats and
rabbits at intravenous doses up to 4 mg/kg per day (approximately 1 and 2 times the
recommended human intravenous dose of 32 mg/day, respectively, based on body surface area)
and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
8.3
Nursing Mothers
Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is
excreted in human milk. Because many drugs are excreted in human milk, caution should be
exercised when ondansetron is administered to a nursing woman.
8.4
Pediatric Use
Little information is available about the use of ondansetron in pediatric surgical patients
younger than 1 month of age. [See Clinical Studies(14.2)]. Little information is available about
the use of ondansetron in pediatric cancer patients younger than 6 months of age. [See Clinical
Studies(14.1) and Dosage and Administration (2)].
The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower
and the half-life is ~2.5 fold longer than patients who are > 4 to 24 months of age. As a
precaution, it is recommended that patients less than 4 months of age receiving this drug be
closely monitored. [See Clinical Pharmacology (12.3)].
8.5
Geriatric Use
Of the total number of subjects enrolled in cancer chemotherapy-induced and
postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65
years of age and over. No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical experience has not identified
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structural formula
differences in responses between the elderly and younger patients, but greater sensitivity of some
older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of
65 [see Clinical Pharmacology (12.3)].
8.6
Hepatic Impairment
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance
is reduced and apparent volume of distribution is increased with a resultant increase in plasma
half-life [see Clinical Pharmacology (12.3)]. In such patients, a total daily dose of 8 mg should
not be exceeded [see Dosage and Administration (2.3)].
8.7
Renal Impairment
Although plasma clearance is reduced in patients with severe renal impairment
(creatinine clearance < 30 mL/min), no dosage adjustment is recommended [see Clinical
Pharmacology (12.3)].
9
DRUG ABUSE AND DEPENDENCE
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor
does it substitute for benzodiazepines in direct addiction studies.
10
OVERDOSAGE
There is no specific antidote for ondansetron overdose. Patients should be managed with
appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily
intravenous doses as large as 252 mg have been inadvertently administered without significant
adverse events. These doses are more than 10 times the recommended daily dose.
In addition to the adverse reactions listed above, the following events have been
described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to
3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg
of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another
patient that took 48 mg of ondansetron hydrochloride tablets. Following infusion of 32 mg over
only a 4-minute period, a vasovagal episode with transient second-degree heart block was
observed. In all instances, the events resolved completely.
11
DESCRIPTION
The active ingredient of ZOFRAN Injection is ondansetron hydrochloride, a selective
blocking agent of the serotonin 5-HT3 receptor type. Its chemical name is (±) 1, 2, 3, 9
tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one,
monohydrochloride, dihydrate. It has the following structural formula:
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The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of
365.9.
Ondansetron HCl is a white to off-white powder that is soluble in water and normal
saline.
Each 1 mL of aqueous solution in the 2 mL single-dose vial contains 2 mg of ondansetron
as the hydrochloride dihydrate; 9 mg of sodium chloride, USP; and 0.5 mg of citric acid
monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for
Injection, USP.
Each 1 mL of aqueous solution in the 20 mL multidose vial contains 2 mg of ondansetron
as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid
monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of
methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection,
USP.
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution for intravenous
use. The pH of the injection solution is 3.3 to 4.0.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron’s mechanism of
action has not been fully characterized, it is not a dopamine-receptor antagonist.
12.2 Pharmacodynamics
In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no
effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small
intestinal transit time. In another study in six normal male volunteers, a 16-mg dose infused over
5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood
pressure, or electrocardiogram (ECG). However, no thorough QT study has been conducted with
ondansetron. Multiday administration of ondansetron has been shown to slow colonic transit in
normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.
In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered
intravenously or intramuscularly was dynamically similar in the prevention of nausea and
vomiting using the ipecacuanha model of emesis.
12.3 Pharmacokinetics
In normal adult volunteers, the following mean pharmacokinetic data have been
determined following a single 0.15-mg/kg intravenous dose.
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Table 3. Pharmacokinetics in Normal Adult Volunteers
Age-group
(years)
n
Peak Plasma
Concentration
(ng/mL)
Mean Elimination
Half-life (h)
Plasma Clearance
(L/h/kg)
19-40
11
102
3.5
0.381
61-74
12
106
4.7
0.319
≥ 75
11
170
5.5
0.262
Absorption: A study was performed in normal volunteers (n = 56) to evaluate the
pharmacokinetics of a single 4-mg dose administered as a 5-minute infusion compared to a
single intramuscular injection. Systemic exposure as measured by mean AUC were equivalent,
with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ng•h/mL for intravenous and
intramuscular groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8,
54.4] ng/mL at 10 minutes after intravenous infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at
41 minutes after intramuscular injection. In normal volunteers (19 to 39 years old, n = 23), the
peak plasma concentration was 264 ng/mL following a single 32-mg dose administered as a
15-minute intravenous infusion.
Distribution: Plasma protein binding of ondansetron as measured in vitro was 70% to
76%, over the pharmacologic concentration range of 10 to 500 ng/mL. Circulating drug also
distributes into erythrocytes.
Metabolism: Ondansetron is extensively metabolized in humans, with approximately 5%
of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic
pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate
conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not
found in plasma at concentrations likely to significantly contribute to the biological activity of
ondansetron. The metabolites are observed in the urine.
In vitro metabolism studies have shown that ondansetron is a substrate for multiple
human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In
terms of overall ondansetron turnover, CYP3A4 plays a predominant role while formation of the
major in vivo metabolites is apparently mediated by CYP1A2. The role of CYP2D6 in
ondansetron in vivo metabolism is relatively minor.
The pharmacokinetics of intravenous ondansetron did not differ between subjects who
were poor metabolisers of CYP2D6 and those who were extensive metabolisers of CYP2D6,
further supporting the limited role of CYP2D6 in ondansetron disposition in vivo.
Elimination: In normal volunteers (19 to 39 years old, n = 23), following a single 32-mg
dose administered as a 15-minute intravenous infusion, the mean elimination half-life was
4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to dose as measured
by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with a small
decrease in systemic clearance with increasing plasma concentrations.
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In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no
difference in the multidose pharmacokinetics over a 4-day period.
Geriatrics: A reduction in clearance and increase in elimination half-life are seen in
patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were
similar in patients over 65 years of age and those under 65 years of age; there was an insufficient
number of patients over 75 years of age to permit conclusions in that age-group. No dosage
adjustment is recommended in the elderly.
Pediatrics: Pharmacokinetic samples were collected from 74 cancer patients 6 to
48 months of age, who received a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours
for 3 doses during a safety and efficacy trial. These data were combined with sequential
pharmacokinetics data from 41 surgery patients 1 month to 24 months of age, who received a
single dose of 0.1 mg/kg of intravenous ondansetron prior to surgery with general anesthesia, and
a population pharmacokinetic analysis was performed on the combined data set. The results of
this analysis are included in Table 4 and are compared to the pharmacokinetic results in cancer
patients 4 to 18 years of age.
Table 4. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Cancer Patients
4 to 18 years of age
N = 21
0.599
1.9
2.8
Population PK Patientsa
1 month to 48 months of age
N = 115
0.582
3.65
4.9
a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age
who receive a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours for 3 doses would be
expected to achieve a systemic exposure (AUC) consistent with the exposure achieved in
previous pediatric studies in cancer patients (4 to 18 years of age) at similar doses.
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery
requiring anesthesia for a duration of 45 minutes to 2 hours, a single intravenous dose of
ondansetron, 2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to
anesthesia induction. Mean weight-normalized clearance and volume of distribution values in
these pediatric surgical patients were similar to those previously reported for young adults. Mean
terminal half-life was slightly reduced in pediatric patients (range, 2.5 to 3 hours) in comparison
with adults (range, 3 to 3.5 hours).
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing
surgery requiring general anesthesia, a single intravenous dose of ondansetron, 0.1 or 0.2 mg/kg,
was administered prior to surgery. As shown in Table 5, the 41 patients with pharmacokinetic
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data were divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months
of age, and are compared to pediatric patients 3 to 12 years of age.
Table 5. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Surgery Patients
3 to 12 years of age
N = 21
0.439
1.65
2.9
Pediatric Surgery Patients
5 to 24 months of age
N = 22
0.581
2.3
2.9
Pediatric Surgery Patients
1 month to 4 months of age
N = 19
0.401
3.5
6.7
In general, surgical and cancer pediatric patients younger than 18 years tend to have a
higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric
patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher
volume of distribution in this age group.
In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three
intravenous doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years
of age exhibited ondansetron pharmacokinetic parameters similar to those of adults.
Renal Impairment: Due to the very small contribution (5%) of renal clearance to the
overall clearance, renal impairment was not expected to significantly influence the total
clearance of ondansetron. However, ondansetron mean plasma clearance was reduced by about
41% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction
in clearance is variable and was not consistent with an increase in half-life. No reduction in dose
or dosing frequency in these patients is warranted.
Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is
reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in those
without hepatic impairment. In patients with severe hepatic impairment (Child-Pugh score of 10
or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased
with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a
total daily dose of 8 mg should not be exceeded.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral
ondansetron doses up to 10 and 30 mg/kg per day, respectively (approximately 2.5 and 3.8 times
the recommended human intravenous dose of 32 mg/day, based on body surface area).
Ondansetron was not mutagenic in standard tests for mutagenicity.
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Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the
recommended human intravenous dose, based on body surface area) did not affect fertility or
general reproductive performance of male and female rats.
14
CLINICAL STUDIES
The clinical efficacy of ondansetron hydrochloride, the active ingredient of ZOFRAN,
was assessed in clinical trials as described below.
14.1 Chemotherapy-Induced Nausea and Vomiting
Adults: In a double-blind study of three different dosing regimens of ZOFRAN Injection,
0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer
chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing
regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the
0.15-mg/kg dosing regimen.
Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, ZOFRAN
Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing
nausea and vomiting induced by cisplatin-based chemotherapy. Therapeutic response was as
shown in Table 6.
Table 6. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and
Vomiting in Single-Day Cisplatin Therapya in Adults
ZOFRAN Injection
(0.15 mg/kg x 3)
Placebo
P Valueb
Number of patients
14
14
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
2 (14%)
8 (57%)
2 (14%)
2 (14%)
0 (0%)
0 (0%)
1 (7%)
13 (93%)
0.001
Median number of emetic episodes
1.5
Undefinedc
Median time to first emetic episode (h)
11.6
2.8
0.001
Median nausea scores (0-100)d
3
59
0.034
Global satisfaction with control of
nausea and vomiting (0-100)
e
96
10.5
0.009
a Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5)
or moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other
chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There
was no difference between treatments in the types of chemotherapy that would account for
differences in response.
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b Efficacy based on "all patients treated" analysis.
c Median undefined since at least 50% of the patients were rescued or had more than five
emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Ondansetron injection (0.15-mg/kg x 3 doses) was compared with metoclopramide (2
mg/kg x 6 doses) in a single-blind trial in 307 patients receiving cisplatin ≥ 100 mg/m2 with or
without other chemotherapeutic agents. Patients received the first dose of ondansetron or
metoclopramide 30 minutes before cisplatin. Two additional ondansetron doses were
administered 4 and 8 hours later, or five additional metoclopramide doses were administered 2, 4,
7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less. Episodes of
vomiting and retching were tabulated over the period of 24 hours after cisplatin. The results of
this study are summarized in Table 7.
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Table 7. Therapeutic Response in Prevention of Vomiting Induced by Cisplatin (≥ 100
mg/m2) Single-Day Therapya in Adults
ZOFRAN Injection
Metoclopramide
P Value
Dose
0.15 mg/kg x 3
2 mg/kg x 6
Number of patients in efficacy population
136
138
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
54 (40%)
34 (25%)
19 (14%)
29 (21%)
41 (30%)
30 (22%)
18 (13%)
49 (36%)
Comparison of treatments with respect to
0 Emetic episodes
More than 5 emetic episodes/rescued
54/136
29/136
41/138
49/138
0.083
0.009
Median number of emetic episodes
1
2
0.005
Median time to first emetic episode (h)
20.5
4.3
< 0.001
Global satisfaction with control of nausea
and vomiting (0-100)b
85
63
0.001
Acute dystonic reactions
0
8
0.005
Akathisia
0
10
0.002
a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including
cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments
in the types of chemotherapy that would account for differences in response.
b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
In a stratified, randomized, double-blind, parallel-group, multicenter study, a single
32-mg dose of ondansetron was compared with three 0.15-mg/kg doses in patients receiving
cisplatin doses of either 50 to 70 mg/m2 or ≥ 100 mg/m2. Patients received the first ondansetron
dose 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and
8 hours later to the group receiving three 0.15-mg/kg doses. In both strata, significantly fewer
patients on the single 32-mg dose than those receiving the three-dose regimen failed. The results
are summarized in Table 8.
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Table 8. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and
Vomiting in 32 mg Single-Dose Therapy in Adults
Ondansetron Dose
P Value
0.15 mg/kg x 3
32 mg x 1
High-dose cisplatin (≥ 100 mg/m2)
Number of patients
100
102
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
41 (41%)
19 (19%)
4 (4%)
36 (36%)
49 (48%)
25 (25%)
8 (8%)
20 (20%)
0.315
0.009
Median time to first emetic episode (h)
21.7
23
0.173
Median nausea scores (0-100)a
28
13
0.004
Medium-dose cisplatin (50-70 mg/m2)
Number of patients
101
93
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
62 (61%)
11 (11%)
6 (6%)
22 (22%)
68 (73%)
14 (15%)
3 (3%)
8 (9%)
0.083
0.011
Median time to first emetic episode (h)
Undefinedb
Undefined
Median nausea scores (0-100)a
9
3
0.131
a Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
b Median undefined since at least 50% of patients did not have any emetic episodes.
Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled
study of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide
(500 to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than
placebo in preventing nausea and vomiting. The results are summarized in Table 9.
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Table 9. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and
Vomiting in Single-Day Cyclophosphamide Therapya in Adults
ZOFRAN Injection
(0.15 mg/kg x 3)
Placebo
P Valueb
Number of patients
10
10
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
7 (70%)
0 (0%)
2 (20%)
1 (10%)
0 (0%)
2 (20%)
4 (40%)
4 (40%)
0.001
0.131
Median number of emetic episodes
0
4
0.008
Median time to first emetic episode (h)
Undefinedc
8.79
Median nausea scores (0-100)d
0
60
0.001
Global satisfaction with control of
nausea and vomiting (0-100)e
100
52
0.008
a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including
fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between
treatments in the type of chemotherapy that would account for differences in response.
b Efficacy based on "all patients treated" analysis.
c Median undefined since at least 50% of patients did not have any emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose,
100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with
ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median,
2; range, 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes
occurred in 217 (81%) re-treatment courses.
Pediatrics: Four open-label, noncomparative (one US, three foreign) trials have been
performed with 209 pediatric cancer patients 4 to 18 years of age given a variety of cisplatin or
noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged from
0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration
of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, ZOFRAN was
administered intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2
to 39 mg. In these studies, 58% of the 196 evaluable patients had a complete response (no emetic
episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was essentially the
same as for patients older than 18 years of age.
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An open-label, multicenter, noncomparative trial has been performed in 75 pediatric
cancer patients 6 to 48 months of age receiving at least one moderately or highly emetogenic
chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were
American Hispanic, and 15% were black patients. ZOFRAN was administered intravenously
over 15 minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before
the start of chemotherapy, the second and third doses were administered 4 and 8 hours after the
first dose, respectively. Eighteen patients (25%) received routine prophylactic dexamethasone
(i.e., not given as rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic
episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was comparable to
the prevention of vomiting in patients 4 years of age and older.
14.2 Prevention of Postoperative Nausea and/or Vomiting
Adults: Adult surgical patients who received ondansetron immediately before the
induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal;
opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare
and/or vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double-
blind US studies involving 554 patients. ZOFRAN Injection (4 mg) intravenous given over 2 to
5 minutes was significantly more effective than placebo. The results of these studies are
summarized in Table 10.
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Table 10. Therapeutic Response in Prevention of Postoperative Nausea and Vomiting in
Adult Patients
Ondansetron
4 mg
Intravenous
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
103 (76%)
13 (10%)
20 (15%)
139
64 (46%)
17 (12%)
58 (42%)
< 0.001
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
134
56 (42%)
136
39 (29%)
Study 2
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
85 (63%)
16 (12%)
35 (26%)
143
63 (44%)
29 (20%)
51 (36%)
0.002
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
125
48 (38%)
133
42 (32%)
The study populations in Table 10 consisted mainly of females undergoing laparoscopic
procedures.
In a placebo-controlled study conducted in 468 males undergoing outpatient procedures, a
single 4-mg intravenous ondansetron dose prevented postoperative vomiting over a 24-hour study
period in 79% of males receiving drug compared to 63% of males receiving placebo (P < 0.001).
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major
abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg intravenous ondansetron
dose for prevention of postoperative nausea and vomiting over a 24-hour study period. At the
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4-mg dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the first
study (P < 0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the
second study (P = 0.001) experienced no emetic episodes. No additional benefit was observed in
patients who received intravenous ondansetron 8 mg compared to patients who received
intravenous ondansetron 4 mg.
Pediatrics: Three double-blind, placebo-controlled studies have been performed (one
US, two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing general
anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or without
adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized
to either single intravenous doses of ondansetron (0.1 mg/kg for pediatric patients weighing
40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was
administered over at least 30 seconds, immediately prior to or following anesthesia induction.
Ondansetron was significantly more effective than placebo in preventing nausea and vomiting.
The results of these studies are summarized in Table 11.
Table 11. Therapeutic Response in Prevention of Postoperative Nausea and Vomiting in
Pediatric Patients 2 to 12 Years of Age
Treatment Response Over
24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Study 1
Number of patients
205
210
0 Emetic episodes
140 (68%)
82 (39%)
≤ 0.001
Failurea
65 (32%)
128 (61%)
Study 2
Number of patients
112
110
0 Emetic episodes
68 (61%)
38 (35%)
≤ 0.001
Failurea
44 (39%)
72 (65%)
Study 3
Number of patients
206
206
0 Emetic episodes
123 (60%)
96 (47%)
≤ 0.01
Failurea
Nausea assessmentsb:
83 (40%)
110 (53%)
Number of patients
185
191
None
119 (64%)
99 (52%)
≤ 0.01
a Failure was one or more emetic episodes, rescued, or withdrawn.
b Nausea measured as none, mild, or severe.
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A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric
patients 1 month to 24 months of age who were undergoing routine surgery under general
anesthesia. Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were
American Hispanic, 2% were Asian, and 6% were “other race” patients. A single 0.1-mg/kg
intravenous dose of ondansetron administered within 5 minutes following induction of anesthesia
was statistically significantly more effective than placebo in preventing vomiting. In the placebo
group, 28% of patients experienced vomiting compared to 11% of subjects who received
ondansetron (P ≤ 0.01). Overall, 32 (10%) of placebo patients and 18 (5%) of patients who
received ondansetron received antiemetic rescue medication(s) or prematurely withdrew from the
study.
14.3 Prevention of Further Postoperative Nausea and Vomiting
Adults: Adult surgical patients receiving general balanced anesthesia (barbiturate:
thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide;
neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and
supplemental isoflurane) who received no prophylactic antiemetics and who experienced nausea
and/or vomiting within 2 hours postoperatively were evaluated in two double-blind US studies
involving 441 patients. Patients who experienced an episode of postoperative nausea and/or
vomiting were given ZOFRAN Injection (4 mg) intravenous over 2 to 5 minutes, and this was
significantly more effective than placebo. The results of these studies are summarized in Table
12.
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Table 12. Therapeutic Response in Prevention of Further Postoperative Nausea and
Vomiting in Adult Patients
Ondansetron
4 mg
Intravenous
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
104
117
0 Emetic episodes
49 (47%)
19 (16%)
< 0.001
1 Emetic episode
12 (12%)
9 (8%)
More than 1 emetic episode/rescued
43 (41%)
89 (76%)
Median time to first emetic episode (min)a
55.0
43.0
Nausea assessments:
Number of patients
98
102
Mean nausea score over 24-h postoperative
periodb
1.7
3.1
Study 2
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
112
108
0 Emetic episodes
49 (44%)
28 (26%)
0.006
1 Emetic episode
14 (13%)
3 (3%)
More than 1 emetic episode/rescued
49 (44%)
77 (71%)
Median time to first emetic episode (min)a
60.5
34.0
Nausea assessments:
Number of patients
105
85
Mean nausea score over 24-h postoperative
periodb
1.9
2.9
a After administration of study drug.
b Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
The study populations in Table 12 consisted mainly of women undergoing laparoscopic
procedures.
Repeat Dosing in Adults: In patients who do not achieve adequate control of
postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous
dose of ondansetron 4 mg, administration of a second intravenous dose of ondansetron 4 mg
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c
o
mpany logo
postoperatively does not provide additional control of nausea and vomiting.
Pediatrics: One double-blind, placebo-controlled, US study was performed in 351 male
and female outpatients (2 to 12 years of age) who received general anesthesia with nitrous oxide
and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who
experienced two or more emetic episodes within 2 hours following discontinuation of nitrous
oxide were randomized to either single intravenous doses of ondansetron (0.1 mg/kg for pediatric
patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo
administered over at least 30 seconds. Ondansetron was significantly more effective than placebo
in preventing further episodes of nausea and vomiting. The results of the study are summarized
in Table 13.
Table 13. Therapeutic Response in Prevention of Further Postoperative Nausea and
Vomiting in Pediatric Patients 2 to 12 Years of Age
Treatment Response
Ondansetron
Placebo
Over 24 Hours
n (%)
n (%)
P Value
Number of patients
180
171
0 Emetic episodes
96 (53%)
29 (17%)
≤ 0.001
Failurea
84 (47%)
142 (83%)
a Failure was one or more emetic episodes, rescued, or withdrawn.
16
HOW SUPPLIED/STORAGE AND HANDLING
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
NDC 0173-0442-02 2-mL single-dose vials (Carton of 5)
NDC 0173-0442-00 20-mL multidose vials (Singles)
Storage: Store vials between 2° and 30°C (36° and 86°F). Protect from light.
17
PATIENT COUNSELING INFORMATION
• Inform patients that ZOFRAN may cause hypersensitivity reactions, some as severe as
anaphylaxis and bronchospasm. The patient should report any signs and symptoms of
hypersensitivity reactions, including fever, chills, rash, or breathing problems.
• The patient should report the use of all medications, especially apomorphine, to their
health care provider. Concomitant use of apomorphine and ZOFRAN may cause a
significant drop in blood pressure and loss of consciousness.
• Inform patients that ZOFRAN may cause headache, drowsiness/sedation, constipation,
fever and diarrhea.
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GlaxoSmithKline
Research Triangle Park, NC 27709
©2011, GlaxoSmithKline. All rights reserved.
ZFJ:XPI
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|
custom-source
|
2025-02-12T13:46:26.058415
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020007s042,020403s020lbl.pdf', 'application_number': 20007, 'submission_type': 'SUPPL ', 'submission_number': 42}
|
12,129
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZOFRAN safely and effectively. See full prescribing information for
ZOFRAN.
ZOFRAN (ondansetron hydrochloride) injection for intravenous use
Initial U.S. Approval: 1991
---------------------------RECENT MAJOR CHANGES -------------------
Dosage and Administration, Prevention of Nausea and
11/2012
Vomiting Associated with Initial and Repeat Courses of
Emetogenic Chemotherapy – Removal of 32 mg single
intravenous dose (2.1)
Warnings and Precautions, QT Prolongation (5.2)
11/2012
----------------------------INDICATIONS AND USAGE--------------------
ZOFRAN Injection is a 5-HT3 receptor antagonist indicated:
Prevention of nausea and vomiting associated with initial and repeat
courses of emetogenic cancer chemotherapy. (1.1)
Prevention of postoperative nausea and/or vomiting. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
Prevention of nausea and vomiting associated with initial and repeat courses
of emetogenic cancer chemotherapy (2.1):
Adults and Pediatric patients (6 months to 18 years): Three 0.15 mg/kg
doses, up to a maximum of 16 mg per dose, infused intravenously over 15
minutes. The first dose should be administered 30 minutes before the start
of chemotherapy. Subsequent doses are administered 4 and 8 hours after
the first dose.
Prevention of postoperative nausea and/or vomiting (2.2):
Population
Age
ZOFRAN
Injection Dosage
Intravenous
Infusion Rate
Adults
> 12 yrs
4 mg x 1
over 2 - 5 min
Pediatrics
(> 40 kg)
1 mo. – 12 yrs
4 mg x 1
over 2 - 5 min
Pediatrics
(≤ 40 kg)
1 mo. – 12 yrs
0.1 mg/kg x 1
over 2 - 5 min
In patients with severe hepatic impairment, a total daily dose of 8 mg
should not be exceeded. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS -------------
ZOFRAN Injection (2 mg/mL): 2 mL single dose vial and 20 mL multidose
vials. (3)
-------------------------------CONTRAINDICATIONS-----------------------
Patients known to have hypersensitivity (e.g., anaphylaxis) to this product
or any of its components. (4)
Concomitant use of apomorphine. (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
Hypersensitivity reactions including anaphylaxis and bronchospasm, have
been reported in patients who have exhibited hypersensitivity to other
selective 5-HT3 receptor antagonists. (5.1)
QT prolongation occurs in a dose-dependent manner. Cases of Torsade de
Pointes have been reported. Avoid ZOFRAN in patients with congenital
long QT syndrome. (5.2)
Use in patients following abdominal surgery or in patients with
chemotherapy-induced nausea and vomiting may mask a progressive ileus
and/or gastric distention. (5.3)(5.4)
------------------------------ ADVERSE REACTIONS ----------------------
Chemotherapy-Induced Nausea and Vomiting –
The most common adverse reactions ( 7%) in adults are diarrhea,
headache, and fever. (6.1)
Postoperative Nausea and Vomiting –
The most common adverse reaction (≥ 10%) which occurs at a higher
frequency compared to placebo in adults is headache. (6.1)
The most common adverse reaction (≥ 2%) which occurs at a higher
frequency compared to placebo in pediatric patients 1 to 24 months of age
is diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS-----------------------
Apomorphine – profound hypotension and loss of consciousness.
Concomitant use with ondansetron is contraindicated. (7.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 11/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Prevention of Nausea and Vomiting Associated with
Initial and Repeat Courses of Emetogenic Cancer
Chemotherapy
1.2
Prevention of Postoperative Nausea and/or Vomiting
2 DOSAGE AND ADMINISTRATION
2.1
Prevention of Nausea and Vomiting Associated with
Initial and Repeat Courses of Emetogenic Chemotherapy
2.2
Prevention of Postoperative Nausea and Vomiting
2.3
Stability and Handling
2.4
Dosage Adjustment for Patients with Impaired Hepatic
Function
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
5.2
QT Prolongation
5.3
Masking of Progressive Ileus and Gastric Distension
5.4
Effect on Peristalsis
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Drugs Affecting Cytochrome P-450 Enzymes
7.2
Apomorphine
7.3
Phenytoin, Carbamazepine, and Rifampin
7.4
Tramadol
7.5
Chemotherapy
7.6
Temazepam
7.7
Alfentanil and Atracurium
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
9
DRUG ABUSE AND DEPENDENCE
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Chemotherapy-Induced Nausea and Vomiting
14.2 Prevention of Postoperative Nausea and/or Vomiting
14.3 Prevention of Further Postoperative Nausea and
Vomiting
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Prevention of Nausea and Vomiting Associated with Initial and Repeat
Courses of Emetogenic Cancer Chemotherapy
ZOFRAN Injection is indicated for the prevention of nausea and vomiting associated
with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin
[see Clinical Studies (14.1)].
ZOFRAN is approved for patients aged 6 months and older.
1.2
Prevention of Postoperative Nausea and/or Vomiting
ZOFRAN Injection is indicated for the prevention of postoperative nausea and/or
vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in
whom there is little expectation that nausea and/or vomiting will occur postoperatively. In
patients in whom nausea and/or vomiting must be avoided postoperatively, ZOFRAN Injection is
recommended even when the incidence of postoperative nausea and/or vomiting is low. For
patients who do not receive prophylactic ZOFRAN Injection and experience nausea and/or
vomiting postoperatively, ZOFRAN Injection may be given to prevent further episodes [see
Clinical Studies (14.3)].
ZOFRAN is approved for patients aged 1 month and older.
2
DOSAGE AND ADMINISTRATION
2.1
Prevention of Nausea and Vomiting Associated with Initial and Repeat
Courses of Emetogenic Chemotherapy
ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium
Chloride Injection before administration.
Adults: The recommended adult intravenous dosage of ZOFRAN is three 0.15-mg/kg
doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)]. The first dose is
infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy.
Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and
8 hours after the first dose of ZOFRAN.
Pediatrics: For pediatric patients 6 months through 18 years of age, the intravenous
dosage of ZOFRAN is three 0.15-mg/kg doses up to a maximum of 16 mg per dose [see Clinical
Studies (14.1) and Clinical Pharmacology (12.2 and 12.3)]. The first dose is to be administered
30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses
(0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first
dose of ZOFRAN. The drug should be infused intravenously over 15 minutes.
2.2
Prevention of Postoperative Nausea and Vomiting
ZOFRAN Injection should not be mixed with solutions for which physical and chemical
compatibility have not been established. In particular, this applies to alkaline solutions as a
precipitate may form.
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Adults: The recommended adult intravenous dosage of ZOFRAN is 4 mg undiluted
administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes,
immediately before induction of anesthesia, or postoperatively if the patient did not receive
prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after
surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection
for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few
patients above 80 kg have been studied. In patients who do not achieve adequate control of
postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous
dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron
postoperatively does not provide additional control of nausea and vomiting.
Pediatrics: For pediatric patients 1 month through 12 years of age, the dosage is a single
0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing
more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2
to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the
patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting
occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in
patients who had not received prophylactic ZOFRAN.
2.3
Stability and Handling
After dilution, do not use beyond 24 hours. Although ZOFRAN Injection is chemically
and physically stable when diluted as recommended, sterile precautions should be observed
because diluents generally do not contain preservative.
ZOFRAN Injection is stable at room temperature under normal lighting conditions for
48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection,
5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and
0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials
stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by
shaking the vial vigorously.
2.4
Dosage Adjustment for Patients with Impaired Hepatic Function
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single
maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the
emetogenic chemotherapy is recommended. There is no experience beyond first-day
administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
ZOFRAN Injection, 2 mg/mL is a clear, colorless, nonpyrogenic, sterile solution available
as a 2 mL single dose vial and 20 mL multidose vial.
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4
CONTRAINDICATIONS
ZOFRAN Injection is contraindicated for patients known to have hypersensitivity (e.g.,
anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported
in patients taking ondansetron. [See Adverse Reactions (6.2)].
The concomitant use of apomorphine with ondansetron is contraindicated based on
reports of profound hypotension and loss of consciousness when apomorphine was administered
with ondansetron.
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported
in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
5.2
QT Prolongation
Ondansetron prolongs the QT interval in a dose-dependent manner [see Clinical
Pharmacology (12.2)]. In addition, post-marketing cases of Torsade de Pointes have been
reported in patients using ondansetron. Avoid ZOFRAN in patients with congenital long QT
syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g.,
hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking
other medicinal products that lead to QT prolongation.
5.3
Masking of Progressive Ileus and Gastric Distension
The use of ZOFRAN in patients following abdominal surgery or in patients with
chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distention.
5.4
Effect on Peristalsis
ZOFRAN is not a drug that stimulates gastric or intestinal peristalsis. It should not be
used instead of nasogastric suction.
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
trials of another drug and may not reflect the rates observed in clinical practice.
The following adverse reactions have been reported in clinical trials of adult patients
treated with ondansetron, the active ingredient of intravenous ZOFRAN across a range of
dosages. A causal relationship to therapy with ZOFRAN (ondansetron) was unclear in many
cases.
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Chemotherapy-Induced Nausea and Vomiting:
Table 1. Adverse Reactions Reported in > 5% of Adult Patients Who Received
Ondansetron at a Dosage of Three 0.15-mg/kg Doses
Adverse Reaction
Number of Adult Patients With Reaction
ZOFRAN
Injection
0.15 mg/kg x 3
n = 419
Metoclopramide
n = 156
Placebo
n = 34
Diarrhea
16%
44%
18%
Headache
17%
7%
15%
Fever
8%
5%
3%
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations,
hypotension, and tachycardia have been reported.
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients
receiving multiday ondansetron.
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline
values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have
been reported to exceed twice the upper limit of normal in approximately 5% of patients. The
increases were transient and did not appear to be related to dose or duration of therapy. On repeat
exposure, similar transient elevations in transaminase values occurred in some courses, but
symptomatic hepatic disease did not occur.
Integumentary: Rash has occurred in approximately 1% of patients receiving
ondansetron.
Neurological: There have been rare reports consistent with, but not diagnostic of,
extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal
seizure.
Other: Rare cases of hypokalemia have been reported.
Postoperative Nausea and Vomiting: The adverse reactions in Table 2 have been
reported in 2% of adults receiving ondansetron at a dosage of 4 mg intravenous over 2 to
5 minutes in clinical trials.
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Table 2. Adverse Reactions Reported in 2% (and With Greater Frequency than the
Placebo Group) of Adult Patients Receiving Ondansetron at a Dosage of 4 mg Intravenous
over 2 to 5 Minutes
Adverse Reactiona,b
ZOFRAN Injection
4 mg Intravenous
n = 547 patients
Placebo
n = 547 patients
Headache
92 (17%)
77 (14%)
Drowsiness/sedation
44 (8%)
37 (7%)
Injection site reaction
21 (4%)
18 (3%)
Fever
10 (2%)
6 (1%)
Cold sensation
9 (2%)
8 (1%)
Pruritus
9 (2%)
3 (< 1%)
Paresthesia
9 (2%)
2 (< 1%)
a Adverse Reactions: Rates of these reactions were not significantly different in the
ondansetron and placebo groups
b Patients were receiving multiple concomitant perioperative and postoperative medications
Pediatric Use: Rates of adverse reactions were similar in both the ondansetron and
placebo groups in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric
patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg)
administered intravenously over at least 30 seconds. Diarrhea was seen more frequently in
patients taking ZOFRAN (2%) compared to placebo (<1%) in the 1 month to 24 month age
group. These patients were receiving multiple concomitant perioperative and postoperative
medications.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
ondansetron. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure. The reactions have been chosen for inclusion due to a combination
of their seriousness, frequency of reporting, or potential causal connection to ondansetron.
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia,
premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic
alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment
depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron,
transient ECG changes including QT/QTc interval prolongation have been reported [see
Warnings and Precautions (5.2)].
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g.,
anaphylatic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension,
laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A
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positive lymphocyte transformation test to ondansetron has been reported, which suggests
immunologic sensitivity to ondansetron.
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death
have been reported in patients with cancer receiving concurrent medications including potentially
hepatotoxic cytotoxic chemotherapy and antibiotics.
Local Reactions: Pain, redness, and burning at site of injection.
Lower Respiratory: Hiccups
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic
reactions. Transient dizziness during or shortly after intravenous infusion.
Skin: Urticaria
Eye Disorders: Cases of transient blindness, predominantly during intravenous
administration, have been reported. These cases of transient blindness were reported to resolve
within a few minutes up to 48 hours. Transient blurred vision, in some cases associated with
abnormalities of accommodation, have also been reported.
7
DRUG INTERACTIONS
7.1
Drugs Affecting Cytochrome P-450 Enzymes
Ondansetron does not appear to induce or inhibit the cytochrome P-450
drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic
cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or
inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron
[see Clinical Pharmacology (12.3)]. On the basis of limited available data, no dosage adjustment
is recommended for patients on these drugs.
7.2
Apomorphine
Based on reports of profound hypotension and loss of consciousness when apomorphine
was administered with ondansetron, the concomitant use of apomorphine with ondansetron is
contradindicated [see Contraindications (4)].
7.3
Phenytoin, Carbamazepine, and Rifampin
In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and
rifampin), the clearance of ondansetron was significantly increased and ondansetron blood
concentrations were decreased. However, on the basis of available data, no dosage adjustment
for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3)].
7.4
Tramadol
Although there are no data on pharmacokinetic drug interactions between ondansetron
and tramadol, data from two small studies indicate that concomitant use of ondansetron may
result in reduced analgesic activity of tramadol. Patients on concomitant ondansetron self
administered tramadol more frequently in these studies, leading to an increased cumulative dose
in patient controlled administration (PCA) of tramadol.
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7.5
Chemotherapy
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of
ondansetron.
In a crossover study in 76 pediatric patients, intravenous ondansetron did not increase
blood levels of high-dose methotrexate.
7.6
Temazepam
The coadministration of ondansetron had no effect on the pharmacokinetics and
pharmacodynamics of temazepam.
7.7
Alfentanil and Atracurium
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the
degree of neuromuscular blockade produced by atracurium. Interactions with general or local
anesthetics have not been studied.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. Reproduction studies have been performed in pregnant rats and
rabbits at intravenous doses up to 4 mg/kg per day (approximately 1.4 and 2.9 times the
recommended human intravenous dose of 0.15 mg/kg given three times a day, respectively, based
on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due
to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed.
8.3
Nursing Mothers
Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is
excreted in human milk. Because many drugs are excreted in human milk, caution should be
exercised when ondansetron is administered to a nursing woman.
8.4
Pediatric Use
Little information is available about the use of ondansetron in pediatric surgical patients
younger than 1 month of age. [See Clinical Studies(14.2)]. Little information is available about
the use of ondansetron in pediatric cancer patients younger than 6 months of age. [See Clinical
Studies(14.1) and Dosage and Administration (2)].
The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower
and the half-life is ~2.5 fold longer than patients who are > 4 to 24 months of age. As a
precaution, it is recommended that patients less than 4 months of age receiving this drug be
closely monitored. [See Clinical Pharmacology (12.3)].
8.5
Geriatric Use
Of the total number of subjects enrolled in cancer chemotherapy-induced and
postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65
years of age and over. No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical experience has not identified
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differences in responses between the elderly and younger patients, but greater sensitivity of some
older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of
65 [see Clinical Pharmacology (12.3)].
8.6
Hepatic Impairment
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance
is reduced and apparent volume of distribution is increased with a resultant increase in plasma
half-life [see Clinical Pharmacology (12.3)]. In such patients, a total daily dose of 8 mg should
not be exceeded [see Dosage and Administration (2.3)].
8.7
Renal Impairment
Although plasma clearance is reduced in patients with severe renal impairment
(creatinine clearance < 30 mL/min), no dosage adjustment is recommended [see Clinical
Pharmacology (12.3)].
9
DRUG ABUSE AND DEPENDENCE
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor
does it substitute for benzodiazepines in direct addiction studies.
10
OVERDOSAGE
There is no specific antidote for ondansetron overdose. Patients should be managed with
appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily
intravenous doses as large as 252 mg have been inadvertently administered without significant
adverse events. These doses are more than 10 times the recommended daily dose.
In addition to the adverse reactions listed above, the following events have been
described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to
3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg
of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another
patient that took 48 mg of ondansetron hydrochloride tablets. Following infusion of 32 mg over
only a 4-minute period, a vasovagal episode with transient second-degree heart block was
observed. In all instances, the events resolved completely.
11
DESCRIPTION
The active ingredient of ZOFRAN Injection is ondansetron hydrochloride, a selective
blocking agent of the serotonin 5-HT3 receptor type. Its chemical name is (±) 1, 2, 3, 9
tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one,
monohydrochloride, dihydrate. It has the following structural formula: structural formula
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The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of
365.9.
Ondansetron HCl is a white to off-white powder that is soluble in water and normal
saline.
Each 1 mL of aqueous solution in the 2 mL single-dose vial contains 2 mg of ondansetron
as the hydrochloride dihydrate; 9 mg of sodium chloride, USP; and 0.5 mg of citric acid
monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for
Injection, USP.
Each 1 mL of aqueous solution in the 20 mL multidose vial contains 2 mg of ondansetron
as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid
monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of
methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection,
USP.
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution for intravenous
use. The pH of the injection solution is 3.3 to 4.0.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron’s mechanism of
action has not been fully characterized, it is not a dopamine-receptor antagonist.
12.2 Pharmacodynamics
QTc interval prolongation was studied in a double blind, single intravenous dose,
placebo- and positive-controlled, crossover study in 58 healthy subjects. The maximum mean
(95% upper confidence bound) difference in QTcF from placebo after baseline-correction was
19.5 (21.8) ms and 5.6 (7.4) ms after 15 minute intravenous infusions of 32 mg and 8 mg
ZOFRAN, respectively. A significant exposure-response relationship was identified between
ondansetron concentration and ΔΔQTcF. Using the established exposure-response relationship,
24 mg infused intravenously over 15 min had a mean predicted (95% upper prediction interval)
ΔΔQTcF of 14.0 (16.3) ms. In contrast, 16 mg infused intravenously over 15 min using the same
model had a mean predicted (95% upper prediction interval) ΔΔQTcF of 9.1 (11.2) ms.
In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no
effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small
intestinal transit time. In another study in six normal male volunteers, a 16-mg dose infused over
5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood
pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown
to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin
concentrations.In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg
administered intravenously or intramuscularly was dynamically similar in the prevention of
nausea and vomiting using the ipecacuanha model of emesis.
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12.3 Pharmacokinetics
In normal adult volunteers, the following mean pharmacokinetic data have been
determined following a single 0.15-mg/kg intravenous dose.
Table 3. Pharmacokinetics in Normal Adult Volunteers
Age-group
(years)
n
Peak Plasma
Concentration
(ng/mL)
Mean Elimination
Half-life (h)
Plasma Clearance
(L/h/kg)
19-40
11
102
3.5
0.381
61-74
12
106
4.7
0.319
75
11
170
5.5
0.262
Absorption: A study was performed in normal volunteers (n = 56) to evaluate the
pharmacokinetics of a single 4-mg dose administered as a 5-minute infusion compared to a
single intramuscular injection. Systemic exposure as measured by mean AUC were equivalent,
with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ngh/mL for intravenous and
intramuscular groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8,
54.4] ng/mL at 10 minutes after intravenous infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at
41 minutes after intramuscular injection.
Distribution: Plasma protein binding of ondansetron as measured in vitro was 70% to
76%, over the pharmacologic concentration range of 10 to 500 ng/mL. Circulating drug also
distributes into erythrocytes.
Metabolism: Ondansetron is extensively metabolized in humans, with approximately 5%
of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic
pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate
conjugation.
Although some nonconjugated metabolites have pharmacologic activity, these are not
found in plasma at concentrations likely to significantly contribute to the biological activity of
ondansetron. The metabolites are observed in the urine.
In vitro metabolism studies have shown that ondansetron is a substrate for multiple
human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In
terms of overall ondansetron turnover, CYP3A4 plays a predominant role while formation of the
major in vivo metabolites is apparently mediated by CYP1A2. The role of CYP2D6 in
ondansetron in vivo metabolism is relatively minor.
The pharmacokinetics of intravenous ondansetron did not differ between subjects who
were poor metabolisers of CYP2D6 and those who were extensive metabolisers of CYP2D6,
further supporting the limited role of CYP2D6 in ondansetron disposition in vivo.
Elimination: In adult cancer patients, the mean ondansetron elimination half-life was
4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4-day period. In
a dose proportionality study, systemic exposure to 32 mg of ondansetron was not proportional to
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dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent
with a small decrease in systemic clearance with increasing plasma concentrations.
Geriatrics: A reduction in clearance and increase in elimination half-life are seen in
patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were
similar in patients over 65 years of age and those under 65 years of age; there was an insufficient
number of patients over 75 years of age to permit conclusions in that age-group. No dosage
adjustment is recommended in the elderly.
Pediatrics: Pharmacokinetic samples were collected from 74 cancer patients 6 to
48 months of age, who received a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours
for 3 doses during a safety and efficacy trial. These data were combined with sequential
pharmacokinetics data from 41 surgery patients 1 month to 24 months of age, who received a
single dose of 0.1 mg/kg of intravenous ondansetron prior to surgery with general anesthesia, and
a population pharmacokinetic analysis was performed on the combined data set. The results of
this analysis are included in Table 4 and are compared to the pharmacokinetic results in cancer
patients 4 to 18 years of age.
Table 4. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Cancer Patients
4 to 18 years of age
N = 21
0.599
1.9
2.8
Population PK Patientsa
1 month to 48 months of age
N = 115
0.582
3.65
4.9
a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age
who receive a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours for 3 doses would be
expected to achieve a systemic exposure (AUC) consistent with the exposure achieved in
previous pediatric studies in cancer patients (4 to 18 years of age) at similar doses.
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery
requiring anesthesia for a duration of 45 minutes to 2 hours, a single intravenous dose of
ondansetron, 2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to
anesthesia induction. Mean weight-normalized clearance and volume of distribution values in
these pediatric surgical patients were similar to those previously reported for young adults. Mean
terminal half-life was slightly reduced in pediatric patients (range, 2.5 to 3 hours) in comparison
with adults (range, 3 to 3.5 hours).
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing
surgery requiring general anesthesia, a single intravenous dose of ondansetron, 0.1 or 0.2 mg/kg,
was administered prior to surgery. As shown in Table 5, the 41 patients with pharmacokinetic
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data were divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months
of age, and are compared to pediatric patients 3 to 12 years of age.
Table 5. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Surgery Patients
3 to 12 years of age
N = 21
0.439
1.65
2.9
Pediatric Surgery Patients
5 to 24 months of age
N = 22
0.581
2.3
2.9
Pediatric Surgery Patients
1 month to 4 months of age
N = 19
0.401
3.5
6.7
In general, surgical and cancer pediatric patients younger than 18 years tend to have a
higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric
patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher
volume of distribution in this age group.
In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three
intravenous doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years
of age exhibited ondansetron pharmacokinetic parameters similar to those of adults.
Renal Impairment: Due to the very small contribution (5%) of renal clearance to the
overall clearance, renal impairment was not expected to significantly influence the total
clearance of ondansetron. However, ondansetron mean plasma clearance was reduced by about
41% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction
in clearance is variable and was not consistent with an increase in half-life. No reduction in dose
or dosing frequency in these patients is warranted.
Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is
reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in those
without hepatic impairment. In patients with severe hepatic impairment (Child-Pugh score of 10
or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased
with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a
total daily dose of 8 mg should not be exceeded.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral
ondansetron doses up to 10 and 30 mg/kg per day, respectively (approximately 3.6 and 5.4 times
the recommended human intravenous dose of 0.15 mg/kg given three times a day, based on body
surface area). Ondansetron was not mutagenic in standard tests for mutagenicity.
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Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the
recommended human intravenous dose, based on body surface area) did not affect fertility or
general reproductive performance of male and female rats.
14
CLINICAL STUDIES
The clinical efficacy of ondansetron hydrochloride, the active ingredient of ZOFRAN,
was assessed in clinical trials as described below.
14.1 Chemotherapy-Induced Nausea and Vomiting
Adults: In a double-blind study of three different dosing regimens of ZOFRAN Injection,
0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer
chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing
regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the
0.15-mg/kg dosing regimen.
Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, ZOFRAN
Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing
nausea and vomiting induced by cisplatin-based chemotherapy. Therapeutic response was as
shown in Table 6.
Table 6. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and
Vomiting in Single-Day Cisplatin Therapya in Adults
ZOFRAN Injection
(0.15 mg/kg x 3)
Placebo
P Valueb
Number of patients
14
14
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
2 (14%)
8 (57%)
2 (14%)
2 (14%)
0 (0%)
0 (0%)
1 (7%)
13 (93%)
0.001
Median number of emetic episodes
1.5
Undefinedc
Median time to first emetic episode (h)
11.6
2.8
0.001
Median nausea scores (0-100)d
3
59
0.034
Global satisfaction with control of
nausea and vomiting (0-100)
e
96
10.5
0.009
a Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5)
or moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other
chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There
was no difference between treatments in the types of chemotherapy that would account for
differences in response.
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b Efficacy based on "all patients treated" analysis.
c Median undefined since at least 50% of the patients were rescued or had more than five
emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Ondansetron injection (0.15-mg/kg x 3 doses) was compared with metoclopramide (2
mg/kg x 6 doses) in a single-blind trial in 307 patients receiving cisplatin 100 mg/m2 with or
without other chemotherapeutic agents. Patients received the first dose of ondansetron or
metoclopramide 30 minutes before cisplatin. Two additional ondansetron doses were
administered 4 and 8 hours later, or five additional metoclopramide doses were administered 2, 4,
7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less. Episodes of
vomiting and retching were tabulated over the period of 24 hours after cisplatin. The results of
this study are summarized in Table 7.
Table 7. Therapeutic Response in Prevention of Vomiting Induced by Cisplatin ( 100
mg/m2) Single-Day Therapya in Adults
ZOFRAN Injection
Metoclopramide
P Value
Dose
0.15 mg/kg x 3
2 mg/kg x 6
Number of patients in efficacy population
136
138
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
54 (40%)
34 (25%)
19 (14%)
29 (21%)
41 (30%)
30 (22%)
18 (13%)
49 (36%)
Comparison of treatments with respect to
0 Emetic episodes
More than 5 emetic episodes/rescued
54/136
29/136
41/138
49/138
0.083
0.009
Median number of emetic episodes
1
2
0.005
Median time to first emetic episode (h)
20.5
4.3
< 0.001
Global satisfaction with control of nausea
and vomiting (0-100)b
85
63
0.001
Acute dystonic reactions
0
8
0.005
Akathisia
0
10
0.002
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a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including
cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments
in the types of chemotherapy that would account for differences in response.
b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled
study of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide
(500 to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than
placebo in preventing nausea and vomiting. The results are summarized in Table 8.
Table 8. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and
Vomiting in Single-Day Cyclophosphamide Therapya in Adults
ZOFRAN Injection
(0.15 mg/kg x 3)
Placebo
P Valueb
Number of patients
10
10
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
7 (70%)
0 (0%)
2 (20%)
1 (10%)
0 (0%)
2 (20%)
4 (40%)
4 (40%)
0.001
0.131
Median number of emetic episodes
0
4
0.008
Median time to first emetic episode (h)
Undefinedc
8.79
Median nausea scores (0-100)d
0
60
0.001
Global satisfaction with control of
nausea and vomiting (0-100)e
100
52
0.008
a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including
fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between
treatments in the type of chemotherapy that would account for differences in response.
b Efficacy based on "all patients treated" analysis.
c Median undefined since at least 50% of patients did not have any emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose,
100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with
ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median,
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2; range, 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes
occurred in 217 (81%) re-treatment courses.
Pediatrics: Four open-label, noncomparative (one US, three foreign) trials have been
performed with 209 pediatric cancer patients 4 to 18 years of age given a variety of cisplatin or
noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged from
0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration
of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, ZOFRAN was
administered intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2
to 39 mg. In these studies, 58% of the 196 evaluable patients had a complete response (no emetic
episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was essentially the
same as for patients older than 18 years of age.
An open-label, multicenter, noncomparative trial has been performed in 75 pediatric
cancer patients 6 to 48 months of age receiving at least one moderately or highly emetogenic
chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were
American Hispanic, and 15% were black patients. ZOFRAN was administered intravenously
over 15 minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before
the start of chemotherapy, the second and third doses were administered 4 and 8 hours after the
first dose, respectively. Eighteen patients (25%) received routine prophylactic dexamethasone
(i.e., not given as rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic
episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was comparable to
the prevention of vomiting in patients 4 years of age and older.
14.2 Prevention of Postoperative Nausea and/or Vomiting
Adults: Adult surgical patients who received ondansetron immediately before the
induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal;
opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare
and/or vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double-
blind US studies involving 554 patients. ZOFRAN Injection (4 mg) intravenous given over 2 to
5 minutes was significantly more effective than placebo. The results of these studies are
summarized in Table 9.
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Table 9. Therapeutic Response in Prevention of Postoperative Nausea and Vomiting in
Adult Patients
Ondansetron
4 mg
Intravenous
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
103 (76%)
13 (10%)
20 (15%)
139
64 (46%)
17 (12%)
58 (42%)
< 0.001
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
134
56 (42%)
136
39 (29%)
Study 2
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
85 (63%)
16 (12%)
35 (26%)
143
63 (44%)
29 (20%)
51 (36%)
0.002
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
125
48 (38%)
133
42 (32%)
The study populations in Table 9 consisted mainly of females undergoing laparoscopic
procedures.
In a placebo-controlled study conducted in 468 males undergoing outpatient procedures, a
single 4-mg intravenous ondansetron dose prevented postoperative vomiting over a 24-hour study
period in 79% of males receiving drug compared to 63% of males receiving placebo (P 0.001).
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major
abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg intravenous ondansetron
dose for prevention of postoperative nausea and vomiting over a 24-hour study period. At the
Reference ID: 3216807
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4-mg dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the first
study (P 0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the
second study (P = 0.001) experienced no emetic episodes. No additional benefit was observed in
patients who received intravenous ondansetron 8 mg compared to patients who received
intravenous ondansetron 4 mg.
Pediatrics: Three double-blind, placebo-controlled studies have been performed (one
US, two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing general
anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or without
adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized
to either single intravenous doses of ondansetron (0.1 mg/kg for pediatric patients weighing
40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was
administered over at least 30 seconds, immediately prior to or following anesthesia induction.
Ondansetron was significantly more effective than placebo in preventing nausea and vomiting.
The results of these studies are summarized in Table 10.
Table 10. Therapeutic Response in Prevention of Postoperative Nausea and Vomiting in
Pediatric Patients 2 to 12 Years of Age
Treatment Response Over
24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Study 1
Number of patients
205
210
0 Emetic episodes
140 (68%)
82 (39%)
0.001
Failurea
65 (32%)
128 (61%)
Study 2
Number of patients
112
110
0 Emetic episodes
68 (61%)
38 (35%)
0.001
Failurea
44 (39%)
72 (65%)
Study 3
Number of patients
206
206
0 Emetic episodes
123 (60%)
96 (47%)
0.01
Failurea
Nausea assessmentsb:
83 (40%)
110 (53%)
Number of patients
185
191
None
119 (64%)
99 (52%)
0.01
a Failure was one or more emetic episodes, rescued, or withdrawn.
b Nausea measured as none, mild, or severe.
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A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric
patients 1 month to 24 months of age who were undergoing routine surgery under general
anesthesia. Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were
American Hispanic, 2% were Asian, and 6% were “other race” patients. A single 0.1-mg/kg
intravenous dose of ondansetron administered within 5 minutes following induction of anesthesia
was statistically significantly more effective than placebo in preventing vomiting. In the placebo
group, 28% of patients experienced vomiting compared to 11% of subjects who received
ondansetron (P 0.01). Overall, 32 (10%) of placebo patients and 18 (5%) of patients who
received ondansetron received antiemetic rescue medication(s) or prematurely withdrew from the
study.
14.3 Prevention of Further Postoperative Nausea and Vomiting
Adults: Adult surgical patients receiving general balanced anesthesia (barbiturate:
thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide;
neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and
supplemental isoflurane) who received no prophylactic antiemetics and who experienced nausea
and/or vomiting within 2 hours postoperatively were evaluated in two double-blind US studies
involving 441 patients. Patients who experienced an episode of postoperative nausea and/or
vomiting were given ZOFRAN Injection (4 mg) intravenous over 2 to 5 minutes, and this was
significantly more effective than placebo. The results of these studies are summarized in Table
11.
Reference ID: 3216807
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Table 11. Therapeutic Response in Prevention of Further Postoperative Nausea and
Vomiting in Adult Patients
Ondansetron
4 mg
Intravenous
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
104
117
0 Emetic episodes
49 (47%)
19 (16%)
< 0.001
1 Emetic episode
12 (12%)
9 (8%)
More than 1 emetic episode/rescued
43 (41%)
89 (76%)
Median time to first emetic episode (min)a
55.0
43.0
Nausea assessments:
Number of patients
98
102
Mean nausea score over 24-h postoperative
periodb
1.7
3.1
Study 2
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
112
108
0 Emetic episodes
49 (44%)
28 (26%)
0.006
1 Emetic episode
14 (13%)
3 (3%)
More than 1 emetic episode/rescued
49 (44%)
77 (71%)
Median time to first emetic episode (min)a
60.5
34.0
Nausea assessments:
Number of patients
105
85
Mean nausea score over 24-h postoperative
periodb
1.9
2.9
a After administration of study drug.
b Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
The study populations in Table 11 consisted mainly of women undergoing laparoscopic
procedures.
Repeat Dosing in Adults: In patients who do not achieve adequate control of
postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous
dose of ondansetron 4 mg, administration of a second intravenous dose of ondansetron 4 mg
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postoperatively does not provide additional control of nausea and vomiting.
Pediatrics: One double-blind, placebo-controlled, US study was performed in 351 male
and female outpatients (2 to 12 years of age) who received general anesthesia with nitrous oxide
and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who
experienced two or more emetic episodes within 2 hours following discontinuation of nitrous
oxide were randomized to either single intravenous doses of ondansetron (0.1 mg/kg for pediatric
patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo
administered over at least 30 seconds. Ondansetron was significantly more effective than placebo
in preventing further episodes of nausea and vomiting. The results of the study are summarized
in Table 12.
Table 12. Therapeutic Response in Prevention of Further Postoperative Nausea and
Vomiting in Pediatric Patients 2 to 12 Years of Age
Treatment Response
Ondansetron
Placebo
Over 24 Hours
n (%)
n (%)
P Value
Number of patients
180
171
0 Emetic episodes
96 (53%)
29 (17%)
0.001
Failurea
84 (47%)
142 (83%)
a Failure was one or more emetic episodes, rescued, or withdrawn.
16
HOW SUPPLIED/STORAGE AND HANDLING
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
NDC 0173-0442-02 2-mL single-dose vials (Carton of 5)
NDC 0173-0442-00 20-mL multidose vials (Singles)
Storage: Store vials between 2° and 30°C (36° and 86°F). Protect from light.
17
PATIENT COUNSELING INFORMATION
Patients should be informed that ZOFRAN may cause serious cardiac arrhythmias such
as QT prolongation. Patients should be instructed to tell their health care provider right
away if they perceive a change in their heart rate, if they feel lightheaded, or if they have
a syncopal episode.
Patients should be informed that the chances of developing severe cardiac arrhythmias
such as QT prolongation and Torsade de Pointes are higher in the following people:
o Patients with a personal or family history of abnormal heart rhythms, such as
congenital long QT syndrome;
o Patients who take medications, such as diuretics, which may cause electrolyte
abnormalities
o Patients with hypokalemia or hypomagnesemia
ZOFRAN should be avoided in these patients, since they may be more at risk for cardiac
arrhythmias such as QT prolongation and Torsade de Pointes.
Reference ID: 3216807
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Inform patients that ZOFRAN may cause hypersensitivity reactions, some as severe as
anaphylaxis and bronchospasm. The patient should report any signs and symptoms of
hypersensitivity reactions, including fever, chills, rash, or breathing problems.
The patient should report the use of all medications, especially apomorphine, to their
health care provider. Concomitant use of apomorphine and ZOFRAN may cause a
significant drop in blood pressure and loss of consciousness.
Inform patients that ZOFRAN may cause headache, drowsiness/sedation, constipation,
fever and diarrhea. company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
©2012, GlaxoSmithKline. All rights reserved.
ZFJ:5PI
Reference ID: 3216807
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|
custom-source
|
2025-02-12T13:46:26.101439
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020007s043lbl.pdf', 'application_number': 20007, 'submission_type': 'SUPPL ', 'submission_number': 43}
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12,131
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3
LOTRISONE®
1
(clotrimazole and
2
betamethasone dipropionate)
3
CREAM and LOTION
4
5
FOR
TOPICAL
USE
ONLY,
NOT
FOR
OPHTHALMIC,
ORAL,
OR
6
INTRAVAGINAL USE, NOT RECOMMENDED FOR PATIENTS UNDER THE
7
AGE OF 17 YEARS AND NOT RECOMMENDED FOR DIAPER DERMATITIS
8
9
DESCRIPTION LOTRISONE Cream and Lotion contain combinations of
10
clotrimazole, a synthetic antifungal agent, and betamethasone dipropionate, a
11
synthetic corticosteroid, for dermatologic use.
12
13
Chemically, clotrimazole is 1–(o-chloro-? ,? -diphenylbenzyl)imidazole, with the
14
empirical formula C22H17CIN2, a molecular weight of 344.84, and the following
15
structural formula:
16
17
18
19
Clotrimazole is an odorless, white crystalline powder, insoluble in water and
20
soluble in ethanol.
21
22
Betamethasone dipropionate has the chemical name 9-fluoro-11?,17,21-
23
trihydroxy-16?-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the
24
empirical formula C28H37FO7, a molecular weight of 504.59, and the following
25
structural formula:
26
27
Betamethasone dipropionate is a white to creamy white, odorless crystalline
28
powder, insoluble in water.
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
30
Each gram of LOTRISONE Cream contains 10 mg clotrimazole and 0.643 mg
31
betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a
32
hydrophilic cream consisting of purified water, mineral oil, white petrolatum,
33
cetearyl alcohol 70/30, ceteareth-30, propylene glycol, monobasic sodium
34
phosphate, and phosphoric acid; benzyl alcohol, as preservative. LORTISONE
35
Cream is smooth, uniform, and white to off-white in color.
36
37
Each gram of LOTRISONE Lotion contains 10 mg clotrimazole and 0.643 mg
38
betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a
39
hydrophilic base of purified water, mineral oil, white petrolatum, cetearyl alcohol
40
70/30, ceteareth-30, propylene glycol, monobasic sodium phosphate, and
41
phosphoric acid, benzyl alcohol as a preservative. LOTRISONE Lotion may
42
contain sodium hydroxide. LOTRISONE Lotion is opaque and white in color.
43
44
CLINICAL PHARMACOLOGY
45
46
Clotrimazole and Betamethasone Dipropionate
47
LORTISONE Cream has been shown to be least as effective as clottrimazole
48
alone in a different cream vehicle. No comparative studies have been conducted
49
with LOTRISONE Lotion and clotrimazole alone. Use of corticosteroids in the
50
treatment of fungal infection may lead to suppression of host inflammation
51
leading to worsening or decreased cure rate.
52
53
Clotrimazole
54
Skin penetration and systemic absorption of clotrimazole following topical
55
application of LOTRISONE Cream or Lotion have not been studied. The following
56
information was obtained using 1% clotrimazole cream and solution formulations.
57
Six hours after the application of radioactive clotrimazole 1% cream and 1%
58
solution onto intact and acutely inflamed skin, the concentration of clotrimazole
59
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
varied from 100 mcg/cm3 in the stratum corneum, to 0.5 to 1 mcg/cm3 in the
60
reticular dermis, and 0.1 mcg/cm3 in the subcutis. No measurable amount of
61
radioactivity (<0.001 mcg/mL) was found in the serum within 48 hours after
62
application under occlusive dressing of 0.5 mL of the solution or 0.8 g of the
63
cream. Only 0.5% or less of the applied radioactivity was excreted in the urine.
64
65
Microbiology
66
Mechanism of Action: Clotrimazole is an imidazole antifungal agent. Imidazoles
67
inhibit 14-? -demethylation of lanosterol in fungi by binding to one of the
68
cytochrome P-450 enzymes. This leads to the accumulation of 14-? -
69
methylsterols and reduced concentrations of ergosterol, a sterol essential for a
70
normal fungal cytoplasmic membrane. The methylsterols may affect the electron
71
transport system, thereby inhibiting growth of fungi.
72
73
Activity In Vivo: Clotrimazole has been shown to be active against most strains of
74
the following dermatophytes, both in vitro and in clinical infections as described in
75
the INDICATIONS AND USAGE section: Epidermophyton floccosum,
76
Trichophyton mentagrophytes, and Trichophyton rubrum.
77
78
Activity In Vitro: In vitro, clotrimazole has been shown to have activity against
79
many dermatophytes, but the clinical significance of this information is
80
unknown.
81
82
Drug Resistance: Strains of dermatophytes having a natural resistance to
83
clotrimazole have not been reported. Resistance to azoles including clotrimazole
84
has been reported in some Candida species.
85
86
No single-step or multiple-step resistance to clotrimazole has developed during
87
successive passages of Trichophyton mentagrophytes.
88
89
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Betamethasone Dipropionate
90
Betamethasone dipropionate, a corticosteroid, has been shown to have topical
91
(dermatologic) and systemic pharmacologic and metabolic effects characteristic
92
of this class of drugs.
93
94
Pharmacokinetics: The extent of percutaneous absorption of topical
95
corticosteroids is determined by many factors, including the vehicle, the integrity
96
of the epidermal barrier and the use of occlusive dressings. (See DOSAGE AND
97
ADMINISTRATION section). Topical corticosteroids can be absorbed from
98
normal intact skin. Inflammation and/or other disease processes in the skin may
99
increase percutaneous absorption of topical corticosteroids. Occlusive dressings
100
substantially increase the percutaneous absorption of topical corticosteroids (See
101
DOSAGE AND ADMINISTRATION section).
102
103
Once absorbed through the skin, the pharmacokinetics of topical corticosteroids
104
are similar to systemically administered corticosteroids. Corticosteroids are
105
bound to plasma proteins in varying degrees. Corticosteroids are metabolized
106
primarily in the liver and are then excreted by the kidneys. Some of the topical
107
corticosteroids and their metabolites are also excreted into the bile.
108
109
Studies performed with LOTRISONE Cream and Lotion indicate that these
110
topical
combination
anti-fungal/corticosteroids
may
have
vasoconstrictor
111
potencies in a range that is comparable to high potency topical corticosteroids.
112
Therefore use is not recommended in patients less than 17 years of age, in
113
diaper dermatitis, and under occlusion.
114
115
CLINICAL STUDIES (LOTRISONE Cream)
116
In clinical studies of tinea corporis, tinea cruris, and tinea pedis, patients treated
117
with LOTRISONE Cream showed a better clinical response at the first return visit
118
than patients treated with clotrimazole cream. In tinea corporis and tinea cruris,
119
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
the patient returned 3 to 5 days after starting treatment, and in tinea pedis, after 1
120
week. Mycological cure rates observed in patients treated with LOTRISONE
121
Cream were as good as or better than in those patients treated with clotrimazole
122
cream. In these same clinical studies, patients treated with LORTISONE Cream
123
showed better clinical responses and mycological cure rates when compared
124
with patients treated with betamethasone dipropionate cream.
125
126
CLINICAL STUDIES (LOTRISONE Lotion)
127
In the treatment of tinea pedis twice daily for four weeks, LOTRISONE Lotion
128
was shown to be superior to vehicle in relieving symptoms of erythema, scaling,
129
pruritus, and maceration at week 2. LOTRISONE Lotion was also shown to have
130
a superior mycological cure rate compared to vehicle two weeks after
131
discontinuation of treatment. It is unclear if the relief of symptoms at 2 weeks in
132
this clinical study with LOTRISONE Lotion was due to the contribution of
133
betamethasone dipropionate, clotrimazole, or both.
134
135
In the treatment of tinea cruris twice daily for two weeks, LOTRISONE Lotion was
136
shown to be superior to vehicle in the relief of symptoms of erythema, scaling,
137
and pruritus after 3 days. It is unclear if the relief of symptoms after 3 days in this
138
clinical study with LOTRISONE Lotion was due to the contribution of
139
betamethasone dipropionate, clotrimazole, or both.
140
141
The comparative efficacy and safety of LOTRISONE Lotion versus clotrimazole
142
alone in a lotion vehicle have not been studied in the treatment of tinea pedis,
143
tinea cruris, and tinea corporis. The comparative efficacy and safety of
144
LOTRISONE Lotion and LOTRISONE Cream have also not been studied.
145
146
INDICATIONS AND USAGE
147
LOTRISONE Cream and Lotion are indicated in patients 17 years and older for
148
the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris and
149
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes,
150
and Trichophyton rubrum. Effective treatment without the risks associated with
151
topical corticosteroid use may be obtained using a topical antifungal agent that
152
does not contain a corticosteroid, especially for noninflammatory tinea infections.
153
The efficacy of LOTRISONE Cream or Lotion for the treatment of infections
154
caused by zoophilic dermatophytes (e.g., Microsporum canis) has not been
155
established. Several cases of treatment failure of LOTRISONE Cream in the
156
treatment of infections caused by Microsporum canis have been reported.
157
158
CONTRAINDICATIONS
159
LOTRISONE Cream or Lotion is contraindicated in patients who are sensitive to
160
clotrimazole, betamethasone dipropionate, other corticosteroids or imidazoles, or
161
to any ingredient in these preparations.
162
163
PRECAUTIONS
164
General: Systemic absorption of topical corticosteroids can produce reversible
165
hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for
166
glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of
167
Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in
168
some patients by systemic absorption of topical corticosteroids while on
169
treatment.
170
171
Conditions which augment systemic absorption include use over large surface
172
areas, prolonged use, and use under occlusive dressings. Use of more than one
173
corticosteriod-containing product at the same time may increase total systemic
174
glucocorticoid exposure. Patients applying LOTRISONE Cream or Lotion to a
175
large surface area or to areas under occlusion should be evaluated periodically
176
for evidence of HPA-axis suppression. This may be done by using the ACTH
177
stimulation, morning plasma cortisol, and urinary free cortisol tests.
178
179
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
If HPA-axis suppression is noted, an attempt should be made to withdraw the
180
drug, to reduce the frequency of application, or to substitute a less potent
181
corticosteroid. Recovery of HPA axis function is generally prompt upon
182
discontinuation of topical corticosteroids. Infrequently, signs and symptoms of
183
glucocorticosteroid insufficiency may occur, requiring supplemental systemic
184
corticosteroids.
185
186
In a small study, LOTRISONE Cream was applied using large dosages, 7 g daily
187
for 14 days (BID) to the crural area of normal adult subjects. Three of the eight
188
normal subjects on whom LOTRISONE Cream was applied exhibited low
189
morning plasma cortisol levels during treatment. One of these subjects had an
190
abnormal Cortrosyn test. The effect on morning plasma cortisol was transient
191
and subjects recovered one week after discontinuing dosing. In addition, two
192
separate studies in pediatric patients demonstrated adrenal suppression as
193
determined by cosyntropin testing (See PRECAUTIONS – Pediatric Use
194
section).
195
196
Pediatric patients may be more susceptible to systemic toxicity from equivalent
197
doses due to their larger skin surface to body mass ratios. (See PRECAUTIONS
198
- Pediatric Use section)
199
200
If irritation develops, LOTRISONE Cream or Lotion should be discontinued and
201
appropriate therapy instituted.
202
203
THE SAFETY OF LOTRISONE CREAM OR LOTION HAS NOT BEEN
204
DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE
205
EVENTS
CONSISTENT
WITH
CORTICOSTEROID
USE
HAVE
BEEN
206
OBSERVED IN PATIENTS TREATED WITH LOTRISONE CREAM FOR
207
DIAPER DERMATITIS. THE USE OF LOTRISONE CREAM OR LOTION IN
208
THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED.
209
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
210
Information for Patients: Patients using LOTRISONE Cream or Lotion should
211
receive the following information and instructions:
212
213
1. The medication is to be used as directed by the physician and is not
214
recommended for use longer than the prescribed time period. It is for
215
external use only. Avoid contact with the eyes, mouth, or intravaginally.
216
217
2. This medication is to be used for the full prescribed treatment time, even
218
though the symptoms may have improved. Notify the physician if there is no
219
improvement after 1 week of treatment for tinea cruris or tinea corporis, or
220
after 2 weeks for tinea pedis.
221
222
3. This medication should only be used for the disorder for which it was
223
prescribed.
224
225
4. Other
corticosteriod-containing
products
should
not
be
used
with
226
LOTRISONE without first talking with your physician.
227
228
5. The treated skin area should not be bandaged, covered, or wrapped so as to
229
be occluded. (See DOSAGE AND ADMINISTRATION section.)
230
231
6. Any signs of local adverse reactions should be reported to your physician.
232
233
7. Patients should avoid sources of infection or reinfection.
234
235
8. When using LOTRISONE Cream or Lotion in the groin area, patients should
236
use the medication for two weeks only, and apply the cream or lotion
237
sparingly. Patients should wear loose-fitting clothing. Notify the physician if
238
the condition persists after 2 weeks.
239
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
240
9. The safety of LORTISONE Cream or Lotion has not been demonstrated in the
241
treatment of diaper dermatitis. Adverse events consistent with corticosteroid
242
use have been observed in patients treated with LOTRISONE Cream for
243
diaper dermatitis. The use of LOTRISONE Cream or Lotion in the treatment
244
of diaper dermatitis is not recommended.
245
246
Laboratory Tests: If there is a lack of response to LOTRISONE Cream or
247
Lotion, appropriate confirmation of the diagnosis, including possible mycological
248
studies, is indicated before instituting another course of therapy.
249
250
The following tests may be helpful in evaluating HPA-axis suppression due to the
251
corticosteroid components:
252
253
Urinary free cortisol test
254
Morning plasma cortisol test
255
ACTH (cosyntropin) stimulation test
256
257
Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no
258
laboratory animal studies with either the combination of clotrimazole and
259
betamethasone dipropionate or with either component individually to evaluate
260
carcinogenesis.
261
262
Betamethasone was negative in the bacterial mutagenicity assay (Salmonella
263
typhimurium and Escherichia coli), and in the mammalian cell mutagenicity assay
264
(CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome
265
aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus
266
assay. This pattern of response is similar to that of dexamethasone and
267
hydrocortisone.
268
269
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
In genotoxicity testing of clotrimazole, chromosomes of the spermatophores of
270
Chinese hamsters, which had been exposed to five daily oral clotrimazole doses
271
of 100 mg/kg body weight, were examined for structural changes during the
272
metaphase. The results of this study showed that clotrimazole had no mutagenic
273
effect.
274
275
Reproductive studies with betamethasone dipropionate carried out in rabbits at
276
doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the
277
intramuscular route indicated no impairment of fertility except for dose-related
278
increases in fetal resorption rates in both species. These doses are
279
approximately 5- and 38- fold the human dose based on a mg/m2 comparison,
280
respectively.
281
282
Oral doses of clotrimazole in mice resulted in decreased litter size at doses of
283
120 mg/kg and higher. This dose is approximately 10- fold the human dose
284
based on a mg/m2 comparison.
285
286
A Segment I (fertility and general reproduction) study of clotrimazole was
287
conducted in rats. Males and females were dosed orally (diet admixture) at
288
doses of 5, 10, 25 or 50 mg/kg/day for 10 weeks prior to mating. At 50 mg/kg
289
(approximately 8 times the human dose based on a mg/m2 comparison), there
290
was an adverse effect on maternal body weight gain and rearing of the offspring.
291
Doses of 25 mg/kg (approximately 4 times the human dose based on a mg/m2
292
comparison) and lower were well tolerated and produced no adverse effects on
293
fertility or reproduction.
294
295
Pregnancy Category C: There have been no teratogenic studies performed in
296
animals or humans with the combination of clotrimazole and betamethasone
297
dipropionate. Corticosteriods are generally teratogenic in laboratory animals
298
when administered at relatively low dosage levels.
299
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
300
A Segment II (teratology) study in pregnant rats with intravaginal doses up to 100
301
mg/kg clotrimazole have revealed no evidence of harm to the fetus. This dose is
302
approximately 17- fold the human dose based on a mg/m2 comparison.
303
304
Segment II (teratology) studies of clotrimazole were conducted by the oral
305
(gavage) route in rats, mice, and rabbits. In rats administered 25, 50, 100, or 200
306
mg/kg/day, no increase in malformations was seen at doses up to 200 mg/kg.
307
Doses of 100 and 200 mg/kg were embryotoxic (increased resorptions) as well
308
as maternally toxic, while doses of 25 and 50 mg/kg were well tolerated by both
309
the dams and the fetuses. These doses were approximately 4-, 8-, 17- and 34-
310
fold the human dose based on a mg/m2 comparison, respectively.
311
312
In pregnant mice, clotrimazole at oral doses of 25, 50, 100, or 200 mg/kg/day
313
was not teratogenic and was well tolerated by both the dams and the fetuses.
314
These doses were approximately 2-, 4-, 8- and 17-fold the human dose based on
315
a mg/m2 comparison, respectively.
316
317
No evidence of maternal toxicity or embryotoxicity was seen in pregnant rabbits
318
dosed orally with 60, 120, or 180 mg/kg/day. These doses were approximately
319
20-, 40- and 61-fold the human dose based on a mg/m2 comparison,
320
respectively.
321
322
Betamethasone dipropionate has been shown to be teratogenic in rabbits when
323
given by the intramuscular route at doses of 0.05 mg/kg. This dose is
324
approximately one-fifth the human dose based on a mg/m2 comparison. The
325
abnormalities observed included umbilical hernias, cephalocele and cleft palates.
326
327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Betamethasone dipropionate has not been tested for teratogenic potential by the
328
dermal route of administration. Some corticosteroids have been shown to be
329
teratogenic after dermal application to laboratory animals.
330
331
Nursing Mothers: Systemically administered corticosteroids appear in human
332
milk and could suppress growth, interfere with endogenous corticosteroid
333
production, or cause other untoward effects. It is not known whether topical
334
administration of corticosteroids could result in sufficient systemic absorption to
335
produce detectable quantities in human milk. Because many drugs are excreted
336
in human milk, caution should be exercised when LOTRISONE Cream or Lotion
337
is administered to a nursing woman.
338
339
Pediatric Use: Adverse events consistent with corticosteroid use have been
340
observed in patients under 12 years of age treated with LOTRISONE cream. In
341
open-label studies, 17 of 43 (39.5%) evaluable pediatric patients (aged 12 to 16
342
years old) using LOTRISONE Cream for treatment of tinea pedis demonstrated
343
adrenal suppression as determined by cosyntropin testing. In another open-label
344
study, 8 of 17 (47.1%) evaluable pediatric patients (aged 12 to 16 years old)
345
using LOTRISONE Cream for treatment of tinea cruris demonstrated adrenal
346
suppression as determined by cosyntropin testing. THE USE OF LOTRISONE
347
CREAM OR LOTION IN THE TREATMENT OF PATIENTS UNDER 17 YEARS
348
OF
AGE
OR
PATIENTS
WITH
DIAPER
DERMATITIS
IS
NOT
349
RECOMMENDED.
350
351
Because of higher ratio of skin surface area to body mass, pediatric patients
352
under the age of 12 years are at a higher risk with LOTRISONE Cream or Lotion.
353
The studies described above suggest that pediatric patients under the age of 17
354
years may also have this risk. They are at increased risk of developing Cushing’s
355
syndrome while on treatment and adrenal insufficiency after withdrawal of
356
treatment. Adverse effects, including striae and growth retardation, have been
357
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
reported with inappropriate use of LOTRISONE Cream in infants and children
358
(see PRECAUTIONS and ADVERSE REACTIONS sections).
359
360
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome,
361
linear growth retardation, delayed weight gain and intracranial hypertension have
362
been reported in children receiving topical corticosteroids. Manifestations of
363
adrenal suppression in children include low plasma cortisol levels and absence of
364
response to ACTH stimulation. Manifestations of intracranial hypertension
365
include bulging fontanelles, headaches, and bilateral papilledema.
366
367
Geriatric Use: Clinical studies of LOTRISONE Cream or Lotion did not include
368
sufficient numbers of subjects aged 65 and over to determine whether they
369
respond differently from younger subjects. Post-market adverse event reporting
370
for LOTRISONE Cream in patients aged 65 and above includes reports of skin
371
atrophy and rare reports of skin ulceration. Caution should be exercised with the
372
use of these corticosteroid containing topical products on thinning skin. THE USE
373
OF LOTRISONE CREAM OR LOTION UNDER OCCLUSION, SUCH AS IN
374
DIAPER DERMATITIS, IS NOT RECOMMENDED.
375
376
ADVERSE REACTIONS
377
Adverse reactions reported for LOTRISONE Cream in clinical trials were
378
paresthesia in 1.9% of patients, and rash, edema, and secondary infection, each
379
in less than 1% of patients.
380
381
Adverse reactions reported for LOTRISONE Lotion in clinical trials were burning
382
and dry skin in 1.6% of patients and stinging is less than 1% of patients.
383
384
The following local adverse reactions have been reported with topical
385
corticosteroids and may occur more frequently with the use of occlusive
386
dressings. These reactions are listed in an approximate decreasing order of
387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform
388
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis,
389
maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. In
390
the pediatric population, reported adverse events for LOTRISONE Cream include
391
growth retardation, benign intracranial hypertension, Cushing’s syndrome (HPA
392
axis suppression), and local cutaneous reactions, including skin atrophy.
393
394
Systemic absorption of topical corticosteroids has produced reversible
395
hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of
396
Cushing’s syndrome, hyperglycemia, and glucosuria in some patients.
397
398
Adverse reactions reported with the use of clotrimazole are as follows: erythema,
399
stinging, blistering, peeling, edema, pruritus, urticaria and general irritation of the
400
skin.
401
402
OVERDOSAGE
403
Amounts greater than 45 g/week of LOTRISONE Cream or 45 mL/week of
404
LOTRISONE Lotion should not be used. Acute overdosage with topical
405
application of LOTRISONE Cream or Lotion is unlikely and would not be
406
expected to lead to life-threatening situation. LOTRISONE Cream or Lotion
407
should not be used for longer than the prescribed time period. Topically applied
408
corticosteroids, such as the one contained in LOTRISONE Cream or Lotion can
409
be absorbed in sufficient amounts to produce systemic effects (see
410
PRECAUTIONS section).
411
412
DOSAGE AND ADMINISTRATION
413
Gently massage sufficient LOTRISONE Cream or Lotion into the affected skin
414
areas twice a day, in the morning and evening.
415
416
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
LOTRISONE Cream or Lotion should not be used longer than 2 weeks in
417
the treatment of tinea corporis or tinea cruris, and amounts greater than 45
418
g per week of LOTRISONE Cream or amounts greater than 45 mL per week
419
of LOTRISONE Lotion should not be used. If a patient with tinea corporis or
420
tinea cruris shows no clinical improvement after one week of treatment with
421
LOTRISONE Cream or Lotion, the diagnosis should be reviewed.
422
423
LOTRISONE Cream or Lotion should not be used longer than 4 weeks in
424
the treatment of tinea pedis and amounts greater than 45 g per week of
425
LOTRISONE Cream or amounts greater than 45 mL per week of
426
LOTRISONE Lotion should not be used. If a patient with tinea pedis shows no
427
clinical improvement after 2 weeks of treatment with LOTRISONE Cream or
428
Lotion, the diagnosis should be reviewed.
429
LOTRISONE Cream or Lotion should not be used with occlusive dressings.
430
431
HOW SUPPLIED
432
LOTRISONE Cream is supplied in 15-gram (NDC 0085-0924-01) and 45-gram
433
tubes (NDC 0085-0924-02); boxes of one. Store between 2°C and 30°C (36°F
434
and 86°F).
435
LOTRISONE Lotion is supplied in 30-mL bottles (NDC 0085-0809-01), box of
436
one. Store at 25°C (77°F) in the upright position only; excursions permitted
437
between 15°C and 30°C (59°F and 86°F).
438
SHAKE WELL BEFORE EACH USE.
439
Rx only
440
Manufactured by: Schering/KEY
441
Schering Corporation/KEY Pharmaceuticals, Inc.
442
Kenilworth, NJ 07033 USA
443
11/08/02
444
445
Copyright® 2000 Schering Corporation. All Rights reserved.
446
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
TEAR AT PERFORATION
447
GIVE TO PATIENT
448
Patient’s Instructions for Use
449
SHAKE WELL BEFORE EACH USE
450
451
LOTRISONE Cream
452
LOTRISONE Lotion
453
454
Patient Information Leaflet
455
456
What is LOTRISONE Cream or Lotion?
457
LOTRISONE Cream and Lotion are medications used on the skin to treat fungal
458
infections of the feet, groin and body, as diagnosed by your doctor. LOTRISONE
459
Cream or Lotion should be used for fungal infections that are inflamed and have
460
symptoms of redness and/or itching. Talk to your doctor if your fungal infection
461
does not have these symptoms. LOTRISONE Cream and Lotion contain a
462
corticosteroid. Notify your doctor if you notice side effects with the use of
463
LOTRISONE Cream or Lotion (see “What are the possible side effects of
464
LOTRISONE Cream and Lotion?” below). LOTRISONE Cream or Lotion is not
465
to be used in the eyes, in the mouth, or in the vagina.
466
467
How do LOTRISONE Cream and Lotion Work?
468
LOTRISONE Cream and Lotion are combinations of an antifungal agent
469
(clotrimazole) and a corticosteroid (betamethasone dipropionate). Clotrimazole
470
works against fungus. Betamethasone dipropionate, a corticosteroid, is used to
471
help relieve redness, swelling, itching, and other discomforts of fungal infections.
472
473
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Who should NOT use LOTRISONE Cream or Lotion?
474
LOTRISONE Cream and Lotion are not recommended for use in patients under
475
the age of 17 years. LOTRISONE Cream or Lotion is not recommended for use
476
in diaper rash.
477
Patients who are sensitive to clotrimazole and betamethasone dipropionate,
478
other corticosteroids or imidazoles or any ingredients in the preparation should
479
not use LOTRISONE Cream and Lotion.
480
481
How should I use LOTRISONE Cream or Lotion?
482
Gently massage sufficient LOTRISONE Cream or Lotion into the affected and
483
surrounding skin areas twice a day, in the morning and evening. Treatment for 2
484
weeks on the groin or on the body, and for 4 weeks on the feet is recommended.
485
The use of LOTRISONE Cream or Lotion for longer than 4 weeks is not
486
recommended for any condition. Prolonged use of LOTRISONE Cream or Lotion
487
may lead to unwanted side effects.
488
489
What other important information should I know about LOTRISONE Cream
490
and Lotion?
491
1. This medication is to be used for the full prescribed treatment time, even
492
though the symptoms may have improved. Notify your doctor if there is no
493
improvement after 1 week of treatment on the groin or body or after 2 weeks
494
on the feet.
495
2. This medication should only be used for the disorder for which it was
496
prescribed.
497
3. The treated skin area should not be bandaged or otherwise covered or
498
wrapped.
499
4. Other
corticosteriod-containing
products
should
not
be
used
with
500
LOTRISONE without first talking with your physician.
501
5. Any signs of side effects where LOTRISONE Cream or Lotion is applied
502
should be reported to your doctor.
503
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
6. When using LOTRISONE Cream or Lotion in the groin area, it is especially
504
important to use the medication for two weeks only, and to apply the cream or
505
lotion sparingly. You should tell your doctor if your problem persists after 2
506
weeks. You should also wear loose-fitting clothing so as to avoid tightly
507
covering the area where LOTRISONE Cream is applied.
508
7. This medication is not recommended for use in diaper rash.
509
510
What are the possible side effects of LOTRISONE Cream and Lotion?
511
The following side effects have been reported with topical corticosteroid
512
medications: itching, irritation, dryness, infection of the hair follicles, increased
513
hair, acne, change in skin color, allergic skin reaction, skin thinning, and stretch
514
marks. In children, reported adverse events for LOTRISONE Cream include
515
slower growth, Cushing’s syndrome (a type of hormone imbalance that can be
516
very serious), and local skin reactions, including thinning skin and stretch marks.
517
Hormone imbalance (adrenal suppression) was demonstrated in clinical studies
518
in children.
519
520
Can LOTRISONE Cream or Lotion be used if I am pregnant or plan to
521
become pregnant or if I am nursing?
522
Before using LOTRISONE Cream or Lotion, tell your doctor if you are pregnant
523
or plan to become pregnant. Also, tell your doctor if you are nursing.
524
525
How should LOTRISONE Cream or Lotion be stored?
526
LOTRISONE Cream should be stored between 2° and 30°C (36° and 86°F).
527
LOTRISONE Lotion should only be stored in an upright position between
528
15°C and 30°C (59°F and 86°F). Shake well before using LOTRISONE Lotion.
529
530
General advice about prescription medicines
531
This medicine was prescribed for your particular condition. Only use
532
LOTRISONE Cream or Lotion to treat the condition for which your doctor has
533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
prescribed. Do not give LOTRISONE Cream or Lotion to other people. It may
534
harm them.
535
536
This leaflet summarizes the most important information about LOTRISONE
537
Cream and Lotion. If you would like more information, talk with your doctor. You
538
can ask your pharmacist or doctor for information about LOTRISONE Cream and
539
Lotion that is written for health professionals.
540
541
Rx only
542
Schering/Key
543
544
Schering Corporation/Key Pharmaceuticals
545
Kenilworth, NJ 07033
546
Copyright? 2000, Schering Corp. All rights reserved.
547
11/08/02
548
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:26.200391
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20010slr003_Lotrisone_lbl.pdf', 'application_number': 20010, 'submission_type': 'SUPPL ', 'submission_number': 3}
|
12,130
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZOFRAN safely and effectively. See full prescribing information for
ZOFRAN.
ZOFRAN (ondansetron hydrochloride) injection for intravenous use
Initial U.S. Approval: 1991
------------------------RECENT MAJOR CHANGES—----------------------
Warnings and Precautions, Serotonin Syndrome (5.3)
09/2014
----------------------------INDICATIONS AND USAGE ---------------------------
ZOFRAN Injection is a 5-HT3 receptor antagonist indicated:
• Prevention of nausea and vomiting associated with initial and repeat
courses of emetogenic cancer chemotherapy. (1.1)
• Prevention of postoperative nausea and/or vomiting. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
Prevention of nausea and vomiting associated with initial and repeat courses
of emetogenic cancer chemotherapy (2.1):
•
Adults and Pediatric patients (6 months to 18 years): Three 0.15 mg/kg
doses, up to a maximum of 16 mg per dose, infused intravenously over 15
minutes. The first dose should be administered 30 minutes before the start
of chemotherapy. Subsequent doses are administered 4 and 8 hours after
the first dose.
Prevention of postoperative nausea and/or vomiting (2.2):
Population
Age
Dosage of
ZOFRAN
Injection
Intravenous
Infusion Rate
Adults
> 12 yrs
4 mg x 1
over 2 - 5 min
Pediatrics
(> 40 kg)
1 mo. – 12 yrs
4 mg x 1
over 2 - 5 min
Pediatrics
(≤ 40 kg)
1 mo. – 12 yrs
0.1 mg/kg x 1
over 2 - 5 min
• In patients with severe hepatic impairment, a total daily dose of 8 mg
should not be exceeded. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
ZOFRAN Injection (2 mg/mL): 20 mL multidose vials. (3)
-------------------------------CONTRAINDICATIONS ------------------------------
• Patients known to have hypersensitivity (e.g., anaphylaxis) to this product
or any of its components. (4)
• Concomitant use of apomorphine. (4)
------------------------ WARNINGS and PRECAUTIONS -----------------------
• Hypersensitivity reactions including anaphylaxis and bronchospasm, have
been reported in patients who have exhibited hypersensitivity to other
selective 5-HT3 receptor antagonists. (5.1)
• QT prolongation occurs in a dose-dependent manner. Cases of Torsade de
Pointes have been reported. Avoid ZOFRAN in patients with congenital
long QT syndrome. (5.2)
• Serotonin syndrome has been reported with 5-HT3 receptor antagonists
alone but particularly with concomitant use of serotonergic drugs. (5.3)
• Use in patients following abdominal surgery or in patients with
chemotherapy-induced nausea and vomiting may mask a progressive ileus
and/or gastric distention. (5.4)(5.5)
------------------------------ ADVERSE REACTIONS -----------------------------
Chemotherapy-Induced Nausea and Vomiting –
• The most common adverse reactions (≥ 7%) in adults are diarrhea,
headache, and fever. (6.1)
Postoperative Nausea and Vomiting –
• The most common adverse reaction (≥ 10%) which occurs at a higher
frequency compared to placebo in adults is headache. (6.1)
• The most common adverse reaction (≥ 2%) which occurs at a higher
frequency compared to placebo in pediatric patients 1 to 24 months of age
is diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• Apomorphine – profound hypotension and loss of consciousness.
Concomitant use with ondansetron is contraindicated. (7.2)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 09/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Prevention of Nausea and Vomiting Associated with
Initial and Repeat Courses of Emetogenic Cancer
Chemotherapy
1.2
Prevention of Postoperative Nausea and/or Vomiting
2 DOSAGE AND ADMINISTRATION
2.1
2.2
Prevention of Postoperative Nausea and Vomiting
2.3
Stability and Handling
2.4
Dosage Adjustment for Patients with Impaired Hepatic
Function
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
5.2
QT Prolongation
5.3
Serotonin Syndrome
5.4
Masking of Progressive Ileus and Gastric Distension
5.5
Effect on Peristalsis
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Drugs Affecting Cytochrome P-450 Enzymes
7.2
Apomorphine
7.3
Phenytoin, Carbamazepine, and Rifampin
7.4
Tramadol
7.5
Serotonergic Drugs
7.6
Chemotherapy
7.7
Temazepam
7.8
Alfentanil and Atracurium
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
9
DRUG ABUSE AND DEPENDENCE
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Chemotherapy-Induced Nausea and Vomiting
14.2 Prevention of Postoperative Nausea and/or Vomiting
14.3 Prevention of Further Postoperative Nausea and
Vomiting
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
1
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
10
15
20
25
30
35
1
FULL PRESCRIBING INFORMATION
2
1
INDICATIONS AND USAGE
3
1.1
Prevention of Nausea and Vomiting Associated with Initial and Repeat
4
Courses of Emetogenic Cancer Chemotherapy
ZOFRAN® Injection is indicated for the prevention of nausea and vomiting associated
6
with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin
7
[see Clinical Studies (14.1)].
8
ZOFRAN is approved for patients aged 6 months and older.
9
1.2
Prevention of Postoperative Nausea and/or Vomiting
ZOFRAN Injection is indicated for the prevention of postoperative nausea and/or
11
vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in
12
whom there is little expectation that nausea and/or vomiting will occur postoperatively. In
13
patients in whom nausea and/or vomiting must be avoided postoperatively, ZOFRAN Injection is
14
recommended even when the incidence of postoperative nausea and/or vomiting is low. For
patients who do not receive prophylactic ZOFRAN Injection and experience nausea and/or
16
vomiting postoperatively, ZOFRAN Injection may be given to prevent further episodes [see
17
Clinical Studies (14.3)].
18
ZOFRAN is approved for patients aged 1 month and older.
19
2
DOSAGE AND ADMINISTRATION
2.1
Prevention of Nausea and Vomiting Associated with Initial and Repeat
21
Courses of Emetogenic Chemotherapy
22
ZOFRAN Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium
23
Chloride Injection before administration.
24
Adults: The recommended adult intravenous dosage of ZOFRAN is three 0.15-mg/kg
doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)]. The first dose is
26
infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy.
27
Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and
28
8 hours after the first dose of ZOFRAN.
29
Pediatrics: For pediatric patients 6 months through 18 years of age, the intravenous
dosage of ZOFRAN is three 0.15-mg/kg doses up to a maximum of 16 mg per dose [see Clinical
31
Studies (14.1), Clinical Pharmacology (12.2, 12.3)]. The first dose is to be administered
32
30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses
33
(0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first
34
dose of ZOFRAN. The drug should be infused intravenously over 15 minutes.
2.2
Prevention of Postoperative Nausea and Vomiting
36
ZOFRAN Injection should not be mixed with solutions for which physical and chemical
37
compatibility have not been established. In particular, this applies to alkaline solutions as a
38
precipitate may form.
2
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
Adults: The recommended adult intravenous dosage of ZOFRAN is 4 mg undiluted
40
administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes,
41
immediately before induction of anesthesia, or postoperatively if the patient did not receive
42
prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after
43
surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection
44
for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few
45
patients above 80 kg have been studied. In patients who do not achieve adequate control of
46
postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous
47
dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron
48
postoperatively does not provide additional control of nausea and vomiting.
49
Pediatrics: For pediatric patients 1 month through 12 years of age, the dosage is a single
50
0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing
51
more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2
52
to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the
53
patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting
54
occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in
55
patients who had not received prophylactic ZOFRAN.
56
2.3
Stability and Handling
57
After dilution, do not use beyond 24 hours. Although ZOFRAN Injection is chemically
58
and physically stable when diluted as recommended, sterile precautions should be observed
59
because diluents generally do not contain preservative.
60
ZOFRAN Injection is stable at room temperature under normal lighting conditions for
61
48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection,
62
5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and
63
0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.
64
Note: Parenteral drug products should be inspected visually for particulate matter and
65
discoloration before administration whenever solution and container permit.
66
Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials
67
stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by
68
shaking the vial vigorously.
69
2.4
Dosage Adjustment for Patients with Impaired Hepatic Function
70
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single
71
maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the
72
emetogenic chemotherapy is recommended. There is no experience beyond first-day
73
administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].
74
3
DOSAGE FORMS AND STRENGTHS
75
ZOFRAN Injection, 2 mg/mL is a clear, colorless, nonpyrogenic, sterile solution available
76
as a 20 mL multidose vial.
3
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
77
4
CONTRAINDICATIONS
78
ZOFRAN Injection is contraindicated for patients known to have hypersensitivity (e.g.,
79
anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported
80
in patients taking ondansetron. [See Adverse Reactions (6.2)].
81
The concomitant use of apomorphine with ondansetron is contraindicated based on
82
reports of profound hypotension and loss of consciousness when apomorphine was administered
83
with ondansetron.
84
5
WARNINGS AND PRECAUTIONS
85
5.1
Hypersensitivity Reactions
86
Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported
87
in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
88
5.2
QT Prolongation
89
Ondansetron prolongs the QT interval in a dose-dependent manner [see Clinical
90
Pharmacology (12.2)]. In addition, post-marketing cases of Torsade de Pointes have been
91
reported in patients using ondansetron. Avoid ZOFRAN in patients with congenital long QT
92
syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g.,
93
hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking
94
other medicinal products that lead to QT prolongation.
95
5.3
Serotonin Syndrome
96
The development of serotonin syndrome has been reported with 5-HT3 receptor
97
antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g.,
98
selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors
99
(SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and
100
intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome
101
occurring with overdose of ZOFRAN alone has also been reported. The majority of reports of
102
serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post-anesthesia care
103
unit or an infusion center.
104
Symptoms associated with serotonin syndrome may include the following combination of
105
signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma),
106
autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing,
107
hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia,
108
incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting,
109
diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with
110
concomitant use of ZOFRAN and other serotonergic drugs. If symptoms of serotonin syndrome
111
occur, discontinue ZOFRAN and initiate supportive treatment. Patients should be informed of
112
the increased risk of serotonin syndrome, especially if ZOFRAN is used concomitantly with
113
other serotonergic drugs [see Drug Interactions (7.5), Overdosage (10), Patient Counseling
114
Information (17)].
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For current labeling information, please visit https://www.fda.gov/drugsatfda
115
5.4
Masking of Progressive Ileus and Gastric Distension
116
The use of ZOFRAN in patients following abdominal surgery or in patients with
117
chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distention.
118
5.5
Effect on Peristalsis
119
ZOFRAN is not a drug that stimulates gastric or intestinal peristalsis. It should not be
120
used instead of nasogastric suction.
121
6
ADVERSE REACTIONS
122
6.1
Clinical Trials Experience
123
Because clinical trials are conducted under widely varying conditions, adverse reaction
124
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
125
trials of another drug and may not reflect the rates observed in clinical practice.
126
The following adverse reactions have been reported in clinical trials of adult patients
127
treated with ondansetron, the active ingredient of intravenous ZOFRAN across a range of
128
dosages. A causal relationship to therapy with ZOFRAN (ondansetron) was unclear in many
129
cases.
130
Chemotherapy-Induced Nausea and Vomiting:
131
132
Table 1. Adverse Reactions Reported in > 5% of Adult Patients Who Received
133
Ondansetron at a Dosage of Three 0.15-mg/kg Doses
Adverse Reaction
Number of Adult Patients with Reaction
ZOFRAN
Injection
0.15 mg/kg x 3
n = 419
Metoclopramide
n = 156
Placebo
n = 34
Diarrhea
16%
44%
18%
Headache
17%
7%
15%
Fever
8%
5%
3%
134
135
Cardiovascular: Rare cases of angina (chest pain), electrocardiographic alterations,
136
hypotension, and tachycardia have been reported.
137
Gastrointestinal: Constipation has been reported in 11% of chemotherapy patients
138
receiving multiday ondansetron.
139
Hepatic: In comparative trials in cisplatin chemotherapy patients with normal baseline
140
values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have
141
been reported to exceed twice the upper limit of normal in approximately 5% of patients. The
142
increases were transient and did not appear to be related to dose or duration of therapy. On repeat
143
exposure, similar transient elevations in transaminase values occurred in some courses, but
144
symptomatic hepatic disease did not occur.
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145
Integumentary: Rash has occurred in approximately 1% of patients receiving
146
ondansetron.
147
Neurological: There have been rare reports consistent with, but not diagnostic of,
148
extrapyramidal reactions in patients receiving ZOFRAN Injection, and rare cases of grand mal
149
seizure.
150
Other: Rare cases of hypokalemia have been reported.
151
Postoperative Nausea and Vomiting: The adverse reactions in Table 2 have been
152
reported in ≥ 2% of adults receiving ondansetron at a dosage of 4 mg intravenous over 2 to
153
5 minutes in clinical trials.
154
155
Table 2. Adverse Reactions Reported in ≥ 2% (and with Greater Frequency than the
156
Placebo Group) of Adult Patients Receiving Ondansetron at a Dosage of 4 mg Intravenous
157
over 2 to 5 Minutes
Adverse Reactiona,b
ZOFRAN Injection
4 mg Intravenous
n = 547 patients
Placebo
n = 547 patients
Headache
92 (17%)
77 (14%)
Drowsiness/sedation
44 (8%)
37 (7%)
Injection site reaction
21 (4%)
18 (3%)
Fever
10 (2%)
6 (1%)
Cold sensation
9 (2%)
8 (1%)
Pruritus
9 (2%)
3 (< 1%)
Paresthesia
9 (2%)
2 (< 1%)
158
a Adverse Reactions: Rates of these reactions were not significantly different in the
159
ondansetron and placebo groups
160
b Patients were receiving multiple concomitant perioperative and postoperative medications
161
162
Pediatric Use: Rates of adverse reactions were similar in both the ondansetron and
163
placebo groups in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric
164
patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg)
165
administered intravenously over at least 30 seconds. Diarrhea was seen more frequently in
166
patients taking ZOFRAN (2%) compared to placebo (<1%) in the 1 month to 24 month age
167
group. These patients were receiving multiple concomitant perioperative and postoperative
168
medications.
169
6.2
Postmarketing Experience
170
The following adverse reactions have been identified during post-approval use of
171
ondansetron. Because these reactions are reported voluntarily from a population of uncertain
172
size, it is not always possible to reliably estimate their frequency or establish a causal
173
relationship to drug exposure. The reactions have been chosen for inclusion due to a combination
174
of their seriousness, frequency of reporting, or potential causal connection to ondansetron.
6
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175
Cardiovascular: Arrhythmias (including ventricular and supraventricular tachycardia,
176
premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic
177
alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment
178
depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron,
179
transient ECG changes including QT/QTc interval prolongation have been reported [see
180
Warnings and Precautions (5.2)].
181
General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g.,
182
anaphylactic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension,
183
laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A
184
positive lymphocyte transformation test to ondansetron has been reported, which suggests
185
immunologic sensitivity to ondansetron.
186
Hepatobiliary: Liver enzyme abnormalities have been reported. Liver failure and death
187
have been reported in patients with cancer receiving concurrent medications including potentially
188
hepatotoxic cytotoxic chemotherapy and antibiotics.
189
Local Reactions: Pain, redness, and burning at site of injection.
190
Lower Respiratory: Hiccups
191
Neurological: Oculogyric crisis, appearing alone, as well as with other dystonic
192
reactions. Transient dizziness during or shortly after intravenous infusion.
193
Skin: Urticaria, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
194
Eye Disorders: Cases of transient blindness, predominantly during intravenous
195
administration, have been reported. These cases of transient blindness were reported to resolve
196
within a few minutes up to 48 hours. Transient blurred vision, in some cases associated with
197
abnormalities of accommodation, have also been reported.
198
7
DRUG INTERACTIONS
199
7.1
Drugs Affecting Cytochrome P-450 Enzymes
200
Ondansetron does not appear to induce or inhibit the cytochrome P-450
201
drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic
202
cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or
203
inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron
204
[see Clinical Pharmacology (12.3)]. On the basis of limited available data, no dosage adjustment
205
is recommended for patients on these drugs.
206
7.2
Apomorphine
207
Based on reports of profound hypotension and loss of consciousness when apomorphine
208
was administered with ondansetron, the concomitant use of apomorphine with ondansetron is
209
contraindicated [see Contraindications (4)].
210
7.3
Phenytoin, Carbamazepine, and Rifampin
211
In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and
212
rifampin), the clearance of ondansetron was significantly increased and ondansetron blood
7
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213
concentrations were decreased. However, on the basis of available data, no dosage adjustment
214
for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3)].
215
7.4
Tramadol
216
Although there are no data on pharmacokinetic drug interactions between ondansetron
217
and tramadol, data from two small studies indicate that concomitant use of ondansetron may
218
result in reduced analgesic activity of tramadol. Patients on concomitant ondansetron self
219
administered tramadol more frequently in these studies, leading to an increased cumulative dose
220
in patient controlled administration (PCA) of tramadol.
221
7.5
Serotonergic Drugs
222
Serotonin syndrome (including altered mental status, autonomic instability, and
223
neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor
224
antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors
225
(SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [see Warnings and
226
Precautions (5.3)].
227
7.6
Chemotherapy
228
In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of
229
ondansetron.
230
In a crossover study in 76 pediatric patients, intravenous ondansetron did not increase
231
blood levels of high-dose methotrexate.
232
7.7
Temazepam
233
The coadministration of ondansetron had no effect on the pharmacokinetics and
234
pharmacodynamics of temazepam.
235
7.8
Alfentanil and Atracurium
236
Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the
237
degree of neuromuscular blockade produced by atracurium. Interactions with general or local
238
anesthetics have not been studied.
239
8
USE IN SPECIFIC POPULATIONS
240
8.1
Pregnancy
241
Pregnancy Category B. Reproduction studies have been performed in pregnant rats and
242
rabbits at intravenous doses up to 4 mg/kg per day (approximately 1.4 and 2.9 times the
243
recommended human intravenous dose of 0.15 mg/kg given three times a day, respectively, based
244
on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due
245
to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women.
246
Because animal reproduction studies are not always predictive of human response, this drug
247
should be used during pregnancy only if clearly needed.
248
8.3
Nursing Mothers
249
Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is
250
excreted in human milk. Because many drugs are excreted in human milk, caution should be
251
exercised when ondansetron is administered to a nursing woman.
8
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252
8.4
Pediatric Use
253
Little information is available about the use of ondansetron in pediatric surgical patients
254
younger than 1 month of age. [See Clinical Studies (14.2)]. Little information is available about
255
the use of ondansetron in pediatric cancer patients younger than 6 months of age. [See Clinical
256
Studies (14.1), Dosage and Administration (2)].
257
The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower
258
and the half-life is ~2.5 fold longer than patients who are > 4 to 24 months of age. As a
259
precaution, it is recommended that patients less than 4 months of age receiving this drug be
260
closely monitored. [See Clinical Pharmacology (12.3)].
261
8.5
Geriatric Use
262
Of the total number of subjects enrolled in cancer chemotherapy-induced and
263
postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65
264
years of age and over. No overall differences in safety or effectiveness were observed between
265
these subjects and younger subjects, and other reported clinical experience has not identified
266
differences in responses between the elderly and younger patients, but greater sensitivity of some
267
older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of
268
65 [see Clinical Pharmacology (12.3)].
269
8.6
Hepatic Impairment
270
In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance
271
is reduced and apparent volume of distribution is increased with a resultant increase in plasma
272
half-life [see Clinical Pharmacology (12.3)]. In such patients, a total daily dose of 8 mg should
273
not be exceeded [see Dosage and Administration (2.3)].
274
8.7
Renal Impairment
275
Although plasma clearance is reduced in patients with severe renal impairment
276
(creatinine clearance < 30 mL/min), no dosage adjustment is recommended [see Clinical
277
Pharmacology (12.3)].
278
9
DRUG ABUSE AND DEPENDENCE
279
Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor
280
does it substitute for benzodiazepines in direct addiction studies.
281
10
OVERDOSAGE
282
There is no specific antidote for ondansetron overdose. Patients should be managed with
283
appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily
284
intravenous doses as large as 252 mg have been inadvertently administered without significant
285
adverse events. These doses are more than 10 times the recommended daily dose.
286
In addition to the adverse reactions listed above, the following events have been
287
described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to
288
3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg
289
of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another
290
patient that took 48 mg of ondansetron hydrochloride tablets. Following infusion of 32 mg over
9
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291
only a 4-minute period, a vasovagal episode with transient second-degree heart block was
292
observed. In all instances, the events resolved completely.
293
Pediatric cases consistent with serotonin syndrome have been reported after inadvertent
294
oral overdoses of ondansetron (exceeding estimated ingestion of 5 mg/kg) in young children.
295
Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension,
296
flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia,
297
and seizure. Patients required supportive care, including intubation in some cases, with complete
298
recovery without sequelae within 1 to 2 days.
299
11
DESCRIPTION
300
The active ingredient of ZOFRAN Injection is ondansetron hydrochloride, a selective
301
blocking agent of the serotonin 5-HT3 receptor type. Its chemical name is (±) 1, 2, 3, 9
302
tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one,
303
monohydrochloride, dihydrate. It has the following structural formula:
304 structural formula
305
306
307
The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of
308
365.9.
309
Ondansetron HCl is a white to off-white powder that is soluble in water and normal
310
saline.
311
Each 1 mL of aqueous solution in the 20 mL multidose vial contains 2 mg of ondansetron
312
as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid
313
monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of
314
methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection,
315
USP.
316
ZOFRAN Injection is a clear, colorless, nonpyrogenic, sterile solution for intravenous
317
use. The pH of the injection solution is 3.3 to 4.0.
318
12
CLINICAL PHARMACOLOGY
319
12.1 Mechanism of Action
320
Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron’s mechanism of
321
action has not been fully characterized, it is not a dopamine-receptor antagonist.
322
12.2 Pharmacodynamics
323
QTc interval prolongation was studied in a double blind, single intravenous dose,
324
placebo- and positive-controlled, crossover study in 58 healthy subjects. The maximum mean
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325
(95% upper confidence bound) difference in QTcF from placebo after baseline-correction was
326
19.5 (21.8) ms and 5.6 (7.4) ms after 15 minute intravenous infusions of 32 mg and 8 mg
327
ZOFRAN, respectively. A significant exposure-response relationship was identified between
328
ondansetron concentration and ΔΔQTcF. Using the established exposure-response relationship,
329
24 mg infused intravenously over 15 min had a mean predicted (95% upper prediction interval)
330
ΔΔQTcF of 14.0 (16.3) ms. In contrast, 16 mg infused intravenously over 15 min using the same
331
model had a mean predicted (95% upper prediction interval) ΔΔQTcF of 9.1 (11.2) ms.
332
In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no
333
effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small
334
intestinal transit time. In another study in six normal male volunteers, a 16-mg dose infused over
335
5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood
336
pressure, or electrocardiogram (ECG). Multiday administration of ondansetron has been shown
337
to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin
338
concentrations. In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg
339
administered intravenously or intramuscularly was dynamically similar in the prevention of
340
nausea and vomiting using the ipecacuanha model of emesis.
341
12.3 Pharmacokinetics
342
In normal adult volunteers, the following mean pharmacokinetic data have been
343
determined following a single 0.15-mg/kg intravenous dose.
344
345
Table 3. Pharmacokinetics in Normal Adult Volunteers
Age-group
(years)
n
Peak Plasma
Concentration
(ng/mL)
Mean Elimination
Half-life (h)
Plasma Clearance
(L/h/kg)
19-40
11
102
3.5
0.381
61-74
12
106
4.7
0.319
≥ 75
11
170
5.5
0.262
346
347
Absorption: A study was performed in normal volunteers (n = 56) to evaluate the
348
pharmacokinetics of a single 4-mg dose administered as a 5-minute infusion compared to a
349
single intramuscular injection. Systemic exposure as measured by mean AUC were equivalent,
350
with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ng•h/mL for intravenous and
351
intramuscular groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8,
352
54.4] ng/mL at 10 minutes after intravenous infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at
353
41 minutes after intramuscular injection.
354
Distribution: Plasma protein binding of ondansetron as measured in vitro was 70% to
355
76%, over the pharmacologic concentration range of 10 to 500 ng/mL. Circulating drug also
356
distributes into erythrocytes.
357
Metabolism: Ondansetron is extensively metabolized in humans, with approximately 5%
358
of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic
11
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359
pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate
360
conjugation.
361
Although some nonconjugated metabolites have pharmacologic activity, these are not
362
found in plasma at concentrations likely to significantly contribute to the biological activity of
363
ondansetron. The metabolites are observed in the urine.
364
In vitro metabolism studies have shown that ondansetron is a substrate for multiple
365
human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In
366
terms of overall ondansetron turnover, CYP3A4 plays a predominant role while formation of the
367
major in vivo metabolites is apparently mediated by CYP1A2. The role of CYP2D6 in
368
ondansetron in vivo metabolism is relatively minor.
369
The pharmacokinetics of intravenous ondansetron did not differ between subjects who
370
were poor metabolisers of CYP2D6 and those who were extensive metabolisers of CYP2D6,
371
further supporting the limited role of CYP2D6 in ondansetron disposition in vivo.
372
Elimination: In adult cancer patients, the mean ondansetron elimination half-life was
373
4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4-day period. In
374
a dose proportionality study, systemic exposure to 32 mg of ondansetron was not proportional to
375
dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent
376
with a small decrease in systemic clearance with increasing plasma concentrations.
377
Geriatrics: A reduction in clearance and increase in elimination half-life are seen in
378
patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were
379
similar in patients over 65 years of age and those under 65 years of age; there was an insufficient
380
number of patients over 75 years of age to permit conclusions in that age-group. No dosage
381
adjustment is recommended in the elderly.
382
Pediatrics: Pharmacokinetic samples were collected from 74 cancer patients 6 to
383
48 months of age, who received a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours
384
for 3 doses during a safety and efficacy trial. These data were combined with sequential
385
pharmacokinetics data from 41 surgery patients 1 month to 24 months of age, who received a
386
single dose of 0.1 mg/kg of intravenous ondansetron prior to surgery with general anesthesia, and
387
a population pharmacokinetic analysis was performed on the combined data set. The results of
388
this analysis are included in Table 4 and are compared to the pharmacokinetic results in cancer
389
patients 4 to 18 years of age.
390
391
Table 4. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Cancer Patients
4 to 18 years of age
N = 21
0.599
1.9
2.8
Population PK Patientsa
1 month to 48 months of age
N = 115
0.582
3.65
4.9
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392
a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.
393
394
Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age
395
who receive a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours for 3 doses would be
396
expected to achieve a systemic exposure (AUC) consistent with the exposure achieved in
397
previous pediatric studies in cancer patients (4 to 18 years of age) at similar doses.
398
In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery
399
requiring anesthesia for a duration of 45 minutes to 2 hours, a single intravenous dose of
400
ondansetron, 2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to
401
anesthesia induction. Mean weight-normalized clearance and volume of distribution values in
402
these pediatric surgical patients were similar to those previously reported for young adults. Mean
403
terminal half-life was slightly reduced in pediatric patients (range, 2.5 to 3 hours) in comparison
404
with adults (range, 3 to 3.5 hours).
405
In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing
406
surgery requiring general anesthesia, a single intravenous dose of ondansetron, 0.1 or 0.2 mg/kg,
407
was administered prior to surgery. As shown in Table 5, the 41 patients with pharmacokinetic
408
data were divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months
409
of age, and are compared to pediatric patients 3 to 12 years of age.
410
411
Table 5. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age
Subjects and Age Group
N
CL
(L/h/kg)
Vdss
(L/kg)
T½
(h)
Geometric Mean
Mean
Pediatric Surgery Patients
3 to 12 years of age
N = 21
0.439
1.65
2.9
Pediatric Surgery Patients
5 to 24 months of age
N = 22
0.581
2.3
2.9
Pediatric Surgery Patients
1 month to 4 months of age
N = 19
0.401
3.5
6.7
412
413
In general, surgical and cancer pediatric patients younger than 18 years tend to have a
414
higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric
415
patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher
416
volume of distribution in this age group.
417
In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three
418
intravenous doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years
419
of age exhibited ondansetron pharmacokinetic parameters similar to those of adults.
420
Renal Impairment: Due to the very small contribution (5%) of renal clearance to the
421
overall clearance, renal impairment was not expected to significantly influence the total
422
clearance of ondansetron. However, ondansetron mean plasma clearance was reduced by about
13
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
423
41% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction
424
in clearance is variable and was not consistent with an increase in half-life. No reduction in dose
425
or dosing frequency in these patients is warranted.
426
Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is
427
reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in those
428
without hepatic impairment. In patients with severe hepatic impairment (Child-Pugh score of 10
429
or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased
430
with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a
431
total daily dose of 8 mg should not be exceeded.
432
13
NONCLINICAL TOXICOLOGY
433
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
434
Carcinogenic effects were not seen in 2-year studies in rats and mice with oral
435
ondansetron doses up to 10 and 30 mg/kg per day, respectively (approximately 3.6 and 5.4 times
436
the recommended human intravenous dose of 0.15 mg/kg given three times a day, based on body
437
surface area). Ondansetron was not mutagenic in standard tests for mutagenicity.
438
Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the
439
recommended human intravenous dose, based on body surface area) did not affect fertility or
440
general reproductive performance of male and female rats.
441
14
CLINICAL STUDIES
442
The clinical efficacy of ondansetron hydrochloride, the active ingredient of ZOFRAN,
443
was assessed in clinical trials as described below.
444
14.1 Chemotherapy-Induced Nausea and Vomiting
445
Adults: In a double-blind study of three different dosing regimens of ZOFRAN Injection,
446
0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer
447
chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing
448
regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the
449
0.15-mg/kg dosing regimen.
450
Cisplatin-Based Chemotherapy: In a double-blind study in 28 patients, ZOFRAN
451
Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing
452
nausea and vomiting induced by cisplatin-based chemotherapy. Therapeutic response was as
453
shown in Table 6.
454
14
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
455
Table 6. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and
456
Vomiting in Single-Day Cisplatin Therapya in Adults
ZOFRAN Injection
(0.15 mg/kg x 3)
Placebo
P Valueb
Number of patients
14
14
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
2 (14%)
8 (57%)
2 (14%)
2 (14%)
0 (0%)
0 (0%)
1 (7%)
13 (93%)
0.001
Median number of emetic episodes
1.5
Undefinedc
Median time to first emetic episode (h)
11.6
2.8
0.001
Median nausea scores (0-100)d
3
59
0.034
Global satisfaction with control of
nausea and vomiting (0-100)
e
96
10.5
0.009
a
457
Chemotherapy was high dose (100 and 120 mg/m2; ZOFRAN Injection n = 6, placebo n = 5)
458
or moderate dose (50 and 80 mg/m2; ZOFRAN Injection n = 8, placebo n = 9). Other
459
chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There
460
was no difference between treatments in the types of chemotherapy that would account for
461
differences in response.
462
b Efficacy based on "all patients treated" analysis.
463
c Median undefined since at least 50% of the patients were rescued or had more than five
464
emetic episodes.
465
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
466
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
467
468
Ondansetron injection (0.15-mg/kg x 3 doses) was compared with metoclopramide (2
469
mg/kg x 6 doses) in a single-blind trial in 307 patients receiving cisplatin ≥ 100 mg/m2 with or
470
without other chemotherapeutic agents. Patients received the first dose of ondansetron or
471
metoclopramide 30 minutes before cisplatin. Two additional ondansetron doses were
472
administered 4 and 8 hours later, or five additional metoclopramide doses were administered 2, 4,
473
7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less. Episodes of
474
vomiting and retching were tabulated over the period of 24 hours after cisplatin. The results of
475
this study are summarized in Table 7.
476
15
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
477
Table 7. Therapeutic Response in Prevention of Vomiting Induced by Cisplatin (≥ 100
478
mg/m2) Single-Day Therapya in Adults
ZOFRAN Injection
Metoclopramide
P Value
Dose
0.15 mg/kg x 3
2 mg/kg x 6
Number of patients in efficacy population
136
138
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
54 (40%)
34 (25%)
19 (14%)
29 (21%)
41 (30%)
30 (22%)
18 (13%)
49 (36%)
Comparison of treatments with respect to
0 Emetic episodes
More than 5 emetic episodes/rescued
54/136
29/136
41/138
49/138
0.083
0.009
Median number of emetic episodes
1
2
0.005
Median time to first emetic episode (h)
20.5
4.3
< 0.001
Global satisfaction with control of nausea
and vomiting (0-100)b
85
63
0.001
Acute dystonic reactions
0
8
0.005
Akathisia
0
10
0.002
479
480
481
482
483
a
b
In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including
cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments
in the types of chemotherapy that would account for differences in response.
Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.
484
Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled
485
study of ZOFRAN Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide
486
(500 to 600 mg/m2) chemotherapy, ZOFRAN Injection was significantly more effective than
487
placebo in preventing nausea and vomiting. The results are summarized in Table 8.
488
16
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
489
Table 8. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and
490
Vomiting in Single-Day Cyclophosphamide Therapya in Adults
ZOFRAN Injection
(0.15 mg/kg x 3)
Placebo
P Valueb
Number of patients
10
10
Treatment response
0 Emetic episodes
1-2 Emetic episodes
3-5 Emetic episodes
More than 5 emetic episodes/rescued
7 (70%)
0 (0%)
2 (20%)
1 (10%)
0 (0%)
2 (20%)
4 (40%)
4 (40%)
0.001
0.131
Median number of emetic episodes
0
4
0.008
Median time to first emetic episode (h)
Undefinedc
8.79
Median nausea scores (0-100)d
0
60
0.001
Global satisfaction with control of
nausea and vomiting (0-100)e
100
52
0.008
491
a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including
492
fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between
493
treatments in the type of chemotherapy that would account for differences in response.
494
b Efficacy based on "all patients treated" analysis.
495
c Median undefined since at least 50% of patients did not have any emetic episodes.
496
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.
497
e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.
498
499
Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose,
500
100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with
501
ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median,
502
2; range, 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes
503
occurred in 217 (81%) re-treatment courses.
504
Pediatrics: Four open-label, noncomparative (one US, three foreign) trials have been
505
performed with 209 pediatric cancer patients 4 to 18 years of age given a variety of cisplatin or
506
noncisplatin regimens. In the three foreign trials, the initial ZOFRAN Injection dose ranged from
507
0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration
508
of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, ZOFRAN was
509
administered intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2
510
to 39 mg. In these studies, 58% of the 196 evaluable patients had a complete response (no emetic
17
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
511
episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was essentially the
512
same as for patients older than 18 years of age.
513
An open-label, multicenter, noncomparative trial has been performed in 75 pediatric
514
cancer patients 6 to 48 months of age receiving at least one moderately or highly emetogenic
515
chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were
516
American Hispanic, and 15% were black patients. ZOFRAN was administered intravenously
517
over 15 minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before
518
the start of chemotherapy, the second and third doses were administered 4 and 8 hours after the
519
first dose, respectively. Eighteen patients (25%) received routine prophylactic dexamethasone
520
(i.e., not given as rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic
521
episodes) on day 1. Thus, prevention of vomiting in these pediatric patients was comparable to
522
the prevention of vomiting in patients 4 years of age and older.
523
14.2 Prevention of Postoperative Nausea and/or Vomiting
524
Adults: Adult surgical patients who received ondansetron immediately before the
525
induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal;
526
opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare
527
and/or vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double
528
blind US studies involving 554 patients. ZOFRAN Injection (4 mg) intravenous given over 2 to
529
5 minutes was significantly more effective than placebo. The results of these studies are
530
summarized in Table 9.
531
18
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
532
Table 9. Therapeutic Response in Prevention of Postoperative Nausea and Vomiting in
533
Adult Patients
Ondansetron
4 mg
Intravenous
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
103 (76%)
13 (10%)
20 (15%)
139
64 (46%)
17 (12%)
58 (42%)
< 0.001
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
134
56 (42%)
136
39 (29%)
Study 2
Emetic episodes:
Number of patients
Treatment response over 24-h
postoperative period
0 Emetic episodes
1 Emetic episode
More than 1 emetic episode/rescued
136
85 (63%)
16 (12%)
35 (26%)
143
63 (44%)
29 (20%)
51 (36%)
0.002
Nausea assessments:
Number of patients
No nausea over 24-h postoperative
period
125
48 (38%)
133
42 (32%)
534
535
The study populations in Table 9 consisted mainly of females undergoing laparoscopic
536
procedures.
19
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
537
In a placebo-controlled study conducted in 468 males undergoing outpatient procedures, a
538
single 4-mg intravenous ondansetron dose prevented postoperative vomiting over a 24-hour study
539
period in 79% of males receiving drug compared to 63% of males receiving placebo (P < 0.001).
540
Two other placebo-controlled studies were conducted in 2,792 patients undergoing major
541
abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg intravenous ondansetron
542
dose for prevention of postoperative nausea and vomiting over a 24-hour study period. At the
543
4-mg dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the first
544
study (P < 0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the
545
second study (P = 0.001) experienced no emetic episodes. No additional benefit was observed in
546
patients who received intravenous ondansetron 8 mg compared to patients who received
547
intravenous ondansetron 4 mg.
548
Pediatrics: Three double-blind, placebo-controlled studies have been performed (one
549
US, two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing general
550
anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or without
551
adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized
552
to either single intravenous doses of ondansetron (0.1 mg/kg for pediatric patients weighing
553
40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was
554
administered over at least 30 seconds, immediately prior to or following anesthesia induction.
555
Ondansetron was significantly more effective than placebo in preventing nausea and vomiting.
556
The results of these studies are summarized in Table 10.
557
20
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
558
Table 10. Therapeutic Response in Prevention of Postoperative Nausea and Vomiting in
559
Pediatric Patients 2 to 12 Years of Age
Treatment Response Over
24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Study 1
Number of patients
0 Emetic episodes
Failurea
205
140 (68%)
65 (32%)
210
82 (39%)
128 (61%)
≤ 0.001
Study 2
Number of patients
0 Emetic episodes
Failurea
112
68 (61%)
44 (39%)
110
38 (35%)
72 (65%)
≤ 0.001
Study 3
Number of patients
0 Emetic episodes
Failurea
206
123 (60%)
83 (40%)
206
96 (47%)
110 (53%)
≤ 0.01
Nausea assessmentsb:
Number of patients
None
185
119 (64%)
191
99 (52%)
≤ 0.01
560
a Failure was one or more emetic episodes, rescued, or withdrawn.
561
b Nausea measured as none, mild, or severe.
562
563
A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric
564
patients 1 month to 24 months of age who were undergoing routine surgery under general
565
anesthesia. Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were
566
American Hispanic, 2% were Asian, and 6% were “other race” patients. A single 0.1-mg/kg
567
intravenous dose of ondansetron administered within 5 minutes following induction of anesthesia
568
was statistically significantly more effective than placebo in preventing vomiting. In the placebo
569
group, 28% of patients experienced vomiting compared to 11% of subjects who received
570
ondansetron (P ≤ 0.01). Overall, 32 (10%) of placebo patients and 18 (5%) of patients who
571
received ondansetron received antiemetic rescue medication(s) or prematurely withdrew from the
572
study.
21
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
573
14.3 Prevention of Further Postoperative Nausea and Vomiting
574
Adults: Adult surgical patients receiving general balanced anesthesia (barbiturate:
575
thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide;
576
neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and
577
supplemental isoflurane) who received no prophylactic antiemetics and who experienced nausea
578
and/or vomiting within 2 hours postoperatively were evaluated in two double-blind US studies
579
involving 441 patients. Patients who experienced an episode of postoperative nausea and/or
580
vomiting were given ZOFRAN Injection (4 mg) intravenous over 2 to 5 minutes, and this was
581
significantly more effective than placebo. The results of these studies are summarized in Table
582
11.
583
22
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
584
Table 11. Therapeutic Response in Prevention of Further Postoperative Nausea and
585
Vomiting in Adult Patients
Ondansetron
4 mg
Intravenous
Placebo
P Value
Study 1
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
104
117
0 Emetic episodes
49 (47%)
19 (16%)
< 0.001
1 Emetic episode
12 (12%)
9 (8%)
More than 1 emetic episode/rescued
43 (41%)
89 (76%)
Median time to first emetic episode (min)a
55.0
43.0
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
98
102
periodb
1.7
3.1
Study 2
Emetic episodes:
Number of patients
Treatment response 24 h after study drug
112
108
0 Emetic episodes
49 (44%)
28 (26%)
0.006
1 Emetic episode
14 (13%)
3 (3%)
More than 1 emetic episode/rescued
49 (44%)
77 (71%)
Median time to first emetic episode (min)a
60.5
34.0
Nausea assessments:
Number of patients
Mean nausea score over 24-h postoperative
105
85
periodb
1.9
2.9
586
a After administration of study drug.
587
b Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.
23
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
588
589
The study populations in Table 11 consisted mainly of women undergoing laparoscopic
590
procedures.
591
Repeat Dosing in Adults: In patients who do not achieve adequate control of
592
postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous
593
dose of ondansetron 4 mg, administration of a second intravenous dose of ondansetron 4 mg
594
postoperatively does not provide additional control of nausea and vomiting.
595
Pediatrics: One double-blind, placebo-controlled, US study was performed in 351 male
596
and female outpatients (2 to 12 years of age) who received general anesthesia with nitrous oxide
597
and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who
598
experienced two or more emetic episodes within 2 hours following discontinuation of nitrous
599
oxide were randomized to either single intravenous doses of ondansetron (0.1 mg/kg for pediatric
600
patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo
601
administered over at least 30 seconds. Ondansetron was significantly more effective than placebo
602
in preventing further episodes of nausea and vomiting. The results of the study are summarized
603
in Table 12.
604
605
Table 12. Therapeutic Response in Prevention of Further Postoperative Nausea and
606
Vomiting in Pediatric Patients 2 to 12 Years of Age
Treatment Response
Over 24 Hours
Ondansetron
n (%)
Placebo
n (%)
P Value
Number of patients
0 Emetic episodes
Failurea
180
96 (53%)
84 (47%)
171
29 (17%)
142 (83%)
≤ 0.001
607
a Failure was one or more emetic episodes, rescued, or withdrawn.
608
16
HOW SUPPLIED/STORAGE AND HANDLING
609
ZOFRAN Injection, 2 mg/mL, is supplied as follows:
610
NDC 0173-0442-00 20-mL multidose vials (Singles)
611
Storage: Store vials between 2° and 30°C (36° and 86°F). Protect from light.
612
17
PATIENT COUNSELING INFORMATION
613
• Patients should be informed that ZOFRAN may cause serious cardiac arrhythmias such
614
as QT prolongation. Patients should be instructed to tell their healthcare provider right
615
away if they perceive a change in their heart rate, if they feel lightheaded, or if they have
616
a syncopal episode.
617
• Patients should be informed that the chances of developing severe cardiac arrhythmias
618
such as QT prolongation and Torsade de Pointes are higher in the following people:
619
o Patients with a personal or family history of abnormal heart rhythms, such as
620
congenital long QT syndrome;
24
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
641
621
o Patients who take medications, such as diuretics, which may cause electrolyte
622
abnormalities
623
o Patients with hypokalemia or hypomagnesemia
624
ZOFRAN should be avoided in these patients, since they may be more at risk for cardiac
625
arrhythmias such as QT prolongation and Torsade de Pointes.
626
• Advise patients of the possibility of serotonin syndrome with concomitant use of
627
ZOFRAN and another serotonergic agent such as medications to treat depression and
628
migraines. Advise patients to seek immediate medical attention if the following
629
symptoms occur: changes in mental status, autonomic instability, neuromuscular
630
symptoms with or without gastrointestinal symptoms.
631
• Inform patients that ZOFRAN may cause hypersensitivity reactions, some as severe as
632
anaphylaxis and bronchospasm. The patient should report any signs and symptoms of
633
hypersensitivity reactions, including fever, chills, rash, or breathing problems.
634
• The patient should report the use of all medications, especially apomorphine, to their
635
healthcare provider. Concomitant use of apomorphine and ZOFRAN may cause a
636
significant drop in blood pressure and loss of consciousness.
637
• Inform patients that ZOFRAN may cause headache, drowsiness/sedation, constipation,
638
fever and diarrhea.
639
640
642
GlaxoSmithKline
643
Research Triangle Park, NC 27709
644
645
©Year, the GSK group of companies. All rights reserved.
646
647
ZFJ:xPI
25
Reference ID: 3630032
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:26.288620
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020007s046lbl.pdf', 'application_number': 20007, 'submission_type': 'SUPPL ', 'submission_number': 46}
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Page 1
LOTRISONE® Cream, USP
1
LOTRISONE® Lotion
2
(clotrimazole, USP and betamethasone dipropionate, USP)
3
FOR TOPICAL USE ONLY, NOT
FOR
OPHTHALMIC,
ORAL,
OR
4
INTRAVAGINAL USE, NOT RECOMMENDED FOR PATIENTS UNDER THE
5
AGE OF 17 YEARS AND NOT RECOMMENDED FOR DIAPER DERMATITIS
6
DESCRIPTION LOTRISONE Cream and Lotion contain combinations of
7
clotrimazole, a synthetic antifungal agent, and betamethasone dipropionate, a
8
synthetic corticosteroid, for dermatologic use.
9
Chemically, clotrimazole is 1–(o-chloro-α,α-diphenylbenzyl)imidazole, with the
10
empirical formula C22H17CIN2, a molecular weight of 344.84, and the following
11
structural formula:
12
13
14
15
16
17
18
Clotrimazole is an odorless, white crystalline powder, insoluble in water and
19
soluble in ethanol.
20
Betamethasone dipropionate has the chemical name 9-fluoro-11β,17,21-
21
trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the
22
empirical formula C28H37FO7, a molecular weight of 504.59, and the following
23
structural formula:
24
25
26
27
28
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2
Betamethasone dipropionate is a white to creamy white, odorless crystalline
30
powder, insoluble in water.
31
Each gram of LOTRISONE Cream contains 10 mg clotrimazole and 0.643 mg
32
betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a
33
hydrophilic cream consisting of purified water, mineral oil, white petrolatum, cetyl
34
alcohol plus stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate
35
monobasic monohydrate, and phosphoric acid; benzyl alcohol, as preservative.
36
LORTISONE Cream is smooth, uniform, and white to off-white in color.
37
Each gram of LOTRISONE Lotion contains 10 mg clotrimazole and 0.643 mg
38
betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a
39
hydrophilic base of purified water, mineral oil, white petrolatum, cetyl alcohol plus
40
stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate monobasic
41
monohydrate, and phosphoric acid, benzyl alcohol as a preservative.
42
LOTRISONE Lotion may contain sodium hydroxide. LOTRISONE Lotion is
43
opaque and white in color.
44
CLINICAL PHARMACOLOGY
45
Clotrimazole and Betamethasone Dipropionate
46
LORTISONE Cream has been shown to be least as effective as clottrimazole
47
alone in a different cream vehicle. No comparative studies have been conducted
48
with LOTRISONE Lotion and clotrimazole alone. Use of corticosteroids in the
49
treatment of fungal infection may lead to suppression of host inflammation
50
leading to worsening or decreased cure rate.
51
Clotrimazole
52
Skin penetration and systemic absorption of clotrimazole following topical
53
application of LOTRISONE Cream or Lotion have not been studied. The following
54
information was obtained using 1% clotrimazole cream and solution formulations.
55
Six hours after the application of radioactive clotrimazole 1% cream and 1%
56
solution onto intact and acutely inflamed skin, the concentration of clotrimazole
57
varied from 100 mcg/cm3 in the stratum corneum, to 0.5 to 1 mcg/cm3 in the
58
reticular dermis, and 0.1 mcg/cm3 in the subcutis. No measurable amount of
59
radioactivity (<0.001 mcg/mL) was found in the serum within 48 hours after
60
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3
application under occlusive dressing of 0.5 mL of the solution or 0.8 g of the
61
cream. Only 0.5% or less of the applied radioactivity was excreted in the urine.
62
Microbiology
63
Mechanism of Action: Clotrimazole is an imidazole antifungal agent. Imidazoles
64
inhibit 14-α-demethylation of lanosterol in fungi by binding to one of the
65
cytochrome P-450 enzymes. This leads to the accumulation of 14-α-
66
methylsterols and reduced concentrations of ergosterol, a sterol essential for a
67
normal fungal cytoplasmic membrane. The methylsterols may affect the electron
68
transport system, thereby inhibiting growth of fungi.
69
Activity In Vivo: Clotrimazole has been shown to be active against most strains of
70
the following dermatophytes, both in vitro and in clinical infections as described in
71
the INDICATIONS AND USAGE section: Epidermophyton floccosum,
72
Trichophyton mentagrophytes, and Trichophyton rubrum.
73
Activity In Vitro: In vitro, clotrimazole has been shown to have activity against
74
most dermatophytes, but the clinical significance of this information is
75
unknown.
76
Drug Resistance: Strains of dermatophytes having a natural resistance to
77
clotrimazole have not been reported. Resistance to azoles including clotrimazole
78
has been reported in some Candida species.
79
No single-step or multiple-step resistance to clotrimazole has developed during
80
successive passages of Trichophyton mentagrophytes.
81
Betamethasone Dipropionate
82
Betamethasone dipropionate, a corticosteroid, has been shown to have topical
83
(dermatologic) and systemic pharmacologic and metabolic effects characteristic
84
of this class of drugs.
85
Pharmacokinetics: The extent of percutaneous absorption of topical
86
corticosteroids is determined by many factors, including the vehicle, the integrity
87
of the epidermal barrier and the use of occlusive dressings. (See DOSAGE AND
88
ADMINISTRATION section). Topical corticosteroids can be absorbed from
89
normal intact skin. Inflammation and/or other disease processes in the skin may
90
increase percutaneous absorption of topical corticosteroids. Occlusive dressings
91
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4
substantially increase the percutaneous absorption of topical corticosteroids (See
92
DOSAGE AND ADMINISTRATION section).
93
Once absorbed through the skin, the pharmacokinetics of topical corticosteroids
94
are similar to systemically administered corticosteroids. Corticosteroids are
95
bound to plasma proteins in varying degrees. Corticosteroids are metabolized
96
primarily in the liver and are then excreted by the kidneys. Some of the topical
97
corticosteroids and their metabolites are also excreted into the bile.
98
Studies performed with LOTRISONE Cream and Lotion indicate that these
99
topical
combination
anti-fungal/corticosteroids
may
have
vasoconstrictor
100
potencies in a range that is comparable to high potency topical corticosteroids.
101
Therefore use is not recommended in patients less than 17 years of age, in
102
diaper dermatitis, and under occlusion.
103
CLINICAL STUDIES (LOTRISONE Cream)
104
In clinical studies of tinea corporis, tinea cruris, and tinea pedis, patients treated
105
with LOTRISONE Cream showed a better clinical response at the first return visit
106
than patients treated with clotrimazole cream. In tinea corporis and tinea cruris,
107
the patient returned 3 to 5 days after starting treatment, and in tinea pedis, after 1
108
week. Mycological cure rates observed in patients treated with LOTRISONE
109
Cream were as good as or better than in those patients treated with clotrimazole
110
cream. In these same clinical studies, patients treated with LORTISONE Cream
111
showed better clinical responses and mycological cure rates when compared
112
with patients treated with betamethasone dipropionate cream.
113
CLINICAL STUDIES (LOTRISONE Lotion)
114
In the treatment of tinea pedis twice daily for four weeks, LOTRISONE Lotion
115
was shown to be superior to vehicle in relieving symptoms of erythema, scaling,
116
pruritus, and maceration at week 2. LOTRISONE Lotion was also shown to have
117
a superior mycological cure rate compared to vehicle two weeks after
118
discontinuation of treatment. It is unclear if the relief of symptoms at 2 weeks in
119
this clinical study with LOTRISONE Lotion was due to the contribution of
120
betamethasone dipropionate, clotrimazole, or both.
121
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Page 5
In the treatment of tinea cruris twice daily for two weeks, LOTRISONE Lotion was
122
shown to be superior to vehicle in the relief of symptoms of erythema, scaling,
123
and pruritus after 3 days. It is unclear if the relief of symptoms after 3 days in this
124
clinical study with LOTRISONE Lotion was due to the contribution of
125
betamethasone dipropionate, clotrimazole, or both.
126
The comparative efficacy and safety of LOTRISONE Lotion versus clotrimazole
127
alone in a lotion vehicle have not been studied in the treatment of tinea pedis,
128
tinea cruris, and tinea corporis. The comparative efficacy and safety of
129
LOTRISONE Lotion and LOTRISONE Cream have also not been studied.
130
INDICATIONS AND USAGE
131
LOTRISONE Cream and Lotion are indicated in patients 17 years and older for
132
the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris and
133
tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes,
134
and Trichophyton rubrum. Effective treatment without the risks associated with
135
topical corticosteroid use may be obtained using a topical antifungal agent that
136
does not contain a corticosteroid, especially for noninflammatory tinea infections.
137
The efficacy of LOTRISONE Cream or Lotion for the treatment of infections
138
caused by zoophilic dermatophytes (e.g., Microsporum canis) has not been
139
established. Several cases of treatment failure of Lotrisone Cream in the
140
treatment of infections caused by Microsporum canis have been reported.
141
CONTRAINDICATIONS
142
LOTRISONE Cream or Lotion is contraindicated in patients who are sensitive to
143
clotrimazole, betamethasone dipropionate, other corticosteroids or imidazoles, or
144
to any ingredient in these preparations.
145
PRECAUTIONS
146
General: Systemic absorption of topical corticosteroids can produce reversible
147
hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for
148
glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of
149
Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in
150
some patients by systemic absorption of topical corticosteroids while on
151
treatment.
152
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Page 6
Conditions which augment systemic absorption include use over large surface
153
areas, prolonged use, and use under occlusive dressings. Use of more than one
154
corticosteriod-containing product at the same time may increase total systemic
155
glucocorticoid exposure. Patients applying LOTRISONE Cream or Lotion to a
156
large surface area or to areas under occlusion should be evaluated periodically
157
for evidence of HPA-axis suppression. This may be done by using the ACTH
158
stimulation, morning plasma cortisol, and urinary free cortisol tests.
159
If HPA-axis suppression is noted, an attempt should be made to withdraw the
160
drug, to reduce the frequency of application, or to substitute a less potent
161
corticosteroid. Recovery of HPA axis function is generally prompt upon
162
discontinuation of topical corticosteroids. Infrequently, signs and symptoms of
163
glucocorticosteroid insufficiency may occur, requiring supplemental systemic
164
corticosteroids.
165
In a small study, LOTRISONE Cream was applied using large dosages, 7 g daily
166
for 14 days (BID) to the crural area of normal adult subjects. Three of the eight
167
normal subjects on whom LOTRISONE Cream was applied exhibited low
168
morning plasma cortisol levels during treatment. One of these subjects had an
169
abnormal Cortrosyn test. The effect on morning plasma cortisol was transient
170
and subjects recovered one week after discontinuing dosing. In addition, two
171
separate studies in pediatric patients demonstrated adrenal suppression as
172
determined by cosyntropin testing (See PRECAUTIONS – Pediatric Use
173
section).
174
Pediatric patients may be more susceptible to systemic toxicity from equivalent
175
doses due to their larger skin surface to body mass ratios. (See PRECAUTIONS
176
- Pediatric Use section)
177
If irritation develops, LOTRISONE Cream or Lotion should be discontinued and
178
appropriate therapy instituted.
179
THE SAFETY OF LOTRISONE CREAM OR LOTION HAS NOT BEEN
180
DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE
181
EVENTS CONSISTENT WITH CORTICOSTEROID USE HAVE BEEN
182
OBSERVED IN PATIENTS TREATED WITH LOTRISONE CREAM FOR
183
This label may not be the latest approved by FDA.
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Page 7
DIAPER DERMATITIS. THE USE OF LOTRISONE CREAM OR LOTION IN
184
THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED.
185
Information for Patients: Patients using LOTRISONE Cream or Lotion should
186
receive the following information and instructions:
187
1. The medication is to be used as directed by the physician and is not
188
recommended for use longer than the prescribed time period. It is for
189
external use only. Avoid contact with the eyes, mouth, or intravaginally.
190
2. This medication is to be used for the full prescribed treatment time, even
191
though the symptoms may have improved. Notify the physician if there is no
192
improvement after 1 week of treatment for tinea cruris or tinea corporis, or
193
after 2 weeks for tinea pedis.
194
3. This medication should only be used for the disorder for which it was
195
prescribed.
196
4. Other
corticosteriod-containing
products
should
not
be
used
with
197
LOTRISONE without first talking with your physician.
198
5. The treated skin area should not be bandaged, covered, or wrapped so as to
199
be occluded. (See DOSAGE AND ADMINISTRATION section.)
200
6. Any signs of local adverse reactions should be reported to your physician.
201
7. Patients should avoid sources of infection or reinfection.
202
8. When using LOTRISONE Cream or Lotion in the groin area, patients should
203
use the medication for two weeks only, and apply the cream or lotion
204
sparingly. Patients should wear loose-fitting clothing. Notify the physician if
205
the condition persists after 2 weeks.
206
9. The safety of LORTISONE Cream or Lotion has not been demonstrated in the
207
treatment of diaper dermatitis. Adverse events consistent with corticosteroid
208
use have been observed in patients treated with LOTRISONE Cream for
209
diaper dermatitis. The use of LOTRISONE Cream or Lotion in the treatment
210
of diaper dermatitis is not recommended.
211
Laboratory Tests: If there is a lack of response to LOTRISONE Cream or
212
Lotion, appropriate confirmation of the diagnosis, including possible mycological
213
studies, is indicated before instituting another course of therapy.
214
This label may not be the latest approved by FDA.
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Page 8
The following tests may be helpful in evaluating HPA-axis suppression due to the
215
corticosteroid components:
216
Urinary free cortisol test
217
Morning plasma cortisol test
218
ACTH (cosyntropin) stimulation test
219
Carcinogenesis, Mutagenesis, Impairment of Fertility: There are no adequate
220
laboratory animal studies with either the combination of clotrimazole and
221
betamethasone dipropionate or with either component individually to evaluate
222
carcinogenesis.
223
Betamethasone was negative in the bacterial mutagenicity assay (Salmonella
224
typhimurium and Escherichia coli), and in the mammalian cell mutagenicity assay
225
(CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome
226
aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus
227
assay. This pattern of response is similar to that of dexamethasone and
228
hydrocortisone.
229
Reproductive studies with betamethasone dipropionate carried out in rabbits at
230
doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the
231
intramuscular route indicated no impairment of fertility except for dose-related
232
increases in fetal resorption rates in both species. These doses are
233
approximately 5- and 38- fold the maximum human dose based on body surface
234
areas, respectively.
235
In a combined study of the effects of clotrimazole on fertility, teratogenicity, and
236
postnatal development, male and female rats were dosed orally (diet admixture)
237
with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum
238
dose in a 60 kg adult based on body surface area) from 10 weeks prior to mating
239
until 4 weeks postpartum. No adverse effects on the duration of estrous cycle,
240
fertility, or duration of pregnancy were noted.
241
Pregnancy: Teratogenic Effects: Pregnancy Category C: There have been no
242
teratogenic studies performed in animals or humans with the combination of
243
clotrimazole and betamethasone dipropionate. Corticosteriods are generally
244
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Page 9
teratogenic in laboratory animals when administered at relatively low dosage
245
levels.
246
Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the
247
maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole
248
exposure.
249
250
No increase in fetal malformations was noted in pregnant rats receiving oral
251
(gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation days 6-
252
15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased
253
resorptions), fetotoxic (reduced fetal weights) and maternally toxic (reduced body
254
weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the
255
maximum human dose) was maternally lethal, and therefore fetuses were not
256
evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the
257
maximum human dose) had no adverse effects on dams or fetuses. However, in
258
the combined fertility, teratogenicity, and postnatal development study described
259
above, 50 mg/kg clotrimazole, was associated with reduced maternal weight gain
260
and reduced numbers of offspring reared to 4 weeks.
261
262
Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the
263
maximum human dose) were not teratogenic in mice. No evidence of maternal
264
toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120,
265
or 180 mg/kg/day (18-55 times the maximum human dose).
266
267
Betamethasone dipropionate has been shown to be teratogenic in rabbits when
268
given by the intramuscular route at doses of 0.05 mg/kg. This dose is
269
approximately one-fifth the maximum human dose. The abnormalities observed
270
included umbilical hernias, cephalocele and cleft palates.
271
272
Betamethasone dipropionate has not been tested for teratogenic potential by the
273
dermal route of administration. Some corticosteroids have been shown to be
274
teratogenic after dermal application to laboratory animals.
275
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10
276
There are no adequate and well-controlled studies in pregnant women of the
277
teratogenic effects of topically applied corticosteroids. Therefore, Lotrisone
278
Cream or Lotion should be used during pregnancy only if the potential benefit
279
justifies the potential risk to the fetus.
280
Nursing Mothers: Systemically administered corticosteroids appear in human
281
milk and could suppress growth, interfere with endogenous corticosteroids
282
production, or cause other untoward effects. It is not known whether topical
283
administration of corticosteroids could result in sufficient systemic absorption to
284
product detectable quantities in human milk. Because many drugs are excreted
285
in human milk, caution should be exercised when LOTRISONE Cream or Lotion
286
is administered to a nursing woman.
287
Pediatric Use: Adverse events consistent with corticosteroid use have been
288
observed in patients under 12 years of age treated with LOTRISONE Cream. In
289
open-label studies, 17 of 43 (39.5%) evaluable pediatric patients (aged 12 to 16
290
years old) using LOTRISONE Cream for treatment of tinea pedis demonstrated
291
adrenal suppression as determined by cosyntropin testing. In another open-label
292
study, 8 of 17 (47.1%) evaluable pediatric patients (aged 12 to 16 years old)
293
using LOTRISONE Cream for treatment of tinea cruris demonstrated adrenal
294
suppression as determined by cosyntropin testing. THE USE OF LOTRISONE
295
CREAM OR LOTION IN THE TREATMENT OF PATIENTS UNDER 17 YEARS
296
OF
AGE
OR
PATIENTS
WITH
DIAPER
DERMATITIS
IS
NOT
297
RECOMMENDED.
298
Because of higher ratio of skin surface area to body mass, pediatric patients
299
under the age of 12 years are at a higher risk with LOTRISONE Cream or Lotion.
300
The studies described above suggest that pediatric patients under the age of 17
301
years may also have this risk. They are at increased risk of developing Cushing’s
302
syndrome while on treatment and adrenal insufficiency after withdrawal of
303
treatment. Adverse effects, including striae and growth retardation, have been
304
reported with inappropriate use of LOTRISONE Cream in infants and children
305
(see PRECAUTIONS and ADVERSE REACTIONS sections).
306
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 11
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome,
307
linear growth retardation, delayed weight gain and intracranial hypertension have
308
been reported in children receiving topical corticosteroids. Manifestations of
309
adrenal suppression in children include low plasma cortisol levels and absence of
310
response to ACTH stimulation. Manifestations of intracranial hypertension
311
include bulging fontanelles, headaches, and bilateral papilledema.
312
Geriatric Use: Clinical studies of LOTRISONE Cream or Lotion did not include
313
sufficient numbers of subjects aged 65 and over to determine whether they
314
respond differently from younger subjects. Post-market adverse events reporting
315
for LOTRISONE Cream in patients aged 65 and above includes reports of skin
316
atrophy and rare reports of skin ulceration. Caution should be exercised with the
317
use of these corticosteroid containing topical products on thinning skin. THE USE
318
OF LOTRISONE CREAM OR LOTION UNDER OCCLUSION, SUCH AS IN
319
DIAPER DERMATITIS, IS NOT RECOMMENDED.
320
ADVERSE REACTIONS
321
Adverse reactions reported for LOTRISONE Cream in clinical trials were
322
paresthesia in 1.9% of patients, and rash, edema, and secondary infection, each
323
in 1% of patients.
324
Adverse reactions reported for LOTRISONE Lotion in clinical trials were burning
325
and dry skin in 1.6% of patients and stinging is less than 1% of patients.
326
The following local adverse reactions have been reported with topical
327
corticosteroids and may occur more frequently with the use of occlusive
328
dressings. These reactions are listed in an approximate decreasing order of
329
occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform
330
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis,
331
maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. In
332
the pediatric population, reported adverse events for LOTRISONE Cream include
333
growth retardation, benign intracranial hypertension, Cushing’s syndrome (HPA
334
axis suppression), and local cutaneous reactions, including skin atrophy.
335
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Page 12
Systemic absorption of topical corticosteroids has produced reversible
336
hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of
337
Cushing’s syndrome, hyperglycemia, and glucosuria in some patients.
338
Adverse reactions reported with the use of clotrimazole are as follows: erythema,
339
stinging, blistering, peeling, edema, pruritus, urticaria and general irritation of the
340
skin.
341
OVERDOSAGE
342
Amounts greater than 45 g/week of LOTRISONE Cream or 45 mL/week of
343
LOTRISONE Lotion should not be used. Acute overdosage with topical
344
application of LOTRISONE Cream or Lotion is unlikely and would not be
345
expected to lead to life-threatening situation. LOTRISONE Cream or Lotion
346
should not be used for longer than the prescribed time period.
347
348
Topically applied corticosteroids, such as the one contained in LOTRISONE
349
Cream or Lotion can be absorbed in sufficient amounts to produce systemic
350
effects (see PRECAUTIONS section).
351
DOSAGE AND ADMINISTRATION
352
Gently massage sufficient LOTRISONE Cream or Lotion into the affected skin
353
areas twice a day, in the morning and evening.
354
LOTRISONE Cream or Lotion should not be used longer than 2 weeks in
355
the treatment of tinea corporis or tinea cruris, and amounts greater than 45
356
g per week of LOTRISONE Cream or amounts greater than 45 mL per week
357
of LOTRISONE Lotion should not be used. If a patient with tinea corporis or
358
tinea cruris shows no clinical improvement after one week of treatment with
359
LOTRISONE Cream or Lotion, the diagnosis should be reviewed.
360
LOTRISONE Cream or Lotion should not be used longer than 4 weeks in
361
the treatment of tinea pedis and amounts greater than 45 g per week of
362
LOTRISONE Cream or amounts greater than 45 mL per week of
363
LOTRISONE Lotion should not be used. If a patient with tinea pedis shows no
364
clinical improvement after 2 weeks of treatment with LOTRISONE Cream or
365
Lotion, the diagnosis should be reviewed.
366
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 13
LOTRISONE Cream or Lotion should not be used with occlusive dressings.
367
HOW SUPPLIED
368
LOTRISONE Cream is supplied in 15-gram (NDC 0085-0924-01) and 45-gram
369
tubes (NDC 0085-0924-02); boxes of one. Store between 2°C and 30°C (36°F
370
and 86°F).
371
LOTRISONE Lotion is supplied in 30-mL bottles (NDC 0085-0809-01), box of
372
one. Store at 25°C (77°F) in the upright position only; excursions permitted
373
between 15°C and 30°C (59°F and 86°F).
374
SHAKE WELL BEFORE EACH USE.
375
Rx only
376
Manufactured by: Schering/KEY
377
Schering Corporation/KEY Pharmaceuticals, Inc.
378
Kenilworth, NJ 07033 USA
379
3/10/03
380
Copyright® 2000 Schering Corporation. All Rights reserved.
381
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 14
TEAR AT PERFORATION
382
GIVE TO PATIENT
383
Patient’s Instructions for Use
384
SHAKE WELL BEFORE EACH USE
385
LOTRISONE® Cream, USP
386
LOTRISONE® Lotion
387
(clotrimazole, USP and betamethasone dipropionate, USP)
388
Patient Information Leaflet
389
What is LOTRISONE Cream or Lotion?
390
LOTRISONE Cream and Lotion are medications used on the skin to treat fungal
391
infections of the feet, groin and body, as diagnosed by your doctor. LOTRISONE
392
Cream or Lotion should be used for fungal infections that are inflamed and have
393
symptoms of redness and/or itching. Talk to your doctor if your fungal infection
394
does not have these symptoms. LOTRISONE Cream and Lotion contain a
395
corticosteroid. Notify your doctor if you notice side effects with the use of
396
LOTRISONE Cream or Lotion (see “What are the possible side effects of
397
LOTRISONE Cream and Lotion?” below). LOTRISONE Cream or Lotion is not
398
to be used in the eyes, in the mouth, or in the vagina.
399
How do LOTRISONE Cream and Lotion Work?
400
LOTRISONE Cream and Lotion are combinations of an antifungal agent
401
(clotrimazole) and a corticosteroid (betamethasone dipropionate). Clotrimazole
402
works against fungus. Betamethasone dipropionate, a corticosteroid, is used to
403
help relieve redness, swelling, itching, and other discomforts of fungal infections.
404
Who should NOT use LOTRISONE Cream or Lotion?
405
LOTRISONE Cream and Lotion are not recommended for use in patients under
406
the age of 17 years. LOTRISONE Cream or Lotion is not recommended for use
407
in diaper rash.
408
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 15
Patients who are sensitive to clotrimazole and betamethasone dipropionate,
409
other corticosteroids or imidazoles or any ingredients in the preparation should
410
not use LOTRISONE Cream and Lotion.
411
How should I use LOTRISONE Cream or Lotion?
412
Gently message sufficient LOTRISONE Cream or Lotion into the affected and
413
surrounding skin areas twice a day, in the morning and evening. Treatment for 2
414
weeks on the groin or on the body, and for 4 weeks on the feet is recommended.
415
The use of LOTRISONE Cream or Lotion for longer than 4 weeks is not
416
recommended for any condition. Prolonged use of LOTRISONE Cream or Lotion
417
may lead to unwanted side effects.
418
What other important information should I know about LOTRISONE Cream
419
and Lotion?
420
1. This medication is to be used for the full prescribed treatment time, even
421
though the symptoms may have improved. Notify your doctor if there is no
422
improvement after 1 week of treatment on the groin or body or after 2 weeks
423
on the feet.
424
2. This medication should only be used for the disorder for which it was
425
prescribed.
426
3. The treated skin area should not be bandaged or otherwise covered or
427
wrapped.
428
4. Other
corticosteriod-containing
products
should
not
be
used
with
429
LOTRISONE without first talking with your physician.
430
5. Any signs of side effects where LOTRISONE Cream or Lotion is applied
431
should be reported to your doctor.
432
6. When using LOTRISONE Cream or Lotion in the groin area, it is especially
433
important to use the medication for two weeks only, and to apply the cream or
434
lotion sparingly. You should tell your doctor if your problem persists after 2
435
weeks. You should also wear loose-fitting clothing so as to avoid tightly
436
covering the area where LOTRISONE Cream is applied.
437
7. This medication is not recommended for use in diaper rash.
438
What are the possible side effects of LOTRISONE Cream and Lotion?
439
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 16
The following side effects have been reported with topical corticosteroid
440
medications: itching, irritation, dryness, infection of the hair follicles, increased
441
hair, acne, change in skin color, allergic skin reaction, skin thinning, and stretch
442
marks. In children, reported adverse events for LOTRISONE Cream include
443
slower growth, Cushing’s syndrome (a type of hormone imbalance that can be
444
very serious), and local skin reactions, including thinning skin and stretch marks.
445
Hormone imbalance (adrenal suppression) was demonstrated in clinical studies
446
in children.
447
Can LOTRISONE Cream or Lotion be used if I am pregnant or plan to
448
become pregnant or if I am nursing?
449
Before using LOTRISONE Cream or Lotion, tell your doctor if you are pregnant
450
or plan to become pregnant. Also, tell your doctor if you are nursing.
451
How should LOTRISONE Cream or Lotion be stored?
452
LOTRISONE Cream should be stored between 2° and 30°C (36° and 86°F).
453
LOTRISONE Lotion should only be stored in an upright position between 15°C
454
and 30°C (59°F and 86°F). Shake well before using LOTRISONE Lotion.
455
General advice about prescription medicines
456
This medicine was prescribed for your particular condition. Only use
457
LOTRISONE Cream or Lotion to treat the condition for which your doctor has
458
prescribed. Do not give LOTRISONE Cream or Lotion to other people. It may
459
harm them.
460
This leaflet summarizes the most important information about LOTRISONE
461
Cream and Lotion. If you would like more information, talk with your doctor. You
462
can ask your pharmacist or doctor for information about LOTRISONE Cream and
463
Lotion that is written for health professionals.
464
Rx only
465
Schering/Key
466
Schering Corporation/Key Pharmaceuticals
467
Kenilworth, NJ 07033
468
Copyright 2000, Schering Corp. All rights reserved.
469
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 17
3/10/03
470
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:26.521057
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20010slr005_lotrisone_lbl.pdf', 'application_number': 20010, 'submission_type': 'SUPPL ', 'submission_number': 5}
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LOTRISONE® Cream
LOTRISONE® Lotion
(clotrimazole and betamethasone dipropionate)
FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR
INTRAVAGINAL USE. NOT RECOMMENDED FOR PATIENTS UNDER THE
AGE OF 17 YEARS AND NOT RECOMMENDED FOR DIAPER DERMATITIS.
DESCRIPTION
LOTRISONE® Cream and Lotion contain combinations of clotrimazole, a
synthetic antifungal agent, and betamethasone dipropionate, a synthetic
corticosteroid, for dermatologic use.
Chemically, clotrimazole is 1–(o-chloro-α,α-diphenylbenzyl) imidazole, with the
empirical formula C H CIN
22
17
2, a molecular weight of 344.84, and the following
structural formula:
Clotrimazole is an odorless, white crystalline powder, insoluble in water and
soluble in ethanol.
Betamethasone dipropionate has the chemical name 9-fluoro-11β,17,21-
trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate, with the
empirical formula C H FO
28
37
7, a molecular weight of 504.59, and the following
structural formula:
1
LRN# 000370-LOS-MTL-USPI-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
LRN# 000370-LOS-MTL-USPI-1
Betamethasone dipropionate is a white to creamy white, odorless crystalline
powder, insoluble in water.
Each gram of LOTRISONE Cream contains 10 mg clotrimazole and 0.643 mg
betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a
hydrophilic cream consisting of purified water, mineral oil, white petrolatum, cetyl
alcohol plus stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate
monobasic monohydrate, and phosphoric acid; benzyl alcohol as preservative.
LOTRISONE Cream may contain sodium hydroxide. LOTRISONE Cream is
smooth, uniform, and white to off-white in color.
Each gram of LOTRISONE Lotion contains 10 mg clotrimazole and 0.643 mg
betamethasone dipropionate (equivalent to 0.5 mg betamethasone), in a
hydrophilic base of purified water, mineral oil, white petrolatum, cetyl alcohol plus
stearyl alcohol, ceteareth-30, propylene glycol, sodium phosphate
monobasic monohydrate, and phosphoric acid; benzyl alcohol as a preservative.
LOTRISONE Lotion may contain sodium hydroxide. LOTRISONE Lotion is
opaque and white in color.
CLINICAL PHARMACOLOGY
Clotrimazole and Betamethasone Dipropionate
LOTRISONE® Cream has been shown to be at least as effective as clotrimazole
alone in a different cream vehicle. No comparative studies have been conducted
with LOTRISONE® Lotion and clotrimazole alone. Use of corticosteroids in the
treatment of a fungal infection may lead to suppression of host inflammation
leading to worsening or decreased cure rate.
Clotrimazole
Skin penetration and systemic absorption of clotrimazole following topical
application of LOTRISONE Cream or Lotion have not been studied. The following
information was obtained using 1% clotrimazole cream and solution formulations.
Six hours after the application of radioactive clotrimazole 1% cream and 1%
solution onto intact and acutely inflamed skin, the concentration of clotrimazole
varied from 100 mcg/cm3 in the stratum corneum, to 0.5 to 1 mcg/cm3 in the
reticular dermis, and 0.1 mcg/cm3 in the subcutis. No measurable amount of
radioactivity (<0.001 mcg/mL) was found in the serum within 48 hours after
application under occlusive dressing of 0.5 mL of the solution or 0.8 g of the
cream. Only 0.5% or less of the applied radioactivity was excreted in the urine.
Microbiology
Mechanism of Action: Clotrimazole is an imidazole antifungal agent. Imidazoles
inhibit 14-α-demethylation of lanosterol in fungi by binding to one of the
cytochrome P-450 enzymes. This leads to the accumulation of 14-α-
methylsterols and reduced concentrations of ergosterol, a sterol essential for a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
LRN# 000370-LOS-MTL-USPI-1
normal fungal cytoplasmic membrane. The methylsterols may affect the electron
transport system, thereby inhibiting growth of fungi.
Activity In Vivo: Clotrimazole has been shown to be active against most strains of
the following dermatophytes, both in vitro and in clinical infections as described in
the INDICATIONS AND USAGE section: Epidermophyton floccosum,
Trichophyton mentagrophytes, and Trichophyton rubrum.
Activity In Vitro: In vitro, clotrimazole has been shown to have activity against
many dermatophytes, but the clinical significance of this information is
unknown.
Drug Resistance: Strains of dermatophytes having a natural resistance to
clotrimazole have not been reported. Resistance to azoles including clotrimazole
has been reported in some Candida species.
No single-step or multiple-step resistance to clotrimazole has developed during
successive passages of Trichophyton mentagrophytes.
Betamethasone Dipropionate
Betamethasone dipropionate, a corticosteroid, has been shown to have topical
(dermatologic) and systemic pharmacologic and metabolic effects characteristic
of this class of drugs.
Pharmacokinetics
The extent of percutaneous absorption of topical corticosteroids is determined by
many factors, including the vehicle, the integrity of the epidermal barrier and the
use of occlusive dressings (see DOSAGE AND ADMINISTRATION). Topical
corticosteroids can be absorbed from normal intact skin. Inflammation and/or
other disease processes in the skin may increase percutaneous absorption of
topical corticosteroids. Occlusive dressings substantially increase the
percutaneous absorption of topical corticosteroids (see DOSAGE AND
ADMINISTRATION).
Once absorbed through the skin, the pharmacokinetics of topical corticosteroids
are similar to systemically administered corticosteroids. Corticosteroids are
bound to plasma proteins in varying degrees. Corticosteroids are metabolized
primarily in the liver and are then excreted by the kidneys. Some of the topical
corticosteroids and their metabolites are also excreted into the bile.
Studies performed with LOTRISONE Cream and Lotion indicate that these
topical
combination
antifungal/corticosteroids
may
have
vasoconstrictor
potencies in a range that is comparable to high potency topical corticosteroids.
Therefore, use is not recommended in patients less than 17 years of age, in
diaper dermatitis, and under occlusion.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
LRN# 000370-LOS-MTL-USPI-1
CLINICAL STUDIES (LOTRISONE® Cream)
In clinical studies of tinea corporis, tinea cruris, and tinea pedis, patients treated
with LOTRISONE Cream showed a better clinical response at the first return visit
than patients treated with clotrimazole cream. In tinea corporis and tinea cruris,
the patient returned 3 to 5 days after starting treatment, and in tinea pedis, after 1
week. Mycological cure rates observed in patients treated with LOTRISONE
Cream were as good as or better than in those patients treated with clotrimazole
cream. In these same clinical studies, patients treated with LOTRISONE Cream
showed better clinical responses and mycological cure rates when compared
with patients treated with betamethasone dipropionate cream.
CLINICAL STUDIES (LOTRISONE® Lotion)
In the treatment of tinea pedis twice daily for 4 weeks, LOTRISONE Lotion was
shown to be superior to vehicle in relieving symptoms of erythema, scaling,
pruritus, and maceration at week 2. LOTRISONE Lotion was also shown to have
a superior mycological cure rate compared to vehicle 2 weeks after
discontinuation of treatment. It is unclear if the relief of symptoms at 2 weeks in
this clinical study with LOTRISONE Lotion was due to the contribution of
betamethasone dipropionate, clotrimazole, or both.
In the treatment of tinea cruris twice daily for 2 weeks, LOTRISONE Lotion was
shown to be superior to vehicle in the relief of symptoms of erythema, scaling,
and pruritus after 3 days. It is unclear if the relief of symptoms after 3 days in this
clinical study with LOTRISONE Lotion was due to the contribution of
betamethasone dipropionate, clotrimazole, or both.
The comparative efficacy and safety of LOTRISONE Lotion versus clotrimazole
alone in a lotion vehicle have not been studied in the treatment of tinea pedis or
tinea cruris or tinea corporis. The comparative efficacy and safety of
LOTRISONE Lotion and LOTRISONE Cream have also not been studied.
INDICATIONS AND USAGE
LOTRISONE® Cream and Lotion are indicated in patients 17 years and older for
the topical treatment of symptomatic inflammatory tinea pedis, tinea cruris, and
tinea corporis due to Epidermophyton floccosum, Trichophyton mentagrophytes,
and Trichophyton rubrum. Effective treatment without the risks associated with
topical corticosteroid use may be obtained using a topical antifungal agent that
does not contain a corticosteroid, especially for noninflammatory tinea infections.
The efficacy of LOTRISONE Cream or Lotion for the treatment of infections
caused by zoophilic dermatophytes (eg, Microsporum canis) has not been
established. Several cases of treatment failure of LOTRISONE Cream in the
treatment of infections caused by Microsporum canis have been reported.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
LRN# 000370-LOS-MTL-USPI-1
CONTRAINDICATIONS
LOTRISONE® Cream or Lotion is contraindicated in patients who are sensitive to
clotrimazole, betamethasone dipropionate, other corticosteroids or imidazoles, or
to any ingredient in these preparations.
PRECAUTIONS
General
Systemic absorption of topical corticosteroids can produce reversible
hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for
glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of
Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in
some patients by systemic absorption of topical corticosteroids while on
treatment.
Conditions which augment systemic absorption include use over large surface
areas, prolonged use, and use under occlusive dressings. Use of more than one
corticosteriod-containing product at the same time may increase total systemic
glucocorticoid exposure. Patients applying LOTRISONE® Cream or Lotion to a
large surface area or to areas under occlusion should be evaluated periodically
for evidence of HPA axis suppression. This may be done by using the ACTH
stimulation, morning plasma cortisol, and urinary-free cortisol tests.
If HPA axis suppression is noted, an attempt should be made to withdraw the
drug, to reduce the frequency of application, or to substitute a less potent
corticosteroid. Recovery of HPA axis function is generally prompt upon
discontinuation of topical corticosteroids. Infrequently, signs and symptoms of
glucocorticosteroid insufficiency may occur, requiring supplemental systemic
corticosteroids.
In a small study, LOTRISONE Cream was applied using large dosages, 7 g daily
for 14 days (BID) to the crural area of normal adult subjects. Three of the eight
normal subjects on whom LOTRISONE Cream was applied exhibited low
morning plasma cortisol levels during treatment. One of these subjects had an
abnormal Cortrosyn test. The effect on morning plasma cortisol was transient
and subjects recovered one week after discontinuing dosing. In addition, two
separate studies in pediatric patients demonstrated adrenal suppression as
determined by cosyntropin testing (see PRECAUTIONS, Pediatric Use section).
Pediatric patients may be more susceptible to systemic toxicity from equivalent
doses due to their larger skin surface to body mass ratios (see PRECAUTIONS,
Pediatric Use section).
If irritation develops, LOTRISONE Cream or Lotion should be discontinued and
appropriate therapy instituted.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
LRN# 000370-LOS-MTL-USPI-1
THE SAFETY OF LOTRISONE CREAM OR LOTION HAS NOT BEEN
DEMONSTRATED IN THE TREATMENT OF DIAPER DERMATITIS. ADVERSE
EVENTS CONSISTENT WITH CORTICOSTEROID USE HAVE BEEN
OBSERVED IN PATIENTS TREATED WITH LOTRISONE CREAM FOR
DIAPER DERMATITIS. THE USE OF LOTRISONE CREAM OR LOTION IN
THE TREATMENT OF DIAPER DERMATITIS IS NOT RECOMMENDED.
Information for Patients
Patients using LOTRISONE Cream or Lotion should receive the following
information and instructions:
1. The medication is to be used as directed by the physician and is not
recommended for use longer than the prescribed time period. It is for
external use only. Avoid contact with the eyes, the mouth, or intravaginally.
2. This medication is to be used for the full prescribed treatment time, even
though the symptoms may have improved. Notify the physician if there is no
improvement after 1 week of treatment for tinea cruris or tinea corporis, or
after 2 weeks for tinea pedis.
3. This medication should only be used for the disorder for which it was
prescribed.
4. Other
corticosteroid-containing
products
should
not
be
used
with
LOTRISONE without first talking with your physician.
5. The treated skin area should not be bandaged, covered, or wrapped so as to
be occluded (see DOSAGE AND ADMINISTRATION).
6. Any signs of local adverse reactions should be reported to your physician.
7. Patients should avoid sources of infection or reinfection.
8. When using LOTRISONE Cream or Lotion in the groin area, patients should
use the medication for 2 weeks only, and apply the cream or lotion sparingly.
Patients should wear loose-fitting clothing. Notify the physician if the condition
persists after 2 weeks.
9. The safety of LOTRISONE Cream or Lotion has not been demonstrated in the
treatment of diaper dermatitis. Adverse events consistent with corticosteroid
use have been observed in patients treated with LOTRISONE Cream for
diaper dermatitis. The use of LOTRISONE Cream or Lotion in the treatment
of diaper dermatitis is not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
LRN# 000370-LOS-MTL-USPI-1
Laboratory Tests
If there is a lack of response to LOTRISONE Cream or Lotion, appropriate
confirmation of the diagnosis, including possible mycological studies, is indicated
before instituting another course of therapy.
The following tests may be helpful in evaluating HPA-axis suppression due to the
corticosteroid components:
Urinary-free cortisol test
Morning plasma cortisol test
ACTH (cosyntropin) stimulation test
Carcinogenesis, Mutagenesis, Impairment of Fertility
There are no adequate laboratory animal studies with either the combination of
clotrimazole and betamethasone dipropionate or with either component
individually to evaluate carcinogenesis.
Betamethasone was negative in the bacterial mutagenicity assay (Salmonella
typhimurium and Escherichia coli) and in the mammalian cell mutagenicity assay
(CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome
aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus
assay. This pattern of response is similar to that of dexamethasone and
hydrocortisone.
Reproductive studies with betamethasone dipropionate carried out in rabbits at
doses of 1.0 mg/kg by the intramuscular route and in mice up to 33 mg/kg by the
intramuscular route indicated no impairment of fertility except for dose-related
increases in fetal resorption rates in both species. These doses are
approximately 5- and 38-fold the maximum human dose based on body surface
areas, respectively.
In a combined study of the effects of clotrimazole on fertility, teratogenicity, and
postnatal development, male and female rats were dosed orally (diet admixture)
with levels of 5, 10, 25, or 50 mg/kg/day (approximately 1-8 times the maximum
dose in a 60 kg adult based on body surface area) from 10 weeks prior to mating
until 4 weeks postpartum. No adverse effects on the duration of estrous cycle,
fertility, or duration of pregnancy were noted.
Pregnancy Teratogenic Effects Pregnancy Category C
There have been no teratogenic studies performed in animals or humans with the
combination of clotrimazole and betamethasone dipropionate. Corticosteroids are
generally teratogenic in laboratory animals when administered at relatively low
dosage levels.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
LRN# 000370-LOS-MTL-USPI-1
Studies in pregnant rats with intravaginal doses up to 100 mg/kg (15 times the
maximum human dose) revealed no evidence of fetotoxicity due to clotrimazole
exposure.
No increase in fetal malformations was noted in pregnant rats receiving oral
(gastric tube) clotrimazole doses up to 100 mg/kg/day during gestation days 6-
15. However, clotrimazole dosed at 100 mg/kg/day was embryotoxic (increased
resorptions), fetotoxic (reduced fetal weights) and maternally toxic (reduced body
weight gain) to rats. Clotrimazole dosed at 200 mg/kg/day (30 times the
maximum human dose) was maternally lethal, and therefore fetuses were not
evaluated in this group. Also in this study, doses up to 50 mg/kg/day (8 times the
maximum human dose) had no adverse effects on dams or fetuses. However, in
the combined fertility, teratogenicity, and postnatal development study described
above, 50 mg/kg clotrimazole, was associated with reduced maternal weight gain
and reduced numbers of offspring reared to 4 weeks.
Oral clotrimazole doses of 25, 50, 100, and 200 mg/kg/day (2-15 times the
maximum human dose) were not teratogenic in mice. No evidence of maternal
toxicity or embryotoxicity was seen in pregnant rabbits dosed orally with 60, 120,
or 180 mg/kg/day (18-55 times the maximum human dose).
Betamethasone dipropionate has been shown to be teratogenic in rabbits when
given by the intramuscular route at doses of 0.05 mg/kg. This dose is
approximately one-fifth the maximum human dose. The abnormalities observed
included umbilical hernias, cephalocele and cleft palates.
Betamethasone dipropionate has not been tested for teratogenic potential by the
dermal route of administration. Some corticosteroids have been shown to be
teratogenic after dermal application to laboratory animals.
There are no adequate and well-controlled studies in pregnant women of the
teratogenic effects of topically applied corticosteroids. Therefore, LOTRISONE
Cream or Lotion should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers
Systemically administered corticosteroids appear in human milk and could
suppress growth, interfere with endogenous corticosteroid production, or cause
other untoward effects. It is not known whether topical administration of
corticosteroids could result in sufficient systemic absorption to produce
detectable quantities in human milk. Because many drugs are excreted in
human milk, caution should be exercised when LOTRISONE Cream or Lotion is
administered to a nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
LRN# 000370-LOS-MTL-USPI-1
Pediatric Use
Adverse events consistent with corticosteroid use have been observed in
patients under 12 years of age treated with LOTRISONE Cream. In open-label
studies, 17 of 43 (39.5%) evaluable pediatric patients (aged 12 to 16 years old)
using LOTRISONE Cream for treatment of tinea pedis demonstrated adrenal
suppression as determined by cosyntropin testing. In another open-label study, 8
of 17 (47.1%) evaluable pediatric patients (aged 12 to 16 years old) using
LOTRISONE Cream for treatment of tinea cruris demonstrated adrenal
suppression as determined by cosyntropin testing. THE USE OF LOTRISONE
CREAM OR LOTION IN THE TREATMENT OF PATIENTS UNDER 17 YEARS
OF
AGE
OR
PATIENTS
WITH
DIAPER
DERMATITIS
IS
NOT
RECOMMENDED.
Because of higher ratio of skin surface area to body mass, pediatric patients
under the age of 12 years are at a higher risk with LOTRISONE Cream or Lotion.
The studies described above suggest that pediatric patients under the age of 17
years may also have this risk. They are at increased risk of developing Cushing’s
syndrome while on treatment and adrenal insufficiency after withdrawal of
treatment. Adverse effects, including striae and growth retardation, have been
reported with inappropriate use of LOTRISONE Cream in infants and children
(see PRECAUTIONS and ADVERSE REACTIONS).
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome,
linear growth retardation, delayed weight gain, and intracranial hypertension
have been reported in children receiving topical corticosteroids. Manifestations
of adrenal suppression in children include low plasma cortisol levels and absence
of response to ACTH stimulation. Manifestations of intracranial hypertension
include bulging fontanelles, headaches, and bilateral papilledema.
Geriatric Use
Clinical studies of LOTRISONE Cream and Lotion did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Postmarket adverse event reporting for
LOTRISONE Cream in patients aged 65 and above includes reports of skin
atrophy and rare reports of skin ulceration. Caution should be exercised with the
use of these corticosteroid-containing topical products on thinning skin. THE USE
OF LOTRISONE CREAM OR LOTION UNDER OCCLUSION, SUCH AS IN
DIAPER DERMATITIS, IS NOT RECOMMENDED.
ADVERSE REACTIONS
Adverse reactions reported for LOTRISONE® Cream in clinical trials were
paresthesia in 1.9% of patients, and rash, edema, and secondary infection, each
in less than 1% of patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
LRN# 000370-LOS-MTL-USPI-1
Adverse reactions reported for LOTRISONE® Lotion in clinical trials were burning
and dry skin in 1.6% of patients and stinging in less than 1% of patients.
The following local adverse reactions have been reported with topical
corticosteroids and may occur more frequently with the use of occlusive
dressings. These reactions are listed in an approximate decreasing order of
occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis,
maceration of the skin, secondary infection, skin atrophy, striae, miliaria, capillary
fragility (ecchymoses), and sensitization (local reactions upon repeated
application of product). In the pediatric population, reported adverse events for
LOTRISONE Cream include growth retardation, benign intracranial hypertension,
Cushing’s syndrome (HPA axis suppression), and local cutaneous reactions,
including skin atrophy.
Systemic absorption of topical corticosteroids has produced reversible
hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of
Cushing’s syndrome, hyperglycemia, and glucosuria in some patients.
Adverse reactions reported with the use of clotrimazole are as follows: erythema,
stinging, blistering, peeling, edema, pruritus, urticaria, and general irritation of the
skin.
OVERDOSAGE
Amounts greater than 45 g/week of LOTRISONE® Cream or 45 mL/week of
LOTRISONE® Lotion should not be used. Acute overdosage with topical
application of LOTRISONE Cream or Lotion is unlikely and would not be
expected to lead to a life-threatening situation. LOTRISONE Cream or Lotion
should not be used for longer than the prescribed time period.
Topically applied corticosteroids, such as the one contained in LOTRISONE
Cream or Lotion can be absorbed in sufficient amounts to produce systemic
effects (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION
Gently massage sufficient LOTRISONE® Cream or Lotion into the affected skin
areas twice a day, in the morning and evening.
LOTRISONE Cream or Lotion should not be used longer than 2 weeks in
the treatment of tinea corporis or tinea cruris, and amounts greater than 45
g per week of LOTRISONE Cream or amounts greater than 45 mL per week
of LOTRISONE Lotion should not be used. If a patient with tinea corporis or
tinea cruris shows no clinical improvement after 1 week of treatment with
LOTRISONE Cream or Lotion, the diagnosis should be reviewed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
LRN# 000370-LOS-MTL-USPI-1
LOTRISONE Cream or Lotion should not be used longer than 4 weeks in
the treatment of tinea pedis and amounts greater than 45 g per week of
LOTRISONE Cream or amounts greater than 45 mL per week of
LOTRISONE Lotion should not be used. If a patient with tinea pedis shows no
clinical improvement after 2 weeks of treatment with LOTRISONE Cream or
Lotion, the diagnosis should be reviewed.
LOTRISONE Cream or Lotion should not be used with occlusive dressings.
HOW SUPPLIED
LOTRISONE® Cream is supplied in 15-g (NDC 0085-0924-01) and 45-g tubes
(NDC 0085-0924-02); boxes of one. Store at 25°C (77°F); excursions
permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
LOTRISONE® Lotion is supplied in 30-mL bottles (NDC 0085-0809-01), box of
one. Store at 25°C (77°F) in the upright position only; excursions permitted
between 15°C and 30°C (59°F and 86°F).
SHAKE LOTION WELL BEFORE EACH USE.
Rx only
Schering Corporation
Kenilworth, NJ 07033 USA
Rev. 01/08
Copyright © 2000, 2007, Schering Corporation. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
LRN# 000370-LOS-MTL-PPI-1
LOTRISONE®
Cream
LOTRISONE®
Lotion
(clotrimazole and betamethasone dipropionate)
Patient’s Instructions for Use
SHAKE LOTION WELL BEFORE EACH USE
Patient Information Leaflet
What is LOTRISONE® Cream or Lotion?
LOTRISONE Cream and Lotion are medications used on the skin to treat fungal
infections of the feet, groin and body, as diagnosed by your doctor. LOTRISONE
Cream or Lotion should be used for fungal infections that are inflamed and have
symptoms of redness and/or itching. Talk to your doctor if your fungal infection
does not have these symptoms. LOTRISONE Cream and Lotion contain a
corticosteroid. Notify your doctor if you notice side effects with the use of
LOTRISONE Cream or Lotion (see “What are the possible side effects of
LOTRISONE Cream and Lotion?” below). LOTRISONE Cream or Lotion is not
to be used in the eyes, in the mouth, or in the vagina.
How do LOTRISONE® Cream and Lotion work?
LOTRISONE Cream and Lotion are combinations of an antifungal agent
(clotrimazole) and a corticosteroid (betamethasone dipropionate). Clotrimazole
works against fungus. Betamethasone dipropionate, a corticosteroid, is used to
help relieve redness, swelling, itching, and other discomforts of fungal infections.
Who should NOT use LOTRISONE® Cream or Lotion?
LOTRISONE Cream and Lotion are not recommended for use in patients under
the age of 17 years. LOTRISONE Cream or Lotion is not recommended for use
in diaper rash.
Patients who are sensitive to clotrimazole and betamethasone dipropionate,
other corticosteroids or imidazoles, or any ingredients in the preparation should
not use LOTRISONE Cream and Lotion.
How should I use LOTRISONE® Cream or Lotion?
Gently massage sufficient LOTRISONE Cream or Lotion into the affected and
surrounding skin areas twice a day, in the morning and evening. Treatment for 2
weeks on the groin or on the body, and for 4 weeks on the feet is recommended.
The use of LOTRISONE Cream or Lotion for longer than 4 weeks is not
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
LRN# 000370-LOS-MTL-PPI-1
recommended for any condition. Prolonged use of LOTRISONE Cream or Lotion
may lead to unwanted side effects.
What other important information should I know about LOTRISONE® Cream
and Lotion?
1. This medication is to be used for the full prescribed treatment time, even
though the symptoms may have improved. Notify your doctor if there is no
improvement after 1 week of treatment on the groin or body or after 2 weeks
on the feet.
2. This medication should only be used for the disorder for which it was
prescribed.
3. The treated skin area should not be bandaged or otherwise covered or
wrapped.
4. Other
corticosteroid-containing
products
should
not
be
used
with
LOTRISONE without first talking with your physician.
5. Any signs of side effects where LOTRISONE Cream or Lotion is applied
should be reported to your doctor.
6. When using LOTRISONE Cream or Lotion in the groin area, it is especially
important to use the medication for 2 weeks only, and to apply the cream or
lotion sparingly. You should tell your doctor if your problem persists after 2
weeks. You should also wear loose-fitting clothing so as to avoid tightly
covering the area where LOTRISONE Cream or Lotion is applied.
7. This medication is not recommended for use in diaper rash.
What are the possible side effects of LOTRISONE® Cream and Lotion?
The following side effects have been reported with topical corticosteroid
medications: itching, irritation, dryness, infection of the hair follicles, increased
hair, acne, fragile blood vessels, sensitization (local reactions upon repeated
application of product), change in skin color, allergic skin reaction, skin thinning,
and stretch marks. In children, reported adverse events for LOTRISONE Cream
include slower growth, Cushing’s syndrome (a type of hormone imbalance that
can be very serious), and local skin reactions, including thinning skin and stretch
marks. Hormone imbalance (adrenal suppression) was demonstrated in clinical
studies in children.
Can LOTRISONE® Cream or Lotion be used if I am pregnant or plan to
become pregnant or if I am nursing?
Before using LOTRISONE Cream or Lotion, tell your doctor if you are pregnant
or plan to become pregnant. Also, tell your doctor if you are nursing.
How should LOTRISONE® Cream or Lotion be stored?
LOTRISONE Cream should be stored at 25°C (77°F); excursions permitted
to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
LRN# 000370-LOS-MTL-PPI-1
LOTRISONE Lotion should be stored at 25°C (77°F) in the upright position
only; excursions permitted between 15°C and 30°C (59°F and 86°F).
Shake well before using LOTRISONE Lotion.
General advice about prescription medicines
This medicine was prescribed for your particular condition. Only use
LOTRISONE® Cream or Lotion to treat the condition for which your doctor has
prescribed. Do not give LOTRISONE Cream or Lotion to other people. It may
harm them.
This leaflet summarizes the most important information about LOTRISONE
Cream and Lotion. If you would like more information, talk with your doctor. You
can ask your pharmacist or doctor for information about LOTRISONE Cream and
Lotion that is written for health professionals.
Rx only
Schering Corporation
Kenilworth, NJ 07033 USA
Copyright © 2000, 2007, Schering Corporation. All rights reserved.
Rev.01/08
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:26.596263
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020010s015lbl.pdf', 'application_number': 20010, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
12,134
|
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
1
This is combined labeling. Examples of different fonts and colors appear below.
• General information
• Information on endometriosis
• Information on uterine fibroids
LUPRON DEPOT® 3.75 mg
(leuprolide acetate for depot suspension)
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-
releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural
hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-
leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural
formula:
O
1-2CH3COOH
·
N
H
H
O
NH2
NH
C
H
N
N
N
OH
N
H
C N CH C N CH C N CH C N CH C N CH C N CH C N CH C
O
O
O
O
O
O
O
O
H
H
H
H
H
H
H
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
OH
CH
CH3
CH3
CH
CH3
CH3
N
C N CH2CH3
H
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized
microspheres which, when mixed with diluent, become a suspension intended as a monthly
intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains
leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids
copolymer (33.1 mg), and D-mannitol (6.6 mg). The second chamber of diluent contains
carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for
injection, USP, and glacial acetic acid, USP to control pH.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the
peptide.
CLINICAL PHARMACOLOGY
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of
LUPRON DEPOT 3.75 mg results in an initial stimulation followed by a prolonged suppression
of pituitary gonadotropins. Repeated dosing at monthly intervals results in decreased secretion
of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their
maintenance become quiescent. This effect is reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally. Intramuscular injection of the depot
formulation provides plasma concentrations of leuprolide over a period of one month.
Pharmacokinetics
Absorption A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular
injection to healthy female volunteers. The absorption of leuprolide was characterized by an
initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL
at four hours postdosing. However, intact leuprolide and an inactive metabolite could not be
distinguished by the assay used in the study. Following the initial rise, leuprolide concentrations
started to plateau within two days after dosing and remained relatively stable for about four to
five weeks with plasma concentrations of about 0.30 ng/mL.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
2
Distribution The mean steady-state volume of distribution of leuprolide following intravenous
bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma
proteins ranged from 43% to 49%.
Metabolism In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously
revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of
approximately 3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to
smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a
dipeptide (Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients
reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the
peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were
approximately 20% of mean leuprolide concentrations.
Excretion Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of
the dose was recovered as parent and M-I metabolite in the urine.
Special Populations The pharmacokinetics of the drug in hepatically and renally impaired
patients have not been determined.
CLINICAL STUDIES
Endometriosis: In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six
months was shown to be comparable to danazol 800 mg/day in relieving the clinical
sign/symptoms of endometriosis (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and
induration) and in reducing the size of endometrial implants as evidenced by laparoscopy. The
clinical significance of a decrease in endometriotic lesions is not known at this time, and in
addition laparoscopic staging of endometriosis does not necessarily correlate with the severity of
symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients
after the first and second treatment months respectively. Most of the remaining patients reported
episodes of only light bleeding or spotting. In the first, second and third post-treatment months,
normal menstrual cycles resumed in 7%, 71% and 95% of patients, respectively, excluding those
who became pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and
sustained relief at 6 and 12 months following discontinuation of treatment for the various
symptoms evaluated during the study. This included all patients at end of treatment and those
who elected to participate in the follow-up periods. This might provide a slight bias in the results
at follow-up as 75% of the original patients entered the follow-up study, and 36% were evaluated
at 6 months and 26% at 12 months.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
3
Hormonal add-back therapy: Two clinical studies with a treatment duration of 12 months
indicate that concurrent hormonal therapy (norethindrone acetate 5 mg daily) is effective in
significantly reducing the loss of bone mineral density associated with LUPRON, without
compromising the efficacy of LUPRON in relieving symptoms of endometriosis. (All patients
in these studies received calcium supplementation with 1000 mg elemental calcium). One
controlled, randomized and double-blind study included 51 women treated with Lupron Depot
alone and 55 women treated with Lupron plus norethindrone acetate 5 mg daily. The second
study was an open label study in which 136 women were treated with Lupron plus
norethindrone acetate 5 mg daily (LD/N) daily. This study confirmed the reduction in loss of
bone mineral density that was observed in the controlled study. Suppression of menses was
maintained throughtout treatment in 84% and 73% of patients receiving LD/N in the controlled
study and the open label study, respectively. The median time for menses resumption after
treatment with LD/N was 8 weeks.
Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
4
Uterine Leiomyomata (Fibroids): In controlled clinical trials, administration of
LUPRON DEPOT 3.75 mg for a period of three or six months was shown to decrease uterine and
fibroid volume, thus allowing for relief of clinical symptoms (abdominal bloating, pelvic pain,
and pressure). Excessive vaginal bleeding (menorrhagia and menometrorrhagia) decreased,
resulting in improvement in hematologic parameters.
In three clinical trials, enrollment was not based on hematologic status. Mean uterine volume
decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound
or MRI. These patients also experienced a decrease in symptoms including excessive vaginal
bleeding and pelvic discomfort. Benefit occurred by three months of therapy, but additional gain
was observed with an additional three months of LUPRON DEPOT 3.75 mg. Ninety-five percent
of these patients became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during
the first, second, and third treatment months respectively.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
5
Post-treatment follow-up was carried out for a small percentage of
LUPRON DEPOT 3.75 mg patients among the 77% who demonstrated a ≥ 25% decrease in
uterine volume while on therapy. Menses usually returned within two months of cessation of
therapy. Mean time to return to pretreatment uterine size was 8.3 months. Regrowth did not
appear to be related to pretreatment uterine volume.
In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or
hemoglobin ≤ 10.2 g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron,
produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of patients at three
months of therapy. The mean change in hematocrit was 10.1% and the mean change in
hemoglobin was 4.2 g/dL. Clinical response was judged to be a hematocrit of
≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to
surgery. At three months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or
menometrorrhagia. As with the previous studies, episodes of spotting and menstrual-like
bleeding were noted in some patients.
In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in 60% and
54% of patients respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of
bloating, pelvic pain, and pressure.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of
LUPRON DEPOT 3.75 mg.
INDICATIONS AND USAGE
Endometriosis:
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief
and reduction of endometriotic lesions. LUPRON DEPOT monthly with norethindrone acetate 5
mg daily is also indicated for initial management of endometriosis and for management of
recurrence of symptoms ( Refer also to norethindrone acetate prescribing information for
WARNINGS, PRECAUTIONS, CONTRAINDICATIONS and ADVERSE REACTIONS
associated with norethindrone acetate). Duration of initial treatment or retreatment should be
limited to 6 months.
Uterine Leiomyomata (Fibroids):
LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the preoperative
hematologic improvement of patients with anemia caused by uterine leiomyomata. The clinician
may wish to consider a one-month trial period on iron alone inasmuch as some of the patients
will respond to iron alone. (See Table 1.) LUPRON may be added if the response to iron alone is
considered inadequate. Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up
to three months.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
6
Experience with LUPRON DEPOT in females has been limited to women 18 years of age
and older.
TABLE 1
PERCENT OF PATIENTS ACHIEVING
HEMOGLOBIN ≥ 12 GM/DL
Treatment Group
Week 4
Week 8
Week 12
LUPRON DEPOT 3.75 mg with Iron
41*
71**
79*
Iron Alone
17
40
56
* P-Value < 0.01
** P-Value < 0.001
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in
LUPRON DEPOT.
2.
Undiagnosed abnormal vaginal bleeding.
3. LUPRON DEPOT is contraindicated in women who are or may become pregnant while
receiving the drug. LUPRON DEPOT may cause fetal harm when administered to a
pregnant woman. Major fetal abnormalities were observed in rabbits but not in rats after
administration of LUPRON DEPOT throughout gestation. There was increased fetal
mortality and decreased fetal weights in rats and rabbits. (See Pregnancy section.) The
effects on fetal mortality are expected consequences of the alterations in hormonal levels
brought about by the drug. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to the
fetus.
4. Use in women who are breast-feeding. (See Nursing Mothers section.)
5. Norethindrone acetate is contraindicated in women with the following conditions:
- Thromophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these
conditions
- Markedly impaired liver function or liver
disease
- Known or suspected carcinona of the breast
WARNINGS
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established
clinically. Before starting treatment with LUPRON DEPOT, pregnancy must be excluded.
When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation
and stops menstruation. Contraception is not insured, however, by taking LUPRON DEPOT.
Therefore, patients should use non-hormonal methods of contraception. Patients should be
advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant
during treatment, the drug must be discontinued and the patient must be apprised of the potential
risk to the fetus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
7
During the early phase of therapy, sex steroids temporarily rise above baseline because of the
physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be
observed during the initial days of therapy, but these will dissipate with continued therapy.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported
post-marketing.
The following applies to co-treatment with Lupron and norethindrone acetate:
Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete
loss of vision or if there is sudden onset of protosis, diplopia, or migraine. If examination reveals
papilledema or retinal vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in
patients taking progestogens, the physician should be alert to the earliest manifestations of the
disease in women taking norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior
to initiation of add-back therapy with norethindrone acetate. Norethindrone acetate should be
used with caustion in women with risk factors, including lipid abnormalities or cigarette smoking.
PRECAUTIONS
Information for Patients An information pamphlet for patients is included with the product.
Patients should be aware of the following information:
1. Since menstruation should stop with effective doses of LUPRON DEPOT, the patient should
notify her physician if regular menstruation persists. Patients missing successive doses of
LUPRON DEPOT may experience breakthrough bleeding.
2. Patients should not use LUPRON DEPOT if they are pregnant, breast feeding, have
undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in
LUPRON DEPOT.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a
non-hormonal method of contraception should be used during treatment. Patients should be
advised that if they miss successive doses of LUPRON DEPOT, breakthrough bleeding or
ovulation may occur with the potential for conception. If a patient becomes pregnant during
treatment, she should discontinue treatment and consult her physician.
4. Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with
hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne,
myalgia, reduction in breast size, and vaginal dryness. Estrogen levels returned to normal
after treatment was discontinued.
5. The induced hypoestrogenic state also results in a loss in bone density over the course of
treatment, some of which may not be reversible. For a period up to six months, this bone loss
should not be clinically significant. Clinical studies show that concurrent hormonal therapy
with norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that
occurs with LUPRON. (All patients received calcium supplementation with 1000 mg
elemental calcium.) (See Changes In Bone Density section).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
8
6. If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-
month course of LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered.
Retreatment beyond this one six month course can not be recommended. It is recommended
that bone density be assessed before retreatment begins to ensure that values are within
normal limits. Retreatment with Lupron Depot alone is not recommended.
7. In patients with major risk factors for decreased bone mineral content such as chronic alcohol
and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can
reduce bone mass such as anticonvulsants or corticosteroids, Lupron Depot therapy may pose
an additional risk. In these patients, the risks and benefits must be weighed carefully before
therapy with LUPRON DEPOT alone is instituted, and concomitant treatment with
norethindrone acetate 5 mg daily should be considered. Retreatment with gonadotropin
releasing hormone analogs, including LUPRON is not advisable in patients with major risk
factors for loss of bone mineral content.
8. Because norethindrone acetate may cause some degree of fluid retention, conditions which
might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal
dysfunctions require careful observation during norethindrone acetate add-back therapy.
9. Patients who have a history of depression should be carefully observed during treatment with
norethindrone acetate and norethindrone acetate should be discontinued if severe depression
occurs.
Laboratory Tests See ADVERSE REACTIONS section.
Drug Interactions No pharmacokinetic-based drug-drug interaction studies have been
conducted with LUPRON DEPOT. However, because leuprolide acetate is a peptide that is
primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific
studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be
expected to occur.
Drug/Laboratory Test Interactions Administration of LUPRON DEPOT in therapeutic doses
results in suppression of the pituitary-gonadal system. Normal function is usually restored within
three months after treatment is discontinued. Therefore, diagnostic tests of pituitary gonadotropic
and gonadal functions conducted during treatment and for up to three months after
discontinuation of LUPRON DEPOT may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was
conducted in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and
benign pituitary adenomas was noted at 24 months when the drug was administered
subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related
increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in
males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced tumors
or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients
have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day
and for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.
Mutagenicity studies have been performed with leuprolide acetate using bacterial and
mammalian systems. These studies provided no evidence of a mutagenic potential.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
9
Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar
analogs have shown reversibility of fertility suppression when the drug is discontinued after
continuous administration for periods of up to 24 weeks. Although no clinical studies have been
completed in children to assess the full reversibility of fertility suppression, animal studies
(prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have
shown functional recovery.
Pregnancy, Teratogenic Effects Pregnancy Category X. (See CONTRAINDICATIONS
section.) When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and
0.024 mg/kg (1/300 to 1/3 of the human dose) to rabbits, LUPRON DEPOT produced a dose-
related increase in major fetal abnormalities. Similar studies in rats failed to demonstrate an
increase in fetal malformations. There was increased fetal mortality and decreased fetal weights
with the two higher doses of LUPRON DEPOT in rabbits and with the highest dose
(0.024 mg/kg) in rats.
Nursing Mothers It is not known whether LUPRON DEPOT is excreted in human milk.
Because many drugs are excreted in human milk, and because the effects of LUPRON DEPOT on
lactation and/or the breast-fed child have not been determined, LUPRON DEPOT should not be
used by nursing mothers.
Pediatric Use Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has
been limited to women 18 years of age and older.
See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension) labeling for the safety and
effectiveness in children with central precocious puberty.
Geriatric Use This product has not been studied in women over 65 years of age and is not
indicated in this population.
ADVERSE REACTIONS
Clinical Trials
Estradiol levels may increase during the first weeks following the initial injection of LUPRON,
but then decline to menopausal levels. This transient increase in estradiol can be associated with
a temporary worsening of signs and symptoms. (See WARNINGS section.)
As would be expected with a drug that lowers serum estradiol levels, the most frequently
reported adverse reactions were those related to hypoestrogenism.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
10
Endometriosis: In controlled studies comparing LUPRON DEPOT 3.75 mg monthly and danazol
(800 mg/day) or placebo, adverse reactions most frequently reported and thought to be possibly or
probably drug-related are shown in Figure 3.
* POSSIBLE EFFECT OF DECREASED ESTROGEN
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
11
In these same studies, other symptoms reported included: Cardiovascular System – Palpitations,
Syncope, Tachycardia; Gastorintestinal System - Appetite changes; Dry mouth, Thirst,
Central/Peripheral Nervous System – Anxiety, Delusions, Memory disorder, * Personality
disorder; Integumentary System – Alopecia, Ecchymosis, Hair disorder; Urogenital System –
Dysuria, * Lactation; Miscellaneous - * Lymphadenopathy, Ophthalmologic disorders.
*Possible effect of decreased estrogen
Table 2 lists the potentially drug-related adverse events observed in at least 5 % of patients in any
treatment group during the first 6 months of treatment in the add back clinical studies.
Table 2:
Treatment-Related Adverse Events Occurring in > 5% Of Patients
Controlled Study
Open Label Study
LD- Only1
N= 51
LD/N2
N=55
LD/N2
N=136
Adverse Events
N
(%)
N
(%)
N
(%)
Any Adverse Event
50
(98)
53
(96)
126
(93)
Body as a Whole
Asthenia
9
(18)
10
(18)
15
(11)
Headache/Migraine
33
(65)
28
(51)
63
(46)
Injection Site Reaction
1
(2)
5
(9)
4
(3)
Pain
12
(24)
16
(29)
29
(21)
Cardiovascular System
Hot flashes/Sweats
50
(98)
48
(87)
78
(57)
Digestive System
Altered Bowel Function
7
(14)
8
(15)
14
(10)
Changes in Appetite
2
(4)
0
(0)
8
(6)
GI Disturbance
2
(4)
4
(7)
6
(4)
Nausea/Vomiting
13
(25)
16
(29)
17
(13)
Metabolic and Nutritional
Disorders
Edema
0
(0)
5
(9)
9
(7)
Weight Changes
6
(12)
7
(13)
6
(4)
Nervous System
Anxiety
3
(6)
0
(0)
11
(8)
Depression/Emotional Lability
16
(31)
15
(27)
46
(34)
Dizziness/Vertigo
8
(16)
6
(11)
10
(7)
Insomnia/Sleep Disorders
16
(31)
7
(13)
20
(15)
Libido Changes
5
(10)
2
(4)
10
(7)
This label may not be the latest approved by FDA.
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Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
12
Memory Disorder
3
(6)
1
(2)
6
(4)
Nervousness
4
(8)
2
(4)
15
(11)
Neuromuscular Disorder
1
(2)
5
(9)
4
(3)
Skin and Appendages
Alopecia
0
(0)
5
(9)
4
(3)
Androgen-Like Effects
2
(4)
3
(5)
24
(18)
Skin/Mucous Membrane
Reaction
2
(4)
5
(9)
15
(11)
Urogential System
Breast Changes/Pain/
Tenderness
3
(6)
7
(13)
11
(8)
Menstrual Disorders
1
(2)
0
(0)
7
(5)
Vaginitis
10
(20)
8
(15)
11
(8)
1 LD Only =Lupron Depot 3.75 mg
2LD/N =Lupron Depot 3.75 mg plus norethindrone acetate 5mg
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%)
patients in the LD/N group reported experiencing hot flashes on one or more occasions
during treatment. During Month 6 of treatment, 32 of 37 (86%) patients in the LD group
and 22 of 38 (58%) patients in the LD/N group reported having experienced hot flashes.
The mean number of days on which hot flashes were reported during this month of
treatment was 19 and 7 in the LD and LD/N treatment groups, respectively. The mean
maximum number of hot flashes in a day during this month of treatment was 5.8 and 1.9 in
the LD and LD/N treatment groups, respectively.
Uterine
Leiomyomata
(Fibroids):
In
controlled
clinical
trials
comparing
LUPRON DEPOT 3.75 mg and placebo, adverse events reported in > 5% of patients and
thought to be potentially related to drug are noted in Table 3.
TABLE 3
ADVERSE EVENTS OBSERVED IN > 5% OF PATIENTS AND THOUGHT
TO BE POTENTIALLY RELATED TO DRUG
Lupron Depot 3.75 mg
Placebo
N=166
(%)
N=163
(%)
Body as a Whole
Asthenia
14
(8.4)
8
(4.9)
General pain
14
(8.4)
10
(6.1)
Headache*
43
(25.9)
29
(17.8)
Cardiovascular System
Hot flashes/sweats*
121
(72.9)
29
(17.8)
Metabolic and Nutritional disorders
Edema
9
(5.4)
2
(1.2)
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Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
13
Musculoskeletal System
Joint disorder*
13
(7.8)
5
(3.1)
Nervous System
Depression/emotional lability*
18
(10.8)
7
(4.3)
Urogenital System
Vaginitis*
19
(11.4)
3
(1.8)
Symptoms reported in < 5% of patients included: Body as Whole - Body odor, Flu
syndrome, Injection site reactions; Cardiovascular System - Tachycardia; Digestive
System - Appetite changes, Dry mouth, GI disturbances, Nausea/vomiting; Metabolic
and Nutritional Disorders - Weight changes; Musculoskeletal System - Myalgia;
Nervous System - Anxiety, Decreased libido,* Dizziness, Insomnia, Nervousness,*
Neuromuscular
disorders,
* Paresthesias;
Respiratory
System
-
Rhinitis;
Integumentary System - Androgen-like effects, Nail disorder, Skin reactions; Special
Senses - Conjunctivitis, Taste perversion; Urogenital System - Breast changes,*
Menstrual disorders.
* = Possible effect of decreased estrogen.
In one controlled clinical trial, patients received a higher dose (7.5 mg) of
LUPRON DEPOT. Events seen with this dose that were thought to be potentially
related to drug and were not seen at the lower dose included palpitations, syncope,
glossitis, ecchymosis, hypesthesia, confusion, lactation, pyelonephritis, and urinary
disorders. Generally, a higher incidence of hypoestrogenic effects was observed at
the higher dose.
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy) or
uterine
fibroids
(three
months
of
therapy)
were
treated
with
LUPRON DEPOT 3.75 mg. In endometriosis patients, vertebral bone density as
measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of
3.2% at six months compared with the pretreatment value. Clinical studies
demonstrate that concurrent hormonal therapy (norethindrone acetate 5 mg daily)
and calcium supplementation is effective in significantly reducing the loss of bone
mineral density that occurs with LUPRON treatment, without compromising the
efficacy of LUPRON in relieving symptoms of endometriosis.
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in
two clinical trials. The results from this regimen were similar in both studies.
LUPRON DEPOT 3.75 mg was used as a control group in one study. The bone
mineral density data of the lumbar spine from these two studies are presented in
Table 4.
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Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
14
Table 4 Mean Percent Change from Baseline in Bone Mineral Density of
Lumbar Spine
1 Includes on-treatment measurements that fell within 2-252 days after the first day of treatment.
2 Includes on-treatment measurements >252 days after the first day of treatment.
When LUPRON DEPOT 3.75 mg was administered for three months in uterine
fibroid patients, vertebral trabecular bone mineral density as assessed by
quantitative digital radiography (QDR) revealed a mean decrease of 2.7% compared
with baseline. Six months after discontinuation of therapy, a trend toward recovery
was observed. Use of LUPRON DEPOT for longer than three months (uterine
fibroids) or six months (endometriosis) or in the presence of other known risk
factors for decreased bone mineral content may cause additional bone loss and is
not recommended.
Changes in Laboratory Values During Treatment
Plasma Enzymes
Endometriosis: During early clinical trials with LUPRON DEPOT 3.75 mg, regular
laboratory monitoring revealed that AST levels were more than twice the upper
limit of normal in only one patient. There was no clinical or other laboratory
evidence of abnormal liver function.
In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT
3.75 mg plus norethindrone acetate 5 mg daily for up to 12 months developed an
elevated (at least twice the upper limit of normal) SGPT or GGT. Five of the 6
increases were observed beyond 6 months of treatment. None were associated with
elevated bilirubin concentration.
Uterine Leiomyomata (Fibroids): In clinical trials with LUPRON DEPOT 3.75 mg, five (3%)
patients had a post-treatment transaminase value that was at least twice the baseline value
and above the upper limit of the normal range. None of the laboratory increases were
associated with clinical symptoms.
Lipids
Lupron Depot
3.75mg
Lupron Depot 3.75 mg plus
norethindrone acetate 5 mg daily
Controlled Study
Controlled Study
Open Label Study
N
Change
N
Change
N
Change
Week 241
41
-3.2%
42
-0.3%
115
-0.2%
Week 522
29
-6.3%
32
-1.0%
84
-1.1%
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Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
15
Endometriosis: In earlier clinical studies, 4% of the LUPRON DEPOT 3.75 mg
patients and 1% of the danazol patients had total cholesterol values above the
normal range at enrollment. These patients also had cholesterol values above the
normal range at the end of treatment.
Of those patients whose pretreatment cholesterol values were in the normal
range, 7% of the LUPRON DEPOT 3.75 mg patients and 9% of the danazol
patients had post-treatment values above the normal range.
The mean (±SEM) pretreatment values for total cholesterol from all patients
were
178.8 (2.9) mg/dL
in
the
LUPRON DEPOT 3.75 mg
groups
and
175.3 (3.0) mg/dL in the danazol group. At the end of treatment, the mean values
for
total
cholesterol
from
all
patients
were
193.3 mg/dL
in
the
LUPRON DEPOT 3.75 mg group and 194.4 mg/dL in the danazol group. These
increases from the pretreatment values were statistically significant (p<0.03) in both
groups.
Triglycerides were increased above the upper limit of normal in 12% of the
patients who received LUPRON DEPOT 3.75 mg and in 6% of the patients who
received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower
limit of the normal range in 2% of the LUPRON DEPOT 3.75 mg patients
compared with 54% of those receiving danazol. LDL cholesterol fractions increased
above the upper limit of the normal range in 6% of the patients receiving
LUPRON DEPOT 3.75 mg compared with 23% of those receiving danazol. There
was
no
increase
in
the
LDL/HDL
ratio
in
patients
receiving
LUPRON DEPOT 3.75 mg but there was approximately a two-fold increase in the
LDL/HDL ratio in patients receiving danazol.
In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone
acetate 5 mg daily were evaluated for 12 months of treatment. LUPRON DEPOT
3.75 mg was used as a control group in one study. Percent changes from baseline
for serum lipids and percentages of patients with serum lipid values outside of the
normal range in the two studies are summarized in the tables below.
Table 5 Serum Lipids: Mean Percent Changes from Baseline Values At Treatment Week 24
Lupron
Lupron plus
Norethindrone Acetate
Controlled Study (n = 39)
Controlled Study (n = 41)
Open Label Study (n = 117)
Baseline Value
*
Week 24
% Change
Baseline
Value *
Week 24
% Change
Baseline
Value *
Week 24
%
Change
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Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
16
Total
Cholesterol
170.5
9.2%
179.3
0.2%
181.2
2.8%
HDL
Cholesterol
52.4
7.4%
51.8
-18.8%
51.0
-14.6%
LDL
Cholesterol
96.6
10.9%
101.5
14.1%
109.1
13.1%
LDL/HDL
RATIO
2.0**
5.0%
2.1**
43.4%
2.3**
39.4%
Triglycerides
107.8
17.5%
130.2
9.5%
105.4
13.8%
* mg/dL
** ratio
Changes from baseline tended to be greater at Week 52. After treatment, mean serum
lipid levels from patients with follow up data returned to pretreatment values.
Table 6 Percentage of Patients With Serum Lipid Values Outside of the Normal Range
* Includes all patients regardless of baseline value.
Low HDL- cholesterol (<40 mg/dL) and elevated LDL- cholesterol (> 160 mg/dL) are
recognized risk factors for cardiovascular disease. The long-term significance of the
observed treatment-related changes in serum lipids in women with endometriosis is
unknown. Therefore assessment of cardiovascular risk factors should be considered
prior to initiation of concurrent treatment with Lupron and norethindrone acetate.
Lupron
Lupron plus
Norethindrone Acetate
Controlled Study (n
= 39)
Controlled Study (n = 41)
Open Label Study (n = 117)
Wk 0
Wk
24*
Wk 0
Wk 24*
Wk 0
Wk 24*
Total Cholesterol ( >240 mg/dL)
15%
23%
15%
20%
6%
7%
HDL Cholesterol ( <40 mg/dL)
15%
10%
15%
44%
15%
41%
LDL Cholesterol ( >160 mg/dL)
0%
8%
5%
7%
9%
11%
LDL/HDL RATIO >4.0
0%
3%
2%
15%
7%
21%
Triglycerides( >200 mg/dL)
13%
13%
12%
10%
5%
9%
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Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
17
Uterine Leiomyomata (Fibroids): In patients receiving LUPRON DEPOT 3.75 mg,
mean changes in cholesterol (+11 mg/dL to +29 mg/dL), LDL cholesterol (+8 mg/dL to
+22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and the LDL/HDL ratio (-0.1 to +0.5)
were observed across studies. In the one study in which triglycerides were determined,
the mean increase from baseline was 32 mg/dL.
Other Changes
Endometriosis: The following changes were seen in approximately 5% to 8% of
patients. In the earlier comparative studies, LUPRON DEPOT 3.75 mg was associated
with elevations of LDH and phosphorus, and decreases in WBC counts. Danazol
therapy was associated with increases in hematocrit, platelet count, and LDH. In the
hormonal add-back studies LUPRON DEPOT in combination with norethindrone
acetate was associated with elevations of GGT and SGPT.
Uterine Leiomyomata (Fibroids):
Hematology: (See CLINICAL STUDIES section.) In LUPRON DEPOT 3.75 mg
treated patients, although there were statistically significant mean decreases in platelet
counts from baseline to final visit, the last mean platelet counts were within the normal
range. Decreases in total WBC count and neutrophils were observed, but were not
clinically significant.
Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN,
creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and
phosphorus. None of these increases were clinically significant.
Postmarketing
During postmarketing surveillance, the following adverse events were reported. Like
other drugs in this class, mood swings, including depression, have been reported. There
have been rare reports of suicidal ideation and attempt. Many, but not all, of these
patients had a history of depression or other psychiatric illness. Patients should be
counseled on the possibility of development or worsening of depression during
treatment with Lupron.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely
reported. Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site
of injection. Symptoms consistent with fibromyalgia (eg: joint and muscle pain,
heachaches, sleep disorder, gastrointestinal distress, and shortness of breath) have been
reported individually and collectively. Other events reported are:
Cardiovascular System - Hypotension; Hemic and Lymphatic System - Decreased
WBC; Central/Peripheral Nervous System - Peripheral neuropathy, Spinal
fracture/paralysis; Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital
System - Prostate pain.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
18
See other LUPRON DEPOT and LUPRON Injection package inserts for other
events reported in different patient populations.
OVERDOSAGE
In rats subcutaneous administration of 250 to 500 times the recommended human dose,
expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local
irritation at the injection site. There is no evidence that there is a clinical counterpart of
this phenomenon. In early clinical trials using daily subcutaneous leuprolide acetate in
patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no
adverse effects differing from those observed with the 1 mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot
formulation. The lyophilized microspheres are to be reconstituted and administered
monthly as a single intramuscular injection, in accord with the following directions:
1. To prepare for injection, screw the white plunger into the end stopper until the
stopper begins to turn
2. Remove and discard the tab around the base of the needle.
3. Holding the syringe upright, release the diluent by SLOWLY PUSHING the plunger
until the first stopper is at the blue line in the middle of the barrel.
4. Gently shake the syringe to thoroughly mix the particles to form a uniform
suspension. The suspension will appear milky.
5. If the microspheres (particles) adhere to the stopper, tap the syringe against your
finger.
6. Then remove the needle guard and advance the plunger to expel the air from the
syringe.
7.
At the time of reconstitution, inject the entire contents of the syringe
intramuscularly as you would for a normal injection. The suspension settles very
quickly
following
reconstitution;
therefore,
it
is
preferable
that
LUPRON DEPOT 3.75 mg be mixed and used immediately. Reshake suspension if
settling occurs.
Since the product does not contain a preservative, the suspension should be discarded if
not used immediately.
Endometriosis: The recommended duration of treatment with LUPRON DEPOT
3.75 mg alone or in combination with norethindrone acetate is six months.
The choice of Lupron alone or Lupron plus norethindrone acetate therapy for initial
management of the symptoms and signs of endometriosis should be made by the health
care professional in consultation with the patient and should take into consideration the
risks and benefits of the addition of norethindrone to Lupron alone.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
19
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-
month course of LUPRON DEPOT monthly and norethindrone acetate 5 mg daily may
be considered. Retreatment beyond this one six month course can not be recommended.
It is recommended that bone density be assessed before retreatment begins to ensure
that values are within normal limits. Lupron Depot alone is not recommended for
retreatment. If norethindrone acetate is contraindicated for the individual patient, then
retreatment is not recommended.
An assessment of cardiovascular risk and management of risk factors such as cigarette
smoking is recommended before beginning treatment with Lupron and norethindrone
acetate.
Uterine Leiomyomata (Fibroids): Recommended duration of therapy with
LUPRON DEPOT 3.75 mg is up to 3 months. The symptoms associated with uterine
leiomyomata will recur following discontinuation of therapy. If additional treatment
with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior
to initiation of therapy to ensure that values are within normal limits.
As with other drugs administered by injection, the injection site should be varied
periodically.
HOW SUPPLIED
LUPRON DEPOT 3.75 mg is packaged as follows:
Kit with prefilled dual chamber syringe
NDC 0300-3641-01
Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated
in a biodegradable copolymer of lactic and glycolic acids. When mixed with diluent,
LUPRON DEPOT 3.75 mg is administered as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
[see USP Controlled Room Temperature]
Rx only
U.S. Patent Nos. 4,652,441; 4,677,191; 4,728,721; 4,849,228; 4,917,893; 4,954,298;
5,330,767; 5,476,663; 5,575,987; 5,631,020; 5,631,021; and 5,716,640.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lupron 3.75 mg Package Insert
03-5043-R12 Vs Revised Add-back (9-21-01)
20
Manufactured for
TAP Pharmaceuticals Inc.
Lake Forest, IL 60045, U.S.A.
by Takeda Chemical Industries, Ltd.
Osaka, JAPAN 541
® — Registered Trademark
(No. 3641)
0X-XXXX-RXX; Revised: Month, Year
©1990 –200X, TAP Pharmaceutical Products Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
PATIENT INFORMATION
ON
TREATMENT WITH
LUPRON DEPOT 3.75 mg
(leuprolide acetate for
depot suspension)
LUPRON DEPOT®
3.75 mg
LEUPROLIDE ACETATE
FOR DEPOT SUSPENSION
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
This is combined labeling. Examples of different colors and fonts appear below.
• General Information
• Information on Endometriosis
• Information on Uterine Fibroids
This patient education booklet provides information on the use of LUPRON
DEPOT 3.75® mg (leuprolide acetate for depot suspension) for two different
medical conditions:
1.
Endometriosis
2.
Anemia due to vaginal bleeding from fibroids
Your health care provider will direct you to the section that will discuss your
condition.
This booklet is not intended to be a substitute for information provided to you by
your health care provider. You should discuss with your health care provider any
questions you have about your diagnosis and treatment, and you may ask your
health care provider for a copy of the information provided to him or her by TAP
Pharmaceuticals Inc.
LUPRON DEPOT 3.75 mg is given to decrease the production of estrogen by
your ovaries. The information provided describes the drug’s action in the
treatment of either condition described in this booklet.
HOW IS LUPRON GIVEN ?
LUPRON DEPOT 3.75 mg is a prescription drug that is prescribed by your health
care provider. Once a month (approximately every 28 to 33 days), you will
receive an injection of LUPRON DEPOT 3.75 mg.
You should get your injections on time. The recommended initial treatment is no
more than six injections for endometriosis and up to 3 injections for uterine
fibroids. If you need retreatment for endometriosis, it should be limited to 6
months.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
WHAT SHOULD I EXPECT?
At first, your estrogen level will increase for one or two weeks. During that time,
you may notice an increase in your current symptoms. Then these hormones will
decline to levels similar to those in menopausal women.
Therefore, the most common side effects of LUPRON DEPOT 3.75 mg include
hot flashes, vaginal dryness, headaches, changes in mood, and a decreased
interest in sex. Your menstrual periods will probably become less regular and
the flow may be heavier or lighter. After a few months of therapy your periods
may stop completely.
WHAT IS THE MOST IMPORTANT RISK OF TAKING LUPRON?
When you take LUPRON DEPOT 3.75 mg, your hormone levels are decreased
to menopausal levels or lower. This low level can result in thinning of the bones,
which may not be completely reversible in some patients. There are certain
conditions that may increase the possibility of the thinning of your bones when
you take a drug such as LUPRON DEPOT 3.75 mg. They are:
• Excessive use of alcohol;
• Smoking;
• Family history of osteoporosis (thinning of the bones with fractures);
• Taking other medications that can cause thinning of the bones.
You should discuss the possibility of osteoporosis or thinning of the bones with
your health care provider before starting LUPRON DEPOT 3.75 mg. You should
also be aware that repeat treatment with LUPRON DEPOT 3.75 mg alone is not
advisable, particularly if you have the above conditions.
WHO SHOULD NOT USE LUPRON DEPOT 3.75 mg?
If you answer YES to any of the following questions, you should not use
LUPRON DEPOT 3.75 mg.
• Are you pregnant?
• Are you breast-feeding?
• Do you have any abnormal vaginal bleeding that has not been evaluated
by your health care provider?
• Have you experienced any type of allergic reaction to a drug like Lupron?
Remember, always ask your health care provider about any concerns you might
have regarding this or any medication.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
WHAT SHOULD I KNOW IF I AM RECEIVING CO-TREATMENT WITH
LUPRON DEPOT 3.75 mg AND NORETHINDRONE ACETATE?
Norethindrone acetate is related to the hormone progesterone and is used in
some birth control pills. Your health care provider may recommend co-treatment
with LUPRON DEPOT 3.75 mg and norethindrone acetate to reduce the risk of
bone loss. It may also reduce some of the menopausal symptoms like hot
flashes. To reduce bone loss, norethindrone acetate should be started with the
first injection of LUPRON DEPOT 3.75 mg. This drug will not interfere with the
desired effects of LUPRON DEPOT 3.75 mg in treating endometriosis.
LUPRON DEPOT 3.75 mg given with norethindrone acetate may lower your
HDL-cholesterol level (the “good” cholesterol). Whether this change increases
your long-term risk of heart disease is not known. Your health care provider
should assess your risk of heart disease prior to starting this co-treatment.
You should not use co-treatment with norethindrone acetate if you have had or
have any of the following conditions:
• Blood clots in your legs (phlebitis), heart disease, or stroke;
• Liver disease;
• Breast cancer.
If you have had any of the following conditions or if any of the following apply to
you, tell your health care provider before beginning norethindrone acetate co-
treatment :
• High levels of cholesterol;
• Migraine headaches;
• Epilepsy;
• Depression;
• Smoking.
After beginning co-treatment, notify your health care provider IMMEDIATELY if
sudden loss of vision, double vision, or migraine headaches occur. In addition,
you should notify your health care provider if any of the following conditions
occur:
• Fluid retention;
• Epilepsy;
• Asthma or worsening asthmatic symptoms;
• Heart or kidney problems.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
If your symptoms return after treatment is finished and repeat treatment is
desired, you will need co-treatment with LUPRON DEPOT 3.75 mg and
norethindrone acetate. Your health care provider should assess your bone
density at this time. Be sure to discuss this with your health care provider.
Co-treatment with LUPRON DEPOT 3.75mg and norethindrone acetate has not
been studied for treatment of fibroids.
COULD I GET PREGNANT?
LUPRON DEPOT 3.75 mg is not a method of birth control. Even though you
may not have periods, unprotected intercourse could result in pregnancy .
Therefore, you should use non-hormonal birth control such as condoms or a
diaphragm with contraceptive gel/cream or an IUD. If you think that you may be
pregnant while receiving LUPRON DEPOT 3.75 mg, contact your health care
provider immediately.
CONDITION DESCRIPTIONS
Endometriosis is a condition in which the endometrium, the tissue that lines the uterus
(womb) is found outside of the uterus. Common sites for such “endometrial implants”
can be the ovaries, the tubes, the outer surface of the uterus, and the bowel. Such
implants can bleed just like the normal endometrium does during your menstrual cycle,
but the blood is trapped so the implants can cause pain and irritation to surrounding
tissues. As a reaction to this irritation, the body sometimes forms scar tissue around and
near the implants. Scar tissues that bind organs together are called adhesions.
Fibroids are not cancer. They are non-cancerous growths of the body of the uterus and they are
very common in women. (They occur in about 20% to 25% of all women and are most common in
women aged 30 to 40.) A woman may have only one fibroid or many. They may occur on the outer
surface of the uterus, totally within the walls of the uterus, or on the inside surface. Many women
who have fibroids are not aware of them because they do not cause problems.
Fibroids can cause problems due to their size, number and location, but a major problem is
excessive menstrual bleeding. LUPRON DEPOT 3.75 mg is used with iron for the improvement of
anemia (some people call this a “low blood count”) due to heavy menstrual bleeding because of
fibroids. Like any growth, fibroids should be checked by a health care provider. Fibroids are also
called myomas or leiomyomas.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
SIGNS AND SYMPTOMS
Endometriosis can be the cause of severe menstrual cramps just before or during your
menstrual cycle as well as pelvic pain or pressure and/or pain during intercourse.
Fibroids may cause you to have unusually heavy menstrual periods, bleeding between periods,
sudden or long-lasting pain or a feeling of pressure in the lower abdomen. Excessive bleeding
may lead to anemia from a shortage of iron in the blood and can make you feel tired or sick.
HOW DOES LUPRON DEPOT 3.75 mg WORK?
LUPRON DEPOT 3.75 mg interrupts the normal menstrual cycle and the production of
estrogen and this may slow the growth of endometrial implants. As a result, pain and
other symptoms resulting from endometriosis can be eased during treatment. In about
50% to 60% of the women treated during clinical studies, LUPRON DEPOT 3.75 mg
afforded relief from symptoms. Some of the symptoms were more responsive to
treatment. The list below shows what percentage of patients who have the specific
symptoms found relief at the end of treatment.
Menstrual pain/cramping
96%
Pelvic pain
53%
Pain with intercourse
56%
Pelvic tenderness
66%
Thickening of pelvic
tissue
71%
Many of the original patients were followed up to 1 year after treatment with LUPRON
DEPOT 3.75 mg was stopped to determine when symptoms of endometriosis recurred.
In these patients, some of the symptoms reappeared faster than others.
Fibroids that do not cause symptoms or occur in women nearing menopause often will not require
treatment. However, if you have heavy bleeding as a result of your fibroids, you may also be
anemic. LUPRON DEPOT 3.75 mg together with iron may stop the bleeding and allow your blood
count to build up to a normal level. The uterine and fibroid volume will decrease and you may also
experience relief from abdominal bloating, pelvic pain and pressure if you have suffered from these
symptoms because of your fibroids.
Your health care provider may consider a one month trial of iron alone as some patient’s anemia
will improve with iron alone.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
WHAT HAPPENS AFTER THERAPY IS FINISHED?
Once you have finished your course of treatment with LUPRON DEPOT 3.75 mg,
your periods will return and the menopausal symptoms you experienced will
usually disappear within ten weeks from the day of your last injection. In some
patients, thinning of the bone structure may not be completely reversible.
CAN I GET PREGNANT AFTER THERAPY IS FINISHED?
Once you have finished your course of treatment with LUPRON DEPOT 3.75 mg for fibroids, your
health care provider may schedule you for surgery. You may be able to get pregnant after your
surgery if only your fibroids are removed. You will not be able to get pregnant if your uterus is
removed during surgery. Fibroids may develop again even after removal. If they do, 20% to 40%
of patients may require more surgery. Your health care provider will help you to make decisions
about any need for more surgery.
This patient education brochure is not intended to be a substitute for information
provided to you by your health care provider or provided to your health care
provider by TAP Pharmaceuticals Inc.
You should discuss with your health care provider any questions you have about
the diagnosis and treatment of your condition.
This information is provided as a service of TAP Pharmaceuticals Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
GLOSSARY
Adhesions – scar tissue.
Anemia – low blood count.
Aygestin®– brand name of norethindrone acetate.
Diaphragm – barrier type birth control device that covers the cervical opening
between the vagina and the uterus.
Estrogen – female hormone produced by the ovaries.
Fibroids – non-cancerous growths of the body of the uterus.
Hysterectomy – surgical procedure to remove the uterus.
Implants – endometrial tissue that fixes itself outside the uterine cavity.
IUD – birth control device temporarily implanted in the uterus.
Menopause – the end of a woman’s reproductive years.
Myomectomy – surgical procedure to remove fibroid growths.
Norethindrone acetate – a drug related to the hormone progesterone.
Osteoporosis – a thinning of the bone structure that is most often found in
women after menopause.
Progesterone – female hormone produced by the ovaries.
Uterus – the womb; muscular organ in which a fertilized egg embeds and is
nourished.
TAP Pharmaceuticals Inc.
Lake Forest, IL 60045
(No. 3641)
XX-XXXX-RX; Revised: Month, Year
® Registered Trademark
Aygestin® is a registered trademark of ESI Lederle Inc.
© 2001 TAP Pharmaceutical Products Inc.
Printed in U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:26.701169
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20011s21lbl.pdf', 'application_number': 20011, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
12,135
|
Lupron Depot (leuprolide acetate for depot suspension) Injection, Powder, Lyophilized, For
Suspension
[Abbott Laboratories]
Rx only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing
hormone (GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The
chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N
ethyl-L-prolinamide acetate (salt) with the following structural formula: Structural Formula
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized
microspheres which, when mixed with diluent, become a suspension intended as a monthly
intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide
acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg), and
D-mannitol (6.6 mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg),
D-mannitol (50 mg), polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to
control pH.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
CLINICAL PHARMACOLOGY
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75
mg results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.
Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids;
consequently, tissues and functions that depend on gonadal steroids for their maintenance become
quiescent. This effect is reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally. Intramuscular injection of the depot formulation
provides plasma concentrations of leuprolide over a period of one month.
Pharmacokinetics
Absorption
A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection to healthy
female volunteers. The absorption of leuprolide was characterized by an initial increase in plasma
concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing.
However, intact leuprolide and an inactive metabolite could not be distinguished by the assay used in
the study. Following the initial rise, leuprolide concentrations started to plateau within two days after
dosing and remained relatively stable for about four to five weeks with plasma concentrations of
about 0.30 ng/mL.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration
to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to
49%.
Metabolism
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the
mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours
based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller
inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide
(Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached
maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug
concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of
mean leuprolide concentrations.
Excretion
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was
recovered as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients have not been
determined.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON
DEPOT. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase
and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46%
bound to plasma proteins, drug interactions would not be expected to occur.
CLINICAL STUDIES
Endometriosis
In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to be
comparable to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic
pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration) and in reducing the size of
endometrial implants as evidenced by laparoscopy. The clinical significance of a decrease in
endometriotic lesions is not known at this time, and in addition laparoscopic staging of endometriosis
does not necessarily correlate with the severity of symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients after the first
and second treatment months respectively. Most of the remaining patients reported episodes of only
light bleeding or spotting. In the first, second and third post-treatment months, normal menstrual
cycles resumed in 7%, 71% and 95% of patients, respectively, excluding those who became
pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and
sustained relief at 6 and 12 months following discontinuation of treatment for the various symptoms
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
evaluated during two controlled clinical studies. This included all patients at end of treatment and
those who elected to participate in the follow-up period. This might provide a slight bias in the results
at follow-up as 75% of the original patients entered the follow-up study, and 36% were evaluated at 6
months and 26% at 12 months. Graph
Hormonal replacement therapy
Two clinical studies with a treatment duration of 12 months indicate that concurrent hormonal therapy
(norethindrone acetate 5 mg daily) is effective in significantly reducing the loss of bone mineral
density associated with LUPRON, without compromising the efficacy of LUPRON in relieving
symptoms of endometriosis. (All patients in these studies received calcium supplementation with
1000 mg elemental calcium). One controlled, randomized and double-blind study included 51 women
treated with LUPRON DEPOT alone and 55 women treated with LUPRON plus norethindrone acetate
5 mg daily. The second study was an open label study in which 136 women were treated with
LUPRON plus norethindrone acetate 5 mg daily. This study confirmed the reduction in loss of bone
mineral density that was observed in the controlled study. Suppression of menses was maintained
throughout treatment in 84% and 73% of patients receiving LD/N in the controlled study and open
label study, respectively. The median time for menses resumption after treatment with LD/N was 8
weeks.
Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Graph
Uterine Leiomyomata (Fibroids)
In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or six
months was shown to decrease uterine and fibroid volume, thus allowing for relief of clinical
symptoms (abdominal bloating, pelvic pain, and pressure). Excessive vaginal bleeding (menorrhagia
and menometrorrhagia) decreased, resulting in improvement in hematologic parameters.
In three clinical trials, enrollment was not based on hematologic status. Mean uterine volume
decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or
MRI. These patients also experienced a decrease in symptoms including excessive vaginal bleeding
and pelvic discomfort. Benefit occurred by three months of therapy, but additional gain was observed
with an additional three months of LUPRON DEPOT 3.75 mg. Ninety-five percent of these patients
became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and
third treatment months respectively.
Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT 3.75 mg
patients among the 77% who demonstrated a ≥ 25% decrease in uterine volume while on therapy.
Menses usually returned within two months of cessation of therapy. Mean time to return to
pretreatment uterine size was 8.3 months. Regrowth did not appear to be related to pretreatment
uterine volume.
In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤
10.2 g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron, produced an
increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of patients at three months of therapy.
The mean change in hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL.
Clinical response was judged to be a hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing
for autologous blood donation prior to surgery. At three months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or menometrorrhagia. As
with the previous studies, episodes of spotting and menstrual-like bleeding were noted in some
patients.
In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in 60% and 54% of
patients respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic
pain, and pressure.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of
LUPRON DEPOT 3.75 mg.
INDICATIONS AND USAGE
Endometriosis
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief and
reduction of endometriotic lesions. LUPRON DEPOT monthly with norethindrone acetate 5 mg daily
is also indicated for initial management of endometriosis and for management of recurrence of
symptoms. (Refer also to norethindrone acetate prescribing information for WARNINGS,
PRECAUTIONS, CONTRAINDICATIONS and ADVERSE REACTIONS associated with
norethindrone acetate). Duration of initial treatment or retreatment should be limited to 6 months.
Uterine Leiomyomata (Fibroids)
LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the preoperative
hematologic improvement of patients with anemia caused by uterine leiomyomata. The clinician may
wish to consider a one-month trial period on iron alone inasmuch as some of the patients will respond
to iron alone. (See Table 1.) LUPRON may be added if the response to iron alone is considered
inadequate. Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to three
months.
Experience with LUPRON DEPOT in females has been limited to women 18 years of age and older.
Table 1 PERCENT OF PATIENTS ACHIEVING HEMOGLOBIN ≥ 12 GM/DL
Treatment Group
Week 4
Week 8
Week 12
LUPRON DEPOT 3.75 mg with Iron
41*
71†
79*
Iron Alone
17
40
56
* P-Value < 0.01
† P-Value < 0.001
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT.
2. Undiagnosed abnormal vaginal bleeding.
3. LUPRON DEPOT is contraindicated in women who are or may become pregnant while
receiving the drug. LUPRON DEPOT may cause fetal harm when administered to a pregnant
woman. Major fetal abnormalities were observed in rabbits but not in rats after administration
of LUPRON DEPOT throughout gestation. There was increased fetal mortality and decreased
fetal weights in rats and rabbits. (See Pregnancy section.) The effects on fetal mortality are
expected consequences of the alterations in hormonal levels brought about by the drug. If this
drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the
patient should be apprised of the potential hazard to the fetus.
4. Use in women who are breast-feeding. (See Nursing Mothers section.)
5. Norethindrone acetate is contraindicated in women with the following conditions:
o Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of
these conditions
o Markedly impaired liver function or liver disease
o Known or suspected carcinoma of the breast
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established
clinically. Before starting treatment with LUPRON DEPOT, pregnancy must be excluded.
When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and stops
menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. Therefore, patients
should use non-hormonal methods of contraception. Patients should be advised to see their physician
if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must
be discontinued and the patient must be apprised of the potential risk to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the
physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be
observed during the initial days of therapy, but these will dissipate with continued therapy.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-
marketing.
The following applies to co-treatment with LUPRON and norethindrone acetate:
Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss
of vision or if there is sudden onset of proptosis, diplopia, or migraine. If examination reveals
papilledema or retinal vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking
progestogens, the physician should be alert to the earliest manifestations of the disease in women
taking norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to
initiation of add-back therapy with norethindrone acetate. Norethindrone acetate should be used with
caution in women with risk factors, including lipid abnormalities or cigarette smoking.
PRECAUTIONS
Information for Patients
An information pamphlet for patients is included with the product. Patients should be aware of the
following information:
1. Since menstruation usually stops with effective doses of LUPRON DEPOT, the patient should
notify her physician if regular menstruation persists. Patients missing successive doses of
LUPRON DEPOT may experience breakthrough bleeding.
2. Patients should not use LUPRON DEPOT if they are pregnant, breast feeding, have
undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in LUPRON
DEPOT.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a non
hormonal method of contraception should be used during treatment. Patients should be
advised that if they miss successive doses of LUPRON DEPOT, breakthrough bleeding or
ovulation may occur with the potential for conception. If a patient becomes pregnant during
treatment, she should discontinue treatment and consult her physician.
4. Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with
hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne,
myalgia, reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after
treatment was discontinued.
5. Patients should be counseled on the possibility of the development or worsening of depression
and the occurrence of memory disorders.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. The induced hypoestrogenic state also results in a loss in bone density over the course of
treatment, some of which may not be reversible. For a period up to six months, this bone loss
should not be clinically significant. Clinical studies show that concurrent hormonal therapy with
norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that
occurs with LUPRON. (All patients received calcium supplementation with 1000 mg elemental
calcium.) (See Changes in Bone Density section).
7. If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month
course of LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered.
Retreatment beyond this one six month course cannot be recommended. It is recommended
that bone density be assessed before retreatment begins to ensure that values are within
normal limits. Retreatment with LUPRON DEPOT alone is not recommended.
8. In patients with major risk factors for decreased bone mineral content such as chronic alcohol
and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can
reduce bone mass such as anticonvulsants or corticosteroids, LUPRON DEPOT therapy may
pose an additional risk. In these patients, the risks and benefits must be weighed carefully
before therapy with LUPRON DEPOT alone is instituted, and concomitant treatment with
norethindrone acetate 5 mg daily should be considered. Retreatment with gonadotropin-
releasing hormone analogs, including LUPRON is not advisable in patients with major risk
factors for loss of bone mineral content.
9. Because norethindrone acetate may cause some degree of fluid retention, conditions which
might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal
dysfunctions require careful observation during norethindrone acetate add-back therapy.
10.Patients who have a history of depression should be carefully observed during treatment with
norethindrone acetate and norethindrone acetate should be discontinued if severe depression
occurs.
Laboratory Tests
See ADVERSE REACTIONS section.
Drug Interactions
See CLINICAL PHARMACOLOGY, Pharmacokinetics.
Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-
gonadal system. Normal function is usually restored within three months after treatment is
discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted
during treatment and for up to three months after discontinuation of LUPRON DEPOT may be
misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of
benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug
was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not
dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell
adenomas in males (highest incidence in the low dose group). In mice, no leuprolide acetate-induced
tumors or pituitary abnormalities were observed at a dose as high as 60 mg/kg for two years. Patients
have been treated with leuprolide acetate for up to three years with doses as high as 10 mg/day and
for two years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian
systems. These studies provided no evidence of a mutagenic potential.
Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs
have shown reversibility of fertility suppression when the drug is discontinued after continuous
administration for periods of up to 24 weeks. Although no clinical studies have been completed in
children to assess the full reversibility of fertility suppression, animal studies (prepubertal and adult
rats and monkeys) with leuprolide acetate and other GnRH analogs have shown functional recovery.
Pregnancy
Teratogenic Effects
Pregnancy Category X (see CONTRAINDICATIONS section).
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg
(1/300 to 1/3 of the human dose) to rabbits, LUPRON DEPOT produced a dose-related increase in
major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal
malformations. There was increased fetal mortality and decreased fetal weights with the two higher
doses of LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats.
Nursing Mothers
It is not known whether LUPRON DEPOT is excreted in human milk. Because many drugs are
excreted in human milk, and because the effects of LUPRON DEPOT on lactation and/or the breast-
fed child have not been determined, LUPRON DEPOT should not be used by nursing mothers.
Pediatric Use
Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has been limited to women
18 years of age and older. See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension)
labeling for the safety and effectiveness in children with central precocious puberty.
Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this
population.
ADVERSE REACTIONS
Clinical Trials
Estradiol levels may increase during the first weeks following the initial injection of LUPRON, but then
decline to menopausal levels. This transient increase in estradiol can be associated with a temporary
worsening of signs and symptoms (see WARNINGS section).
As would be expected with a drug that lowers serum estradiol levels, the most frequently reported
adverse reactions were those related to hypoestrogenism.
The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical trials that
studied the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse events reported in
≥5% of patients in either of these populations and thought to be potentially related to drug are noted
in the following table.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN ≥ 5% OF
PATIENTS
Endometriosis (2 Studies)
Uterine Fibroids (4 Studies)
LUPRON
DEPOT 3.75 mg
N=166
Danazol
N=136
Placebo
N=31
N
(%)
N
(%)
N
(%)
LUPRON
DEPOT 3.75 mg
N=166
Placebo
N=163
N
(%)
N
(%)
Body as a Whole
Asthenia
5
(3)
9
(7)
0
(0)
14
(8.4)
8
(4.9)
General pain
31
(19)
22
(16)
1
(3)
14
(8.4)
10
(6.1)
Headache*
Cardiovascular System
53
(32)
30
(22)
2
(6)
43
(25.9)
29 (17.8)
Hot flashes/sweats*
Gastrointestinal System
139
(84)
77
(57)
9
(29)
121
(72.9)
29 (17.8)
Nausea/vomiting
21
(13)
17
(13)
1
(3)
8
(4.8)
6
(3.7)
GI disturbances*
Metabolic and Nutritional Disorders
11
(7)
8
(6)
1
(3)
5
(3.0)
2
(1.2)
Edema
12
(7)
17
(13)
1
(3)
9
(5.4)
2
(1.2)
Weight gain/loss
Endocrine System
22
(13)
36
(26)
0
(0)
5
(3.0)
2
(1.2)
Acne
17
(10)
27
(20)
0
(0)
0
(0)
0
(0)
Hirsutism
Musculoskeletal System
2
(1)
9
(7)
1
(3)
1
(0.6)
0
(0)
Joint disorder*
14
(8)
11
(8)
0
(0)
13
(7.8)
5
(3.1)
Myalgia*
Nervous System
1
(1)
7
(5)
0
(0)
1
(0.6)
0
(0)
Decreased libido*
19
(11)
6
(4)
0
(0)
3
(1.8)
0
(0)
Depression/emotional lability*
36
(22)
27
(20)
1
(3)
18
(10.8)
7
(4.3)
Dizziness
19
(11)
4
(3)
0
(0)
3
(1.8)
6
(3.7)
Nervousness*
8
(5)
11
(8)
0
(0)
8
(4.8)
1
(0.6)
Neuromuscular disorders*
11
(7)
17
(13)
0
(0)
3
(1.8)
0
(0)
Paresthesias
Skin and Appendages
12
(7)
11
(8)
0
(0)
2
(1.2)
1
(0.6)
Skin reactions
Urogenital System
17
(10)
20
(15)
1
(3)
5
(3.0)
2
(1.2)
Breast changes/tenderness/pain*
10
(6)
12
(9)
0
(0)
3
(1.8)
7
(4.3)
Vaginitis*
46
(28)
23
(17)
0
(0)
19
(11.4)
3
(1.8)
In these same studies, symptoms reported in <5% of patients included: Body as a Whole - Body odor, Flu
syndrome, Injection site reactions; Cardiovascular System - Palpitations, Syncope, Tachycardia; Digestive
System - Appetite changes, Dry mouth, Thirst; Endocrine System - Androgen-like effects; Hemic and Lymphatic
System - Ecchymosis, Lymphadenopathy; Nervous System – Anxiety*, Insomnia/Sleep disorders*, Delusions,
Memory disorder, Personality disorder; Respiratory System - Rhinitis; Skin and Appendages - Alopecia, Hair
disorder, Nail disorder; Special Senses - Conjunctivitis, Ophthalmologic disorders*, Taste perversion; Urogenital
System - Dysuria*, Lactation, Menstrual disorders.
*
= Possible effect of decreased estrogen.
In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients
diagnosed with uterine fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Events seen
with this dose that were thought to be potentially related to drug and were not seen at the lower dose
included glossitis, hypesthesia, lactation, pyelonephritis, and urinary disorders. Generally, a higher
incidence of hypoestrogenic effects was observed at the higher dose.
Table 3 lists the potentially drug-related adverse events observed in at least 5% of patients in any
treatment group during the first 6 months of treatment in the add-back clinical studies.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%) patients in
the LD/N group reported experiencing hot flashes on one or more occasions during treatment. During
Month 6 of treatment, 32 of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in the
LD/N group reported having experienced hot flashes. The mean number of days on which hot flashes
were reported during this month of treatment was 19 and 7 in the LD and LD/N treatment groups,
respectively. The mean maximum number of hot flashes in a day during this month of treatment was
5.8 and 1.9 in the LD and LD/N treatment groups, respectively.
Table 3 TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN ≥5% OF PATIENTS
Controlled Study
Open Label Study
LD - Only*
LD/N†
LD/N†
N=51
N=55
N=136
Adverse Events
N
(%)
N
(%)
N
(%)
Any Adverse Event
50
(98)
53
(96)
126
(93)
Body as a Whole
Asthenia
9
(18)
10
(18)
15
(11)
Headache/Migraine
33
(65)
28
(51)
63
(46)
Injection Site Reaction
1
(2)
5
(9)
4
(3)
Pain
12
(24)
16
(29)
29
(21)
Cardiovascular System
Hot flashes/sweats
50
(98)
48
(87)
78
(57)
Digestive System
Altered Bowel Function
7
(14)
8
(15)
14
(10)
Changes in Appetite
2
(4)
0
(0)
8
(6)
GI Disturbance
2
(4)
4
(7)
6
(4)
Nausea/Vomiting
13
(25)
16
(29)
17
(13)
Metabolic and Nutritional Disorders
Edema
0
(0)
5
(9)
9
(7)
Weight Changes
6
(12)
7
(13)
6
(4)
Nervous System
Anxiety
3
(6)
0
(0)
11
(8)
Depression/Emotional Lability
16
(31)
15
(27)
46
(34)
Dizziness/Vertigo
8
(16)
6
(11)
10
(7)
Insomnia/Sleep Disorder
16
(31)
7
(13)
20
(15)
Libido Changes
5
(10)
2
(4)
10
(7)
Memory Disorder
3
(6)
1
(2)
6
(4)
Nervousness
4
(8)
2
(4)
15
(11)
Neuromuscular Disorder
1
(2)
5
(9)
4
(3)
Skin and Appendages
Alopecia
0
(0)
5
(9)
4
(3)
Androgen-Like Effects
2
(4)
3
(5)
24
(18)
Skin/Mucous Membrane Reaction
2
(4)
5
(9)
15
(11)
Urogenital System
Breast Changes/Pain/Tenderness
3
(6)
7
(13)
11
(8)
Menstrual Disorders
1
(2)
0
(0)
7
(5)
Vaginitis
10
(20)
8
(15)
11
(8)
*
LD-Only = LUPRON DEPOT 3.75 mg
†
LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids
(three months of therapy) were treated with LUPRON DEPOT 3.75 mg. In endometriosis patients,
vertebral bone density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
average of 3.2% at six months compared with the pretreatment value. Clinical studies demonstrate
that concurrent hormonal therapy (norethindrone acetate 5 mg daily) and calcium supplementation is
effective in significantly reducing the loss of bone mineral density that occurs with LUPRON
treatment, without compromising the efficacy of LUPRON in relieving symptoms of endometriosis.
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two clinical trials.
The results from this regimen were similar in both studies. LUPRON DEPOT 3.75 mg was used as a
control group in one study. The bone mineral density data of the lumbar spine from these two studies
are presented in Table 4.
Table 4 MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF LUMBAR
SPINE
LUPRON DEPOT 3.75mg LUPRON DEPOT 3.75 mg plus norethindrone acetate 5
mg daily
Controlled Study
Controlled Study
Open Label Study
N
Change
N
Change
N
Change
Week 24*
41
-3.2%
42
-0.3%
115
-0.2%
Week 52†
29
-6.3%
32
-1.0%
84
-1.1%
*
Includes on-treatment measurements that fell within 2–252 days after the first day of treatment.
†
Includes on-treatment measurements >252 days after the first day of treatment.
When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients,
vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR)
revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of
therapy, a trend toward recovery was observed. Use of LUPRON DEPOT for longer than three
months (uterine fibroids) or six months (endometriosis) or in the presence of other known risk factors
for decreased bone mineral content may cause additional bone loss and is not recommended.
Changes in Laboratory Values During Treatment
Plasma Enzymes
Endometriosis
During early clinical trials with LUPRON DEPOT 3.75 mg, regular laboratory monitoring revealed that
AST levels were more than twice the upper limit of normal in only one patient. There was no clinical
or other laboratory evidence of abnormal liver function.
In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus norethindrone
acetate 5 mg daily for up to 12 months developed an elevated (at least twice the upper limit of
normal) SGPT or GGT. Five of the 6 increases were observed beyond 6 months of treatment. None
were associated with elevated bilirubin concentration.
Uterine Leiomyomata (Fibroids)
In clinical trials with LUPRON DEPOT 3.75 mg, five (3%) patients had a post-treatment transaminase
value that was at least twice the baseline value and above the upper limit of the normal range. None
of the laboratory increases were associated with clinical symptoms.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lipids
Endometriosis
In earlier clinical studies, 4% of the LUPRON DEPOT 3.75 mg patients and 1% of the danazol
patients had total cholesterol values above the normal range at enrollment. These patients also had
cholesterol values above the normal range at the end of treatment.
Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the
LUPRON DEPOT 3.75 mg patients and 9% of the danazol patients had post-treatment values above
the normal range.
The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8 (2.9) mg/dL
in the LUPRON DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the danazol group. At the end of
treatment, the mean values for total cholesterol from all patients were 193.3 mg/dL in the LUPRON
DEPOT 3.75 mg group and 194.4 mg/dL in the danazol group. These increases from the
pretreatment values were statistically significant (p<0.03) in both groups.
Triglycerides were increased above the upper limit of normal in 12% of the patients who received
LUPRON DEPOT 3.75 mg and in 6% of the patients who received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the normal
range in 2% of the LUPRON DEPOT 3.75 mg patients compared with 54% of those receiving
danazol. LDL cholesterol fractions increased above the upper limit of the normal range in 6% of the
patients receiving LUPRON DEPOT 3.75 mg compared with 23% of those receiving danazol. There
was no increase in the LDL/HDL ratio in patients receiving LUPRON DEPOT 3.75 mg but there was
approximately a two-fold increase in the LDL/HDL ratio in patients receiving danazol.
In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was
evaluated for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as a control group in one
study. Percent changes from baseline for serum lipids and percentages of patients with serum lipid
values outside of the normal range in the two studies are summarized in the tables below.
Table 5 SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT
TREATMENT WEEK 24
LUPRON
LUPRON plus norethindrone acetate 5 mg daily
Controlled Study (n=39)
Controlled Study (n=41)
Open Label Study (n=117)
Baseline Value*
Wk 24
Baseline Value*
Wk 24
Baseline Value*
Wk 24
% Change
% Change
% Change
Total Cholesterol
170.5
9.2%
179.3
0.2%
181.2
2.8%
HDL Cholesterol
52.4
7.4%
51.8
-18.8%
51.0
-14.6%
LDL Cholesterol
96.6
10.9%
101.5
14.1%
109.1
13.1%
LDL/HDL Ratio
2.0†
5.0%
2.1†
43.4%
2.3†
39.4%
Triglycerides
107.8
17.5%
130.2
9.5%
105.4
13.8%
*
mg/dL
†
ratio
Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels
from patients with follow up data returned to pretreatment values.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6 PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE NORMAL
RANGE
LUPRON
LUPRON plus norethindrone acetate 5 mg
daily
Controlled Study
Controlled Study
Open Label Study
(n=39)
(n=41)
(n=117)
Wk 0
Wk 24*
Wk 0
Wk 24*
Wk 0
Wk 24*
Total Cholesterol (>240 mg/dL)
15%
23%
15%
20%
6%
7%
HDL Cholesterol (<40 mg/dL)
15%
10%
15%
44%
15%
41%
LDL Cholesterol (>160 mg/dL)
0%
8%
5%
7%
9%
11%
LDL/HDL Ratio (>4.0)
0%
3%
2%
15%
7%
21%
Triglycerides (>200 mg/dL)
13%
13%
12%
10%
5%
9%
*
Includes all patients regardless of baseline value.
Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized risk
factors for cardiovascular disease. The long-term significance of the observed treatment-related
changes in serum lipids in women with endometriosis is unknown. Therefore assessment of
cardiovascular risk factors should be considered prior to initiation of concurrent treatment with
LUPRON and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
In patients receiving LUPRON DEPOT 3.75 mg, mean changes in cholesterol (+11 mg/dL to +29
mg/dL), LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and the LDL/HDL
ratio (-0.1 to +0.5) were observed across studies. In the one study in which triglycerides were
determined, the mean increase from baseline was 32 mg/dL.
Other Changes
Endometriosis
The following changes were seen in approximately 5% to 8% of patients. In the earlier comparative
studies, LUPRON DEPOT 3.75 mg was associated with elevations of LDH and phosphorus, and
decreases in WBC counts. Danazol therapy was associated with increases in hematocrit, platelet
count, and LDH. In the hormonal add-back studies LUPRON DEPOT in combination with
norethindrone acetate was associated with elevations of GGT and SGPT.
Uterine Leiomyomata (Fibroids)
Hematology: (see CLINICAL STUDIES section) In LUPRON DEPOT 3.75 mg treated patients,
although there were statistically significant mean decreases in platelet counts from baseline to final
visit, the last mean platelet counts were within the normal range. Decreases in total WBC count and
neutrophils were observed, but were not clinically significant.
Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine,
total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorus. None of these
increases were clinically significant.
Postmarketing
During postmarketing surveillance, the following adverse events were reported. Like other drugs in
this class, mood swings, including depression, have been reported. There have been rare reports of
suicidal ideation and attempt. Many, but not all, of these patients had a history of depression or other
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
psychiatric illness. Patients should be counseled on the possibility of development or worsening of
depression during treatment with LUPRON.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash,
urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Symptoms consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorder,
gastrointestinal distress, and shortness of breath) have been reported individually and collectively.
Other events reported are:
Cardiovascular System – Hypotension, Pulmonary embolism; Hemic and Lymphatic System -
Decreased WBC; Central/Peripheral Nervous System - Convulsion, Peripheral neuropathy, Spinal
fracture/paralysis; Musculoskeletal System - Tenosynovitis-like symptoms; Urogenital System -
Prostate pain.
Pituitary apoplexy
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to
infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing
hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority
of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour.
In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes,
ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical
attention has been required.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in
different patient populations.
OVERDOSAGE
In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed
on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection
site. There is no evidence that there is a clinical counterpart of this phenomenon. In early clinical trials
using daily subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20
mg/day for up to two years caused no adverse effects differing from those observed with the 1
mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
Endometriosis
The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in combination with
norethindrone acetate is six months. The choice of LUPRON DEPOT alone or LUPRON DEPOT plus
norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis
should be made by the health care professional in consultation with the patient and should take into
consideration the risks and benefits of the addition of norethindrone to LUPRON DEPOT alone.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course
of LUPRON DEPOT monthly and norethindrone acetate 5 mg daily may be considered. Retreatment
beyond this one six-month course cannot be recommended. It is recommended that bone density be
assessed before retreatment begins to ensure that values are within normal limits. LUPRON DEPOT
alone is not recommended for retreatment. If norethindrone acetate is contraindicated for the
individual patient, then retreatment is not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is
recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months. The symptoms
associated with uterine leiomyomata will recur following discontinuation of therapy. If additional
treatment with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior to
initiation of therapy to ensure that values are within normal limits.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot formulation. The
lyophilized microspheres are to be reconstituted and administered monthly as a single intramuscular
injection. For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the
following instructions:
1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE
USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is
considered normal. The diluent should appear clear.
2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins
to turn.
3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the
plunger until the first stopper is at the blue line in the middle of the barrel.
4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to form a
uniform suspension. The suspension will appear milky. If the powder adheres to the stopper or
caking/clumping is present, tap the syringe with your finger to disperse. DO NOT USE if any of
the powder has not gone into suspension.
5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without
twisting.
6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe.
7. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The
suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should be
mixed and used immediately.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is
accidentally penetrated. If present, blood can be seen through the transparent LuproLoc™
safety device.
AFTER INJECTION
8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by pushing the arrow
forward with the thumb or finger until the device is fully extended and a CLICK is heard or felt.
Since the product does not contain a preservative, the suspension should be discarded if not used
immediately.
As with other drugs administered by injection, the injection site should be varied periodically.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains:
•
one prefilled dual-chamber syringe
•
one plunger
•
two alcohol swabs
•
instructions for how to mix and administer
•
an information pamphlet for patients
•
a complete prescribing information enclosure
Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated in a
biodegradable copolymer of lactic and glycolic acids. When mixed with diluent, LUPRON DEPOT
3.75 mg is administered as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room
Temperature]
U.S. Patent Nos. 4,652,441; 4,677,191; 4,728,721; 4,849,228; 4,917,893; 5,330,767; 5,476,663;
5,575,987; 5,631,020; 5,631,021; 5,716,640; 5,823,997; 5,980,488; and 6,036,976.
Other patents pending.
Manufactured for
Abbott Laboratories
North Chicago, IL 60064
by Takeda Pharmaceutical Company Limited
Osaka, Japan 540-8645
™ - Trademark
® - Registered Trademark
(No. 3641)
Revised: October, 2008
©2008, Abbott Laboratories
Abbott Laboratories
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:26.832926
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019943s029,020011s036lbl.pdf', 'application_number': 20011, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
12,136
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LUPRON DEPOT® 3.75 mg
(leuprolide acetate for depot suspension)
Rx only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone
(GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5
oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide
acetate (salt) with the following structural formula: structural formula
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres
which, when mixed with diluent, become a suspension intended as a monthly intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate
(3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol (6.6
mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg),
polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
CLINICAL PHARMACOLOGY
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg
results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.
Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues
and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is
reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally. Intramuscular injection of the depot formulation provides
plasma concentrations of leuprolide over a period of one month.
Reference ID: 2960300
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Absorption
A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection to healthy female
volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with
peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing. However, intact leuprolide and
an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise,
leuprolide concentrations started to plateau within two days after dosing and remained relatively stable for
about four to five weeks with plasma concentrations of about 0.30 ng/mL.
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to
healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean
systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two
compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive
peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV).
These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum
concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One
week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide
concentrations.
Excretion
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered
as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT.
However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by
cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma
proteins, drug interactions would not be expected to occur.
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CLINICAL STUDIES
Endometriosis
In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to be comparable
to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic pain, dysmenorrhea,
dyspareunia, pelvic tenderness, and induration) and in reducing the size of endometrial implants as evidenced
by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known at this time, and
in addition laparoscopic staging of endometriosis does not necessarily correlate with the severity of symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients after the first and
second treatment months respectively. Most of the remaining patients reported episodes of only light bleeding
or spotting. In the first, second and third post-treatment months, normal menstrual cycles resumed in 7%, 71%
and 95% of patients, respectively, excluding those who became pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and sustained relief
at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during two
controlled clinical studies. This included all patients at end of treatment and those who elected to participate in
the follow-up period. This might provide a slight bias in the results at follow-up as 75% of the original
patients entered the follow-up study, and 36% were evaluated at 6 months and 26% at 12 months. graph
Hormonal replacement therapy
Two clinical studies with a treatment duration of 12 months indicate that concurrent hormonal therapy
(norethindrone acetate 5 mg daily) is effective in significantly reducing the loss of bone mineral density
Reference ID: 2960300
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associated with LUPRON, without compromising the efficacy of LUPRON in relieving symptoms of
endometriosis. (All patients in these studies received calcium supplementation with 1000 mg elemental
calcium). One controlled, randomized and double-blind study included 51 women treated with LUPRON
DEPOT alone and 55 women treated with LUPRON plus norethindrone acetate 5 mg daily. The second study
was an open label study in which 136 women were treated with LUPRON plus norethindrone acetate 5 mg
daily. This study confirmed the reduction in loss of bone mineral density that was observed in the controlled
study. Suppression of menses was maintained throughout treatment in 84% and 73% of patients receiving
LD/N in the controlled study and open label study, respectively. The median time for menses resumption after
treatment with LD/N was 8 weeks.
Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study. graph
Uterine Leiomyomata (Fibroids)
In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or six months
was shown to decrease uterine and fibroid volume, thus allowing for relief of clinical symptoms (abdominal
bloating, pelvic pain, and pressure). Excessive vaginal bleeding (menorrhagia and menometrorrhagia)
decreased, resulting in improvement in hematologic parameters.
In three clinical trials, enrollment was not based on hematologic status. Mean uterine volume decreased by
41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI. These patients
also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Benefit
occurred by three months of therapy, but additional gain was observed with an additional three months of
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LUPRON DEPOT 3.75 mg. Ninety-five percent of these patients became amenorrheic with 61%, 25%, and
4% experiencing amenorrhea during the first, second, and third treatment months respectively.
Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT 3.75 mg patients among
the 77% who demonstrated a ≥ 25% decrease in uterine volume while on therapy. Menses usually returned
within two months of cessation of therapy. Mean time to return to pretreatment uterine size was 8.3 months.
Regrowth did not appear to be related to pretreatment uterine volume.
In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤ 10.2
g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron, produced an increase of ≥ 6%
hematocrit and ≥ 2 g/dL hemoglobin in 77% of patients at three months of therapy. The mean change in
hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL. Clinical response was judged to be a
hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to
surgery. At three months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or menometrorrhagia. As with
the previous studies, episodes of spotting and menstrual-like bleeding were noted in some patients.
In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in 60% and 54% of patients
respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and
pressure.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of LUPRON DEPOT
3.75 mg.
INDICATIONS AND USAGE
Endometriosis
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief and reduction
of endometriotic lesions. LUPRON DEPOT monthly with norethindrone acetate 5 mg daily is also indicated
for initial management of endometriosis and for management of recurrence of symptoms. (Refer also to
norethindrone acetate prescribing information for WARNINGS, PRECAUTIONS, CONTRAINDICATIONS
and ADVERSE REACTIONS associated with norethindrone acetate). Duration of initial treatment or
retreatment should be limited to 6 months.
Uterine Leiomyomata (Fibroids)
LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the preoperative hematologic
improvement of patients with anemia caused by uterine leiomyomata. The clinician may wish to consider a
one-month trial period on iron alone inasmuch as some of the patients will respond to iron alone. (See Table
1.) LUPRON may be added if the response to iron alone is considered inadequate. Recommended duration of
therapy with LUPRON DEPOT 3.75 mg is up to three months.
Experience with LUPRON DEPOT in females has been limited to women 18 years of age and older.
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Table 1 PERCENT OF PATIENTS ACHIEVING HEMOGLOBIN ≥ 12 GM/DL
Treatment Group
Week 4
Week 8
Week 12
LUPRON DEPOT 3.75 mg with Iron
41*
71†
79*
Iron Alone
17
40
56
* P-Value < 0.01
† P-Value < 0.001
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT.
2. Undiagnosed abnormal vaginal bleeding.
3. LUPRON DEPOT is contraindicated in women who are or may become pregnant while receiving the
drug. LUPRON DEPOT may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rabbits but not in rats after administration of LUPRON DEPOT
throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits.
(See Pregnancy section.) The effects on fetal mortality are expected consequences of the alterations in
hormonal levels brought about by the drug. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
4. Use in women who are breast-feeding. (See Nursing Mothers section.)
5. Norethindrone acetate is contraindicated in women with the following conditions:
o Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these
conditions
o Markedly impaired liver function or liver disease
o Known or suspected carcinoma of the breast
WARNINGS
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established clinically. Before
starting treatment with LUPRON DEPOT, pregnancy must be excluded.
When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and stops
menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. Therefore, patients should
use non-hormonal methods of contraception.
Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes
pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk
to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic
effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial
days of therapy, but these will dissipate with continued therapy.
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Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The following applies to co-treatment with LUPRON and norethindrone acetate:
Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision
or if there is sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal
vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking
progestogens, the physician should be alert to the earliest manifestations of the disease in women taking
norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to initiation of
add-back therapy with norethindrone acetate. Norethindrone acetate should be used with caution in women
with risk factors, including lipid abnormalities or cigarette smoking.
PRECAUTIONS
Information for Patients
An information pamphlet for patients is included with the product. Patients should be aware of the following
information:
1. Since menstruation usually stops with effective doses of LUPRON DEPOT, the patient should notify her
physician if regular menstruation persists. Patients missing successive doses of LUPRON DEPOT may
experience breakthrough bleeding.
2. Patients should not use LUPRON DEPOT if they are pregnant, breast feeding, have undiagnosed
abnormal vaginal bleeding, or are allergic to any of the ingredients in LUPRON DEPOT.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a non-hormonal method
of contraception should be used during treatment. Patients should be advised that if they miss successive
doses of LUPRON DEPOT, breakthrough bleeding or ovulation may occur with the potential for
conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult
her physician.
4. Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with
hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne, myalgia,
reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after treatment was
discontinued.
5. Patients should be counseled on the possibility of the development or worsening of depression and the
occurrence of memory disorders.
6. The induced hypoestrogenic state also results in a loss in bone density over the course of treatment, some
of which may not be reversible. Clinical studies show that concurrent hormonal therapy with
norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that occurs with
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LUPRON. (All patients received calcium supplementation with 1000 mg elemental calcium.) (See
Changes in Bone Density section).
7. If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of
LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this one
six month course cannot be recommended. It is recommended that bone density be assessed before
retreatment begins to ensure that values are within normal limits. Retreatment with LUPRON DEPOT
alone is not recommended.
8. In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or
tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such
as anticonvulsants or corticosteroids, LUPRON DEPOT therapy may pose an additional risk. In these
patients, the risks and benefits must be weighed carefully before therapy with LUPRON DEPOT alone is
instituted, and concomitant treatment with norethindrone acetate 5 mg daily should be considered.
Retreatment with gonadotropin-releasing hormone analogs, including LUPRON is not advisable in
patients with major risk factors for loss of bone mineral content.
9. Because norethindrone acetate may cause some degree of fluid retention, conditions which might be
influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunctions require careful
observation during norethindrone acetate add-back therapy.
10. Patients who have a history of depression should be carefully observed during treatment with
norethindrone acetate and norethindrone acetate should be discontinued if severe depression occurs.
Laboratory Tests
SeeADVERSE REACTIONS section.
Drug Interactions
See CLINICAL PHARMACOLOGY, Pharmacokinetics.
Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal
system. Normal function is usually restored within three months after treatment is discontinued. Therefore,
diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three
months after discontinuation of LUPRON DEPOT may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign
pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered
subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of
pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest
incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities
were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate
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for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day
without demonstrable pituitary abnormalities.
Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems.
These studies provided no evidence of a mutagenic potential.
Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs have
shown reversibility of fertility suppression when the drug is discontinued after continuous administration for
periods of up to 24 weeks. Although no clinical studies have been completed in children to assess the full
reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide
acetate and other GnRH analogs have shown functional recovery.
Pregnancy
Teratogenic Effects
Pregnancy Category X (see CONTRAINDICATIONS section).
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3
of the human dose) to rabbits, LUPRON DEPOT produced a dose-related increase in major fetal
abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was
increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits
and with the highest dose (0.024 mg/kg) in rats.
Nursing Mothers
It is not known whether LUPRON DEPOT is excreted in human milk. Because many drugs are excreted in
human milk, and because the effects of LUPRON DEPOT on lactation and/or the breast-fed child have not
been determined, LUPRON DEPOT should not be used by nursing mothers.
Pediatric Use
Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has been limited to women 18
years of age and older. See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension) labeling for the
safety and effectiveness in children with central precocious puberty.
Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this population.
ADVERSE REACTIONS
Clinical Trials
Estradiol levels may increase during the first weeks following the initial injection of LUPRON, but then
decline to menopausal levels. This transient increase in estradiol can be associated with a temporary
worsening of signs and symptoms (see WARNINGS section).
Reference ID: 2960300
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As would be expected with a drug that lowers serum estradiol levels, the most frequently reported adverse
reactions were those related to hypoestrogenism.
The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical trials that studied
the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse events reported in ≥5% of patients in
either of these populations and thought to be potentially related to drug are noted in the following table.
Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN ≥ 5% OF PATIENTS
Endometriosis (2 Studies)
Uterine Fibroids (4 Studies)
LUPRON DEPOT
3.75 mg
N=166
Danazol
N=136
Placebo
N=31
N
(%)
N
(%)
N
(%)
LUPRON DEPOT
3.75 mg
N=166
Placebo
N=163
N
(%)
N
(%)
Body as a Whole
Asthenia
5
(3)
9
(7)
0
(0)
14
(8.4)
8
(4.9)
General pain
31
(19)
22
(16)
1
(3)
14
(8.4)
10
(6.1)
Headache*
Cardiovascular System
53
(32)
30
(22)
2
(6)
43
(25.9)
29
(17.8)
Hot flashes/sweats*
Gastrointestinal System
139
(84)
77
(57)
9
(29)
121
(72.9)
29
(17.8)
Nausea/vomiting
21
(13)
17
(13)
1
(3)
8
(4.8)
6
(3.7)
GI disturbances*
Metabolic and Nutritional Disorders
11
(7)
8
(6)
1
(3)
5
(3.0)
2
(1.2)
Edema
12
(7)
17
(13)
1
(3)
9
(5.4)
2
(1.2)
Weight gain/loss
Endocrine System
22
(13)
36
(26)
0
(0)
5
(3.0)
2
(1.2)
Acne
17
(10)
27
(20)
0
(0)
0
(0)
0
(0)
Hirsutism
Musculoskeletal System
2
(1)
9
(7)
1
(3)
1
(0.6)
0
(0)
Joint disorder*
14
(8)
11
(8)
0
(0)
13
(7.8)
5
(3.1)
Myalgia*
Nervous System
1
(1)
7
(5)
0
(0)
1
(0.6)
0
(0)
Decreased libido*
19
(11)
6
(4)
0
(0)
3
(1.8)
0
(0)
Depression/emotional lability*
36
(22)
27
(20)
1
(3)
18
(10.8)
7
(4.3)
Dizziness
19
(11)
4
(3)
0
(0)
3
(1.8)
6
(3.7)
Nervousness*
8
(5)
11
(8)
0
(0)
8
(4.8)
1
(0.6)
Neuromuscular disorders*
11
(7)
17
(13)
0
(0)
3
(1.8)
0
(0)
Paresthesias
Skin and Appendages
12
(7)
11
(8)
0
(0)
2
(1.2)
1
(0.6)
Skin reactions
Urogenital System
17
(10)
20
(15)
1
(3)
5
(3.0)
2
(1.2)
Breast changes/tenderness/pain*
10
(6)
12
(9)
0
(0)
3
(1.8)
7
(4.3)
Vaginitis*
46
(28)
23
(17)
0
(0)
19
(11.4)
3
(1.8)
In these same studies, symptoms reported in <5% of patients included: Body as a Whole - Body odor, Flu syndrome, Injection site
reactions; Cardiovascular System - Palpitations, Syncope, Tachycardia; Digestive System - Appetite changes, Dry mouth, Thirst;
Endocrine System - Androgen-like effects; Hemic and Lymphatic System - Ecchymosis, Lymphadenopathy; Nervous System –
Anxiety*, Insomnia/Sleep disorders*, Delusions, Memory disorder, Personality disorder; Respiratory System - Rhinitis; Skin and
Appendages - Alopecia, Hair disorder, Nail disorder; Special Senses - Conjunctivitis, Ophthalmologic disorders*, Taste perversion;
Urogenital System - Dysuria*, Lactation, Menstrual disorders.
* = Possible effect of decreased estrogen.
In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients diagnosed with
uterine fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Events seen with this dose that were
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thought to be potentially related to drug and were not seen at the lower dose included glossitis, hypesthesia,
lactation, pyelonephritis, and urinary disorders. Generally, a higher incidence of hypoestrogenic effects was
observed at the higher dose.
Table 3 lists the potentially drug-related adverse events observed in at least 5% of patients in any treatment
group during the first 6 months of treatment in the add-back clinical studies.
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%) patients in the
LD/N group reported experiencing hot flashes on one or more occasions during treatment. During Month 6 of
treatment, 32 of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in the LD/N group reported
having experienced hot flashes. The mean number of days on which hot flashes were reported during this
month of treatment was 19 and 7 in the LD and LD/N treatment groups, respectively. The mean maximum
number of hot flashes in a day during this month of treatment was 5.8 and 1.9 in the LD and LD/N treatment
groups, respectively.
Reference ID: 2960300
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Table 3 TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN ≥5% OF PATIENTS
Controlled Study
Open Label Study
LD - Only*
LD/N†
LD/N†
N=51
N=55
N=136
Adverse Events
N
(%)
N
(%)
N
(%)
Any Adverse Event
50
(98)
53
(96)
126
(93)
Body as a Whole
Asthenia
9
(18)
10
(18)
15
(11)
Headache/Migraine
33
(65)
28
(51)
63
(46)
Injection Site Reaction
1
(2)
5
(9)
4
(3)
Pain
12
(24)
16
(29)
29
(21)
Cardiovascular System
Hot flashes/sweats
50
(98)
48
(87)
78
(57)
Digestive System
Altered Bowel Function
7
(14)
8
(15)
14
(10)
Changes in Appetite
2
(4)
0
(0)
8
(6)
GI Disturbance
2
(4)
4
(7)
6
(4)
Nausea/Vomiting
13
(25)
16
(29)
17
(13)
Metabolic and Nutritional Disorders
Edema
0
(0)
5
(9)
9
(7)
Weight Changes
6
(12)
7
(13)
6
(4)
Nervous System
Anxiety
3
(6)
0
(0)
11
(8)
Depression/Emotional Lability
16
(31)
15
(27)
46
(34)
Dizziness/Vertigo
8
(16)
6
(11)
10
(7)
Insomnia/Sleep Disorder
16
(31)
7
(13)
20
(15)
Libido Changes
5
(10)
2
(4)
10
(7)
Memory Disorder
3
(6)
1
(2)
6
(4)
Nervousness
4
(8)
2
(4)
15
(11)
Neuromuscular Disorder
1
(2)
5
(9)
4
(3)
Skin and Appendages
Alopecia
0
(0)
5
(9)
4
(3)
Androgen-Like Effects
2
(4)
3
(5)
24
(18)
Skin/Mucous Membrane Reaction
2
(4)
5
(9)
15
(11)
Urogenital System
Breast Changes/Pain/Tenderness
3
(6)
7
(13)
11
(8)
Menstrual Disorders
1
(2)
0
(0)
7
(5)
Vaginitis
10
(20)
8
(15)
11
(8)
* LD-Only = LUPRON DEPOT 3.75 mg
† LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three
months of therapy) were treated with LUPRON DEPOT 3.75 mg. In endometriosis patients, vertebral bone
density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.2% at six
months compared with the pretreatment value. Clinical studies demonstrate that concurrent hormonal therapy
(norethindrone acetate 5 mg daily) and calcium supplementation is effective in significantly reducing the loss
of bone mineral density that occurs with LUPRON treatment, without compromising the efficacy of LUPRON
in relieving symptoms of endometriosis.
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LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two clinical trials. The
results from this regimen were similar in both studies. LUPRON DEPOT 3.75 mg was used as a control group
in one study. The bone mineral density data of the lumbar spine from these two studies are presented in
Table 4.
Table 4 MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF LUMBAR SPINE
LUPRON DEPOT 3.75mg
Controlled Study
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily
Controlled Study
Open Label Study
N
Change
(Mean, 95% CI)#
N
Change
(Mean, 95% CI)#
N
Change
(Mean, 95% CI)#
Week 24*
Week 52†
41
29
-3.2% (-3.8, -2.6)
-6.3% (-7.1, -5.4)
42
32
-0.3% (-0.8, 0.3)
-1.0% (-1.9, -0.1)
115
84
-0.2% (-0.6, 0.2)
-1.1% (-1.6, -0.5)
* Includes on-treatment measurements that fell within 2–252 days after the first day of treatment.
† Includes on-treatment measurements >252 days after the first day of treatment.
# 95% CI: 95% Confidence Interval
When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients, vertebral
trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean
decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward
recovery was observed. Use of LUPRON DEPOT for longer than three months (uterine fibroids) or six
months (endometriosis) or in the presence of other known risk factors for decreased bone mineral content may
cause additional bone loss and is not recommended.
Changes in Laboratory Values During Treatment
Plasma Enzymes
Endometriosis
During early clinical trials with LUPRON DEPOT 3.75 mg, regular laboratory monitoring revealed that AST
levels were more than twice the upper limit of normal in only one patient. There was no clinical or other
laboratory evidence of abnormal liver function.
In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus norethindrone acetate 5
mg daily for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT or GGT.
Five of the 6 increases were observed beyond 6 months of treatment. None were associated with elevated
bilirubin concentration.
Uterine Leiomyomata (Fibroids)
In clinical trials with LUPRON DEPOT 3.75 mg, five (3%) patients had a post-treatment transaminase value
that was at least twice the baseline value and above the upper limit of the normal range. None of the laboratory
increases were associated with clinical symptoms.
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Lipids
Endometriosis
In earlier clinical studies, 4% of the LUPRON DEPOT 3.75 mg patients and 1% of the danazol patients had
total cholesterol values above the normal range at enrollment. These patients also had cholesterol values above
the normal range at the end of treatment.
Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the LUPRON
DEPOT 3.75 mg patients and 9% of the danazol patients had post-treatment values above the normal range.
The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8 (2.9) mg/dL in the
LUPRON DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the danazol group. At the end of treatment, the
mean values for total cholesterol from all patients were 193.3 mg/dL in the LUPRON DEPOT 3.75 mg group
and 194.4 mg/dL in the danazol group. These increases from the pretreatment values were statistically
significant (p<0.03) in both groups.
Triglycerides were increased above the upper limit of normal in 12% of the patients who received LUPRON
DEPOT 3.75 mg and in 6% of the patients who received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the normal range in 2%
of the LUPRON DEPOT 3.75 mg patients compared with 54% of those receiving danazol. LDL cholesterol
fractions increased above the upper limit of the normal range in 6% of the patients receiving LUPRON
DEPOT 3.75 mg compared with 23% of those receiving danazol. There was no increase in the LDL/HDL ratio
in patients receiving LUPRON DEPOT 3.75 mg but there was approximately a two-fold increase in the
LDL/HDL ratio in patients receiving danazol.
In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated
for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as a control group in one study. Percent
changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the
normal range in the two studies are summarized in the tables below.
Table 5 SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT TREATMENT WEEK 24
LUPRON
LUPRON plus norethindrone acetate 5 mg daily
Controlled Study (n=39)
Controlled Study (n=41)
Open Label Study (n=117)
Baseline Value*
Wk 24
Baseline Value*
Wk 24
Baseline Value*
Wk 24
% Change
% Change
% Change
Total Cholesterol
170.5
9.2%
179.3
0.2%
181.2
2.8%
HDL Cholesterol
52.4
7.4%
51.8
-18.8%
51.0
-14.6%
LDL Cholesterol
96.6
10.9%
101.5
14.1%
109.1
13.1%
LDL/HDL Ratio
2.0†
5.0%
2.1†
43.4%
2.3†
39.4%
Triglycerides
107.8
17.5%
130.2
9.5%
105.4
13.8%
* mg/dL
† ratio
Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients
with follow up data returned to pretreatment values.
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Table 6 PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE NORMAL RANGE
LUPRON
LUPRON plus norethindrone acetate 5 mg daily
Controlled Study (n=39) Controlled Study (n=41) Open Label Study (n=117)
Wk 0
Wk 24*
Wk 0
Wk 24*
Wk 0
Wk 24*
Total Cholesterol (>240 mg/dL)
15%
23%
15%
20%
6%
7%
HDL Cholesterol (<40 mg/dL)
15%
10%
15%
44%
15%
41%
LDL Cholesterol (>160 mg/dL)
0%
8%
5%
7%
9%
11%
LDL/HDL Ratio (>4.0)
0%
3%
2%
15%
7%
21%
Triglycerides (>200 mg/dL)
13%
13%
12%
10%
5%
9%
* Includes all patients regardless of baseline value.
Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized risk factors
for cardiovascular disease. The long-term significance of the observed treatment-related changes in serum
lipids in women with endometriosis is unknown. Therefore assessment of cardiovascular risk factors should be
considered prior to initiation of concurrent treatment with LUPRON and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
In patients receiving LUPRON DEPOT 3.75 mg, mean changes in cholesterol (+11 mg/dL to +29 mg/dL),
LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and the LDL/HDL ratio (-0.1 to
+0.5) were observed across studies. In the one study in which triglycerides were determined, the mean
increase from baseline was 32 mg/dL.
Other Changes
Endometriosis
The following changes were seen in approximately 5% to 8% of patients. In the earlier comparative studies,
LUPRON DEPOT 3.75 mg was associated with elevations of LDH and phosphorus, and decreases in WBC
counts. Danazol therapy was associated with increases in hematocrit, platelet count, and LDH. In the
hormonal add-back studies LUPRON DEPOT in combination with norethindrone acetate was associated with
elevations of GGT and SGPT.
Uterine Leiomyomata (Fibroids)
Hematology: (see CLINICAL STUDIES section) In LUPRON DEPOT 3.75 mg treated patients, although
there were statistically significant mean decreases in platelet counts from baseline to final visit, the last mean
platelet counts were within the normal range. Decreases in total WBC count and neutrophils were observed,
but were not clinically significant.
Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine, total
protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorus. None of these increases
were clinically significant.
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Postmarketing
During postmarketing surveillance, the following adverse events were reported. Like other drugs in this class,
mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and
attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients
should be counseled on the possibility of development or worsening of depression during treatment with
LUPRON.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria,
and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection. Symptoms
consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorder, gastrointestinal distress,
and shortness of breath) have been reported individually and collectively.
Other events reported are:
Cardiovascular System – Hypotension;
Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis,
pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal
relationship was reported in some cases, most cases were confounded by risk factors or concomitant
medication use. It is unknown if there is a causal association between the use of GnRH analogs and these
events.
Hemic and Lymphatic System - Decreased WBC;
Central/Peripheral Nervous System - Convulsion, Peripheral neuropathy, Spinal fracture/paralysis;
Musculoskeletal System - Tenosynovitis-like symptoms;
Urogenital System - Prostate pain.
Pituitary apoplexy
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to
infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing
hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of
pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these
cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia,
altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in different
patient populations.
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OVERDOSAGE
In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per
body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no
evidence that there is a clinical counterpart of this phenomenon. In early clinical trials using daily
subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two
years caused no adverse effects differing from those observed with the 1 mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
Endometriosis
The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in combination with
norethindrone acetate is six months. The choice of LUPRON DEPOT alone or LUPRON DEPOT plus
norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis should be
made by the health care professional in consultation with the patient and should take into consideration the
risks and benefits of the addition of norethindrone to LUPRON DEPOT alone.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of
LUPRON DEPOT monthly and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this
one six-month course cannot be recommended. It is recommended that bone density be assessed before
retreatment begins to ensure that values are within normal limits. LUPRON DEPOT alone is not
recommended for retreatment. If norethindrone acetate is contraindicated for the individual patient, then
retreatment is not recommended.
An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is
recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months. The symptoms
associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment
with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior to initiation of therapy
to ensure that values are within normal limits.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot formulation. The lyophilized
microspheres are to be reconstituted and administered monthly as a single intramuscular injection.
For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following
instructions:
1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if
clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal. The
diluent should appear clear.
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•
•
•
•
•
•
2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn.
3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger
until the first stopper is at the blue line in the middle of the barrel.
4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to form a uniform
suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is
present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into
suspension.
5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting.
6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe.
7. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension
settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used
immediately.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is
accidentally penetrated. If present, blood can be seen through the transparent LuproLoc™ safety device.
AFTER INJECTION
8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by pushing the arrow forward
with the thumb or finger until the device is fully extended and a CLICK is heard or felt.
Since the product does not contain a preservative, the suspension should be discarded if not used immediately.
As with other drugs administered by injection, the injection site should be varied periodically.
HOW SUPPLIED
Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains:
one prefilled dual-chamber syringe
one plunger
two alcohol swabs
instructions for how to mix and administer
an information pamphlet for patients
a complete prescribing information enclosure
Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated in a biodegradable
copolymer of lactic and glycolic acids. When mixed with diluent, LUPRON DEPOT 3.75 mg is administered
as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]
Reference ID: 2960300
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REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in
healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers
for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS
(NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to
Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J
Health-Syst Pharm. 2006; 63; 1172-1193.
4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and
recommendations for practice (2nd. Ed.) Pittsburgh, PA: Oncology Nursing Society.
Manufactured for
Abbott Laboratories
North Chicago, IL 60064
by Takeda Pharmaceutical Company Limited
Osaka, Japan 540-8645
Rev. 06/2011
Reference ID: 2960300
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custom-source
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2025-02-12T13:46:26.927154
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019943s032,020011s039lbl.pdf', 'application_number': 20011, 'submission_type': 'SUPPL ', 'submission_number': 39}
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LUPRON DEPOT® 3.75 mg
(leuprolide acetate for depot suspension)
Rx only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone
(GnRH or LH-RH). The analog possesses greater potency than the natural hormone. The chemical name is 5
oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide
acetate (salt) with the following structural formula: structural formula
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres
which, when mixed with diluent, become a suspension intended as a monthly intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains leuprolide acetate
(3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer (33.1 mg), and D-mannitol (6.6
mg). The second chamber of diluent contains carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg),
polysorbate 80 (1 mg), water for injection, USP, and glacial acetic acid, USP to control pH.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
CLINICAL PHARMACOLOGY
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg
results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins.
Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues
and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is
reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally. Intramuscular injection of the depot formulation provides
plasma concentrations of leuprolide over a period of one month.
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Pharmacokinetics
Absorption
A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection to healthy female
volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with
peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing. However, intact leuprolide and
an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise,
leuprolide concentrations started to plateau within two days after dosing and remained relatively stable for
about four to five weeks with plasma concentrations of about 0.30 ng/mL.
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to
healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.
Metabolism
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean
systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two
compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to smaller inactive
peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV).
These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum
concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One
week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide
concentrations.
Excretion
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered
as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT.
However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by
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cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma
proteins, drug interactions would not be expected to occur.
CLINICAL STUDIES
Endometriosis
In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to be comparable
to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic pain, dysmenorrhea,
dyspareunia, pelvic tenderness, and induration) and in reducing the size of endometrial implants as evidenced
by laparoscopy. The clinical significance of a decrease in endometriotic lesions is not known at this time, and
in addition laparoscopic staging of endometriosis does not necessarily correlate with the severity of symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients after the first and
second treatment months respectively. Most of the remaining patients reported episodes of only light bleeding
or spotting. In the first, second and third post-treatment months, normal menstrual cycles resumed in 7%, 71%
and 95% of patients, respectively, excluding those who became pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and sustained relief
at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during two
controlled clinical studies. This included all patients at end of treatment and those who elected to participate in
the follow-up period. This might provide a slight bias in the results at follow-up as 75% of the original
patients entered the follow-up study, and 36% were evaluated at 6 months and 26% at 12 months. structural formula
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Hormonal replacement therapy
Two clinical studies with a treatment duration of 12 months indicate that concurrent hormonal therapy
(norethindrone acetate 5 mg daily) is effective in significantly reducing the loss of bone mineral density
associated with LUPRON, without compromising the efficacy of LUPRON in relieving symptoms of
endometriosis. (All patients in these studies received calcium supplementation with 1000 mg elemental
calcium). One controlled, randomized and double-blind study included 51 women treated with LUPRON
DEPOT alone and 55 women treated with LUPRON plus norethindrone acetate 5 mg daily. The second study
was an open label study in which 136 women were treated with LUPRON plus norethindrone acetate 5 mg
daily. This study confirmed the reduction in loss of bone mineral density that was observed in the controlled
study. Suppression of menses was maintained throughout treatment in 84% and 73% of patients receiving
LD/N in the controlled study and open label study, respectively. The median time for menses resumption after
treatment with LD/N was 8 weeks.
Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study. structural formula
Uterine Leiomyomata (Fibroids)
In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or six months
was shown to decrease uterine and fibroid volume, thus allowing for relief of clinical symptoms (abdominal
bloating, pelvic pain, and pressure). Excessive vaginal bleeding (menorrhagia and menometrorrhagia)
decreased, resulting in improvement in hematologic parameters.
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In three clinical trials, enrollment was not based on hematologic status. Mean uterine volume decreased by
41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI. These patients
also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort. Benefit
occurred by three months of therapy, but additional gain was observed with an additional three months of
LUPRON DEPOT 3.75 mg. Ninety-five percent of these patients became amenorrheic with 61%, 25%, and
4% experiencing amenorrhea during the first, second, and third treatment months respectively.
Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT 3.75 mg patients among
the 77% who demonstrated a ≥ 25% decrease in uterine volume while on therapy. Menses usually returned
within two months of cessation of therapy. Mean time to return to pretreatment uterine size was 8.3 months.
Regrowth did not appear to be related to pretreatment uterine volume.
In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤ 10.2
g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron, produced an increase of ≥ 6%
hematocrit and ≥ 2 g/dL hemoglobin in 77% of patients at three months of therapy. The mean change in
hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL. Clinical response was judged to be a
hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to
surgery. At three months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or menometrorrhagia. As with
the previous studies, episodes of spotting and menstrual-like bleeding were noted in some patients.
In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in 60% and 54% of patients
respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and
pressure.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of LUPRON DEPOT
3.75 mg.
INDICATIONS AND USAGE
Endometriosis
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief and reduction
of endometriotic lesions. LUPRON DEPOT monthly with norethindrone acetate 5 mg daily is also indicated
for initial management of endometriosis and for management of recurrence of symptoms. (Refer also to
norethindrone acetate prescribing information for WARNINGS, PRECAUTIONS, CONTRAINDICATIONS
and ADVERSE REACTIONS associated with norethindrone acetate). Duration of initial treatment or
retreatment should be limited to 6 months.
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Uterine Leiomyomata (Fibroids)
LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the preoperative hematologic
improvement of patients with anemia caused by uterine leiomyomata. The clinician may wish to consider a
one-month trial period on iron alone inasmuch as some of the patients will respond to iron alone. (See Table
1.) LUPRON may be added if the response to iron alone is considered inadequate. Recommended duration of
therapy with LUPRON DEPOT 3.75 mg is up to three months.
Experience with LUPRON DEPOT in females has been limited to women 18 years of age and older.
Table 1 PERCENT OF PATIENTS ACHIEVING HEMOGLOBIN ≥ 12 GM/DL
Treatment Group
Week 4
Week 8
Week 12
LUPRON DEPOT 3.75 mg with Iron
41*
71†
79*
Iron Alone
17
40
56
* P-Value < 0.01
† P-Value < 0.001
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON DEPOT.
2. Undiagnosed abnormal vaginal bleeding.
3. LUPRON DEPOT is contraindicated in women who are or may become pregnant while receiving the
drug. LUPRON DEPOT may cause fetal harm when administered to a pregnant woman. Major fetal
abnormalities were observed in rabbits but not in rats after administration of LUPRON DEPOT
throughout gestation. There was increased fetal mortality and decreased fetal weights in rats and rabbits.
(See Pregnancy section.) The effects on fetal mortality are expected consequences of the alterations in
hormonal levels brought about by the drug. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
4. Use in women who are breast-feeding. (See Nursing Mothers section.)
5. Norethindrone acetate is contraindicated in women with the following conditions:
o Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of these
conditions
o Markedly impaired liver function or liver disease
o Known or suspected carcinoma of the breast
WARNINGS
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established clinically. Before
starting treatment with LUPRON DEPOT, pregnancy must be excluded.
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When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and stops
menstruation. Contraception is not insured, however, by taking LUPRON DEPOT. Therefore, patients should
use non-hormonal methods of contraception.
Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes
pregnant during treatment, the drug must be discontinued and the patient must be apprised of the potential risk
to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiologic
effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial
days of therapy, but these will dissipate with continued therapy.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-marketing.
The following applies to co-treatment with LUPRON and norethindrone acetate:
Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete loss of vision
or if there is sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal
vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients taking
progestogens, the physician should be alert to the earliest manifestations of the disease in women taking
norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to initiation of
add-back therapy with norethindrone acetate. Norethindrone acetate should be used with caution in women
with risk factors, including lipid abnormalities or cigarette smoking.
PRECAUTIONS
Information for Patients
An information pamphlet for patients is included with the product. Patients should be aware of the following
information:
1. Since menstruation usually stops with effective doses of LUPRON DEPOT, the patient should notify her
physician if regular menstruation persists. Patients missing successive doses of LUPRON DEPOT may
experience breakthrough bleeding.
2. Patients should not use LUPRON DEPOT if they are pregnant, breast feeding, have undiagnosed
abnormal vaginal bleeding, or are allergic to any of the ingredients in LUPRON DEPOT.
3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a non-hormonal method
of contraception should be used during treatment. Patients should be advised that if they miss successive
doses of LUPRON DEPOT, breakthrough bleeding or ovulation may occur with the potential for
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conception. If a patient becomes pregnant during treatment, she should discontinue treatment and consult
her physician.
4. Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with
hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne, myalgia,
reduction in breast size, and vaginal dryness. Estrogen levels returned to normal after treatment was
discontinued.
5. Patients should be counseled on the possibility of the development or worsening of depression and the
occurrence of memory disorders.
6. The induced hypoestrogenic state also results in a loss in bone density over the course of treatment, some
of which may not be reversible. Clinical studies show that concurrent hormonal therapy with
norethindrone acetate 5 mg daily is effective in reducing loss of bone mineral density that occurs with
LUPRON. (All patients received calcium supplementation with 1000 mg elemental calcium.) (See
Changes in Bone Density section).
7. If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of
LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this one
six month course cannot be recommended. It is recommended that bone density be assessed before
retreatment begins to ensure that values are within normal limits. Retreatment with LUPRON DEPOT
alone is not recommended.
8. In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or
tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such
as anticonvulsants or corticosteroids, LUPRON DEPOT therapy may pose an additional risk. In these
patients, the risks and benefits must be weighed carefully before therapy with LUPRON DEPOT alone is
instituted, and concomitant treatment with norethindrone acetate 5 mg daily should be considered.
Retreatment with gonadotropin-releasing hormone analogs, including LUPRON is not advisable in
patients with major risk factors for loss of bone mineral content.
9. Because norethindrone acetate may cause some degree of fluid retention, conditions which might be
influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunctions require careful
observation during norethindrone acetate add-back therapy.
10. Patients who have a history of depression should be carefully observed during treatment with
norethindrone acetate and norethindrone acetate should be discontinued if severe depression occurs.
Laboratory Tests
SeeADVERSE REACTIONS section.
Drug Interactions
See CLINICAL PHARMACOLOGY, Pharmacokinetics.
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Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-gonadal
system. Normal function is usually restored within three months after treatment is discontinued. Therefore,
diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment and for up to three
months after discontinuation of LUPRON DEPOT may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase of benign
pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered
subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of
pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest
incidence in the low dose group). In mice, no leuprolide acetate-induced tumors or pituitary abnormalities
were observed at a dose as high as 60 mg/kg for two years. Patients have been treated with leuprolide acetate
for up to three years with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day
without demonstrable pituitary abnormalities.
Mutagenicity studies have been performed with leuprolide acetate using bacterial and mammalian systems.
These studies provided no evidence of a mutagenic potential.
Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar analogs have
shown reversibility of fertility suppression when the drug is discontinued after continuous administration for
periods of up to 24 weeks. Although no clinical studies have been completed in children to assess the full
reversibility of fertility suppression, animal studies (prepubertal and adult rats and monkeys) with leuprolide
acetate and other GnRH analogs have shown functional recovery.
Pregnancy
Teratogenic Effects
Pregnancy Category X (see CONTRAINDICATIONS section).
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (1/300 to 1/3
of the human dose) to rabbits, LUPRON DEPOT produced a dose-related increase in major fetal
abnormalities. Similar studies in rats failed to demonstrate an increase in fetal malformations. There was
increased fetal mortality and decreased fetal weights with the two higher doses of LUPRON DEPOT in rabbits
and with the highest dose (0.024 mg/kg) in rats.
Nursing Mothers
It is not known whether LUPRON DEPOT is excreted in human milk. Because many drugs are excreted in
human milk, and because the effects of LUPRON DEPOT on lactation and/or the breast-fed child have not
been determined, LUPRON DEPOT should not be used by nursing mothers.
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Pediatric Use
Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has been limited to women 18
years of age and older. See LUPRON DEPOT-PED® (leuprolide acetate for depot suspension) labeling for the
safety and effectiveness in children with central precocious puberty.
Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this population.
ADVERSE REACTIONS
Clinical Trials
Estradiol levels may increase during the first weeks following the initial injection of LUPRON, but then
decline to menopausal levels. This transient increase in estradiol can be associated with a temporary
worsening of signs and symptoms (see WARNINGS section).
As would be expected with a drug that lowers serum estradiol levels, the most frequently reported adverse
reactions were those related to hypoestrogenism.
The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical trials that studied
the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse events reported in ≥5% of patients in
either of these populations and thought to be potentially related to drug are noted in the following table.
Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN ≥ 5% OF PATIENTS
Endometriosis (2 Studies)
Uterine Fibroids (4 Studies)
LUPRON DEPOT
3.75 mg
N=166
Danazol
N=136
Placebo
N=31
N
(%)
N
(%)
N
(%)
LUPRON DEPOT
3.75 mg
N=166
Placebo
N=163
N
(%)
N
(%)
Body as a Whole
Asthenia
5
(3)
9
(7)
0
(0)
14
(8.4)
8
(4.9)
General pain
31
(19)
22
(16)
1
(3)
14
(8.4)
10
(6.1)
Headache*
Cardiovascular System
53
(32)
30
(22)
2
(6)
43
(25.9)
29
(17.8)
Hot flashes/sweats*
Gastrointestinal System
139
(84)
77
(57)
9
(29)
121
(72.9)
29
(17.8)
Nausea/vomiting
21
(13)
17
(13)
1
(3)
8
(4.8)
6
(3.7)
GI disturbances*
Metabolic and Nutritional Disorders
11
(7)
8
(6)
1
(3)
5
(3.0)
2
(1.2)
Edema
12
(7)
17
(13)
1
(3)
9
(5.4)
2
(1.2)
Weight gain/loss
Endocrine System
22
(13)
36
(26)
0
(0)
5
(3.0)
2
(1.2)
Acne
17
(10)
27
(20)
0
(0)
0
(0)
0
(0)
Hirsutism
Musculoskeletal System
2
(1)
9
(7)
1
(3)
1
(0.6)
0
(0)
Joint disorder*
14
(8)
11
(8)
0
(0)
13
(7.8)
5
(3.1)
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Myalgia*
1
(1)
7
(5)
0
(0)
1
(0.6)
0
(0)
Nervous System
Decreased libido*
19
(11)
6
(4)
0
(0)
3
(1.8)
0
(0)
Depression/emotional lability*
36
(22)
27
(20)
1
(3)
18
(10.8)
7
(4.3)
Dizziness
19
(11)
4
(3)
0
(0)
3
(1.8)
6
(3.7)
Nervousness*
8
(5)
11
(8)
0
(0)
8
(4.8)
1
(0.6)
Neuromuscular disorders*
11
(7)
17
(13)
0
(0)
3
(1.8)
0
(0)
Paresthesias
12
(7)
11
(8)
0
(0)
2
(1.2)
1
(0.6)
Skin and Appendages
Skin reactions
17
(10)
20
(15)
1
(3)
5
(3.0)
2
(1.2)
Urogenital System
Breast changes/tenderness/pain*
10
(6)
12
(9)
0
(0)
3
(1.8)
7
(4.3)
Vaginitis*
46
(28)
23
(17)
0
(0)
19
(11.4)
3
(1.8)
In these same studies, symptoms reported in <5% of patients included: Body as a Whole - Body odor, Flu syndrome, Injection site
reactions; Cardiovascular System - Palpitations, Syncope, Tachycardia; Digestive System - Appetite changes, Dry mouth, Thirst;
Endocrine System - Androgen-like effects; Hemic and Lymphatic System - Ecchymosis, Lymphadenopathy; Nervous System –
Anxiety*, Insomnia/Sleep disorders*, Delusions, Memory disorder, Personality disorder; Respiratory System - Rhinitis; Skin and
Appendages - Alopecia, Hair disorder, Nail disorder; Special Senses - Conjunctivitis, Ophthalmologic disorders*, Taste perversion;
Urogenital System - Dysuria*, Lactation, Menstrual disorders.
* = Possible effect of decreased estrogen.
In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients diagnosed with
uterine fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Events seen with this dose that were
thought to be potentially related to drug and were not seen at the lower dose included glossitis, hypesthesia,
lactation, pyelonephritis, and urinary disorders. Generally, a higher incidence of hypoestrogenic effects was
observed at the higher dose.
Table 3 lists the potentially drug-related adverse events observed in at least 5% of patients in any treatment
group during the first 6 months of treatment in the add-back clinical studies.
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%) patients in the
LD/N group reported experiencing hot flashes on one or more occasions during treatment. During Month 6 of
treatment, 32 of 37 (86%) patients in the LD group and 22 of 38 (58%) patients in the LD/N group reported
having experienced hot flashes. The mean number of days on which hot flashes were reported during this
month of treatment was 19 and 7 in the LD and LD/N treatment groups, respectively. The mean maximum
number of hot flashes in a day during this month of treatment was 5.8 and 1.9 in the LD and LD/N treatment
groups, respectively.
Table 3 TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN ≥5% OF PATIENTS
Adverse Events
Any Adverse Event
Body as a Whole
Asthenia
Headache/Migraine
Injection Site Reaction
Controlled Study
LD - Only*
N=51
LD/N†
N=55
N
(%)
N
(%)
50
(98)
53
(96)
9
(18)
10
(18)
33
(65)
28
(51)
1
(2)
5
(9)
Open Label Study
LD/N†
N=136
N
(%)
126
(93)
15
(11)
63
(46)
4
(3)
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Pain
12
(24)
16
(29)
29
(21)
Cardiovascular System
Hot flashes/sweats
50
(98)
48
(87)
78
(57)
Digestive System
Altered Bowel Function
7
(14)
8
(15)
14
(10)
Changes in Appetite
2
(4)
0
(0)
8
(6)
GI Disturbance
2
(4)
4
(7)
6
(4)
Nausea/Vomiting
13
(25)
16
(29)
17
(13)
Metabolic and Nutritional Disorders
Edema
0
(0)
5
(9)
9
(7)
Weight Changes
6
(12)
7
(13)
6
(4)
Nervous System
Anxiety
3
(6)
0
(0)
11
(8)
Depression/Emotional Lability
16
(31)
15
(27)
46
(34)
Dizziness/Vertigo
8
(16)
6
(11)
10
(7)
Insomnia/Sleep Disorder
16
(31)
7
(13)
20
(15)
Libido Changes
5
(10)
2
(4)
10
(7)
Memory Disorder
3
(6)
1
(2)
6
(4)
Nervousness
4
(8)
2
(4)
15
(11)
Neuromuscular Disorder
1
(2)
5
(9)
4
(3)
Skin and Appendages
Alopecia
0
(0)
5
(9)
4
(3)
Androgen-Like Effects
2
(4)
3
(5)
24
(18)
Skin/Mucous Membrane Reaction
2
(4)
5
(9)
15
(11)
Urogenital System
Breast Changes/Pain/Tenderness
3
(6)
7
(13)
11
(8)
Menstrual Disorders
1
(2)
0
(0)
7
(5)
Vaginitis
10
(20)
8
(15)
11
(8)
* LD-Only = LUPRON DEPOT 3.75 mg
† LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine fibroids (three
months of therapy) were treated with LUPRON DEPOT 3.75 mg. In endometriosis patients, vertebral bone
density as measured by dual energy x-ray absorptiometry (DEXA) decreased by an average of 3.2% at six
months compared with the pretreatment value. Clinical studies demonstrate that concurrent hormonal therapy
(norethindrone acetate 5 mg daily) and calcium supplementation is effective in significantly reducing the loss
of bone mineral density that occurs with LUPRON treatment, without compromising the efficacy of LUPRON
in relieving symptoms of endometriosis.
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two clinical trials. The
results from this regimen were similar in both studies. LUPRON DEPOT 3.75 mg was used as a control group
in one study. The bone mineral density data of the lumbar spine from these two studies are presented in Table
4.
Table 4 MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF LUMBAR SPINE
LUPRON DEPOT 3.75mg
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily
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Controlled Study
Controlled Study
Open Label Study
N
Change
(Mean, 95% CI)#
N
Change
(Mean, 95% CI)#
N
Change
(Mean, 95% CI)#
Week 24*
Week 52†
41
29
-3.2% (-3.8, -2.6)
-6.3% (-7.1, -5.4)
42
32
-0.3% (-0.8, 0.3)
-1.0% (-1.9, -0.1)
115
84
-0.2% (-0.6, 0.2)
-1.1% (-1.6, -0.5)
* Includes on-treatment measurements that fell within 2–252 days after the first day of treatment.
† Includes on-treatment measurements >252 days after the first day of treatment.
# 95% CI: 95% Confidence Interval
When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients, vertebral
trabecular bone mineral density as assessed by quantitative digital radiography (QDR) revealed a mean
decrease of 2.7% compared with baseline. Six months after discontinuation of therapy, a trend toward
recovery was observed. Use of LUPRON DEPOT for longer than three months (uterine fibroids) or six
months (endometriosis) or in the presence of other known risk factors for decreased bone mineral content may
cause additional bone loss and is not recommended.
Changes in Laboratory Values During Treatment
Plasma Enzymes
Endometriosis
During early clinical trials with LUPRON DEPOT 3.75 mg, regular laboratory monitoring revealed that AST
levels were more than twice the upper limit of normal in only one patient. There was no clinical or other
laboratory evidence of abnormal liver function.
In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus norethindrone acetate 5
mg daily for up to 12 months developed an elevated (at least twice the upper limit of normal) SGPT or GGT.
Five of the 6 increases were observed beyond 6 months of treatment. None were associated with elevated
bilirubin concentration.
Uterine Leiomyomata (Fibroids)
In clinical trials with LUPRON DEPOT 3.75 mg, five (3%) patients had a post-treatment transaminase value
that was at least twice the baseline value and above the upper limit of the normal range. None of the laboratory
increases were associated with clinical symptoms.
Lipids
Endometriosis
In earlier clinical studies, 4% of the LUPRON DEPOT 3.75 mg patients and 1% of the danazol patients had
total cholesterol values above the normal range at enrollment. These patients also had cholesterol values above
the normal range at the end of treatment.
Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the LUPRON
DEPOT 3.75 mg patients and 9% of the danazol patients had post-treatment values above the normal range.
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The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8 (2.9) mg/dL in the
LUPRON DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the danazol group. At the end of treatment, the
mean values for total cholesterol from all patients were 193.3 mg/dL in the LUPRON DEPOT 3.75 mg group
and 194.4 mg/dL in the danazol group. These increases from the pretreatment values were statistically
significant (p<0.03) in both groups.
Triglycerides were increased above the upper limit of normal in 12% of the patients who received LUPRON
DEPOT 3.75 mg and in 6% of the patients who received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the normal range in 2%
of the LUPRON DEPOT 3.75 mg patients compared with 54% of those receiving danazol. LDL cholesterol
fractions increased above the upper limit of the normal range in 6% of the patients receiving LUPRON
DEPOT 3.75 mg compared with 23% of those receiving danazol. There was no increase in the LDL/HDL ratio
in patients receiving LUPRON DEPOT 3.75 mg but there was approximately a two-fold increase in the
LDL/HDL ratio in patients receiving danazol.
In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated
for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as a control group in one study. Percent
changes from baseline for serum lipids and percentages of patients with serum lipid values outside of the
normal range in the two studies are summarized in the tables below.
Table 5 SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT TREATMENT WEEK 24
LUPRON
LUPRON plus norethindrone acetate 5 mg daily
Controlled Study (n=39)
Controlled Study (n=41)
Open Label Study (n=117)
Baseline Value*
Wk 24
Baseline Value*
Wk 24
Baseline Value*
Wk 24
% Change
% Change
% Change
Total Cholesterol
170.5
9.2%
179.3
0.2%
181.2
2.8%
HDL Cholesterol
52.4
7.4%
51.8
-18.8%
51.0
-14.6%
LDL Cholesterol
96.6
10.9%
101.5
14.1%
109.1
13.1%
LDL/HDL Ratio
2.0†
5.0%
2.1†
43.4%
2.3†
39.4%
Triglycerides
107.8
17.5%
130.2
9.5%
105.4
13.8%
* mg/dL
† ratio
Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels from patients
with follow up data returned to pretreatment values.
Table 6 PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE NORMAL RANGE
LUPRON
LUPRON plus norethindrone acetate 5 mg daily
Controlled Study (n=39) Controlled Study (n=41) Open Label Study (n=117)
Wk 0
Wk 24*
Wk 0
Wk 24*
Wk 0
Wk 24*
Total Cholesterol (>240 mg/dL)
15%
23%
15%
20%
6%
7%
HDL Cholesterol (<40 mg/dL)
15%
10%
15%
44%
15%
41%
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LDL Cholesterol (>160 mg/dL)
0%
8%
5%
7%
9%
11%
LDL/HDL Ratio (>4.0)
0%
3%
2%
15%
7%
21%
Triglycerides (>200 mg/dL)
13%
13%
12%
10%
5%
9%
* Includes all patients regardless of baseline value.
Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized risk factors
for cardiovascular disease. The long-term significance of the observed treatment-related changes in serum
lipids in women with endometriosis is unknown. Therefore assessment of cardiovascular risk factors should be
considered prior to initiation of concurrent treatment with LUPRON and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
In patients receiving LUPRON DEPOT 3.75 mg, mean changes in cholesterol (+11 mg/dL to +29 mg/dL),
LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and the LDL/HDL ratio (-0.1 to
+0.5) were observed across studies. In the one study in which triglycerides were determined, the mean
increase from baseline was 32 mg/dL.
Other Changes
Endometriosis
The following changes were seen in approximately 5% to 8% of patients. In the earlier comparative studies,
LUPRON DEPOT 3.75 mg was associated with elevations of LDH and phosphorus, and decreases in WBC
counts. Danazol therapy was associated with increases in hematocrit, platelet count, and LDH. In the
hormonal add-back studies LUPRON DEPOT in combination with norethindrone acetate was associated with
elevations of GGT and SGPT.
Uterine Leiomyomata (Fibroids)
Hematology: (see CLINICAL STUDIES section) In LUPRON DEPOT 3.75 mg treated patients, although
there were statistically significant mean decreases in platelet counts from baseline to final visit, the last mean
platelet counts were within the normal range. Decreases in total WBC count and neutrophils were observed,
but were not clinically significant.
Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN, creatinine, total
protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and phosphorus. None of these increases
were clinically significant.
Postmarketing
The following adverse reactions have been identified during postapproval use of LUPRON DEPOT. Because
these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
During postmarketing surveillance, the following adverse events were reported. Like other drugs in this class,
mood swings, including depression, have been reported. There have been rare reports of suicidal ideation and
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attempt. Many, but not all, of these patients had a history of depression or other psychiatric illness. Patients
should be counseled on the possibility of development or worsening of depression during treatment with
LUPRON.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported. Rash, urticaria,
and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection. Symptoms
consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorder, gastrointestinal distress,
and shortness of breath) have been reported individually and collectively.
Other events reported are:
Hepato-biliary disorder: Rarely reported serious liver injury
Injury, poisoning and procedural complications: Spinal fracture
Investigations: Decreased WBC
Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms
Nervous System Disorder: Convulsion, peripheral neuropathy, paralysis
Vascular Disorder: Hypotension
Cases of serious venous and arterial thromboembolism have been reported, including deep vein thrombosis,
pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal
relationship was reported in some cases, most cases were confounded by risk factors or concomitant
medication use. It is unknown if there is a causal association between the use of GnRH analogs and these
events.
Pituitary apoplexy
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to
infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing
hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed, with a majority of
pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these
cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia,
altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required.
16 of 19
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See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in different
patient populations.
OVERDOSAGE
In rats subcutaneous administration of 250 to 500 times the recommended human dose, expressed on a per
body weight basis, resulted in dyspnea, decreased activity, and local irritation at the injection site. There is no
evidence that there is a clinical counterpart of this phenomenon. In early clinical trials using daily
subcutaneous leuprolide acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two
years caused no adverse effects differing from those observed with the 1 mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
Endometriosis
The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in combination with
norethindrone acetate is six months. The choice of LUPRON DEPOT alone or LUPRON DEPOT plus
norethindrone acetate therapy for initial management of the symptoms and signs of endometriosis should be
made by the health care professional in consultation with the patient and should take into consideration the
risks and benefits of the addition of norethindrone to LUPRON DEPOT alone.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month course of
LUPRON DEPOT monthly and norethindrone acetate 5 mg daily may be considered. Retreatment beyond this
one six-month course cannot be recommended. It is recommended that bone density be assessed before
retreatment begins to ensure that values are within normal limits. LUPRON DEPOT alone is not
recommended for retreatment. If norethindrone acetate is contraindicated for the individual patient, then
retreatment is not recommended.
An assessment of cardiovascular risk and management of risk factors such as cigarette smoking is
recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months. The symptoms
associated with uterine leiomyomata will recur following discontinuation of therapy. If additional treatment
with LUPRON DEPOT 3.75 mg is contemplated, bone density should be assessed prior to initiation of therapy
to ensure that values are within normal limits.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot formulation. The lyophilized
microspheres are to be reconstituted and administered monthly as a single intramuscular injection.
For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the following
instructions:
17 of 19
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1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE USED if
clumping or caking is evident. A thin layer of powder on the wall of the syringe is considered normal. The
diluent should appear clear.
2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins to turn.
3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds) the plunger
until the first stopper is at the blue line in the middle of the barrel.
4. Keep the syringe UPRIGHT. Gently mix the microspheres (powder) thoroughly to form a uniform
suspension. The suspension will appear milky. If the powder adheres to the stopper or caking/clumping is
present, tap the syringe with your finger to disperse. DO NOT USE if any of the powder has not gone into
suspension.
5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without twisting.
6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe.
7. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The suspension
settles very quickly following reconstitution; therefore, LUPRON DEPOT should be mixed and used
immediately.
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood vessel is
accidentally penetrated. If present, blood can be seen through the transparent LuproLoc™ safety device.
AFTER INJECTION
8. Withdraw the needle. Immediately activate the LuproLoc™ safety device by pushing the arrow forward
with the thumb or finger until the device is fully extended and a CLICK is heard or felt.
Since the product does not contain a preservative, the suspension should be discarded if not used immediately.
As with other drugs administered by injection, the injection site should be varied periodically.
HOW SUPPLIED
Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains:
one prefilled dual-chamber syringe
one plunger
two alcohol swabs
instructions for how to mix and administer
an information pamphlet for patients
a complete prescribing information enclosure
18 of 19
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Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated in a biodegradable
copolymer of lactic and glycolic acids. When mixed with diluent, LUPRON DEPOT 3.75 mg is administered
as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]
REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in
healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers
for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS
(NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to
Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J
Health-Syst Pharm. 2006; 63; 1172-1193.
4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and
recommendations for practice (2nd. Ed.) Pittsburgh, PA: Oncology Nursing Society.
Manufactured for
Abbott Laboratories
North Chicago, IL 60064
by Takeda Pharmaceutical Company Limited
Osaka, Japan 540-8645
Rev. 1/2012
19 of 19
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custom-source
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2025-02-12T13:46:27.005346
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020011s040lbl.pdf', 'application_number': 20011, 'submission_type': 'SUPPL ', 'submission_number': 40}
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LUPRON DEPOT® 3.75 mg
(leuprolide acetate for depot suspension)
Rx only
DESCRIPTION
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-
releasing hormone (GnRH or LH-RH). The analog possesses greater potency than the natural
hormone. The chemical name is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D
leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate (salt) with the following structural
formula: structural formula
LUPRON DEPOT is available in a prefilled dual-chamber syringe containing sterile lyophilized
microspheres which, when mixed with diluent, become a suspension intended as a monthly
intramuscular injection.
The front chamber of LUPRON DEPOT 3.75 mg prefilled dual-chamber syringe contains
leuprolide acetate (3.75 mg), purified gelatin (0.65 mg), DL-lactic and glycolic acids copolymer
(33.1 mg), and D-mannitol (6.6 mg). The second chamber of diluent contains
carboxymethylcellulose sodium (5 mg), D-mannitol (50 mg), polysorbate 80 (1 mg), water for
injection, USP, and glacial acetic acid, USP to control pH.
During the manufacture of LUPRON DEPOT 3.75 mg, acetic acid is lost, leaving the peptide.
CLINICAL PHARMACOLOGY
Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON
DEPOT 3.75 mg results in an initial stimulation followed by a prolonged suppression of pituitary
gonadotropins.
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Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids;
consequently, tissues and functions that depend on gonadal steroids for their maintenance
become quiescent. This effect is reversible on discontinuation of drug therapy.
Leuprolide acetate is not active when given orally. Intramuscular injection of the depot
formulation provides plasma concentrations of leuprolide over a period of one month.
Pharmacokinetics
Absorption
A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection to
healthy female volunteers. The absorption of leuprolide was characterized by an initial increase
in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours
postdosing. However, intact leuprolide and an inactive metabolite could not be distinguished by
the assay used in the study. Following the initial rise, leuprolide concentrations started to plateau
within two days after dosing and remained relatively stable for about four to five weeks with
plasma concentrations of about 0.30 ng/mL.
Distribution
The mean steady-state volume of distribution of leuprolide following intravenous bolus
administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins
ranged from 43% to 49%.
Metabolism
In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that
the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately
3 hours based on a two compartment model.
In rats and dogs, administration of 14C-labeled leuprolide was shown to be metabolized to
smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a
dipeptide (Metabolite IV). These fragments may be further catabolized.
The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients
reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the
peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were
approximately 20% of mean leuprolide concentrations.
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Excretion
Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose
was recovered as parent and M-I metabolite in the urine.
Special Populations
The pharmacokinetics of the drug in hepatically and renally impaired patients have not been
determined.
Drug Interactions
No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON
DEPOT. However, because leuprolide acetate is a peptide that is primarily degraded by
peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is
only about 46% bound to plasma proteins, drug interactions would not be expected to occur.
CLINICAL STUDIES
Endometriosis
In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to
be comparable to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis
(pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration) and in reducing the
size of endometrial implants as evidenced by laparoscopy. The clinical significance of a decrease
in endometriotic lesions is not known at this time, and in addition laparoscopic staging of
endometriosis does not necessarily correlate with the severity of symptoms.
LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the patients after
the first and second treatment months respectively. Most of the remaining patients reported
episodes of only light bleeding or spotting. In the first, second and third post-treatment months,
normal menstrual cycles resumed in 7%, 71% and 95% of patients, respectively, excluding those
who became pregnant.
Figure 1 illustrates the percent of patients with symptoms at baseline, final treatment visit and
sustained relief at 6 and 12 months following discontinuation of treatment for the various
symptoms evaluated during two controlled clinical studies. This included all patients at end of
treatment and those who elected to participate in the follow-up period. This might provide a
slight bias in the results at follow-up as 75% of the original patients entered the follow-up study,
and 36% were evaluated at 6 months and 26% at 12 months.
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graph
Hormonal replacement therapy
Two clinical studies with a treatment duration of 12 months indicate that concurrent hormonal
therapy (norethindrone acetate 5 mg daily) is effective in significantly reducing the loss of bone
mineral density associated with LUPRON, without compromising the efficacy of LUPRON in
relieving symptoms of endometriosis. (All patients in these studies received calcium
supplementation with 1000 mg elemental calcium). One controlled, randomized and double-
blind study included 51 women treated with LUPRON DEPOT alone and 55 women treated with
LUPRON plus norethindrone acetate 5 mg daily. The second study was an open label study in
which 136 women were treated with LUPRON plus norethindrone acetate 5 mg daily. This study
confirmed the reduction in loss of bone mineral density that was observed in the controlled
study. Suppression of menses was maintained throughout treatment in 84% and 73% of patients
receiving LD/N in the controlled study and open label study, respectively. The median time for
menses resumption after treatment with LD/N was 8 weeks.
Figure 2 illustrates the mean pain scores for the LD/N group from the controlled study.
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graph
Uterine Leiomyomata (Fibroids)
In controlled clinical trials, administration of LUPRON DEPOT 3.75 mg for a period of three or
six months was shown to decrease uterine and fibroid volume, thus allowing for relief of clinical
symptoms (abdominal bloating, pelvic pain, and pressure). Excessive vaginal bleeding
(menorrhagia and menometrorrhagia) decreased, resulting in improvement in hematologic
parameters.
In three clinical trials, enrollment was not based on hematologic status. Mean uterine volume
decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by
ultrasound or MRI. These patients also experienced a decrease in symptoms including excessive
vaginal bleeding and pelvic discomfort. Benefit occurred by three months of therapy, but
additional gain was observed with an additional three months of LUPRON DEPOT 3.75 mg.
Ninety-five percent of these patients became amenorrheic with 61%, 25%, and 4% experiencing
amenorrhea during the first, second, and third treatment months respectively.
Post-treatment follow-up was carried out for a small percentage of LUPRON DEPOT 3.75 mg
patients among the 77% who demonstrated a ≥ 25% decrease in uterine volume while on
therapy. Menses usually returned within two months of cessation of therapy. Mean time to return
to pretreatment uterine size was 8.3 months. Regrowth did not appear to be related to
pretreatment uterine volume.
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In another controlled clinical study, enrollment was based on hematocrit ≤ 30% and/or
hemoglobin ≤ 10.2 g/dL. Administration of LUPRON DEPOT 3.75 mg, concomitantly with iron,
produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of patients at three
months of therapy. The mean change in hematocrit was 10.1% and the mean change in
hemoglobin was 4.2 g/dL. Clinical response was judged to be a hematocrit of ≥ 36% and
hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to surgery. At three
months, 75% of patients met this criterion.
At three months, 80% of patients experienced relief from either menorrhagia or
menometrorrhagia. As with the previous studies, episodes of spotting and menstrual-like
bleeding were noted in some patients.
In this same study, a decrease of ≥ 25% was seen in uterine and myoma volumes in 60% and
54% of patients respectively. LUPRON DEPOT 3.75 mg was found to relieve symptoms of
bloating, pelvic pain, and pressure.
There is no evidence that pregnancy rates are enhanced or adversely affected by the use of
LUPRON DEPOT 3.75 mg.
INDICATIONS AND USAGE
Endometriosis
LUPRON DEPOT 3.75 mg is indicated for management of endometriosis, including pain relief
and reduction of endometriotic lesions. LUPRON DEPOT monthly with norethindrone acetate 5
mg daily is also indicated for initial management of endometriosis and for management of
recurrence of symptoms. (Refer also to norethindrone acetate prescribing information for
WARNINGS, PRECAUTIONS, CONTRAINDICATIONS and ADVERSE REACTIONS
associated with norethindrone acetate). Duration of initial treatment or retreatment should be
limited to 6 months.
Uterine Leiomyomata (Fibroids)
LUPRON DEPOT 3.75 mg concomitantly with iron therapy is indicated for the preoperative
hematologic improvement of patients with anemia caused by uterine leiomyomata. The clinician
may wish to consider a one-month trial period on iron alone inasmuch as some of the patients
will respond to iron alone. (See Table 1.) LUPRON may be added if the response to iron alone is
considered inadequate. Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up
to three months.
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Experience with LUPRON DEPOT in females has been limited to women 18 years of age and
older.
Table 1 PERCENT OF PATIENTS ACHIEVING HEMOGLOBIN ≥ 12 GM/DL
Treatment Group
Week 4
Week 8
Week 12
LUPRON DEPOT 3.75 mg with Iron
41*
71†
79*
Iron Alone
17
40
56
* P-Value < 0.01
† P-Value < 0.001
CONTRAINDICATIONS
1. Hypersensitivity to GnRH, GnRH agonist analogs or any of the excipients in LUPRON
DEPOT.
2. Undiagnosed abnormal vaginal bleeding.
3. LUPRON DEPOT is contraindicated in women who are or may become pregnant while
receiving the drug. LUPRON DEPOT may cause fetal harm when administered to a pregnant
woman. Major fetal abnormalities were observed in rabbits but not in rats after
administration of LUPRON DEPOT throughout gestation. There was increased fetal
mortality and decreased fetal weights in rats and rabbits. (See Pregnancy section.) The
effects on fetal mortality are expected consequences of the alterations in hormonal levels
brought about by the drug. If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the potential hazard to the
fetus.
4. Use in women who are breast-feeding. (See Nursing Mothers section.)
5. Norethindrone acetate is contraindicated in women with the following conditions:
o Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a past history of
these conditions
o Markedly impaired liver function or liver disease
o Known or suspected carcinoma of the breast
WARNINGS
Safe use of leuprolide acetate or norethindrone acetate in pregnancy has not been established
clinically. Before starting treatment with LUPRON DEPOT, pregnancy must be excluded.
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When used monthly at the recommended dose, LUPRON DEPOT usually inhibits ovulation and
stops menstruation. Contraception is not insured, however, by taking LUPRON DEPOT.
Therefore, patients should use non-hormonal methods of contraception.
Patients should be advised to see their physician if they believe they may be pregnant. If a patient
becomes pregnant during treatment, the drug must be discontinued and the patient must be
apprised of the potential risk to the fetus.
During the early phase of therapy, sex steroids temporarily rise above baseline because of the
physiologic effect of the drug. Therefore, an increase in clinical signs and symptoms may be
observed during the initial days of therapy, but these will dissipate with continued therapy.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported post-
marketing.
The following applies to co-treatment with LUPRON and norethindrone acetate:
Norethindrone acetate treatment should be discontinued if there is a sudden partial or complete
loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. If examination
reveals papilledema or retinal vascular lesions, medication should be withdrawn.
Because of the occasional occurrence of thrombophlebitis and pulmonary embolism in patients
taking progestogens, the physician should be alert to the earliest manifestations of the disease in
women taking norethindrone acetate.
Assessment and management of risk factors for cardiovascular disease is recommended prior to
initiation of add-back therapy with norethindrone acetate. Norethindrone acetate should be used
with caution in women with risk factors, including lipid abnormalities or cigarette smoking.
PRECAUTIONS
Information for Patients
Patients should be aware of the following information:
1. Since menstruation usually stops with effective doses of LUPRON DEPOT, the patient
should notify her physician if regular menstruation persists. Patients missing successive
doses of LUPRON DEPOT may experience breakthrough bleeding.
2. Patients should not use LUPRON DEPOT if they are pregnant, breast feeding, have
undiagnosed abnormal vaginal bleeding, or are allergic to any of the ingredients in LUPRON
DEPOT.
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3. Safe use of the drug in pregnancy has not been established clinically. Therefore, a non-
hormonal method of contraception should be used during treatment. Patients should be
advised that if they miss successive doses of LUPRON DEPOT, breakthrough bleeding or
ovulation may occur with the potential for conception. If a patient becomes pregnant during
treatment, she should discontinue treatment and consult her physician.
4. Adverse events occurring in clinical studies with LUPRON DEPOT that are associated with
hypoestrogenism include: hot flashes, headaches, emotional lability, decreased libido, acne,
myalgia, reduction in breast size, and vaginal dryness. Estrogen levels returned to normal
after treatment was discontinued.
5. Patients should be counseled on the possibility of the development or worsening of
depression and the occurrence of memory disorders.
6. The induced hypoestrogenic state also results in a loss in bone density over the course of
treatment, some of which may not be reversible. Clinical studies show that concurrent
hormonal therapy with norethindrone acetate 5 mg daily is effective in reducing loss of bone
mineral density that occurs with LUPRON. (All patients received calcium supplementation
with 1000 mg elemental calcium.) (See Changes in Bone Density section).
7. If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-
month course of LUPRON DEPOT and norethindrone acetate 5 mg daily may be considered.
Retreatment beyond this one six month course cannot be recommended. It is recommended
that bone density be assessed before retreatment begins to ensure that values are within
normal limits. Retreatment with LUPRON DEPOT alone is not recommended.
8. In patients with major risk factors for decreased bone mineral content such as chronic alcohol
and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can
reduce bone mass such as anticonvulsants or corticosteroids, LUPRON DEPOT therapy may
pose an additional risk. In these patients, the risks and benefits must be weighed carefully
before therapy with LUPRON DEPOT alone is instituted, and concomitant treatment with
norethindrone acetate 5 mg daily should be considered. Retreatment with gonadotropin-
releasing hormone analogs, including LUPRON is not advisable in patients with major risk
factors for loss of bone mineral content.
9. Because norethindrone acetate may cause some degree of fluid retention, conditions which
might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal
dysfunctions require careful observation during norethindrone acetate add-back therapy.
10. Patients who have a history of depression should be carefully observed during treatment with
norethindrone acetate and norethindrone acetate should be discontinued if severe depression
occurs.
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Convulsions
There have been postmarketing reports of convulsions in patients on leuprolide acetate therapy.
These included patients with and without concurrent medications and comorbid conditions.
Laboratory Tests
See ADVERSE REACTIONS section.
Drug Interactions
See CLINICAL PHARMACOLOGY, Pharmacokinetics.
Drug/Laboratory Test Interactions
Administration of LUPRON DEPOT in therapeutic doses results in suppression of the pituitary-
gonadal system. Normal function is usually restored within three months after treatment is
discontinued. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions
conducted during treatment and for up to three months after discontinuation of LUPRON
DEPOT may be misleading.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in rats and mice. In rats, a dose-related increase
of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the
drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a
significant but not dose-related increase of pancreatic islet-cell adenomas in females and of
testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice,
no leuprolide acetate-induced tumors or pituitary abnormalities were observed at a dose as high
as 60 mg/kg for two years. Patients have been treated with leuprolide acetate for up to three years
with doses as high as 10 mg/day and for two years with doses as high as 20 mg/day without
demonstrable pituitary abnormalities.
Mutagenicity studies have been performed with leuprolide acetate using bacterial and
mammalian systems. These studies provided no evidence of a mutagenic potential.
Clinical and pharmacologic studies in adults (>18 years) with leuprolide acetate and similar
analogs have shown reversibility of fertility suppression when the drug is discontinued after
continuous administration for periods of up to 24 weeks. Although no clinical studies have been
completed in children to assess the full reversibility of fertility suppression, animal studies
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(prepubertal and adult rats and monkeys) with leuprolide acetate and other GnRH analogs have
shown functional recovery.
Pregnancy
Teratogenic Effects
Pregnancy Category X (see CONTRAINDICATIONS section).
When administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg
(1/300 to 1/3 of the human dose) to rabbits, LUPRON DEPOT produced a dose-related increase
in major fetal abnormalities. Similar studies in rats failed to demonstrate an increase in fetal
malformations. There was increased fetal mortality and decreased fetal weights with the two
higher doses of LUPRON DEPOT in rabbits and with the highest dose (0.024 mg/kg) in rats.
Nursing Mothers
It is not known whether LUPRON DEPOT is excreted in human milk. Because many drugs are
excreted in human milk, and because the effects of LUPRON DEPOT on lactation and/or the
breast-fed child have not been determined, LUPRON DEPOT should not be used by nursing
mothers.
Pediatric Use
Experience with LUPRON DEPOT 3.75 mg for treatment of endometriosis has been limited to
women 18 years of age and older. See LUPRON DEPOT-PED® (leuprolide acetate for depot
suspension) labeling for the safety and effectiveness in children with central precocious puberty.
Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this
population.
ADVERSE REACTIONS
Clinical Trials
Estradiol levels may increase during the first weeks following the initial injection of LUPRON,
but then decline to menopausal levels. This transient increase in estradiol can be associated with
a temporary worsening of signs and symptoms (see WARNINGS section).
As would be expected with a drug that lowers serum estradiol levels, the most frequently
reported adverse reactions were those related to hypoestrogenism.
Reference ID: 3398785
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The monthly formulation of LUPRON DEPOT 3.75 mg was utilized in controlled clinical
trials that studied the drug in 166 endometriosis and 166 uterine fibroids patients. Adverse events
reported in ≥5% of patients in either of these populations and thought to be potentially related to
drug are noted in the following table.
Table 2 ADVERSE EVENTS REPORTED TO BE CAUSALLY RELATED TO DRUG IN ≥ 5% OF
PATIENTS
Endometriosis (2 Studies)
Uterine Fibroids (4 Studies)
LUPRON
DEPOT 3.75 mg
N=166
Danazol
N=136
Placebo
N=31
LUPRON
DEPOT 3.75 mg
N=166
Placebo
N=163
N
(%)
N
(%) N (%)
N
(%)
N
(%)
Body as a Whole
Asthenia
5
(3)
9
(7)
0
(0)
14
(8.4)
8
(4.9)
General pain
31
(19)
22 (16)
1
(3)
14
(8.4)
10
(6.1)
Headache*
53
(32)
30 (22)
2
(6)
43
(25.9)
29 (17.8)
Cardiovascular System
Hot flashes/sweats*
139
(84)
77 (57)
9
(29)
121
(72.9)
29 (17.8)
Gastrointestinal System
Nausea/vomiting
21
(13)
17 (13)
1
(3)
8
(4.8)
6
(3.7)
GI disturbances*
11
(7)
8
(6)
1
(3)
5
(3.0)
2
(1.2)
Metabolic and Nutritional Disorders
Edema
12
(7)
17 (13)
1
(3)
9
(5.4)
2
(1.2)
Weight gain/loss
22
(13)
36 (26)
0
(0)
5
(3.0)
2
(1.2)
Endocrine System
Acne
17
(10)
27 (20)
0
(0)
0
(0)
0
(0)
Hirsutism
2
(1)
9
(7)
1
(3)
1
(0.6)
0
(0)
Musculoskeletal System
Joint disorder*
14
(8)
11
(8)
0
(0)
13
(7.8)
5
(3.1)
Myalgia*
1
(1)
7
(5)
0
(0)
1
(0.6)
0
(0)
Nervous System
Decreased libido*
19
(11)
6
(4)
0
(0)
3
(1.8)
0
(0)
Depression/emotional lability*
36
(22)
27 (20)
1
(3)
18
(10.8)
7
(4.3)
Dizziness
19
(11)
4
(3)
0
(0)
3
(1.8)
6
(3.7)
Nervousness*
8
(5)
11
(8)
0
(0)
8
(4.8)
1
(0.6)
Neuromuscular disorders*
11
(7)
17 (13)
0
(0)
3
(1.8)
0
(0)
Paresthesias
12
(7)
11
(8)
0
(0)
2
(1.2)
1
(0.6)
Skin and Appendages
Skin reactions
17
(10)
20 (15)
1
(3)
5
(3.0)
2
(1.2)
Urogenital System
Breast changes/tenderness/pain*
10
(6)
12
(9)
0
(0)
3
(1.8)
7
(4.3)
Vaginitis*
46
(28)
23 (17)
0
(0)
19
(11.4)
3
(1.8)
In these same studies, symptoms reported in <5% of patients included: Body as a Whole - Body odor, Flu syndrome,
Injection site reactions; Cardiovascular System - Palpitations, Syncope, Tachycardia; Digestive System - Appetite
changes, Dry mouth, Thirst; Endocrine System - Androgen-like effects; Hemic and Lymphatic System - Ecchymosis,
Lymphadenopathy; Nervous System – Anxiety*, Insomnia/Sleep disorders*, Delusions, Memory disorder,
Personality disorder; Respiratory System - Rhinitis; Skin and Appendages - Alopecia, Hair disorder, Nail disorder;
Reference ID: 3398785
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Special Senses - Conjunctivitis, Ophthalmologic disorders*, Taste perversion; Urogenital System - Dysuria*,
Lactation, Menstrual disorders.
* = Possible effect of decreased estrogen.
In one controlled clinical trial utilizing the monthly formulation of LUPRON DEPOT, patients
diagnosed with uterine fibroids received a higher dose (7.5 mg) of LUPRON DEPOT. Events
seen with this dose that were thought to be potentially related to drug and were not seen at the
lower dose included glossitis, hypesthesia, lactation, pyelonephritis, and urinary disorders.
Generally, a higher incidence of hypoestrogenic effects was observed at the higher dose.
Table 3 lists the potentially drug-related adverse events observed in at least 5% of patients in any
treatment group during the first 6 months of treatment in the add-back clinical studies.
In the controlled clinical trial, 50 of 51 (98%) patients in the LD group and 48 of 55 (87%)
patients in the LD/N group reported experiencing hot flashes on one or more occasions during
treatment. During Month 6 of treatment, 32 of 37 (86%) patients in the LD group and 22 of 38
(58%) patients in the LD/N group reported having experienced hot flashes. The mean number of
days on which hot flashes were reported during this month of treatment was 19 and 7 in the LD
and LD/N treatment groups, respectively. The mean maximum number of hot flashes in a day
during this month of treatment was 5.8 and 1.9 in the LD and LD/N treatment groups,
respectively.
Table 3 TREATMENT-RELATED ADVERSE EVENTS OCCURRING IN ≥5% OF PATIENTS
Controlled Study
Open Label Study
LD - Only*
N=51
LD/N†
N=55
LD/N†
N=136
Adverse Events
N
(%)
N
(%)
N
(%)
Any Adverse Event
50
(98)
53
(96)
126
(93)
Body as a Whole
Asthenia
9
(18)
10
(18)
15
(11)
Headache/Migraine
33
(65)
28
(51)
63
(46)
Injection Site Reaction
1
(2)
5
(9)
4
(3)
Pain
12
(24)
16
(29)
29
(21)
Cardiovascular System
Hot flashes/sweats
50
(98)
48
(87)
78
(57)
Digestive System
Altered Bowel Function
7
(14)
8
(15)
14
(10)
Changes in Appetite
2
(4)
0
(0)
8
(6)
GI Disturbance
2
(4)
4
(7)
6
(4)
Nausea/Vomiting
13
(25)
16
(29)
17
(13)
Metabolic and Nutritional Disorders
Edema
0
(0)
5
(9)
9
(7)
Weight Changes
6
(12)
7
(13)
6
(4)
Nervous System
Reference ID: 3398785
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Anxiety
3
(6)
0
(0)
11
(8)
Depression/Emotional Lability
16
(31)
15
(27)
46
(34)
Dizziness/Vertigo
8
(16)
6
(11)
10
(7)
Insomnia/Sleep Disorder
16
(31)
7
(13)
20
(15)
Libido Changes
5
(10)
2
(4)
10
(7)
Memory Disorder
3
(6)
1
(2)
6
(4)
Nervousness
4
(8)
2
(4)
15
(11)
Neuromuscular Disorder
1
(2)
5
(9)
4
(3)
Skin and Appendages
Alopecia
0
(0)
5
(9)
4
(3)
Androgen-Like Effects
2
(4)
3
(5)
24
(18)
Skin/Mucous Membrane Reaction
2
(4)
5
(9)
15
(11)
Urogenital System
Breast Changes/Pain/Tenderness
3
(6)
7
(13)
11
(8)
Menstrual Disorders
1
(2)
0
(0)
7
(5)
Vaginitis
10
(20)
8
(15)
11
(8)
* LD-Only = LUPRON DEPOT 3.75 mg
† LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
Changes in Bone Density
In controlled clinical studies, patients with endometriosis (six months of therapy) or uterine
fibroids (three months of therapy) were treated with LUPRON DEPOT 3.75 mg. In
endometriosis patients, vertebral bone density as measured by dual energy x-ray absorptiometry
(DEXA) decreased by an average of 3.2% at six months compared with the pretreatment value.
Clinical studies demonstrate that concurrent hormonal therapy (norethindrone acetate 5 mg
daily) and calcium supplementation is effective in significantly reducing the loss of bone mineral
density that occurs with LUPRON treatment, without compromising the efficacy of LUPRON in
relieving symptoms of endometriosis.
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was evaluated in two clinical
trials. The results from this regimen were similar in both studies. LUPRON DEPOT 3.75 mg was
used as a control group in one study. The bone mineral density data of the lumbar spine from
these two studies are presented in Table 4.
Table 4 MEAN PERCENT CHANGE FROM BASELINE IN BONE MINERAL DENSITY OF LUMBAR
SPINE
LUPRON DEPOT 3.75mg
LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg
daily
Controlled Study
Controlled Study
Open Label Study
N
Change
(Mean, 95% CI)#
N
Change
(Mean, 95% CI)#
N
Change
(Mean, 95% CI)#
Week 24*
41
-3.2% (-3.8, -2.6)
42
-0.3% (-0.8, 0.3)
115
-0.2% (-0.6, 0.2)
Week 52†
29
-6.3% (-7.1, -5.4)
32
-1.0% (-1.9, -0.1)
84
-1.1% (-1.6, -0.5)
* Includes on-treatment measurements that fell within 2–252 days after the first day of treatment.
Reference ID: 3398785
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For current labeling information, please visit https://www.fda.gov/drugsatfda
† Includes on-treatment measurements >252 days after the first day of treatment.
# 95% CI: 95% Confidence Interval
When LUPRON DEPOT 3.75 mg was administered for three months in uterine fibroid patients,
vertebral trabecular bone mineral density as assessed by quantitative digital radiography (QDR)
revealed a mean decrease of 2.7% compared with baseline. Six months after discontinuation of
therapy, a trend toward recovery was observed. Use of LUPRON DEPOT for longer than three
months (uterine fibroids) or six months (endometriosis) or in the presence of other known risk
factors for decreased bone mineral content may cause additional bone loss and is not
recommended.
Changes in Laboratory Values During Treatment
Plasma Enzymes
Endometriosis
During early clinical trials with LUPRON DEPOT 3.75 mg, regular laboratory monitoring
revealed that AST levels were more than twice the upper limit of normal in only one patient.
There was no clinical or other laboratory evidence of abnormal liver function.
In two other clinical trials, 6 of 191 patients receiving LUPRON DEPOT 3.75 mg plus
norethindrone acetate 5 mg daily for up to 12 months developed an elevated (at least twice the
upper limit of normal) SGPT or GGT. Five of the 6 increases were observed beyond 6 months of
treatment. None were associated with elevated bilirubin concentration.
Uterine Leiomyomata (Fibroids)
In clinical trials with LUPRON DEPOT 3.75 mg, five (3%) patients had a post-treatment
transaminase value that was at least twice the baseline value and above the upper limit of the
normal range. None of the laboratory increases were associated with clinical symptoms.
Lipids
Endometriosis
In earlier clinical studies, 4% of the LUPRON DEPOT 3.75 mg patients and 1% of the danazol
patients had total cholesterol values above the normal range at enrollment. These patients also
had cholesterol values above the normal range at the end of treatment.
Of those patients whose pretreatment cholesterol values were in the normal range, 7% of the
LUPRON DEPOT 3.75 mg patients and 9% of the danazol patients had post-treatment values
above the normal range.
Reference ID: 3398785
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The mean (±SEM) pretreatment values for total cholesterol from all patients were 178.8 (2.9)
mg/dL in the LUPRON DEPOT 3.75 mg groups and 175.3 (3.0) mg/dL in the danazol group. At
the end of treatment, the mean values for total cholesterol from all patients were 193.3 mg/dL in
the LUPRON DEPOT 3.75 mg group and 194.4 mg/dL in the danazol group. These increases
from the pretreatment values were statistically significant (p<0.03) in both groups.
Triglycerides were increased above the upper limit of normal in 12% of the patients who
received LUPRON DEPOT 3.75 mg and in 6% of the patients who received danazol.
At the end of treatment, HDL cholesterol fractions decreased below the lower limit of the normal
range in 2% of the LUPRON DEPOT 3.75 mg patients compared with 54% of those receiving
danazol. LDL cholesterol fractions increased above the upper limit of the normal range in 6% of
the patients receiving LUPRON DEPOT 3.75 mg compared with 23% of those receiving
danazol. There was no increase in the LDL/HDL ratio in patients receiving LUPRON DEPOT
3.75 mg but there was approximately a two-fold increase in the LDL/HDL ratio in patients
receiving danazol.
In two other clinical trials, LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily was
evaluated for 12 months of treatment. LUPRON DEPOT 3.75 mg was used as a control group in
one study. Percent changes from baseline for serum lipids and percentages of patients with serum
lipid values outside of the normal range in the two studies are summarized in the tables below.
Table 5 SERUM LIPIDS: MEAN PERCENT CHANGES FROM BASELINE VALUES AT TREATMENT
WEEK 24
LUPRON
LUPRON plus norethindrone acetate 5 mg daily
Controlled Study (n=39)
Controlled Study (n=41)
Open Label Study (n=117)
Baseline Value*
Wk 24
% Change
Baseline Value*
Wk 24
% Change
Baseline Value*
Wk 24
% Change
Total Cholesterol
170.5
9.2%
179.3
0.2%
181.2
2.8%
HDL Cholesterol
52.4
7.4%
51.8
-18.8%
51.0
-14.6%
LDL Cholesterol
96.6
10.9%
101.5
14.1%
109.1
13.1%
LDL/HDL Ratio
2.0†
5.0%
2.1†
43.4%
2.3†
39.4%
Triglycerides
107.8
17.5%
130.2
9.5%
105.4
13.8%
* mg/dL
† ratio
Changes from baseline tended to be greater at Week 52. After treatment, mean serum lipid levels
from patients with follow up data returned to pretreatment values.
Table 6 PERCENTAGE OF PATIENTS WITH SERUM LIPID VALUES OUTSIDE OF THE NORMAL
RANGE
LUPRON plus norethindrone acetate 5 mg
LUPRON
daily
Reference ID: 3398785
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Controlled Study
(n=39)
Controlled Study
(n=41)
Open Label Study
(n=117)
Wk 0
Wk 24*
Wk 0
Wk 24*
Wk 0
Wk 24*
Total Cholesterol (>240 mg/dL)
15%
23%
15%
20%
6%
7%
HDL Cholesterol (<40 mg/dL)
15%
10%
15%
44%
15%
41%
LDL Cholesterol (>160 mg/dL)
0%
8%
5%
7%
9%
11%
LDL/HDL Ratio (>4.0)
0%
3%
2%
15%
7%
21%
Triglycerides (>200 mg/dL)
13%
13%
12%
10%
5%
9%
* Includes all patients regardless of baseline value.
Low HDL-cholesterol (<40 mg/dL) and elevated LDL-cholesterol (>160 mg/dL) are recognized
risk factors for cardiovascular disease. The long-term significance of the observed treatment-
related changes in serum lipids in women with endometriosis is unknown. Therefore assessment
of cardiovascular risk factors should be considered prior to initiation of concurrent treatment
with LUPRON and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
In patients receiving LUPRON DEPOT 3.75 mg, mean changes in cholesterol (+11 mg/dL to
+29 mg/dL), LDL cholesterol (+8 mg/dL to +22 mg/dL), HDL cholesterol (0 to +6 mg/dL), and
the LDL/HDL ratio (-0.1 to +0.5) were observed across studies. In the one study in which
triglycerides were determined, the mean increase from baseline was 32 mg/dL.
Other Changes
Endometriosis
The following changes were seen in approximately 5% to 8% of patients. In the earlier
comparative studies, LUPRON DEPOT 3.75 mg was associated with elevations of LDH and
phosphorus, and decreases in WBC counts. Danazol therapy was associated with increases in
hematocrit, platelet count, and LDH. In the hormonal add-back studies LUPRON DEPOT in
combination with norethindrone acetate was associated with elevations of GGT and SGPT.
Uterine Leiomyomata (Fibroids)
Hematology: (see CLINICAL STUDIES section) In LUPRON DEPOT 3.75 mg treated
patients, although there were statistically significant mean decreases in platelet counts from
baseline to final visit, the last mean platelet counts were within the normal range. Decreases in
total WBC count and neutrophils were observed, but were not clinically significant.
Reference ID: 3398785
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Chemistry: Slight to moderate mean increases were noted for glucose, uric acid, BUN,
creatinine, total protein, albumin, bilirubin, alkaline phosphatase, LDH, calcium, and
phosphorus. None of these increases were clinically significant.
Postmarketing
The following adverse reactions have been identified during postapproval use of LUPRON
DEPOT. Because these reactions are reported voluntarily from a population of uncertain size, it
is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
During postmarketing surveillance, the following adverse events were reported. Like other drugs
in this class, mood swings, including depression, have been reported. There have been rare
reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of
depression or other psychiatric illness. Patients should be counseled on the possibility of
development or worsening of depression during treatment with LUPRON.
Symptoms consistent with an anaphylactoid or asthmatic process have been rarely reported.
Rash, urticaria, and photosensitivity reactions have also been reported.
Localized reactions including induration and abscess have been reported at the site of injection.
Symptoms consistent with fibromyalgia (eg: joint and muscle pain, headaches, sleep disorder,
gastrointestinal distress, and shortness of breath) have been reported individually and
collectively.
Other events reported are:
Hepato-biliary disorder: Rarely reported serious liver injury
Injury, poisoning and procedural complications: Spinal fracture
Investigations: Decreased WBC
Musculoskeletal and Connective tissue disorder: Tenosynovitis-like symptoms
Nervous System Disorder: Convulsion, peripheral neuropathy, paralysis
Vascular Disorder: Hypotension
Cases of serious venous and arterial thromboembolism have been reported, including deep vein
thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack.
Reference ID: 3398785
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Although a temporal relationship was reported in some cases, most cases were confounded by
risk factors or concomitant medication use. It is unknown if there is a causal association between
the use of GnRH analogs and these events.
Pituitary apoplexy
During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome
secondary to infarction of the pituitary gland) have been reported after the administration of
gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was
diagnosed, with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose,
and some within the first hour. In these cases, pituitary apoplexy has presented as sudden
headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes
cardiovascular collapse. Immediate medical attention has been required.
See other LUPRON DEPOT and LUPRON Injection package inserts for other events reported in
different patient populations.
OVERDOSAGE
In rats subcutaneous administration of 250 to 500 times the recommended human dose,
expressed on a per body weight basis, resulted in dyspnea, decreased activity, and local irritation
at the injection site. There is no evidence that there is a clinical counterpart of this phenomenon.
In early clinical trials using daily subcutaneous leuprolide acetate in patients with prostate
cancer, doses as high as 20 mg/day for up to two years caused no adverse effects differing from
those observed with the 1 mg/day dose.
DOSAGE AND ADMINISTRATION
LUPRON DEPOT Must Be Administered Under The Supervision Of A Physician.
Endometriosis
The recommended duration of treatment with LUPRON DEPOT 3.75 mg alone or in
combination with norethindrone acetate is six months. The choice of LUPRON DEPOT alone or
LUPRON DEPOT plus norethindrone acetate therapy for initial management of the symptoms
and signs of endometriosis should be made by the health care professional in consultation with
the patient and should take into consideration the risks and benefits of the addition of
norethindrone to LUPRON DEPOT alone.
If the symptoms of endometriosis recur after a course of therapy, retreatment with a six-month
course of LUPRON DEPOT administered monthly and norethindrone acetate 5 mg daily may be
Reference ID: 3398785
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For current labeling information, please visit https://www.fda.gov/drugsatfda
considered. Retreatment beyond this one six-month course cannot be recommended. It is
recommended that bone density be assessed before retreatment begins to ensure that values are
within normal limits. LUPRON DEPOT alone is not recommended for retreatment. If
norethindrone acetate is contraindicated for the individual patient, then retreatment is not
recommended.
An assessment of cardiovascular risk and management of risk factors such as cigarette smoking
is recommended before beginning treatment with LUPRON DEPOT and norethindrone acetate.
Uterine Leiomyomata (Fibroids)
Recommended duration of therapy with LUPRON DEPOT 3.75 mg is up to 3 months. The
symptoms associated with uterine leiomyomata will recur following discontinuation of therapy. If
additional treatment with LUPRON DEPOT 3.75 mg is contemplated, bone density should be
assessed prior to initiation of therapy to ensure that values are within normal limits.
The recommended dose of LUPRON DEPOT is 3.75 mg, incorporated in a depot formulation.
For optimal performance of the prefilled dual chamber syringe (PDS), read and follow the
following instructions:
Reconstitution and Administration Instructions
• The lyophilized microspheres are to be reconstituted and administered as a single
intramuscular injection.
• Since LUPRON DEPOT does not contain a preservative, the suspension should be injected
immediately or discarded if not used within two hours.
• As with other drugs administered by injection, the injection site should be varied
periodically.
1. The LUPRON DEPOT powder should be visually inspected and the syringe should NOT BE
USED if clumping or caking is evident. A thin layer of powder on the wall of the syringe is
considered normal prior to mixing with the diluent. The diluent should appear clear.
2. To prepare for injection, screw the white plunger into the end stopper until the stopper begins
to turn.
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usage illustration
3. Hold the syringe UPRIGHT. Release the diluent by SLOWLY PUSHING (6 to 8 seconds)
the plunger until the first stopper is at the blue line in the middle of the barrel. usage illustration
4. Keep the syringe UPRIGHT. Mix the microspheres (powder) thoroughly by gently shaking
the syringe until the powder forms a uniform suspension. The suspension will appear milky.
If the powder adheres to the stopper or caking/clumping is present, tap the syringe with your
finger to disperse. DO NOT USE if any of the powder has not gone into suspension. usage illustration
5. Hold the syringe UPRIGHT. With the opposite hand pull the needle cap upward without
twisting.
Reference ID: 3398785
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6. Keep the syringe UPRIGHT. Advance the plunger to expel the air from the syringe. Now the
syringe is ready for injection.
7. After cleaning the injection site with an alcohol swab, the intramuscular injection should be
performed by inserting the needle at a 90 degree angle into the gluteal area, anterior thigh, or
deltoid; injection sites should be alternated. usage illustration
NOTE: Aspirated blood would be visible just below the luer lock connection if a blood
vessel is accidentally penetrated. If present, blood can be seen through the transparent
LuproLoc® safety device. If blood is present remove the needle immediately. Do not inject
the medication. usage illustration
8. Inject the entire contents of the syringe intramuscularly at the time of reconstitution. The
suspension settles very quickly following reconstitution; therefore, LUPRON DEPOT should
be mixed and used immediately.
AFTER INJECTION
9. Withdraw the needle. Once the syringe has been withdrawn, activate immediately the
LuproLoc® safety device by pushing the arrow on the lock upward towards the needle tip
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with the thumb or finger, as illustrated, until the needle cover of the safety device over the
needle is fully extended and a CLICK is heard or felt. usage illustration
ADDITIONAL INFORMATION
• Dispose of the syringe according to local regulations/procedures.
HOW SUPPLIED
Each LUPRON DEPOT 3.75 mg kit (NDC 0074-3641-03) contains:
• one prefilled dual-chamber syringe
• one plunger
• two alcohol swabs
• a complete prescribing information enclosure
Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated in a
biodegradable copolymer of lactic and glycolic acids. When mixed with diluent, LUPRON
DEPOT 3.75 mg is administered as a single monthly IM injection.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room
Temperature]
REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs
in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health
Service, Centers for Disease Control and Prevention, National Institute for Occupational
Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational
Exposure to Hazardous Drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
Reference ID: 3398785
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous
drugs. Am J Health-Syst Pharm. 2006; 63; 1172-1193.
4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice (2nd. Ed.) Pittsburgh, PA: Oncology Nursing
Society.
Manufactured for
AbbVie Inc.
North Chicago, IL 60064
by Takeda Pharmaceutical Company Limited
Osaka, Japan 540-8645
October, 2013
Reference ID: 3398785
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:27.175235
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020011s041lbl.pdf', 'application_number': 20011, 'submission_type': 'SUPPL ', 'submission_number': 41}
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12,139
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UNIMED
Maxaquin®
(lomefloxacin hydrochloride)
Film-coated Tablets
DESCRIPTION
Maxaquin (lomefloxacin HCl) is a synthetic broad-spectrum antimicrobial agent for oral administration.
Lomefloxacin HCl, a difluoroquinolone, is the monohydrochloride salt of (±)-1-ethyl-6,8-difluoro-1,4-
dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid. Its empirical formula is
C17H19F2N3O3 · HCl, and its structural formula is:
Lomefloxacin HCl is a white to pale yellow powder with a molecular weight of 387.8. It is slightly
soluble in water and practically insoluble in alcohol. Lomefloxacin HCl is stable to heat and moisture but
is sensitive to light in dilute aqueous solution.
Maxaquin is available as a film-coated tablet formulation containing 400 mg of lomefloxacin base,
present as the hydrochloride salt. The base content of the hydrochloride salt is 90.6%. The inactive
ingredients are carboxymethylcellulose calcium, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
lactose, magnesium stearate, polyethylene glycol, polyoxyl 40 stearate, and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacokinetics in healthy volunteers: In 6 fasting healthy male volunteers, approximately 95% to
98% of a single oral dose of lomefloxacin was absorbed. Absorption was rapid following single doses
of 200 and 400 mg (Tmax 0.8 to 1.4 hours). Mean plasma concentration increased proportionally
between 100 and 400 mg as shown below:
Dose (mg)
Mean Peak Plasma
Concentration (µg/mL)
Area Under Curve (AUC)
(µg·h/mL)
100
0.8
5.6
200
1.4
10.9
400
3.2
26.1
In 6 healthy male volunteers administered 400 mg of lomefloxacin on an empty stomach qd for 7 days,
the following mean pharmacokinetic parameter values were obtained:
Cmax
2.8 µg/mL
Cmin
0.27 µg/mL
AUC0-24 h
25.9 µg·h/mL
Tmax
1.5 h
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t1/2
7.75 h
The elimination half-life in 8 subjects with normal renal function was approximately 8 hours. At 24 hours
postdose, subjects with normal renal function receiving single doses of 200 or 400 mg had mean plasma
lomefloxacin concentrations of 0.10 and 0.24 µg/mL, respectively. Steady-state concentrations were
achieved within 48 hours of initiating therapy with one-a-day dosing. There was no drug accumulation
with single-daily dosing in patients with normal renal function.
Approximately 65% of an orally administered dose was excreted in the urine as unchanged drug in
patients with normal renal function. Following a 400-mg dose of lomefloxacin administered qd for 7
days, the mean urine concentration 4 hours postdose was in excess of 300 µg/mL. The mean urine
concentration exceeded 35 µg/mL for at least 24 hours after dosing.
Following a single 400-mg dose, the solubility of lomefloxacin in urine usually exceeded its peak urinary
concentration 2- to 6-fold. In this study, urine pH affected the solubility of lomefloxacin with solubilities
ranging from 7.8 mg/mL at pH 5.2, to 2.4 mg/mL at pH 6.5, and 3.03 mg/mL at pH 8.12.
The urinary excretion of lomefloxacin was virtually complete within 72 hours after cessation of dosing,
with approximately 65% of the dose being recovered as parent drug and 9% as its glucuronide
metabolite. The mean renal clearance was 145 mL/min in subjects with normal renal function (GFR =
120 mL/min). This may indicate tubular secretion.
Food effect: When lomefloxacin and food were administered concomitantly, the rate of drug
absorption was delayed (Tmax increased to 2 hours [delayed by 41%], Cmax decreased by 18%), and
the extent of absorption (AUC) was decreased by 12%.
Pharmacokinetics in the geriatric population: In 16 healthy elderly volunteers (61 to 76 years of
age) with normal renal function for their age, the half-life of lomefloxacin (mean of 8 hours) and its peak
plasma concentration (mean of 4.2 µg/mL) following a single 400-mg dose were similar to those in 8
younger subjects dosed with a single 400-mg dose. Thus, drug absorption appears unaffected in the
elderly. Plasma clearance was, however, reduced in this elderly population by approximately 25%, and
the AUC was increased by approximately 33%. This slower elimination most likely reflects the
decreased renal function normally observed in the geriatric population.
Pharmacokinetics in renally impaired patients: In 8 patients with creatinine clearance (ClCr) between
10 and 40 mL/min/1.73 m2, the mean AUC after a single 400-mg dose of lomefloxacin increased 335%
over the AUC demonstrated in patients with a ClCr > 80 mL/min/1.73 m2. Also, in these patients, the
mean t1/2 increased to 21 hours. In 8 patients with ClCr < 10 mL/min/1.73 m2, the mean AUC after a
single 400-mg dose of lomefloxacin increased 700% over the AUC demonstrated in patients with a ClCr
> 80 mL/min/1.73 m2. In these patients with ClCr < 10 mL/min/1.73 m2, the mean t1/2 increased to 45
hours. The plasma clearance of lomefloxacin was closely correlated with creatinine clearance, ranging
from 31 mL/min/1.73 m2 when creatinine clearance was zero to 271 mL/min/1.73 m2 at a normal
creatinine clearance of 110 mL/min/1.73 m2. Peak lomefloxacin concentrations were not affected by the
degree of renal function when single doses of lomefloxacin were administered. Adjustment of dosage
schedules for patients with such decreases in renal function is warranted. (See Dosage and
Administration.)
Pharmacokinetics in patients with cirrhosis: In 12 patients with histologically confirmed cirrhosis, no
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significant changes in rate or extent of lomefloxacin exposure (Cmax, Tmax, t1/2, or AUC) were observed
when they were administered 400 mg of lomefloxacin as a single dose. No data are available in cirrhotic
patients treated with multiple doses of lomefloxacin. Cirrhosis does not appear to reduce the nonrenal
clearance of lomefloxacin. There does not appear to be a need for a dosage reduction in cirrhotic
patients, provided adequate renal function is present.
Metabolism and pharmacodynamics of lomefloxacin: Lomefloxacin is minimally metabolized
although 5 metabolites have been identified in human urine. The glucuronide metabolite is found in the
highest concentration and accounts for approximately 9% of the administered dose. The other 4
metabolites together account for < 0.5% of the dose.
Approximately 10% of an oral dose was recovered as unchanged drug in the feces.
Serum protein binding of lomefloxacin is approximately 10%.
The following are mean tissue- or fluid-to-plasma ratios of lomefloxacin following oral administration.
Studies have not been conducted to assess the penetration of lomefloxacin into human cerebrospinal
fluid.
Mean Tissue- or Fluid-
Tissue or Body Fluid
to-Plasma Ratio
Bronchial mucosa
2.1
Bronchial secretions
0.6
Prostatic tissue
2.0
Sputum
1.3
Urine
140.0
In two studies including 74 healthy volunteers, the minimal dose of UVA light needed to cause erythema
(MED-UVA) was inversely proportional to plasma lomefloxacin concentration. The MED-UVA values
(16 hours and 12 hours postdose) were significantly higher than the MED-UVA values 2 hours
postdose at steady state. Increasing the interval between lomefloxacin dosing and exposure to UVA
light increased the amount of light energy needed for photoreaction. In a study of 27 healthy volunteers,
the steady state AUC values and Cmin values were equivalent whether the drug was administered in the
morning or in the evening.
Microbiology: Lomefloxacin has in vitro activity against a wide range of gram-negative and gram-
positive microorganisms. The bactericidal action of lomefloxacin and other fluoroquinolone
antimicrobials results from inhibition of bacterial topoisomerase IV and DNA gyrase (both of which
are type II topoisomerases), enzymes required for DNA replication, transcription, repair and
recombination. The minimum bactericidal concentration (MBC) generally does not exceed the
minimum inhibitory concentration (MIC) by more than a factor of 2, except for staphylococci, which
usually have MBCs 2 to 4 times the MIC.
Lomefloxacin shares a number of general characteristics with other members of the quinolone class.
Beta-lactamase production has no effect on the in vitro activity of lomefloxacin or other
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fluoroquinolones. Like other members of the quinolone class of antimicrobials, lomefloxacin appears
slightly less active in vitro when tested at acidic pH, an increase in inoculum size has little effect on in
vitro activity, and in vitro resistance develops slowly (multiple-step mutation). Rapid one-step
development of resistance occurs only rarely (10-9) in vitro.
Cross-resistance between lomefloxacin and other quinolone-class antimicrobial agents has been
reported; however, cross-resistance between lomefloxacin and members of other classes of
antimicrobial agents, such as aminoglycosides, penicillins, tetracyclines, cephalosporins, or
sulfonamides has not yet been reported. Lomefloxacin is active in vitro against some strains of
cephalosporin and aminoglycoside-resistant gram-negative bacteria.
Lomefloxacin has been shown to be active against most strains of the following microorganisms both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
Aerobic gram-positive microorganisms
Staphylococcus saprophyticus (many strains are only moderately susceptible)
Aerobic gram-negative microorganisms
Citrobacter (diversus) koseri
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Pseudomonas aeruginosa (urinary tract only--See Indications and Usage and Warnings)
The following in vitro data are available, but their clinical significance is unknown.
Lomefloxacin exhibits in vitro minimum inhibitory concentrations (MlC's)of 2 µg/mL or less against
most ($90%)strains of the following microorganisms; however, the safety and effectiveness of
lomefloxacin in treating clinical infections due to these microorganisms have not been established in
adequate and well-controlled trials.
Aerobic gram-positive microorganisms
Staphylococcus aureus (methicillin-susceptible strains only)
Aerobic gram-negative microorganisms
Aeromonas hydrophila
Enterobacter aerogenes
Haemophilus parainfluenzae
Hafnia alvei
Klebsiella oxytoca
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Legionella pneumophila
Morganella morganii
Proteus vulgaris
Most group A, B, D, and G streptococci, Streptococcus pneumoniae, Burkholderia cepacia,
Ureaplasma urealyticum, Mycoplasma hominis, and anaerobic bacteria are resistant to
lomefloxacin.
Susceptibility Tests
Dilution techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MlCs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. The MIC values should be determined using a standardized procedure. Standardized
procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum
concentrations and standardized concentrations of lomefloxacin powder. The MIC values should be
interpreted according to the following criteria:
For testing Enterobacteriaceae, Staphylococcus species, and Pseudomonas aeruginosa:
MIC (µg/mL)
Interpretation
#2
Susceptible (S)
4
Intermediate (I)
$8
Resistant (R)
For testing Haemophilus influenzaea;
MIC (µg/mL)
Interpretation
#2
Susceptible (S)
a This interpretive standard is applicable only to broth microdilution susceptibility testing with
Haemophilus influenzae using Haemophilus Test Medium (HTM)1.
The current absence of data on resistant strains precludes defining any results other than "Susceptible".
Strains yielding MIC results suggestive of a "nonsusceptible” category should be submitted to a
reference laboratory for further testing.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial
compound in the blood reaches the concentration usually achievable. A report of "Intermediate"
indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies possible
clinical applicability in body sites where the drug is physiologically concentrated or in situations where
high dosage of drug can be used. This category also provides a buffer zone which prevents small
uncontrolled technical factors from causing major discrepancies in interpretation. A report of
"Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the
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blood reaches the concentration usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to
control the technical aspects of the laboratory procedures. Standard lomefloxacin powder should
provide the following MIC values:
Microorganism
MIC Range (µg/mL)
Escherichia coli
ATCC 25922
0.03-0.12
Haemophilus influenzae
ATCC 49247b
0.03-0.12
Pseudomonas aeruginosa
ATCC 27853
1.0-4.0
Staphylococcus aureus
ATCC 29213
0.25-2.0
b This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth
microdilution procedure using Haemophilus Test Medium (HTM)1.
Diffusion Techniques;
Quantitative methods that require measurement of zone diameters also provide reproducible estimates
of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires
the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with
10-µg lomefloxacin to test the susceptibility of microorganisms to lomefloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10-µg
lomefloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Staphylococcus species, and Pseudomonas aeruginosa:
Zone Diameter (mm)
Interpretation
$22
Susceptible (S)
19-21
Intermediate (I)
#18
Resistant (R)
For testing Haemophilus influenzae c
Zone Diameter (mm)
Interpretation
$22
Susceptible (S)
c This interpretive standard is applicable only to disk diffusion susceptibility testing with Haemophilus
influenzae using Haemophilus Test Medium (HTM)2
The current absence of data on resistant strains precludes defining any results other than "Susceptible".
Strains yielding zone diameter results suggestive of a "nonsusceptible" category should be submitted to a
reference laboratory for further testing.
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Interpretation should be as stated above for results using dilution techniques. Interpretation involves
correlation of the diameter obtained in the disk test with the MIC for lomefloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control
microorganisms that are used to control the technical aspects of the laboratory procedures. For the
diffusion technique, the 10-µg lomefloxacin disk should provide the following zone diameters in these
laboratory quality control strains:
Microorganism
Zone Diameter (mm)
Escherichia coli
ATCC 25922
27-33
Haemophilus influenzae
ATCC 49247d
33-41
Pseudomonas aeruginosa
ATCC 27853
22-28
Staphylococcus aureus
ATCC 25923
23-29
d This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion
procedure using Haemophilus Test Medium (HTM)2.
INDICATIONS AND USAGE
Treatment:
Maxaquin (lomefloxacin HCl) film-coated tablets are indicated for the treatment of adults with mild to
moderate infections caused by susceptible strains of the designated microorganisms in the conditions
listed below: (See Dosage and Administration for specific dosing recommendations.)
LOWER RESPIRATORY TRACT
Acute Bacterial Exacerbation of Chronic Bronchitis caused by Haemophilus influenzae or Moraxella
catarrhalis.*
NOTE: MAXAQUIN IS NOT INDICATED FOR THE EMPIRIC TREATMENT OF ACUTE
BACTERIAL EXACERBATION OF CHRONIC BRONCHITIS WHEN IT IS PROBABLE THAT
S PNEUMONIAE IS A CAUSATIVE PATHOGEN. S PNEUMONIAE EXHIBITS IN VITRO
RESISTANCE TO LOMEFLOXACIN, AND THE SAFETY AND EFFICACY OF
LOMEFLOXACIN IN THE TREATMENT OF PATIENTS WITH ACUTE BACTERIAL
EXACERBATION OF CHRONIC BRONCHITIS CAUSED BY S PNEUMONIAE HAVE NOT
BEEN DEMONSTRATED. IF LOMEFLOXACIN IS TO BE PRESCRIBED FOR GRAM-
STAIN-GUIDED EMPIRIC THERAPY OF ACUTE BACTERIAL EXACERBATION OF
CHRONIC BRONCHITIS, IT SHOULD BE USED ONLY IF SPUTUM GRAM STAIN
DEMONSTRATES AN ADEQUATE QUALITY OF SPECIMEN (> 25 PMNs/LPF) AND
THERE IS BOTH A PREDOMINANCE OF GRAM-NEGATIVE MICROORGANISMS AND
NOT A PREDOMINANCE OF GRAM-POSITIVE MICROORGANISMS.
URINARY TRACT
Uncomplicated Urinary Tract Infections (cystitis) caused by Escherichia coli, Klebsiella pneumoniae,
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Proteus mirabilis, or Staphylococcus saprophyticus. (See DOSAGE AND ADMINISTRATION
and CLINICAL STUDIES—UNCOMPLICATED CYSTITIS.)
Complicated Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Proteus
mirabilis, Pseudomonas aeruginosa, Citrobacter diversus,* or Enterobacter cloacae.*
NOTE: In clinical trials with patients experiencing complicated urinary tract infections (UTIs) due to P
aeruginosa, 12 of 16 patients had the microorganism eradicated from the urine after therapy with
lomefloxacin. None of the patients had concomitant bacteremia. Serum levels of lomefloxacin do not
reliably exceed the MIC of Pseudomonas isolates. THE SAFETY AND EFFICACY OF
LOMEFLOXACIN IN TREATING PATIENTS WITH PSEUDOMONAS BACTEREMIA HAVE
NOT BEEN ESTABLISHED.
*Although treatment of infections due to this microorganism in this organ system demonstrated a
clinically acceptable overall outcome, efficacy was studied in fewer than 10 infections.
Appropriate culture and susceptibility tests should be performed before antimicrobial treatment in order
to isolate and identify microorganisms causing infection and to determine their susceptibility to
lomefloxacin. In patients with UTIs, therapy with Maxaquin film-coated tablets may be initiated before
results of these tests are known; once these results become available, appropriate therapy should be
continued. In patients with an acute bacterial exacerbation of chronic bronchitis, therapy should not be
started empirically with lomefloxacin when there is a probability the causative pathogen is S
pneumoniae.
Beta-lactamase production should have no effect on lomefloxacin activity.
Prevention / prophylaxis:
Maxaquin is indicated preoperatively for the prevention of infection in the following situations:
• Transrectal prostate biopsy: to reduce the incidence of urinary tract infection, in the early and late
postoperative periods (3-5 days and 3-4 weeks postsurgery).
• Transurethral surgical procedures: to reduce the incidence of urinary tract infection in the early
postoperative period (3-5 days postsurgery).
Efficacy in decreasing the incidence of infections other than urinary tract infection has not been
established. Maxaquin, like all drugs for prophylaxis of transurethral surgical procedures, usually should
not be used in minor urologic procedures for which prophylaxis is not indicated (eg, simple cystoscopy
or retrograde pyelography). (See Dosage and Administration.)
CONTRAINDICATIONS
Maxaquin (lomefloxacin HCl) is contraindicated in persons with a history of hypersensitivity to
lomefloxacin or any member of the quinolone group of antimicrobial agents.
WARNINGS
MODERATE TO SEVERE PHOTOTOXIC REACTIONS HAVE OCCURRED IN
PATIENTS EXPOSED TO DIRECT OR INDIRECT SUNLIGHT OR TO ARTIFICIAL
ULTRAVIOLET LIGHT (eg, sunlamps) DURING OR FOLLOWING TREATMENT WITH
LOMEFLOXACIN. THESE REACTIONS HAVE ALSO OCCURRED IN PATIENTS
EXPOSED TO SHADED OR DIFFUSE LIGHT, INCLUDING EXPOSURE THROUGH
GLASS. PATIENTS SHOULD BE ADVISED TO DISCONTINUE LOMEFLOXACIN
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THERAPY AT THE FIRST SIGNS OR SYMPTOMS OF A PHOTOTOXICITY REACTION
SUCH AS A SENSATION OF SKIN BURNING, REDNESS, SWELLING, BLISTERS,
RASH, ITCHING, OR DERMATITIS.
These phototoxic reactions have occurred with and without the use of sunscreens or
sunblocks. Single doses of lomefloxacin have been associated with these types of reactions.
In a few cases, recovery was prolonged for several weeks. As with some other types of
phototoxicity, there is the potential for exacerbation of the reaction on re-exposure to
sunlight or artificial ultraviolet light prior to complete recovery from the reaction. In rare
cases, reactions have recurred up to several weeks after stopping lomefloxacin therapy.
EXPOSURE TO DIRECT OR INDIRECT SUNLIGHT (EVEN WHEN USING
SUNSCREENS OR SUNBLOCKS) SHOULD BE AVOIDED WHILE TAKING
LOMEFLOXACIN
AND
FOR
SEVERAL
DAYS
FOLLOWING
THERAPY.
LOMEFLOXACIN THERAPY SHOULD BE DISCONTINUED IMMEDIATELY AT THE
FIRST SIGNS OR SYMPTOMS OF PHOTOTOXICITY. RISK OF PHOTOTOXICITY
MAY BE REDUCED BY TAKING LOMEFLOXACIN IN THE EVENING (See Dosage and
Administration.)
THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN PEDIATRIC PATIENTS AND
ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND
LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS—
Pediatric Use, Pregnancy and Nursing Mothers subsections.) The oral administration of multiple
doses of lomefloxacin to juvenile dogs at 0.3 times and to rats at 5.4 times the recommended adult
human dose based on mg/m2 (0.6 and 34 times the recommended adult human dose based on mg/kg,
respectively) caused arthropathy and lameness. Histopathologic examination of the weight-bearing joints
of these animals revealed permanent lesions of the cartilage. Other quinolones also produce erosions of
cartilage of weight-bearing joints and other signs of arthropathy in juvenile animals of various species.
(See Animal Pharmacology.)
Convulsions have been reported in patients receiving lomefloxacin. Whether the convulsions
were directly related to lomefloxacin administration has not yet been established. However, convulsions,
increased intracranial pressure, and toxic psychoses have been reported in patients receiving other
quinolones. Nevertheless, lomefloxacin has been associated with a possible increased risk of seizures
compared to other quinolones. Some of these may occur with a relative absence of predisposing
factors. Quinolones may also cause central nervous system (CNS) stimulation, which may lead to
tremors, restlessness, lightheadedness, confusion, and hallucinations. If any of these reactions occurs in
patients receiving lomefloxacin, the drug should be discontinued and appropriate measures instituted.
However, until more information becomes available, lomefloxacin, like all other quinolones, should be
used with caution in patients with known or suspected CNS disorders, such as severe cerebral
arteriosclerosis, epilepsy, or other factors that predispose to seizures. (See Adverse Reactions.)
Psychiatric disturbances, agitation, anxiety, and sleep disorders may be more common with lomefloxacin
than other products in the quinolone class.
The safety and efficacy of lomefloxacin in the treatment of acute bacterial exacerbation of chronic
bronchitis due to S pneumoniae have not been demonstrated. This product should not be used
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empirically in the treatment of acute bacterial exacerbation of chronic bronchitis when it is probable that
S pneumoniae is a causative pathogen.
In clinical trials of complicated UTIs due to P aeruginosa, 12 of 16 patients had the microorganism
eradicated from the urine after therapy with lomefloxacin. No patients had concomitant bacteremia.
Serum levels of lomefloxacin do not reliably exceed the MIC of Pseudomonas isolates. THE SAFETY
AND EFFICACY OF LOMEFLOXACIN IN TREATING PATIENTS WITH PSEUDOMONAS
BACTEREMIA HAVE NOT BEEN ESTABLISHED.
Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions, some following
the first dose, have been reported in patients receiving quinolone therapy. Some reactions were
accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema,
dyspnea, urticaria, or itching. Only a few of these patients had a history of previous hypersensitivity
reactions. Serious hypersensitivity reactions have also been reported following treatment with
lomefloxacin. If an allergic reaction to lomefloxacin occurs, discontinue the drug. Serious acute
hypersensitivity reactions may require immediate emergency treatment with epinephrine. Oxygen,
intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including
intubation, should be administered as indicated.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
lomefloxacin, and may range from mild to life-threatening in severity. Therefore, it is
important to consider this diagnosis in patients who present with diarrhea subsequent to the
administration of antibacterial agents. Treatment with antimicrobial agents alters the normal flora of
the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by
Clostridium difficile is a primary cause of “antibiotic-associated colitis.” After the diagnosis of
pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of
pseudomembranous colitis usually respond to discontinuation of drug alone. In moderate to severe
cases, consideration should be given to management with fluids and electrolytes, protein
supplementation, and treatment with an antibacterial drug clinically effective against C difficile colitis.
Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in
prolonged disability have been reported with lomefloxacin. Lomefloxacin should be discontinued if the
patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from
exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. Tendon rupture
can occur at any time during or after therapy with lomefloxacin.
PRECAUTIONS
General:
Alteration of the dosage regimen is recommended for patients with impairment of renal function (ClCr <
40 mL/min/1.73 m2). (See Dosage and Administration.)
Information for patients:
Patients should be advised
• to avoid to the maximum extent possible direct or indirect sunlight (including exposure through glass
and exposure through sunscreens and sunblocks) and artificial ultraviolet light (eg, sunlamps) during
treatment with lomefloxacin and for several days after therapy;
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• that they may reduce the risk of developing phototoxicity from sunlight by taking the daily dose of
lomefloxacin at least 12 hours before exposure to the sun (eg, in the evening);
• to discontinue lomefloxacin therapy at the first signs or symptoms of phototoxicity reaction such as a
sensation of skin burning, redness, swelling, blisters, rash, itching, or dermatitis;
• that a patient who has experienced a phototoxic reaction should avoid re-exposure to sunlight and
artificial ultraviolet light until he has completely recovered from the reaction. In rare cases, reactions
have recurred up to several weeks after stopping lomefloxacin therapy.
• to drink fluids liberally;
• that lomefloxacin can be taken without regard to meals;
• that mineral supplements or vitamins with iron or minerals should not be taken within the 2-hour
period before or after taking lomefloxacin (see Drug Interactions);
• that sucralfate and antacids containing magnesium or aluminum, or Videx® (didanosine),
chewable/buffered tablets or the pediatric powder for oral solution should not be taken within 4
hours before or 2 hours after taking lomefloxacin. (See PRECAUTIONS — Drug Interactions.)
• that lomefloxacin can cause dizziness and lightheadedness and, therefore, patients should know how
they react to lomefloxacin before they operate an automobile or machinery or engage in activities
requiring mental alertness and coordination;
• to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture
of a tendon, and to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture
has been confidently excluded;
• that lomefloxacin may be associated with hypersensitivity reactions, even following the first dose,
and to discontinue the drug at the first sign of a skin rash or other allergic reaction;
• that convulsions have been reported in patients taking quinolones, including lomefloxacin, and to
notify their physician before taking this drug if there is a history of this condition.
Drug interactions:
Theophylline: In three pharmacokinetic studies including 46 normal, healthy subjects, theophylline
clearance and concentration were not significantly altered by the addition of lomefloxacin. In clinical
studies where patients were on chronic theophylline therapy, lomefloxacin had no measurable effect on
the mean distribution of theophylline concentrations or the mean estimates of theophylline clearance.
Though individual theophylline levels fluctuated, there were no clinically significant symptoms of drug
interaction.
Antacids and sucralfate: Sucralfate and antacids containing magnesium or aluminum, as well as
formulations containing divalent and trivalent cations such as Videx® (didanosine), chewable/buffered
tablets or the pediatric powder for oral solution can form chelation complexes with lomefloxacin and
interfere with its bioavailability. Sucralfate administered 2 hours before lomefloxacin resulted in a slower
absorption (mean Cmax decreased by 30% and mean Tmax increased by 1 hour) and a lesser extent of
absorption (mean AUC decreased by approximately 25%). Magnesium- and aluminum-containing
antacids, administered concomitantly with lomefloxacin, significantly decreased the bioavailability (48%)
of lomefloxacin. Separating the doses of antacid and lomefloxacin minimizes this decrease in
bioavailability; therefore, administration of these agents should precede lomefloxacin dosing by 4 hours
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or follow lomefloxacin dosing by at least 2 hours.
Caffeine: Two hundred mg of caffeine (equivalent to 1 to 3 cups of American coffee) was administered
to 16 normal, healthy volunteers who had achieved steady-state blood concentrations of lomefloxacin
after being dosed at 400 mg qd. This did not result in any statistically or clinically relevant changes in the
pharmacokinetic parameters of either caffeine or its major metabolite, paraxanthine. No data are
available on potential interactions in individuals who consume greater than 200 mg of caffeine per day or
in those, such as the geriatric population, who are generally believed to be more susceptible to the
development of drug-induced CNS-related adverse effects. Other quinolones have demonstrated
moderate to marked interference with the metabolism of caffeine, resulting in a reduced clearance, a
prolongation of plasma half-life, and an increase in symptoms that accompany high levels of caffeine.
Cimetidine: Cimetidine has been demonstrated to interfere with the elimination of other quinolones.
This interference has resulted in significant increases in half-life and AUC. The interaction between
lomefloxacin and cimetidine has not been studied.
Cyclosporine: Elevated serum levels of cyclosporine have been reported with concomitant use of
cyclosporine with other members of the quinolone class. Interaction between lomefloxacin and
cyclosporine has not been studied.
Omeprazole: No clinically significant changes in lomefloxacin pharmacokinetics (AUC, Cmax, or Tmax)
were observed when a single dose of lomefloxacin 400 mg was given after multiple doses of
omeprazole (20 mg qd) in 13 healthy volunteers. Changes in omeprazole pharmacokinetics were not
studied.
Phenytoin: No significant differences were observed in mean phenytoin AUC, Cmax, Cmin or Tmax
(although Cmax increased by 11%) when extended phenytoin sodium capsules (100 mg tid) were
coadministered with lomefloxacin (400 mg qd) for five days in 15 healthy males. Lomefloxacin is
unlikely to have a significant effect on phenytoin metabolism.
Probenecid: Probenecid slows the renal elimination of lomefloxacin. An increase of 63% in the mean
AUC and increases of 50% and 4%, respectively, in the mean Tmax and mean Cmax were noted in 1
study of 6 individuals.
Terfenadine: No clinically significant changes occurred in heart rate or corrected QT intervals, or in
terfenadine metabolite or lomefloxacin pharmacokinetics, during concurrent administration of
lomefloxacin and terfenadine at steady-state in 28 healthy males.
Warfarin: Quinolones may enhance the effects of the oral anticoagulant, warfarin, or its derivatives.
When these products are administered concomitantly, prothrombin or other suitable coagulation tests
should be monitored closely. However, no clinically or statistically significant differences in prothrombin
time ratio or warfarin enantiomer pharmacokinetics were observed in a small study of 7 healthy males
who received both warfarin and lomefloxacin under steady-state conditions.
Carcinogenesis, mutagenesis, impairment of fertility:
Carcinogenesis: Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two
weeks for up to 52 weeks while concurrently being administered lomefloxacin. The lomefloxacin doses
used in this study caused a phototoxic response. In mice treated with both UVA and lomefloxacin
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concomitantly, the time to development of skin tumors was 16 weeks. In mice treated concomitantly in
this model with both UVA and other quinolones, the times to development of skin tumors ranged from
28 to 52 weeks.
Ninety-two percent (92%) of the mice treated concomitantly with both UVA and lomefloxacin
developed well-differentiated squamous cell carcinomas of the skin. These squamous cell carcinomas
were nonmetastatic and were endophytic in character. Two-thirds of these squamous cell carcinomas
contained large central keratinous inclusion masses and were thought to arise from the vestigial hair
follicles in these hairless animals.
In this model, mice treated with lomefloxacin alone did not develop skin or systemic tumors.
There are no data from similar models using pigmented mice and/or fully haired mice.
The clinical significance of these findings to humans is unknown.
Mutagenesis: One in vitro mutagenicity test (CHO/HGPRT assay) was weakly positive at lomefloxacin
concentrations $ 226 µg/mL and negative at concentrations < 226 µg/mL. Two other in vitro
mutagenicity tests (chromosomal aberrations in Chinese hamster ovary cells, chromosomal aberrations
in human lymphocytes) and two in vivo mouse micronucleus mutagenicity tests were all negative.
Impairment of fertility: Lomefloxacin did not affect the fertility of male and female rats at oral doses
up to 8 times the recommended human dose based on mg/m2 (34 times the recommended human dose
based on mg/kg).
Pregnancy: Teratogenic effects. Pregnancy Category C.
Reproductive function studies have been performed in rats at doses up to 8 times the recommended
human dose based on mg/m2 (34 times the recommended human dose based on mg/kg), and no
impaired fertility or harm to the fetus was reported due to lomefloxacin. Increased incidence of fetal loss
in monkeys has been observed at approximately 3 to 6 times the recommended human dose based on
mg/m2 (6 to 12 times the recommended human dose based on mg/kg). No teratogenicity has been
observed in rats and monkeys at up to 16 times the recommended human dose exposure. In the rabbit,
maternal toxicity and associated fetotoxicity, decreased placental weight, and variations of the coccygeal
vertebrae occurred at doses 2 times the recommended human exposure based on mg/m2. There are,
however, no adequate and well-controlled studies in pregnant women. Lomefloxacin should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing mothers:
It is not known whether lomefloxacin is excreted in human milk. However, it is known that other drugs
of this class are excreted in human milk and that lomefloxacin is excreted in the milk of lactating rats.
Because of the potential for serious adverse reactions from lomefloxacin in nursing infants, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric use:
The safety and effectiveness of lomefloxacin in pediatric patients and adolescents less than 18 years of
age have not been established. Lomefloxacin causes arthropathy in juvenile animals of several species.
(See Warnings and Animal Pharmacology.)
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Geriatric use:
Of the total number of subjects in clinical studies of lomefloxacin, 25% were $65 years and 9% were
$75 years. No overall differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals cannot be
ruled out.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal
function. (See Clinical Pharmacology — Pharmacokinetics in the geriatric population.)
ADVERSE REACTIONS
In clinical trials, most of the adverse events reported were mild to moderate in severity and transient in
nature. During these clinical investigations, 5,623 patients received Maxaquin. In 2.2% of the patients,
lomefloxacin was discontinued because of adverse events, primarily involving the gastrointestinal system
(0.7%), skin (0.7%), or CNS (0.5%).
Adverse clinical events:
The events with the highest incidence ($1%) in patients, regardless of relationship to drug, were
headache (3.6%), nausea (3.5%), photosensitivity (2.3%) [see Warnings], dizziness (2.1%), diarrhea
(1.4%), and abdominal pain (1.2%).
Additional clinical events reported in < 1% of patients treated with Maxaquin, regardless of relationship
to drug, are listed below:
Autonomic: increased sweating, dry mouth, flushing, syncope.
Body as a whole: fatigue, back pain, malaise, asthenia, chest pain, face edema, hot flashes, influenza-
like symptoms, edema, chills, allergic reaction, anaphylactoid reaction, decreased heat tolerance.
Cardiovascular: tachycardia, hypertension, hypotension, myocardial infarction, angina pectoris,
cardiac failure, bradycardia, arrhythmia, phlebitis, pulmonary embolism, extrasystoles, cerebrovascular
disorder, cyanosis, cardiomyopathy.
Central and peripheral nervous system: tremor, vertigo, paresthesias, twitching, hypertonia,
convulsions, hyperkinesia, coma.
Gastrointestinal: dyspepsia, vomiting, flatulence, constipation, gastrointestinal bleeding, dysphagia,
stomatitis, tongue discoloration, gastrointestinal inflammation.
Hearing: earache, tinnitus.
Hematologic: purpura, lymphadenopathy, thrombocythemia, anemia, thrombocytopenia, increased
fibrinolysis.
Hepatic: abnormal liver function.
Metabolic: thirst, hyperglycemia, hypoglycemia, gout.
Musculoskeletal: arthralgia, myalgia, leg cramps.
Ophthalmologic: abnormal vision, conjunctivitis, photophobia, eye pain, abnormal lacrimation.
Psychiatric: insomnia, nervousness, somnolence, anorexia, depression, confusion, agitation, increased
appetite, depersonalization, paranoid reaction, anxiety, paroniria, abnormal thinking, concentration
impairment.
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Reproductive system: Female: vaginal moniliasis, vaginitis, leukorrhea, menstrual disorder, perineal
pain, intermenstrual bleeding. Male: epididymitis, orchitis.
Resistance mechanism: viral infection, moniliasis, fungal infection.
Respiratory: respiratory infection, rhinitis, pharyngitis, dyspnea, cough, epistaxis, bronchospasm,
respiratory disorder, increased sputum, stridor, respiratory depression.
Skin/Allergic: pruritus, rash, urticaria, skin exfoliation, bullous eruption, eczema, skin disorder, acne,
skin discoloration, skin ulceration, angioedema. (See also Body as a whole.)
Special senses: taste perversion.
Urinary: hematuria, micturition disorder, dysuria, strangury, anuria.
Adverse laboratory events:
Changes in laboratory parameters, listed as adverse events, without regard to drug relationship include:
Hematologic: monocytosis (0.2%), eosinophilia (0.1%), leukopenia (0.1%), leukocytosis (0.1%).
Renal: elevated BUN (0.1%), decreased potassium (0.1%), increased creatinine (0.1%).
Hepatic: elevations of ALT (SGPT) (0.4%), AST (SGOT) (0.3%), bilirubin (0.1%), alkaline
phosphatase (0.1%).
Additional laboratory changes occurring in < 0.1% in the clinical studies included: elevation of serum
gamma glutamyl transferase, decrease in total protein or albumin, prolongation of prothrombin time,
anemia, decrease in hemoglobin, thrombocythemia, thrombocytopenia, abnormalities of urine specific
gravity or serum electrolytes, increased albumin, elevated ESR, albuminuria, macrocytosis.
Quinolone-class adverse events:
Post-marketing adverse events: Adverse events reported from worldwide marketing experience with
lomefloxacin are: anaphylaxis, cardiopulmonary arrest, laryngeal or pulmonary edema, ataxia, cerebral
thrombosis, hallucinations, painful oral mucosa, pseudomembranous colitis, hemolytic anemia, hepatitis,
tendinitis, diplopia, photophobia, phobia, exfoliative dermatitis, hyperpigmentation, Stevens-Johnson
syndrome, toxic epidermal necrolysis, dysgeusia, interstitial nephritis, polyuria, renal failure, urinary
retention, and vasculitis.
Quinolone-class adverse events: Additional quinolone-class adverse events include: erythema
nodosum, hepatic necrosis, possible exacerbation of myasthenia gravis, dysphasia, nystagmus, intestinal
perforation, manic reaction, renal calculi, acidosis and hiccough.
Laboratory adverse events include: agranulocytosis, elevation of serum triglycerides, elevation of serum
cholesterol, elevation of blood glucose, elevation of serum potassium, albuminuria, candiduria, and
crystalluria.
OVERDOSAGE
Information on overdosage in humans is limited. In the event of acute overdosage, the stomach should
be emptied by inducing vomiting or by gastric lavage, and the patient should be carefully observed and
given supportive treatment. Adequate hydration must be maintained. Hemodialysis or peritoneal dialysis
is unlikely to aid in the removal of lomefloxacin as < 3% is removed by these modalities.
Clinical signs of acute toxicity in rodents progressed from salivation to tremors, decreased activity,
dyspnea, and clonic convulsions prior to death. These signs were noted in rats and mice as lomefloxacin
doses were increased.
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DOSAGE AND ADMINISTRATION
Maxaquin (lomefloxacin HCl) may be taken without regard to meals. Sucralfate and antacids containing
magnesium or aluminum, or Videx® (didanosine), chewable/buffered tablets or the pediatric powder for
oral solution should not be taken within 4 hours before or 2 hours after taking lomefloxacin. Risk of
reaction to solar UVA light may be reduced by taking Maxaquin at least 12 hours before exposure to
the sun (eg, in the evening). (See Clinical Pharmacology.)
See Indications and Usage for information on appropriate pathogens and patient populations.
Treatment:
Patients with normal renal function: The recommended daily dose of Maxaquin is described in the
following chart:
Unit
Daily
Infection
Dose
Frequency
Duration
Dose
Acute bacterial
exacerbation of
400 mg
qd
10 days
400 mg
chronic bronchitis
Uncomplicated cystitis
400 mg
qd
3 days
400 mg
in females caused by E coli
(see CLINICAL STUDIES—UNCOMPLICATED CYSTITIS.)
Uncomplicated cystitis
caused by K pneumoniae,
400 mg qd
10 days
400 mg
P mirabilis, or S saprophyticus
Complicated UTI
400 mg
qd
14 days
400 mg
Elderly patients: No dosage adjustment is needed for elderly patients with normal renal function (ClCr
$40 mL/min/1.73 m2).
Patients with impaired renal function: Lomefloxacin is primarily eliminated by renal excretion. (See
Clinical Pharmacology.) Modification of dosage is recommended in patients with renal dysfunction. In
patients with a creatinine clearance > 10 mL/min/1.73 m2 but < 40 mL/min/1.73 m2, the recommended
dosage is an initial loading dose of 400 mg followed by daily maintenance doses of 200 mg (1/2 tablet)
once daily for the duration of treatment. It is suggested that serial determinations of lomefloxacin levels
be performed to determine any necessary alteration in the appropriate next dosing interval.
If only the serum creatinine is known, the following formula may be used to estimate creatinine
clearance.
(weight in kg) x (140 - age)
Men:---------------------------------------------
(72) x serum creatinine (mg/dL)
Women:(0.85) x (calculated value for men)
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Dialysis patients: Hemodialysis removes only a negligible amount of lomefloxacin (3% in 4 hours).
Hemodialysis patients should receive an initial loading dose of 400 mg followed by daily maintenance
doses of 200 mg (1/2 tablet) once daily for the duration of treatment.
Patients with cirrhosis: Cirrhosis does not reduce the nonrenal clearance of lomefloxacin. The need
for a dosage reduction in this population should be based on the degree of renal function of the patient
and on the plasma concentrations. (See Clinical Pharmacology and Dosage and Administration—
Patients with impaired renal function.)
Prevention / prophylaxis:
The recommended dose of Maxaquin is described in the following chart:
Procedure
Dose
Oral Administration
Transrectal
400 mg
1-6 hours prior to
prostate
single dose
procedure
biopsy
Transurethral
400 mg
2-6 hours prior to
surgical
single dose
procedure
procedures*
*When preoperative prophylaxis is considered appropriate.
HOW SUPPLIED
Maxaquin (lomefloxacin HCl) is supplied as a scored, film-coated tablet containing the equivalent of
400 mg of lomefloxacin base present as the hydrochloride. The tablet is oval, white, and film-coated
with “MAXAQUIN 400” debossed on one side and scored on the other side and is supplied in:
NDC Number Size
0051-1651-02 bottle of 20
0051-1651-32 carton of 100 unit dose
Store at 59° to 77°F (15° to 25°C).
CLINICAL STUDIES—UNCOMPLICATED CYSTITIS
In three controlled clinical studies of uncomplicated cystitis in females, two performed in the United
States and one in Canada, lomefloxacin was compared to other oral antimicrobial agents. In these
studies, using very strict evaluability criteria and microbiological criteria at 5-9 days post-therapy follow-
up, the following bacterial eradication outcomes were obtained:
STUDIES 1, 2, AND 3
U.S. AND CANADIAN STUDIES
Trimethoprim/
Lomefloxacin
Norfloxacin
Ofloxacin
sulfamethoxazole
3-Day Treatment
3-Day Treatment 3-Day Treatment 10-Day Treatment
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E coli
133/135 (99%)
36/39 (92%)
65/67 (97%)
33/34 (97%)
K pneumoniae
7/7 (100%)
2/2 (100%)
4/4 (100%)
2/2 (100%)
P mirabilis
8/8 (100%)
1/1 (100%)
2/2 (100%)
1/1 (100%)
S saprophyticus
11/11 (100%)
3/3 (100%)
1/1 (100%)
0/0
STUDY 4
In a controlled clinical study of uncomplicated cystitis performed in Sweden, lomefloxacin 3-day
treatment was compared with lomefloxacin 7-day treatment and norfloxacin 7-day treatment. In
this study, using very strict evaluability criteria and microbiological criteria at 5-9 days post-
therapy follow-up, the following bacterial eradication outcomes were obtained:
SWEDISH STUDY
Lomefloxacin
Lomefloxacin
Norfloxacin
3-Day Treatment
7-Day Treatment
7-Day Treatment
E coli
101/109 (93%)
102/104 (98%)
108/110 (98%)
K pneumoniae
2/2 (100%)
5/5 (100%)
1/1 (100%)
P mirabilis
0/0
6/6 (100%)
4/4 (100%)
S saprophyticus
11/17 (65%)
23/23 (100%)
16/16 (100%)
ANIMAL PHARMACOLOGY
Lomefloxacin and other quinolones have been shown to cause arthropathy in juvenile animals.
Arthropathy, involving multiple diarthrodial joints, was observed in juvenile dogs administered
lomefloxacin at doses as low as 4.5 mg/kg for 7 to 8 days (0.3 times the recommended human dose
based on mg/m2 or 0.6 times the recommended human dose based on mg/kg). In juvenile rats, no
changes were observed in the joints with doses up to 91 mg/kg for 7 days (2 times the recommended
human dose based on mg/m2 or 11 times the recommended human dose based on mg/kg). (See
Warnings.)
In a 13-week oral rat study, gamma globulin decreased when lomefloxacin was administered at less
than the recommended human exposure. Beta globulin decreased when lomefloxacin was administered
at 0.6 to 2 times the recommended human dose based on mg/m2. The A/G ratio increased when
lomefloxacin was administered at 6 to 20 times the human dose. Following a 4-week recovery period,
beta globulins in the females and A/G ratios in the females returned to control values. Gamma globulin
values in the females and beta and gamma globulins and A/G ratios in the males were still statistically
significantly different from control values. No effects on globulins were seen in oral studies in dogs or
monkeys in the limited number of specimens collected.
Twenty-seven NSAIDs, administered concomitantly with lomefloxacin, were tested for seizure induction
in mice at approximately 2 times the recommended human dose based on mg/m2. At a dose of
lomefloxacin equivalent to the recommended human exposure based on mg/m2 (10 times the human
dose based on mg/kg), only fenbufen, when coadministered, produced an increase in seizures.
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Crystalluria and ocular toxicity, seen with some related quinolones, were not observed in any
lomefloxacin-treated animals, either in studies designed to look for these effects specifically or in
subchronic and chronic toxicity studies in rats, dogs, and monkeys.
Long-term, high-dose systemic use of other quinolones in experimental animals has caused lenticular
opacities; however, this finding was not observed with lomefloxacin.
REFERENCES
1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth Edition. NCCLS
Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000. 2. National Committee for
Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests;
Approved Standard-Seventh Edition. NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne,
PA, January, 2000.
Rx only
XX/XX/00
Manufactured for
Unimed Pharmaceuticals, Inc.
Buffalo Grove IL 60089
by Searle & Co.
San Juan PR 00936
Address medical inquiries to:
Unimed Pharmaceuticals, Inc.
2150 E. Lake Cook Road
Buffalo Grove IL 60089
Maxaquin is a registered trademark of G.D. Searle & Co.
©1999, Unimed Pharmaceuticals, Inc.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
--------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Renata Albrecht
10/24/01 06:59:50 PM
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|
custom-source
|
2025-02-12T13:46:27.330809
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20013s8lbl.pdf', 'application_number': 20013, 'submission_type': 'SUPPL ', 'submission_number': 8}
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12,140
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Maxaquin®
lomefloxacin hydrochloride tablets
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Maxaquin and other antibacterial drugs, Maxaquin should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
Maxaquin (lomefloxacin HCl) is a synthetic broad-spectrum antimicrobial agent for oral
administration. Lomefloxacin HCl, a difluoroquinolone, is the monohydrochloride salt of
(±)-1-ethyl-6, 8-difluoro-1, 4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-
quinolinecarboxylic acid. Its empirical formula is C17H19F2N3O3·HCl, and its structural
formula is:
Lomefloxacin HCl is a white to pale yellow powder with a molecular weight of
387.8. It is slightly soluble in water and practically insoluble in alcohol. Lomefloxacin HCl is
stable to heat and moisture but is sensitive to light in dilute aqueous solution.
Maxaquin is available as a film-coated tablet formulation containing 400 mg of
lomefloxacin base, present as the hydrochloride salt. The base content of the hydrochloride
salt is 90.6%. The inactive ingredients are carboxymethylcellulose calcium, hydroxypropyl
cellulose, hypromellose, lactose, magnesium stearate, polyethylene glycol, polyoxyl
40 stearate, and titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacokinetics in healthy volunteers: In 6 fasting healthy male volunteers, approximately
95% to 98% of a single oral dose of lomefloxacin was absorbed. Absorption was rapid
following single doses of 200 and 400 mg (Tmax 0.8 to 1.4 hours). Mean plasma concentration
increased proportionally between 100 and 400 mg as shown below:
Dose (mg)
Mean Peak Plasma
Concentration
(µg/mL)
Area Under Curve
(AUC)
(µg·h/mL)
100
0.8
5.6
200
1.4
10.9
400
3.2
26.1
In 6 healthy male volunteers administered 400 mg of lomefloxacin on an empty stomach qd
for 7 days, the following mean pharmacokinetic parameter values were obtained:
Cmax
2.8 µg/mL
Cmin
0.27 µg/mL
AUC0 –24 h
25.9 µg·h/mL
Tmax
1.5 h
t1/2
7.75 h
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The elimination half-life in 8 subjects with normal renal function was approximately 8 hours.
At 24 hours postdose, subjects with normal renal function receiving single doses of 200 or
400 mg had mean plasma lomefloxacin concentrations of 0.10 and 0.24 µg/mL, respectively.
Steady-state concentrations were achieved within 48 hours of initiating therapy with one-a-
day dosing. There was no drug accumulation with single-daily dosing in patients with normal
renal function.
Approximately 65% of an orally administered dose was excreted in the urine as
unchanged drug in patients with normal renal function. Following a 400-mg dose of
lomefloxacin administered qd for 7 days, the mean urine concentration 4 hours postdose was
in excess of 300 µg/mL. The mean urine concentration exceeded 35 µg/mL for at least 24
hours after dosing.
Following a single 400-mg dose, the solubility of lomefloxacin in urine usually
exceeded its peak urinary concentration 2- to 6-fold. In this study, urine pH affected the
solubility of lomefloxacin with solubilities ranging from 7.8 mg/mL at pH 5.2, to 2.4 mg/mL
at pH 6.5, and 3.03 mg/mL at pH 8.12.
The urinary excretion of lomefloxacin was virtually complete within 72 hours after
cessation of dosing, with approximately 65% of the dose being recovered as parent drug and
9% as its glucuronide metabolite. The mean renal clearance was 145 mL/min in subjects with
normal renal function (GFR = 120 mL/min). This may indicate tubular secretion.
Food effect: When lomefloxacin and food were administered concomitantly, the rate of drug
absorption was delayed (Tmax increased to 2 hours [delayed by 41%], Cmax decreased by
18%), and the extent of absorption (AUC) was decreased by 12%.
Pharmacokinetics in the geriatric population: In 16 healthy elderly volunteers (61 to 76
years of age) with normal renal function for their age, the half-life of lomefloxacin (mean of
8 hours) and its peak plasma concentration (mean of 4.2 µg/mL) following a single 400-mg
dose were similar to those in 8 younger subjects dosed with a single 400-mg dose. Thus, drug
absorption appears unaffected in the elderly. Plasma clearance was, however, reduced in this
elderly population by approximately 25%, and the AUC was increased by approximately
33%. This slower elimination most likely reflects the decreased renal function normally
observed in the geriatric population.
Pharmacokinetics in renally impaired patients: In 8 patients with creatinine clearance (ClCr)
between 10 and 40 mL/min/1.73 m2, the mean AUC after a single 400-mg dose of
lomefloxacin increased 335% over the AUC demonstrated in patients with a ClCr >80
mL/min/1.73 m2. Also, in these patients, the mean t1/2 increased to 21 hours. In 8 patients
with ClCr <10 mL/min/1.73 m2, the mean AUC after a single 400-mg dose of lomefloxacin
increased 700% over the AUC demonstrated in patients with a ClCr >80 mL/min/1.73 m2. In
these patients with ClCr <10 mL/min/1.73 m2, the mean t1/2 increased to 45 hours. The plasma
clearance of lomefloxacin was closely correlated with creatinine clearance, ranging from 31
mL/min/1.73 m2 when creatinine clearance was zero to 271 mL/min/1.73 m2 at a normal
creatinine clearance of 110 mL/min/1.73 m2. Peak lomefloxacin concentrations were not
affected by the degree of renal function when single doses of lomefloxacin were
administered. Adjustment of dosage schedules for patients with such decreases in renal
function is warranted. (See Dosage and Administration.)
Pharmacokinetics in patients with cirrhosis: In 12 patients with histologically confirmed
cirrhosis, no significant changes in rate or extent of lomefloxacin exposure (Cmax, Tmax, t1/2,
or AUC) were observed when they were administered 400 mg of lomefloxacin as a single
dose. No data are available in cirrhotic patients treated with multiple doses of lomefloxacin.
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Cirrhosis does not appear to reduce the non-renal clearance of lomefloxacin. There does not
appear to be a need for a dosage reduction in cirrhotic patients, provided adequate renal
function is present.
Metabolism and pharmacodynamics of lomefloxacin: Lomefloxacin is minimally
metabolized although 5 metabolites have been identified in human urine. The glucuronide
metabolite is found in the highest concentration and accounts for approximately 9% of the
administered dose. The other 4 metabolites together account for <0.5% of the dose.
Approximately 10% of an oral dose was recovered as unchanged drug in the feces.
Serum protein binding of lomefloxacin is approximately 10%.
The following are mean tissue- or fluid-to-plasma ratios of lomefloxacin following
oral administration. Studies have not been conducted to assess the penetration of
lomefloxacin into human cerebrospinal fluid.
Tissue or Body Fluid
Mean Tissue- or Fluid-
to-Plasma Ratio
Bronchial mucosa
2.1
Bronchial secretions
0.6
Prostatic tissue
2.0
Sputum
1.3
Urine
140.0
In two studies including 74 healthy volunteers, the minimal dose of UVA light needed to
cause erythema (MED-UVA) was inversely proportional to plasma lomefloxacin
concentration. The MED-UVA values (16 hours and 12 hours postdose) were significantly
higher than the MED-UVA values 2 hours postdose at steady state. Increasing the interval
between lomefloxacin dosing and exposure to UVA light increased the amount of light
energy needed for photoreaction. In a study of 27 healthy volunteers, the steady state AUC
values and Cmin values were equivalent whether the drug was administered in the morning or
in the evening.
Microbiology: Lomefloxacin is a bactericidal agent with in vitro activity against a wide range
of gram-negative and gram-positive organisms. The bactericidal action of lomefloxacin
results from interference with the activity of the bacterial enzyme DNA gyrase, which is
needed for the transcription and replication of bacterial DNA. The minimum bactericidal
concentration (MBC) generally does not exceed the minimum inhibitory concentration (MIC)
by more than a factor of 2, except for staphylococci, which usually have MBCs 2 to 4 times
the MIC.
Lomefloxacin has been shown to be active against most strains of the following
organisms both in vitro and in clinical infections: (See Indications and Usage.)
Gram-positive aerobes
Staphylococcus saprophyticus
Gram-negative aerobes
Citrobacter diversus
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
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Pseudomonas aeruginosa (urinary tract only—See Indications and Usage and
Warnings)
The following in vitro data are available; however, their clinical significance is
unknown.
Lomefloxacin exhibits in vitro MICs of 2 µg/mL or less against most strains of the
following organisms; however, the safety and effectiveness of lomefloxacin in treating
clinical infections due to these organisms have not been established in adequate and well-
controlled trials:
Gram-positive aerobes
Staphylococcus aureus (including methicillin-resistant strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
Gram-negative aerobes
Aeromonas hydrophila
Citrobacter freundii
Enterobacter aerogenes
Enterobacter agglomerans
Haemophilus parainfluenzae
Hafnia alvei
Klebsiella oxytoca
Klebsiella ozaenae
Morganella morganii
Proteus vulgaris
Providencia alcalifaciens
Providencia rettgeri
Serratia liquefaciens
Serratia marcescens
Other organisms:
Legionella pneumophila
Beta-lactamase production should have no effect on the in vitro activity of
lomefloxacin. Most group A, B, D, and G streptococci, Streptococcus pneumoniae,
Pseudomonas cepacia, Ureaplasma urealyticum, Mycoplasma hominis, and anaerobic
bacteria are resistant to lomefloxacin.
Lomefloxacin appears slightly less active in vitro when tested at acidic pH. An
increase in inoculum size has little effect on the in vitro activity of lomefloxacin. In vitro
resistance to lomefloxacin develops slowly (multiple-step mutation). Rapid one-step
development of resistance occurs only rarely (<10–9) in vitro.
Cross-resistance between lomefloxacin and other quinolone-class antimicrobial
agents has been reported; however, cross-resistance between lomefloxacin and members of
other classes of antimicrobial agents, such as aminoglycosides, penicillins, tetracyclines,
cephalosporins, or sulfonamides has not yet been reported. Lomefloxacin is active in vitro
against some strains of cephalosporin- and aminoglycoside-resistant gram-negative bacteria.
Susceptibility tests
Diffusion techniques: Quantitative methods that require measurement of zone diameters give
the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such
standardized procedure1 that has been recommended for use with disks to test the
susceptibility of organisms to lomefloxacin uses the 10-µg lomefloxacin disk. Interpretation
involves correlation of the diameter obtained in the disk test with the MIC for lomefloxacin.
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Reports from the laboratory giving results of the standard single-disk susceptibility
test with a 10-µg lomefloxacin disk should be interpreted according to the following criteria:
Zone Diameter (mm)
Interpretation
≥22
Susceptible (S)
19 –21
Intermediate (I)
≤18
Resistant (R)
A report of “susceptible” indicates that the pathogen is likely to be inhibited by generally
achievable drug concentrations. A report of “intermediate” indicates that the result should be
considered equivocal, and, if the organism is not fully susceptible to alternative clinically
feasible drugs, the test should be repeated. This category provides a buffer zone that prevents
small uncontrolled technical factors from causing major discrepancies in interpretation. A
report of “resistant” indicates that achievable drug concentrations are unlikely to be
inhibitory, and other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control
organisms. The 10-µg lomefloxacin disk should give the following zone diameters:
Organism
Zone Diameter (mm)
S aureus (ATCC 25923)
23 –29
E coli (ATCC 25922)
27 –33
P aeruginosa (ATCC 27853)
22 –28
Dilution techniques: Use a standardized dilution method2 (broth, agar, or microdilution) or
equivalent with lomefloxacin powder. The MIC values obtained should be interpreted
according to the following criteria:
MIC (µg/mL)
Interpretation
≤2
Susceptible (S)
4
Intermediate (I)
≥8
Resistant (R)
As with standard diffusion techniques, dilution methods require the use of laboratory control
organisms. Standard lomefloxacin powder should provide the following MIC values:
Organism
MIC (µg/mL)
S aureus (ATCC 29213)
0.25–2.0
E coli (ATCC 25922)
0.03–0.12
P aeruginosa (ATCC 27853)
1.0–4.0
INDICATIONS AND USAGE
Treatment:
Maxaquin (lomefloxacin HCl) film-coated tablets are indicated for the treatment of adults
with mild to moderate infections caused by susceptible strains of the designated micro-
organisms in the conditions listed below: (See Dosage and Administration for specific
dosing recommendations.)
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LOWER RESPIRATORY TRACT
Acute Bacterial Exacerbation of Chronic Bronchitis caused by Haemophilus influenzae or
Moraxella catarrhalis.*
NOTE: MAXAQUIN IS NOT INDICATED FOR THE EMPIRIC TREATMENT OF
ACUTE BACTERIAL EXACERBATION OF CHRONIC BRONCHITIS WHEN IT IS
PROBABLE THAT S PNEUMONIAE IS A CAUSATIVE PATHOGEN. S PNEUMONIAE
EXHIBITS IN VITRO RESISTANCE TO LOMEFLOXACIN, AND THE SAFETY AND
EFFICACY OF LOMEFLOXACIN IN THE TREATMENT OF PATIENTS WITH ACUTE
BACTERIAL EXACERBATION OF CHRONIC BRONCHITIS CAUSED BY S
PNEUMONIAE HAVE NOT BEEN DEMONSTRATED. IF LOMEFLOXACIN IS TO BE
PRESCRIBED FOR GRAM-STAIN–GUIDED EMPIRIC THERAPY OF ACUTE
BACTERIAL EXACERBATION OF CHRONIC BRONCHITIS, IT SHOULD BE USED
ONLY IF SPUTUM GRAM STAIN DEMONSTRATES AN ADEQUATE QUALITY OF
SPECIMEN (>25 PMNs/LPF) AND THERE IS BOTH A PREDOMINANCE OF GRAM-
NEGATIVE MICROORGANISMS AND NOT A PREDOMINANCE OF GRAM-
POSITIVE MICROORGANISMS.
URINARY TRACT
Uncomplicated Urinary Tract Infections (cystitis) caused by Escherichia coli, Klebsiella
pneumoniae, Proteus mirabilis or Staphylococcus saprophyticus. (See DOSAGE AND
ADMINISTRATION and CLINICAL STUDIES—UNCOMPLICATED CYSTITIS.)
Complicated Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae,
Proteus mirabilis, Pseudomonas aeruginosa, Citrobacter diversus,* or Enterobacter
cloacae.*
NOTE: In clinical trials with patients experiencing complicated urinary tract infections
(UTIs) due to P aeruginosa, 12 of 16 patients had the microorganism eradicated from the
urine after therapy with lomefloxacin. None of the patients had concomitant bacteremia.
Serum levels of lomefloxacin do not reliably exceed the MIC of Pseudomonas isolates. THE
SAFETY AND EFFICACY OF LOMEFLOXACIN IN TREATING PATIENTS WITH
PSEUDOMONAS BACTEREMIA HAVE NOT BEEN ESTABLISHED.
*Although treatment of infections due to this microorganism in this organ system
demonstrated a clinically acceptable overall outcome, efficacy was studied in fewer than 10
infections.
Appropriate culture and susceptibility tests should be performed before antimicrobial
treatment in order to isolate and identify microorganisms causing infection and to determine
their susceptibility to lomefloxacin. In patients with UTIs, therapy with Maxaquin film-
coated tablets may be initiated before results of these tests are known; once these results
become available, appropriate therapy should be continued. In patients with an acute
bacterial exacerbation of chronic bronchitis, therapy should not be started empirically with
lomefloxacin when there is a probability the causative pathogen is S pneumoniae.
Beta-lactamase production should have no effect on lomefloxacin activity.
Prevention /prophylaxis:
Maxaquin is indicated preoperatively for the prevention of infection in the following
situations:
•
Transrectal prostate biopsy: to reduce the incidence of urinary tract infection, in the early
and late postoperative periods (3–5 days and 3–4 weeks postsurgery).
•
Transurethral surgical procedures: to reduce the incidence of urinary tract infection in the
early postoperative period (3–5 days postsurgery).
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Efficacy in decreasing the incidence of infections other than urinary tract infection has not
been established. Maxaquin, like all drugs for prophylaxis of transurethral surgical
procedures, usually should not be used in minor urologic procedures for which prophylaxis is
not indicated (eg, simple cystoscopy or retrograde pyelography). (See Dosage and
Administration.)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Maxaquin and other antibacterial drugs, Maxaquin should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by susceptible bacteria. When
culture and susceptibility information are available, they should be considered in selecting or
modifying antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
Maxaquin (lomefloxacin HCl) is contraindicated in persons with a history of hypersensitivity
to lomefloxacin or any member of the quinolone group of antimicrobial agents.
WARNINGS
MODERATE TO SEVERE PHOTOTOXIC REACTIONS HAVE OCCURRED IN
PATIENTS EXPOSED TO DIRECT OR INDIRECT SUNLIGHT OR TO
ARTIFICIAL ULTRAVIOLET LIGHT (eg, sunlamps) DURING OR FOLLOWING
TREATMENT WITH LOMEFLOXACIN. THESE REACTIONS HAVE ALSO
OCCURRED IN PATIENTS EXPOSED TO SHADED OR DIFFUSE LIGHT,
INCLUDING EXPOSURE THROUGH GLASS. PATIENTS SHOULD BE ADVISED
TO DISCONTINUE LOMEFLOXACIN THERAPY AT THE FIRST SIGNS OR
SYMPTOMS OF A PHOTOTOXICITY REACTION SUCH AS A SENSATION OF
SKIN BURNING, REDNESS, SWELLING, BLISTERS, RASH, ITCHING, OR
DERMATITIS.
These phototoxic reactions have occurred with and without the use of sunscreens
or sunblocks. Single doses of lomefloxacin have been associated with these types
of reactions. In a few cases, recovery was prolonged for several weeks. As with
some other types of phototoxicity, there is the potential for exacerbation of the
reaction on re-exposure to sunlight or artificial ultraviolet light prior to
complete recovery from the reaction. In rare cases, reactions have recurred up
to several weeks after stopping lomefloxacin therapy.
EXPOSURE TO DIRECT OR INDIRECT SUNLIGHT (EVEN WHEN USING
SUNSCREENS OR SUNBLOCKS) SHOULD BE AVOIDED WHILE TAKING
LOMEFLOXACIN AND FOR SEVERAL DAYS FOLLOWING THERAPY.
LOMEFLOXACIN THERAPY SHOULD BE DISCONTINUED IMMEDIATELY AT
THE FIRST SIGNS OR SYMPTOMS OF PHOTOTOXICITY. RISK OF
PHOTOTOXICITY MAY BE REDUCED BY TAKING LOMEFLOXACIN IN THE
EVENING (See Dosage and Administration.)
THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN PEDIATRIC PATIENTS
AND ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN,
AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See
PRECAUTIONS —Pediatric Use, Pregnancy and Nursing Mothers subsections.) The
oral administration of multiple doses of lomefloxacin to juvenile dogs at 0.3 times and to rats
at 5.4 times the recommended adult human dose based on mg/m2 (0.6 and 34 times the
recommended adult human dose based on mg/kg, respectively) caused arthropathy and
lameness. Histopathologic examination of the weight-bearing joints of these animals revealed
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permanent lesions of the cartilage. Other quinolones also produce erosions of cartilage of
weight-bearing joints and other signs of arthropathy in juvenile animals of various species.
(See Animal Pharmacology.)
Convulsions have been reported in patients receiving lomefloxacin. Whether the
convulsions were directly related to lomefloxacin administration has not yet been established.
However, convulsions, increased intracranial pressure, and toxic psychoses have been
reported in patients receiving other quinolones. Nevertheless, lomefloxacin has been
associated with a possible increased risk of seizures compared to other quinolones. Some of
these may occur with a relative absence of predisposing factors. Quinolones may also cause
central nervous system (CNS) stimulation, which may lead to tremors, restlessness,
lightheadedness, confusion, and hallucinations. If any of these reactions occurs in patients
receiving lomefloxacin, the drug should be discontinued and appropriate measures instituted.
However, until more information becomes available, lomefloxacin, like all other quinolones,
should be used with caution in patients with known or suspected CNS disorders, such as
severe cerebral arteriosclerosis, epilepsy, or other factors that predispose to seizures. (See
Adverse Reactions.) Psychiatric disturbances, agitation, anxiety, and sleep disorders may be
more common with lomefloxacin than other products in the quinolone class.
The safety and efficacy of lomefloxacin in the treatment of acute bacterial
exacerbation of chronic bronchitis due to pneumoniae have not been demonstrated. This
product should not be used empirically in the treatment of acute bacterial exacerbation of
chronic bronchitis when it is probable that S pneumoniae is a causative pathogen.
In clinical trials of complicated UTIs due to P aeruginosa, 12 of 16 patients had the
microorganism eradicated from the urine after therapy with lomefloxacin. No patients had
concomitant bacteremia. Serum levels of lomefloxacin do not reliably exceed the MIC of
Pseudomonas isolates. THE SAFETY AND EFFICACY OF LOMEFLOXACIN IN
TREATING PATIENTS WITH PSEUDOMONAS BACTEREMIA HAVE NOT BEEN
ESTABLISHED.
Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic)
reactions, some following the first dose, have been reported in patients receiving quinolone
therapy. Some reactions were accompanied by cardiovascular collapse, loss of
consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, or itching. Only a
few of these patients had a history of previous hypersensitivity reactions. Serious
hypersensitivity reactions have also been reported following treatment with lomefloxacin. If
an allergic reaction to lomefloxacin occurs, discontinue the drug. Serious acute
hypersensitivity reactions may require immediate emergency treatment with epinephrine.
Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway
management, including intubation, should be administered as indicated.
Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including lomefloxacin, and may range from mild to life-threatening in severity.
Therefore, it is important to consider this diagnosis in patients who present with
diarrhea subsequent to the administration of antibacterial agents. Treatment with
antimicrobial agents alters the normal flora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of
“antibiotic-associated colitis.” After the diagnosis of pseudomembranous colitis has been
established, therapeutic measures should be initiated. Mild cases of pseudomembranous
colitis usually respond to discontinuation of drug alone. In moderate to severe cases,
consideration should be given to management with fluids and electrolytes, protein
supplementation, and treatment with an antibacterial drug clinically effective against C diffi-
cile colitis.
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Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or
resulted in prolonged disability have been reported with lomefloxacin. Lomefloxacin should
be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients
should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has
been confidently excluded. Tendon rupture can occur at any time during or after therapy with
lomefloxacin.
PRECAUTIONS
General:
Alteration of the dosage regimen is recommended for patients with impairment of renal
function (ClCr <40 mL/min/1.73 m2). (See Dosage and Administration.)
Prescribing Maxaquin in the absence of a proven or strongly suspected bacterial
infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria.
Information for patients:
Patients should be advised
•
to avoid to the maximum extent possible direct or indirect sunlight (including exposure
through glass and exposure through sunscreens and sunblocks) and artificial ultraviolet
light (eg, sunlamps) during treatment with lomefloxacin and for several days after
therapy;
•
that they may reduce the risk of developing phototoxicity from sunlight by taking the
daily dose of lomefloxacin at least 12 hours before exposure to the sun (eg, in the
evening);
•
to discontinue lomefloxacin therapy at the first signs or symptoms of phototoxicity
reaction such as a sensation of skin burning, redness, swelling, blisters, rash, itching, or
dermatitis;
•
that a patient who has experienced a phototoxic reaction should avoid re-exposure to
sunlight and artificial ultraviolet light until he has completely recovered from the
reaction. In rare cases, reactions have recurred up to several weeks after stopping
lomefloxacin therapy.
•
to drink fluids liberally;
•
that lomefloxacin can be taken without regard to meals;
•
that mineral supplements or vitamins with iron or minerals should not be taken within the
2-hour period before or after taking lomefloxacin (see Drug Interactions);
•
that sucralfate and antacids containing magnesium or aluminum, or Videx® (didanosine),
chewable/buffered tablets or the pediatric powder for oral solution should not be taken
within 4 hours before or 2 hours after taking lomefloxacin. (See PRECAUTIONS—
Drug Interactions.)
•
that lomefloxacin can cause dizziness and lightheadedness and, therefore, patients should
know how they react to lomefloxacin before they operate an automobile or machinery or
engage in activities requiring mental alertness and coordination;
•
to discontinue treatment and inform their physician if they experience pain,
inflammation, or rupture of a tendon, and to rest and refrain from exercise until the
diagnosis of tendinitis or tendon rupture has been confidently excluded;
•
that lomefloxacin may be associated with hypersensitivity reactions, even following the
first dose, and to discontinue the drug at the first sign of a skin rash or other allergic
reaction;
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•
that convulsions have been reported in patients taking quinolones, including
lomefloxacin, and to notify their physician before taking this drug if there is a history of
this condition.
•
that antibacterial drugs including Maxaquin should only be used to treat bacterial
infections. They do not treat viral infections (e.g., the common cold). When Maxaquin is
prescribed to treat a bacterial infection, patients should be told that although it is common
to feel better early in the course of therapy, the medication should be taken exactly as
directed. Skipping doses or not completing the full course of therapy may (1) decrease
the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria
will develop resistance and will not be treatable by Maxaquin or other antibacterial drugs
in the future.
Drug interactions:
Theophylline: In three pharmacokinetic studies including 46 normal, healthy subjects,
theophylline clearance and concentration were not significantly altered by the addition of
lomefloxacin. In clinical studies where patients were on chronic theophylline therapy,
lomefloxacin had no measurable effect on the mean distribution of theophylline
concentrations or the mean estimates of theophylline clearance. Though individual
theophylline levels fluctuated, there were no clinically significant symptoms of drug
interaction.
Antacids and sucralfate: Sucralfate and antacids containing magnesium or aluminum, as well
as formulations containing divalent and trivalent cations such as Videx® (didanosine),
chewable/buffered tablets or the pediatric powder for oral solution can form chelation
complexes with lomefloxacin and interfere with its bioavailability. Sucralfate administered 2
hours before lomefloxacin resulted in a slower absorption (mean Cmax decreased by 30% and
mean Tmax increased by 1 hour) and a lesser extent of absorption (mean AUC decreased by
approximately 25%). Magnesium- and aluminum-containing antacids, administered
concomitantly with lomefloxacin, significantly decreased the bioavailability (48%) of
lomefloxacin. Separating the doses of antacid and lomefloxacin minimizes this decrease in
bioavailability; therefore, administration of these agents should precede lomefloxacin dosing
by 4 hours or follow lomefloxacin dosing by at least 2 hours.
Caffeine: Two hundred mg of caffeine (equivalent to 1 to 3 cups of American coffee) was
administered to 16 normal, healthy volunteers who had achieved steady-state blood
concentrations of lomefloxacin after being dosed at 400 mg qd. This did not result in any
statistically or clinically relevant changes in the pharmacokinetic parameters of either
caffeine or its major metabolite, paraxanthine. No data are available on potential interactions
in individuals who consume greater than 200 mg of caffeine per day or in those, such as the
geriatric population, who are generally believed to be more susceptible to the development of
drug-induced CNS-related adverse effects. Other quinolones have demonstrated moderate to
marked interference with the metabolism of caffeine, resulting in a reduced clearance, a
prolongation of plasma half-life, and an increase in symptoms that accompany high levels of
caffeine.
Cimetidine: Cimetidine has been demonstrated to interfere with the elimination of other
quinolones. This interference has resulted in significant increases in half-life and AUC. The
interaction between lomefloxacin and cimetidine has not been studied.
Cyclosporine: Elevated serum levels of cyclosporine have been reported with concomitant
use of cyclosporine with other members of the quinolone class. Interaction between
lomefloxacin and cyclosporine has not been studied.
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Omeprazole: No clinically significant changes in lomefloxacin pharmacokinetics (AUC,
Cmax, or Tmax) were observed when a single dose of lomefloxacin 400 mg was given after
multiple doses of omeprazole (20 mg qd) in 13 healthy volunteers. Changes in omeprazole
pharmacokinetics were not studied.
Phenytoin: No significant differences were observed in mean phenytoin AUC, Cmax, Cmin or
Tmax (although Cmax increased by 11%) when extended phenytoin sodium capsules (100 mg
tid) were coadministered with lomefloxacin (400 mg qd) for five days in 15 healthy males.
Lomefloxacin is unlikely to have a significant effect on phenytoin metabolism.
Probenecid: Probenecid slows the renal elimination of lomefloxacin. An increase of 63% in
the mean AUC and increases of 50% and 4%, respectively, in the mean Tmax and mean Cmax
were noted in 1 study of 6 individuals.
Terfenadine: No clinically significant changes occurred in heart rate or corrected QT
intervals, or in terfenadine metabolite or lomefloxacin pharmacokinetics, during concurrent
administration of lomefloxacin and terfenadine at steady-state in 28 healthy males.
Warfarin: Quinolones may enhance the effects of the oral anticoagulant, warfarin, or its
derivatives. When these products are administered concomitantly, prothrombin or other
suitable coagulation tests should be monitored closely. However, no clinically or statistically
significant differences in prothrombin time ratio or warfarin enantiomer pharmacokinetics
were observed in a small study of 7 healthy males who received both warfarin and
lomefloxacin under steady-state conditions.
Carcinogenesis, mutagenesis, impairment of fertility:
Carcinogenesis: Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times
every two weeks for up to 52 weeks while concurrently being administered lomefloxacin.
The lomefloxacin doses used in this study caused a phototoxic response. In mice treated with
both UVA and lomefloxacin concomitantly, the time to development of skin tumors was 16
weeks. In mice treated concomitantly in this model with both UVA and other quinolones, the
times to development of skin tumors ranged from 28 to 52 weeks.
Ninety-two percent (92%) of the mice treated concomitantly with both UVA and
lomefloxacin developed well-differentiated squamous cell carcinomas of the skin. These
squamous cell carcinomas were nonmetastatic and were endophytic in character. Two-thirds
of these squamous cell carcinomas contained large central keratinous inclusion masses and
were thought to arise from the vestigial hair follicles in these hairless animals.
In this model, mice treated with lomefloxacin alone did not develop skin or systemic
tumors.
There are no data from similar models using pigmented mice and/or fully haired
mice.
The clinical significance of these findings to humans is unknown.
Mutagenesis: One in vitro mutagenicity test (CHO/HGPRT assay) was weakly positive at
lomefloxacin concentrations ≥226 µg/mL and negative at concentrations <226 µg/mL. Two
other in vitro mutagenicity tests (chromosomal aberrations in Chinese hamster ovary cells,
chromosomal aberrations in human lymphocytes) and two in vivo mouse micronucleus
mutagenicity tests were all negative.
Impairment of fertility: Lomefloxacin did not affect the fertility of male and female rats at
oral doses up to 8 times the recommended human dose based on mg/m2 (34 times the
recommended human dose based on mg/kg).
Pregnancy: Teratogenic effects. Pregnancy Category C.
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Reproductive function studies have been performed in rats at doses up to 8 times the
recommended human dose based on mg/m2 (34 times the recommended human dose based
on mg/kg), and no impaired fertility or harm to the fetus was reported due to lomefloxacin.
Increased incidence of fetal loss in monkeys has been observed at approximately 3 to 6 times
the recommended human dose based on mg/m2 (6 to 12 times the recommended human dose
based on mg/kg). No teratogenicity has been observed in rats and monkeys at up to 16 times
the recommended human dose exposure. In the rabbit, maternal toxicity and associated
fetotoxicity, decreased placental weight, and variations of the coccygeal vertebrae occurred
at doses 2 times the recommended human exposure based on mg/m2. There are, however, no
adequate and well-controlled studies in pregnant women. Lomefloxacin should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing mothers:
It is not known whether lomefloxacin is excreted in human milk. However, it is known that
other drugs of this class are excreted in human milk and that lomefloxacin is excreted in the
milk of lactating rats. Because of the potential for serious adverse reactions from
lomefloxacin in nursing infants, a decision should be made whether to discontinue nursing or
to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric use:
The safety and effectiveness of lomefloxacin in pediatric patients and adolescents less than
18 years of age have not been established. Lomefloxacin causes arthropathy in juvenile
animals of several species. (See Warnings and Animal Pharmacology.)
Geriatric use:
Of the total number of subjects in clinical studies of lomefloxacin, 25% were ≥65 years and
9% were ≥75 years. No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical experience has not identified
differences inmresponses between the elderly and younger patients, but greater sensitivity of
some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function. (See Clinical Pharmacology—
Pharmacokinetics in the geriatric population.)
ADVERSE REACTIONS
In clinical trials, most of the adverse events reported were mild to moderate in severity and
transient in nature. During these clinical investigations, 5,623 patients received Maxaquin. In
2.2% of the patients, lomefloxacin was discontinued because of adverse events, primarily
involving the gastrointestinal system (0.7%), skin (0.7%), or CNS (0.5%).
Adverse clinical events:
The events with the highest incidence (≥1%) in patients, regardless of relationship to drug,
were headache (3.6%), nausea (3.5%), photosensitivity (2.3%) [see Warnings], dizziness
(2.1%), diarrhea (1.4%), and abdominal pain (1.2%).
Additional clinical events reported in <1% of patients treated with Maxaquin,
regardless of relationship to drug, are listed below:
Autonomic: increased sweating, dry mouth, flushing, syncope.
Body as a whole: fatigue, back pain, malaise, asthenia, chest pain, face edema, hot flashes,
influenza-like symptoms, edema, chills, allergic reaction, anaphylactoid reaction, decreased
heat tolerance.
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Cardiovascular: tachycardia, hypertension, hypotension, myocardial infarction, angina
pectoris, cardiac failure, bradycardia, arrhythmia, phlebitis, pulmonary embolism,
extrasystoles, cerebrovascular disorder, cyanosis, cardiomyopathy.
Central and peripheral nervous system: tremor, vertigo, paresthesias, twitching, hypertonia,
convulsions, hyperkinesia, coma.
Gastrointestinal: dyspepsia, vomiting, flatulence, constipation, gastrointestinal bleeding,
dysphagia, stomatitis, tongue discoloration, gastrointestinal inflammation.
Hearing: earache, tinnitus.
Hematologic: purpura, lymphadenopathy, thrombocythemia, anemia, thrombocytopenia,
increased fibrinolysis.
Hepatic: abnormal liver function.
Metabolic: thirst, hyperglycemia, hypoglycemia, gout.
Musculoskeletal: arthralgia, myalgia, leg cramps.
Ophthalmologic: abnormal vision, conjunctivitis, photophobia, eye pain, abnormal
lacrimation.
Psychiatric: insomnia, nervousness, somnolence, anorexia, depression, confusion, agitation,
increased appetite, depersonalization, paranoid reaction, anxiety, paroniria, abnormal
thinking, concentration impairment.
Reproductive system: Female: vaginal moniliasis, vaginitis, leukorrhea, menstrual disorder,
perineal pain, intermenstrual bleeding. Male: epididymitis, orchitis.
Resistance mechanism: viral infection, moniliasis, fungal infection.
Respiratory: respiratory infection, rhinitis, pharyngitis, dyspnea, cough, epistaxis,
bronchospasm, respiratory disorder, increased sputum, stridor, respiratory depression.
Skin/Allergic: pruritus, rash, urticaria, skin exfoliation, bullous eruption, eczema, skin
disorder, acne, skin discoloration, skin ulceration, angioedema. (See also Body as a whole.)
Special senses: taste perversion.
Urinary: hematuria, micturition disorder, dysuria, strangury, anuria.
Adverse laboratory events:
Changes in laboratory parameters, listed as adverse events, without regard to drug
relationship include:
Hematologic: monocytosis (0.2%), eosinophilia (0.1%), leukopenia (0.1%), leukocytosis
(0.1%).
Renal: elevated BUN (0.1%), decreased potassium (0.1%), increased creatinine (0.1%).
Hepatic: elevations of ALT (SGPT) (0.4%), AST (SGOT) (0.3%), bilirubin (0.1%), alkaline
phosphatase (0.1%).
Additional laboratory changes occurring in <0.1% in the clinical studies included:
elevation of serum gamma glutamyl transferase, decrease in total protein or albumin,
prolongation of prothrombin time, anemia, decrease in hemoglobin, thrombocythemia,
thrombocytopenia, abnormalities of urine specific gravity or serum electrolytes, increased
albumin, elevated ESR, albuminuria, macrocytosis.
Quinolone-class adverse events:
Post-marketing adverse events: Adverse events reported from worldwide marketing
experience with lomefloxacin are: anaphylaxis, cardiopulmonary arrest, laryngeal or
pulmonary edema, ataxia, cerebral thrombosis, hallucinations, painful oral mucosa,
pseudomembranous colitis, hemolytic anemia, hepatitis, tendinitis, diplopia, photophobia,
phobia, exfoliative dermatitis, hyperpigmentation, Stevens-Johnson syndrome, toxic
epidermal necrolysis, dysgeusia, interstitial nephritis, polyuria, renal failure, urinary
retention, and vasculitis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Quinolone-class adverse events: Additional quinolone-class adverse events include:
erythema nodosum, hepatic necrosis, possible exacerbation of myasthenia gravis, dysphasia,
nystagmus, intestinal perforation, manic reaction, renal calculi, acidosis and hiccough.
Laboratory adverse events include: agranulocytosis, elevation of serum triglycerides,
elevation of serum cholesterol, elevation of blood glucose, elevation of serum potassium,
albuminuria, candiduria, and crystalluria.
OVERDOSAGE
Information on overdosage in humans is limited. In the event of acute overdosage, the
stomach should be emptied by inducing vomiting or by gastric lavage, and the patient should
be carefully observed and given supportive treatment. Adequate hydration must be
maintained. Hemodialysis or peritoneal dialysis is unlikely to aid in the removal of
lomefloxacin as <3% is removed by these modalities.
Clinical signs of acute toxicity in rodents progressed from salivation to tremors,
decreased activity, dyspnea, and clonic convulsions prior to death. These signs were noted in
rats and mice as lomefloxacin doses were increased.
DOSAGE AND ADMINISTRATION
Maxaquin (lomefloxacin HCl) may be taken without regard to meals. Sucralfate and antacids
containing magnesium or aluminum, or Videx® (didanosine), chewable/buffered tablets or
the pediatric powder for oral solution should not be taken within 4 hours before or 2 hours
after taking lomefloxacin. Risk of reaction to solar UVA light may be reduced by taking
Maxaquin at least 12 hours before exposure to the sun (eg, in the evening). (See Clinical
Pharmacology.)
See Indications and Usage for information on appropriate pathogens and patient
populations.
Treatment:
Patients with normal renal function: The recommended daily dose of Maxaquin is described
in the following chart:
Infection
Unit
Dose
Frequency
Duration
Daily
Dose
Acute bacterial
exacerbation of
chronic bronchitis
400 mg
qd
10 days
400 mg
Uncomplicated cystitis
in females caused by E coli
400 mg
qd
3 days
400 mg
(see CLINICAL STUDIES —UNCOMPLICATED CYSTITIS.)
Uncomplicated cystitis
caused by K pneumoniae,
P mirabilis, or S
saprophyticus
400 mg
qd
10 days
400 mg
Complicated UTI
400 mg
qd
14 days
400 mg
Elderly patients: No dosage adjustment is needed for elderly patients with normal renal
function (ClCr ≥ 40 mL/min/ 1.73 m2).
Patients with impaired renal function: Lomefloxacin is primarily eliminated by renal
excretion. (See Clinical Pharmacology.) Modification of dosage is recommended in patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
with renal dysfunction. In patients with a creatinine clearance >10 mL/min/1.73 m2 but <40
mL/min/1.73 m2, the recommended dosage is an initial loading dose of 400 mg followed by
daily maintenance doses of 200 mg (1/2 tablet) once daily for the duration of treatment. It is
suggested that serial determinations of lomefloxacin levels be performed to determine any
necessary alteration in the appropriate next dosing interval.
If only the serum creatinine is known, the following formula may be used to estimate
creatinine clearance.
Men:
(weight in kg) x (140–age)
(72) x serum creatinine (mg/dL)
Women:
(0.85) x (calculated value for men)
Dialysis patients: Hemodialysis removes only a negligible amount of lomefloxacin (3% in 4
hours). Hemodialysis patients should receive an initial loading dose of 400 mg followed by
daily maintenance doses of 200 mg (1/2 tablet) once daily for the duration of treatment.
Patients with cirrhosis: Cirrhosis does not reduce the nonrenal clearance of lomefloxacin.
The need for a dosage reduction in this population should be based on the degree of renal
function of the patient and on the plasma concentrations. (See Clinical Pharmacology and
Dosage and Administration—Patients with impaired renal function.)
Prevention /prophylaxis:
The recommended dose of Maxaquin is described in the following chart:
Procedure
Dose
Oral Administration
Transrectal
prostate
biopsy
400 mg
single dose
1–6 hours prior to
procedure
Transurethral
surgical
procedures*
400 mg
single dose
2–6 hours prior to
procedure
*When preoperative prophylaxis is considered appropriate.
HOW SUPPLIED
Maxaquin (lomefloxacin HCl) is supplied as a scored, film-coated tablet containing the
equivalent of 400 mg of lomefloxacin base present as the hydrochloride. The tablet is oval,
white, and film-coated with “MAXAQUIN 400” debossed on one side and scored on the
other side and is supplied in:
NDC Number
Size
0025-5501-01
bottle of 20
Store at 59° to 77° F (15° to 25°C).
CLINICAL STUDIES —UNCOMPLICATED CYSTITIS
In three controlled clinical studies of uncomplicated cystitis in females, two performed in the
United States and one in Canada, lomefloxacin was compared to other oral antimicrobial
agents. In these studies, using very strict evaluability criteria and microbiological criteria at
5–9 days post-therapy follow-up, the following bacterial eradication outcomes were
obtained:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
STUDIES 1, 2, AND 3
U.S. AND CANADIAN STUDIES
Lomefloxacin
3-Day Treatment
Norfloxacin
3-Day Treatment
Ofloxacin
3-Day Treatment
Trimethoprim/
sulfamethoxazole
10-Day Treatment
E coli
133/135 (99%)
36/39 (92%)
65/67 (97%)
33/34 (97%)
K pneumoniae
7/7 (100%)
2/2 (100%)
4/4 (100%)
2/2 (100%)
P mirabilis
8/8 (100%)
1/1 (100%)
2/2 (100%)
1/1 (100%)
S saprophyticus
11/11 (100%)
3/3 (100%)
1/1 (100%)
0/0
STUDY 4
In a controlled clinical study of uncomplicated cystitis performed in Sweden, lomefloxacin 3-
day treatment was compared with lomefloxacin 7-day treatment and norfloxacin 7-day
treatment. In this study, using very strict evaluability criteria and microbiological criteria at
5–9 days post-therapy follow-up, the following bacterial eradication outcomes were
obtained:
SWEDISH STUDY
Lomefloxacin
3-Day Treatment
Lomefloxacin
7-Day Treatment
Norfloxacin
7-Day Treatment
E coli
101/109 (93%)
102/104 (98%)
108/110 (98%)
K pneumoniae
2/2 (100%)
5/5 (100%)
1/1 (100%)
P mirabilis
0/0
6/6 (100%)
4/4 (100%)
S saprophyticus
11/17 (65%)
23/23 (100%)
16/16 (100%)
ANIMAL PHARMACOLOGY
Lomefloxacin and other quinolones have been shown to cause arthropathy in juvenile
animals. Arthropathy, involving multiple diarthrodial joints, was observed in juvenile dogs
administered lomefloxacin at doses as low as 4.5 mg/kg for 7 to 8 days (0.3 times the
recommended human dose based on mg/m2 or 0.6 times the recommended human dose based
on mg/kg). In juvenile rats, no changes were observed in the joints with doses up to 91 mg/kg
for 7 days (2 times the recommended human dose based on mg/m2 or 11 times the
recommended human dose based on mg/kg). (See Warnings.)
In a 13-week oral rat study, gamma globulin decreased when lomefloxacin was
administered at less than the recommended human exposure. Beta globulin decreased when
lomefloxacin was administered at 0.6 to 2 times the recommended human dose based on
mg/m2. The A/G ratio increased when lomefloxacin was administered at 6 to 20 times the
human dose. Following a 4-week recovery period, beta globulins in the females and A/G
ratios in the females returned to control values. Gamma globulin values in the females and
beta and gamma globulins and A/G ratios in the males were still statistically significantly
different from control values. No effects on globulins were seen in oral studies in dogs or
monkeys in the limited number of specimens collected.
Twenty-seven NSAIDs, administered concomitantly with lomefloxacin, were tested
for seizure induction in mice at approximately 2 times the recommended human dose based
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
on mg/m2. At a dose of lomefloxacin equivalent to the recommended human exposure based
on mg/m2 (10 times the human dose based on mg/kg), only fenbufen, when coadministered,
produced an increase in seizures.
Crystalluria and ocular toxicity, seen with some related quinolones, were not
observed in any lomefloxacin-treated animals, either in studies designed to look for these
effects specifically or in subchronic and chronic toxicity studies in rats, dogs, and monkeys.
Long-term, high-dose systemic use of other quinolones in experimental animals has
caused lenticular opacities; however, this finding was not observed with lomefloxacin.
REFERENCES
1. National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Disk Susceptibility Tests—4th ed. Approved Standard NCCLS Document M2–
A4, vol 10, No. 7, NCCLS, Villanova, Pa, 1990. 2. National Committee for Clinical
Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria
that Grow Aerobically—2nd ed. Approved Standard NCCLS Document M7 –A2, vol 10, No.
8, NCCLS, Villanova, Pa, 1990.
Rx only
Revised: September 2003
Manufactured for:
G.D. Searle LLC
A subsidiary of Pharmacia Corporation
Chicago, IL 60680, USA
by: Searle & Co.
Caguas, PR 00725
819 442 001
P04035-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20013slr014_mazaquin_lbl.pdf', 'application_number': 20013, 'submission_type': 'SUPPL ', 'submission_number': 14}
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Attachment 1
Page 1
Class Suicidality Labeling Language for Antidepressants
[This section should be located at the beginning of the package insert with bolded font and
enclosed in a black box]
[Insert established name]
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of [Insert established name] or any other
antidepressant in a child or adolescent must balance this risk with the clinical need. Patients
who are started on therapy should be observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. [Insert established name] is not approved
for use in pediatric patients. (See Warnings and Precautions: Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs
(SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive
compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over
4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or
behavior (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%,
twice the placebo risk of 2%. No suicides occurred in these trials.
[This section should be located under WARNINGS. Please note that the title of this
section should be bolded, and it should be the first paragraph in this section.]
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. There has been a long-standing concern that antidepressants
may have a role in inducing worsening of depression and the emergence of suicidality in certain
patients. A causal role for antidepressants in inducing suicidality has been established in pediatric
patients.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in
children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving
over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or
thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The
average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 2
There was considerable variation in risk among drugs, but a tendency toward an increase for almost
all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there
were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive
disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is
unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond
several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes, either increases or
decreases. Such observation would generally include at least weekly face-to-face contact with
patients or their family members or caregivers during the first 4 weeks of treatment, then every
other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12
weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and suicidality,
especially during the initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being treated with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between
the emergence of such symptoms and either the worsening of depression and/or the emergence of
suicidal impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is
feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with
[Insert established name] , for a description of the risks of discontinuation of [Insert established
name]).
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted
about the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality, and
to report such symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for [Insert established name] should be
written for the smallest quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose. Families and caregivers of adults being treated for depression should be similarly
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 1
Page 3
advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled trials) that treating
such an episode with an antidepressant alone may increase the likelihood of precipitation of a
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described
above represent such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a
family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established
name] is not approved for use in treating bipolar depression.
[This section should be located under PRECAUTIONS, Information for Patients.]
Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with [Insert established name] and should
counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in
Children and Adolescents is available for [Insert established name]. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide
and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur
while taking [Insert established name].
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other
unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during
antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients
should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes
may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior
and indicate a need for very close monitoring and possibly changes in the medication.
[This section should be located under PRECAUTIONS, Pediatric Use.]
Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX
WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Three placebo-controlled
trials in 752 pediatric patients with MDD have been conducted with Paxil, and the data were not
sufficient to support a claim for use in pediatric patients. Anyone considering the use of [Insert
established name] in a child or adolescent must balance the potential risks with the clinical need.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 1
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal
thoughts and actions can also be caused by depression, a serious medical condition that is commonly
treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called
suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with depression or
other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to
4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar
pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became
suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or
his moods or actions, especially if the changes occur suddenly. Other important people in your child's
life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other
important people). The changes to look out for are listed in Section 3, on what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see other side)
You should call your child's healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child's healthcare provider right away if your child exhibits any of the following signs for
the first time, or if they seem worse, or worry you, your child, or your child's teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without first talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can
lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal
thinking or actions. It is important to discuss all the risks of treating depression and also the risks of
not treating it. You and your child should discuss all treatment choices with your healthcare provider,
not just the use of antidepressants.
Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric
depression.
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) .
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 3
Your healthcare provider may suggest other antidepressants based on the past experience of your child
or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants.
Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is
prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare
provider or pharmacist where to find more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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1
PRESCRIBING INFORMATION
1
PAXIL®
2
(paroxetine hydrochloride)
3
Tablets and Oral Suspension
4
5
Suicidality and Antidepressant Drugs
6
Antidepressants increased the risk compared to placebo of suicidal thinking and
7
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
8
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
9
use of PAXIL or any other antidepressant in a child, adolescent, or young adult must
10
balance this risk with the clinical need. Short-term studies did not show an increase in the
11
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
12
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
13
older. Depression and certain other psychiatric disorders are themselves associated with
14
increases in the risk of suicide. Patients of all ages who are started on antidepressant
15
therapy should be monitored appropriately and observed closely for clinical worsening,
16
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
17
the need for close observation and communication with the prescriber. PAXIL is not
18
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
19
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
20
DESCRIPTION
21
PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the
22
hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-
23
fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate
24
and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8
25
(329.4 as free base). The structural formula of paroxetine hydrochloride is:
26
27
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
28
120° to 138°C and a solubility of 5.4 mg/mL in water.
29
Tablets: Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as
30
follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive
31
ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate,
32
polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
the following: D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 2, FD&C Yellow No. 6.
34
Suspension for Oral Administration: Each 5 mL of orange-colored, orange-flavored liquid
35
contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist
36
of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methyl
37
paraben, propyl paraben, sodium citrate dihydrate, citric acid anhydrate, sodium saccharin,
38
flavorings, FD&C Yellow No. 6, and simethicone emulsion, USP.
39
CLINICAL PHARMACOLOGY
40
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
41
disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD),
42
generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be
43
linked to potentiation of serotonergic activity in the central nervous system resulting from
44
inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically
45
relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into
46
human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly
47
selective inhibitor of neuronal serotonin reuptake and has only very weak effects on
48
norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate
49
that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine
50
(D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic,
51
and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and
52
cardiovascular effects for other psychotropic drugs.
53
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
54
compound, they are essentially inactive.
55
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
56
solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours
57
(CV 32%) after oral dosing of 30 mg tablets of PAXIL daily for 30 days. Paroxetine is
58
extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in
59
pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part
60
by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the
61
feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are
62
deficient in CYP2D6 (poor metabolizers).
63
Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension
64
and tablet.
65
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
66
hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets
67
daily for 30 days, steady-state paroxetine concentrations were achieved by approximately
68
10 days for most subjects, although it may take substantially longer in an occasional patient. At
69
steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr.
70
(CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax
71
and Cmin values were about 6 and 14 times what would be predicted from single-dose studies.
72
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3
Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been
73
predicted from single-dose data in these subjects. The excess accumulation is a consequence of
74
the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.
75
The effects of food on the bioavailability of paroxetine were studied in subjects administered
76
a single dose with and without food. AUC was only slightly increased (6%) when drug was
77
administered with food but the Cmax was 29% greater, while the time to reach peak plasma
78
concentration decreased from 6.4 hours post-dosing to 4.9 hours.
79
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
80
plasma.
81
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
82
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
83
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
84
warfarin.
85
Metabolism and Excretion: The mean elimination half-life is approximately 21 hours
86
(CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose
87
proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg
88
daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was
89
observed in both populations, again reflecting a saturable metabolic pathway. In comparison to
90
Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than
91
doubled.
92
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
93
polar and conjugated products of oxidation and methylation, which are readily cleared.
94
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
95
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
96
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
97
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
98
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
99
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
100
interactions (see PRECAUTIONS).
101
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
102
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
103
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
104
1% as the parent compound over the 10-day post-dosing period.
105
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
106
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic
107
impairment. The mean plasma concentrations in patients with creatinine clearance below
108
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
109
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
110
about a 2-fold increase in plasma concentrations (AUC, Cmax).
111
The initial dosage should therefore be reduced in patients with severe renal or hepatic
112
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4
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
113
AND ADMINISTRATION).
114
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20,
115
30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin
116
concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be
117
reduced (see DOSAGE AND ADMINISTRATION).
118
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
119
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
120
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
121
desipramine, risperidone, and atomoxetine (see PRECAUTIONS—Drug Interactions).
122
Clinical Trials
123
Major Depressive Disorder: The efficacy of PAXIL as a treatment for major depressive
124
disorder has been established in 6 placebo-controlled studies of patients with major depressive
125
disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective
126
than placebo in treating major depressive disorder by at least 2 of the following measures:
127
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
128
Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in
129
improvement of the HDRS sub-factor scores, including the depressed mood item, sleep
130
disturbance factor, and anxiety factor.
131
A study of outpatients with major depressive disorder who had responded to PAXIL (HDRS
132
total score <8) during an initial 8-week open-treatment phase and were then randomized to
133
continuation on PAXIL or placebo for 1 year demonstrated a significantly lower relapse rate for
134
patients taking PAXIL (15%) compared to those on placebo (39%). Effectiveness was similar for
135
male and female patients.
136
Obsessive Compulsive Disorder: The effectiveness of PAXIL in the treatment of obsessive
137
compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled
138
studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD
139
(DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale
140
(YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients
141
were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily
142
doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses
143
of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points,
144
respectively, on the YBOCS total score which was significantly greater than the approximate 4-
145
point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a
146
flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg
147
daily). In this study, patients receiving paroxetine experienced a mean reduction of
148
approximately 7 points on the YBOCS total score, which was significantly greater than the mean
149
reduction of approximately 4 points in placebo-treated patients.
150
The following table provides the outcome classification by treatment group on Global
151
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5
Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
152
153
Outcome Classification (%) on CGI-Global Improvement Item
for Completers in Study 1
Outcome
Classification
Placebo
(n = 74)
PAXIL 20 mg
(n = 75)
PAXIL 40 mg
(n = 66)
PAXIL 60 mg
(n = 66)
Worse
14%
7%
7%
3%
No Change
44%
35%
22%
19%
Minimally Improved
24%
33%
29%
34%
Much Improved
11%
18%
22%
24%
Very Much Improved
7%
7%
20%
20%
154
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
155
function of age or gender.
156
The long-term maintenance effects of PAXIL in OCD were demonstrated in a long-term
157
extension to Study 1. Patients who were responders on paroxetine during the 3-month
158
double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were
159
randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase.
160
Patients randomized to paroxetine were significantly less likely to relapse than comparably
161
treated patients who were randomized to placebo.
162
Panic Disorder: The effectiveness of PAXIL in the treatment of panic disorder was
163
demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients
164
(Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia.
165
In these studies, PAXIL was shown to be significantly more effective than placebo in treating
166
panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical
167
Global Impression Severity of Illness score.
168
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine
169
doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed
170
only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were
171
free of panic attacks, compared to 44% of placebo-treated patients.
172
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and
173
placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of
174
placebo-treated patients.
175
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to
176
placebo in patients concurrently receiving standardized cognitive behavioral therapy. At
177
endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks
178
compared to 14% of placebo patients.
179
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was
180
approximately 40 mg/day of paroxetine.
181
Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an
182
extension to Study 1. Patients who were responders during the 10-week double-blind phase and
183
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6
during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or
184
40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized
185
to paroxetine were significantly less likely to relapse than comparably treated patients who were
186
randomized to placebo.
187
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
188
function of age or gender.
189
Social Anxiety Disorder: The effectiveness of PAXIL in the treatment of social anxiety
190
disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1,
191
2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the
192
effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of
193
responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very
194
much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social
195
Anxiety Scale (LSAS).
196
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and
197
placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the
198
CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In
199
Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to
200
29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI
201
Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients,
202
respectively.
203
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with
204
placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the
205
LSAS Total Score and the CGI Improvement responder criterion; there were trends for
206
superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in
207
this study of any additional benefit for doses higher than 20 mg/day.
208
Subgroup analyses generally did not indicate differences in treatment outcomes as a function
209
of age, race, or gender.
210
Generalized Anxiety Disorder: The effectiveness of PAXIL in the treatment of Generalized
211
Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled
212
studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).
213
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with
214
placebo. Doses of 20 mg or 40 mg of PAXIL were both demonstrated to be significantly superior
215
to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not
216
sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to
217
the 20 mg/day dose.
218
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo.
219
PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating
220
Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine
221
(20 mg to 50 mg daily), did not demonstrate statistically significant superiority of PAXIL over
222
placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.
223
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7
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or
224
gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
225
In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety
226
Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to
227
50 mg/day of PAXIL, were randomized to continuation of PAXIL at their same dose, or to
228
placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase
229
was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of
230
Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase
231
of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or
232
withdrawal due to lack of efficacy. Patients receiving continued PAXIL experienced a
233
significantly lower relapse rate over the subsequent 24 weeks compared to those receiving
234
placebo.
235
Posttraumatic Stress Disorder: The effectiveness of PAXIL in the treatment of
236
Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-
237
controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The
238
mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year
239
to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD
240
anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out
241
of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered
242
PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement
243
Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the
244
following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal.
245
The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2
246
total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were
247
defined as patients having a score of 1 (very much improved) or 2 (much improved).
248
Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to
249
placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to
250
placebo on change from baseline for the CAPS-2 total score and on proportion of responders on
251
the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the
252
40 mg/day dose compared to the 20 mg/day dose.
253
Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to
254
placebo. PAXIL was demonstrated to be significantly superior to placebo on change from
255
baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.
256
A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,
257
demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS-
258
2 total score, but not on proportion of responders on the CGI-I.
259
The majority of patients in these trials were women (68% women: 377 out of 551 subjects in
260
Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not
261
indicate differences in treatment outcomes as a function of gender. There were an insufficient
262
number of patients who were 65 years and older or were non-Caucasian to conduct subgroup
263
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8
analyses on the basis of age or race, respectively.
264
INDICATIONS AND USAGE
265
Major Depressive Disorder: PAXIL is indicated for the treatment of major depressive
266
disorder.
267
The efficacy of PAXIL in the treatment of a major depressive episode was established in
268
6-week controlled trials of outpatients whose diagnoses corresponded most closely to the
269
DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical
270
Trials). A major depressive episode implies a prominent and relatively persistent depressed or
271
dysphoric mood that usually interferes with daily functioning (nearly every day for at least
272
2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in
273
sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in
274
sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
275
concentration, and a suicide attempt or suicidal ideation.
276
The effects of PAXIL in hospitalized depressed patients have not been adequately studied.
277
The efficacy of PAXIL in maintaining a response in major depressive disorder for up to 1 year
278
was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical
279
Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should
280
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
281
Obsessive Compulsive Disorder: PAXIL is indicated for the treatment of obsessions and
282
compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV.
283
The obsessions or compulsions cause marked distress, are time-consuming, or significantly
284
interfere with social or occupational functioning.
285
The efficacy of PAXIL was established in two 12-week trials with obsessive compulsive
286
outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive
287
compulsive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
288
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
289
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
290
intentional behaviors (compulsions) that are recognized by the person as excessive or
291
unreasonable.
292
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In
293
this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on
294
placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician
295
who elects to use PAXIL for extended periods should periodically re-evaluate the long-term
296
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
297
Panic Disorder: PAXIL is indicated for the treatment of panic disorder, with or without
298
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
299
unexpected panic attacks and associated concern about having additional attacks, worry about
300
the implications or consequences of the attacks, and/or a significant change in behavior related to
301
the attacks.
302
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9
The efficacy of PAXIL was established in three 10- to 12-week trials in panic disorder
303
patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
304
CLINICAL PHARMACOLOGY—Clinical Trials).
305
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
306
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
307
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
308
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
309
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
310
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
311
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
312
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
313
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In
314
this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate
315
compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials).
316
Nevertheless, the physician who prescribes PAXIL for extended periods should periodically
317
re-evaluate the long-term usefulness of the drug for the individual patient.
318
Social Anxiety Disorder: PAXIL is indicated for the treatment of social anxiety disorder,
319
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
320
characterized by a marked and persistent fear of 1 or more social or performance situations in
321
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
322
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
323
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
324
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
325
the person's normal routine, occupational or academic functioning, or social activities or
326
relationships, or there is marked distress about having the phobias. Lesser degrees of
327
performance anxiety or shyness generally do not require psychopharmacological treatment.
328
The efficacy of PAXIL was established in three 12-week trials in adult patients with social
329
anxiety disorder (DSM-IV). PAXIL has not been studied in children or adolescents with social
330
phobia (see CLINICAL PHARMACOLOGY—Clinical Trials).
331
The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more
332
than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
333
Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically
334
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
335
ADMINISTRATION).
336
Generalized Anxiety Disorder: PAXIL is indicated for the treatment of Generalized Anxiety
337
Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of
338
everyday life usually does not require treatment with an anxiolytic.
339
The efficacy of PAXIL in the treatment of GAD was established in two 8-week
340
placebo-controlled trials in adults with GAD. PAXIL has not been studied in children or
341
adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY—Clinical
342
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10
Trials).
343
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry
344
(apprehensive expectation) that is persistent for at least 6 months and which the person finds
345
difficult to control. It must be associated with at least 3 of the following 6 symptoms:
346
Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or
347
mind going blank, irritability, muscle tension, sleep disturbance.
348
The efficacy of PAXIL in maintaining a response in patients with Generalized Anxiety
349
Disorder, who responded during an 8-week acute treatment phase while taking PAXIL and were
350
then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-
351
controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the
352
physician who elects to use PAXIL for extended periods should periodically re-evaluate the
353
long-term usefulness of the drug for the individual patient (see DOSAGE AND
354
ADMINISTRATION).
355
Posttraumatic Stress Disorder: PAXIL is indicated for the treatment of Posttraumatic
356
Stress Disorder (PTSD).
357
The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebo-
358
controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY—Clinical
359
Trials).
360
PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or
361
threatened death or serious injury, or threat to the physical integrity of self or others, and a
362
response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of
363
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
364
thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity
365
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
366
inability to recall details of the event, and/or numbing of general responsiveness manifested as
367
diminished interest in significant activities, estrangement from others, restricted range of affect,
368
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
369
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
370
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
371
and that they cause clinically significant distress or impairment in social, occupational, or other
372
important areas of functioning.
373
The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has
374
not been systematically evaluated in placebo-controlled trials. Therefore, the physician who
375
elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term
376
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
377
CONTRAINDICATIONS
378
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or
379
thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).
380
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
381
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the
382
inactive ingredients in PAXIL.
383
WARNINGS
384
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
385
both adult and pediatric, may experience worsening of their depression and/or the emergence of
386
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
387
are taking antidepressant medications, and this risk may persist until significant remission
388
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
389
disorders themselves are the strongest predictors of suicide. There has been a long-standing
390
concern, however, that antidepressants may have a role in inducing worsening of depression and
391
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
392
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
393
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
394
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
395
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
396
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
397
antidepressants compared to placebo in adults aged 65 and older.
398
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
399
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-
400
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-
401
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
402
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
403
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
404
increase in the younger patients for almost all drugs studied. There were differences in absolute
405
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
406
differences (drug vs placebo), however, were relatively stable within age strata and across
407
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
408
per 1,000 patients treated) are provided in Table 1.
409
410
Table 1
411
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
413
the number was not sufficient to reach any conclusion about drug effect on suicide.
414
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
415
months. However, there is substantial evidence from placebo-controlled maintenance trials in
416
adults with depression that the use of antidepressants can delay the recurrence of depression.
417
All patients being treated with antidepressants for any indication should be monitored
418
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
419
in behavior, especially during the initial few months of a course of drug therapy, or at times
420
of dose changes, either increases or decreases.
421
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
422
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
423
been reported in adult and pediatric patients being treated with antidepressants for major
424
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
425
Although a causal link between the emergence of such symptoms and either the worsening of
426
depression and/or the emergence of suicidal impulses has not been established, there is concern
427
that such symptoms may represent precursors to emerging suicidality.
428
Consideration should be given to changing the therapeutic regimen, including possibly
429
discontinuing the medication, in patients whose depression is persistently worse, or who are
430
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
431
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
432
patient’s presenting symptoms.
433
Families and caregivers of patients being treated with antidepressants for major
434
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
435
alerted about the need to monitor patients for the emergence of agitation, irritability,
436
unusual changes in behavior, and the other symptoms described above, as well as the
437
emergence of suicidality, and to report such symptoms immediately to healthcare
438
providers. Such monitoring should include daily observation by families and caregivers.
439
Prescriptions for PAXIL should be written for the smallest quantity of tablets consistent with
440
good patient management, in order to reduce the risk of overdose.
441
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
442
presentation of bipolar disorder. It is generally believed (though not established in controlled
443
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
444
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
445
symptoms described above represent such a conversion is unknown. However, prior to initiating
446
treatment with an antidepressant, patients with depressive symptoms should be adequately
447
screened to determine if they are at risk for bipolar disorder; such screening should include a
448
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
449
depression. It should be noted that PAXIL is not approved for use in treating bipolar depression.
450
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
451
another serotonin reuptake inhibitor drug in combination with a monoamine oxidase
452
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including
453
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of
454
vital signs, and mental status changes that include extreme agitation progressing to
455
delirium and coma. These reactions have also been reported in patients who have recently
456
discontinued that drug and have been started on an MAOI. Some cases presented with
457
features resembling neuroleptic malignant syndrome. While there are no human data
458
showing such an interaction with PAXIL, limited animal data on the effects of combined
459
use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate
460
blood pressure and evoke behavioral excitation. Therefore, it is recommended that PAXIL
461
not be used in combination with an MAOI, or within 14 days of discontinuing treatment
462
with an MAOI. At least 2 weeks should be allowed after stopping PAXIL before starting an
463
MAOI.
464
Serotonin Syndrome: The development of a potentially life-threatening serotonin
465
syndrome may occur with SNRIs and SSRIs, including PAXIL, particularly with
466
concomitant use of serotonergic drugs (including triptans) and with drugs which impair
467
metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include
468
mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
469
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g.,
470
hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting,
471
diarrhea).
472
The concomitant use of PAXIL with MAOIs intended to treat depression is
473
contraindicated (see CONTRAINDICATIONS and WARNINGS—Potential for
474
Interaction With Monoamine Oxidase Inhibitors).
475
If concomitant treatment with PAXIL with a 5-hydroxytryptamine receptor agonist
476
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
477
during treatment initiation and dose increases (see PRECAUTIONS—Drug Interactions).
478
The concomitant use of PAXIL with serotonin precursors (such as tryptophan) is not
479
recommended (see PRECAUTIONS—Drug Interactions).
480
Potential Interaction With Thioridazine: Thioridazine administration alone produces
481
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
482
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
483
dose related.
484
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
485
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
486
used in combination with thioridazine (see CONTRAINDICATIONS and
487
PRECAUTIONS).
488
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
489
infants born to women who had first trimester paroxetine exposure had an increased risk of
490
cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs).
491
In general, septal defects range from those that are symptomatic and may require surgery to those
492
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while
493
taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of
494
paroxetine to the mother justify continuing treatment, consideration should be given to either
495
discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS—
496
Discontinuation of Treatment with PAXIL). For women who intend to become pregnant or are in
497
their first trimester of pregnancy, paroxetine should only be initiated after consideration of the
498
other available treatment options.
499
A study based on Swedish national registry data evaluated infants of 6,896 women exposed to
500
antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for
501
paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of
502
cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry
503
population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations
504
following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population.
505
Among the same paroxetine exposed infants, an examination of the data showed no increase in
506
the overall risk for congenital malformations.
507
A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants
508
of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815 for
509
paroxetine). This study showed a trend towards an increased risk for cardiovascular
510
malformations for paroxetine compared to other antidepressants (OR 1.5; 95% confidence
511
interval 0.8-2.9). The prevalence of cardiovascular malformations following first trimester
512
dispensing was 1.5% for paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with
513
cardiovascular malformations whose mothers were dispensed paroxetine in the first trimester had
514
VSDs. This study also suggested an increased risk of overall major congenital malformations
515
(inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR
516
1.8; 95% confidence interval 1.2-2.8). The prevalence of all congenital malformations following
517
first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants.
518
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
519
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
520
8 (rat) and 2 (rabbit) times the MRHD on an mg/m2 basis. These studies have revealed no
521
evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the
522
first 4 days of lactation when dosing occurred during the last trimester of gestation and continued
523
throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of
524
the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The
525
cause of these deaths is not known.
526
Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs or serotonin and
527
norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
528
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
529
complications can arise immediately upon delivery. Reported clinical findings have included
530
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
531
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
532
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
533
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
534
clinical picture is consistent with serotonin syndrome (see WARNINGS—Potential for
535
Interaction With Monoamine Oxidase Inhibitors).
536
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
537
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
538
the general population and is associated with substantial neonatal morbidity and mortality. In a
539
retrospective case-control study of 377 women whose infants were born with PPHN and 836
540
women whose infants were born healthy, the risk for developing PPHN was approximately six-
541
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
542
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
543
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
544
study that has investigated the potential risk. The study did not include enough cases with
545
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
546
There have also been postmarketing reports of premature births in pregnant women exposed
547
to paroxetine or other SSRIs.
548
When treating a pregnant woman with paroxetine during the third trimester, the physician
549
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
550
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
551
women with a history of major depression who were euthymic at the beginning of pregnancy,
552
women who discontinued antidepressant medication during pregnancy were more likely to
553
experience a relapse of major depression than women who continued antidepressant medication.
554
PRECAUTIONS
555
General: Activation of Mania/Hypomania: During premarketing testing, hypomania or
556
mania occurred in approximately 1.0% of unipolar patients treated with PAXIL compared to
557
1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients
558
classified as bipolar, the rate of manic episodes was 2.2% for PAXIL and 11.6% for the
559
combined active-control groups. As with all drugs effective in the treatment of major depressive
560
disorder, PAXIL should be used cautiously in patients with a history of mania.
561
Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with
562
PAXIL, a rate similar to that associated with other drugs effective in the treatment of major
563
depressive disorder. PAXIL should be used cautiously in patients with a history of seizures. It
564
should be discontinued in any patient who develops seizures.
565
Discontinuation of Treatment With PAXIL: Recent clinical trials supporting the various
566
approved indications for PAXIL employed a taper-phase regimen, rather than an abrupt
567
discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials
568
involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a
569
daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before
570
treatment was stopped.
571
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
With this regimen in those studies, the following adverse events were reported at an incidence
572
of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams,
573
paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and
574
were self-limiting and did not require medical intervention.
575
During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports
576
of adverse events occurring, upon the discontinuation of these drugs (particularly when abrupt),
577
including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances
578
(e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache,
579
lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-
580
limiting, there have been reports of serious discontinuation symptoms.
581
Patients should be monitored for these symptoms when discontinuing treatment with PAXIL.
582
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
583
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
584
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
585
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
586
ADMINISTRATION).
587
See also PRECAUTIONS—Pediatric Use, for adverse events reported upon discontinuation
588
of treatment with PAXIL in pediatric patients.
589
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
590
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
591
such as an inability to sit or stand still usually associated with subjective distress. This is most
592
likely to occur within the first few weeks of treatment.
593
Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia
594
appeared to be reversible when PAXIL was discontinued. The majority of these occurrences
595
have been in elderly individuals, some in patients taking diuretics or who were otherwise volume
596
depleted.
597
Abnormal Bleeding: Published case reports have documented the occurrence of bleeding
598
episodes in patients treated with psychotropic agents that interfere with serotonin reuptake.
599
Subsequent epidemiological studies, both of the case-control and cohort design, have
600
demonstrated an association between use of psychotropic drugs that interfere with serotonin
601
reuptake and the occurrence of upper gastrointestinal bleeding. In 2 studies, concurrent use of a
602
nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see
603
Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is
604
reason to believe that bleeding at other sites may be similarly potentiated. Patients should be
605
cautioned regarding the risk of bleeding associated with the concomitant use of paroxetine with
606
NSAIDs, aspirin, or other drugs that affect coagulation.
607
Use in Patients With Concomitant Illness: Clinical experience with PAXIL in patients
608
with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in
609
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
610
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
611
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
PAXIL. A few cases of acute angle closure glaucoma associated with paroxetine therapy have
612
been reported in the literature. As mydriasis can cause acute angle closure in patients with
613
narrow angle glaucoma, caution should be used when PAXIL is prescribed for patients with
614
narrow angle glaucoma.
615
PAXIL has not been evaluated or used to any appreciable extent in patients with a recent
616
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
617
excluded from clinical studies during the product’s premarket testing. Evaluation of
618
electrocardiograms of 682 patients who received PAXIL in double-blind, placebo-controlled
619
trials, however, did not indicate that PAXIL is associated with the development of significant
620
ECG abnormalities. Similarly, PAXIL does not cause any clinically important changes in heart
621
rate or blood pressure.
622
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
623
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
624
be used in such patients (see DOSAGE AND ADMINISTRATION).
625
Information for Patients: PAXIL should not be chewed or crushed, and should be swallowed
626
whole.
627
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
628
PAXIL and triptans, tramadol, or other serotonergic agents.
629
Prescribers or other health professionals should inform patients, their families, and their
630
caregivers about the benefits and risks associated with treatment with PAXIL and should counsel
631
them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines,
632
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available
633
for PAXIL. The prescriber or health professional should instruct patients, their families, and their
634
caregivers to read the Medication Guide and should assist them in understanding its contents.
635
Patients should be given the opportunity to discuss the contents of the Medication Guide and to
636
obtain answers to any questions they may have. The complete text of the Medication Guide is
637
reprinted at the end of this document.
638
Patients should be advised of the following issues and asked to alert their prescriber if these
639
occur while taking PAXIL.
640
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should
641
be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
642
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
643
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
644
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
645
down. Families and caregivers of patients should be advised to look for the emergence of such
646
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
647
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
648
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
649
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
650
close monitoring and possibly changes in the medication.
651
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Patients
652
should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs
653
that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin
654
reuptake and these agents has been associated with an increased risk of bleeding.
655
Interference With Cognitive and Motor Performance: Any psychoactive drug may
656
impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been
657
shown to impair psychomotor performance, patients should be cautioned about operating
658
hazardous machinery, including automobiles, until they are reasonably certain that therapy with
659
PAXIL does not affect their ability to engage in such activities.
660
Completing Course of Therapy: While patients may notice improvement with treatment
661
with PAXIL in 1 to 4 weeks, they should be advised to continue therapy as directed.
662
Concomitant Medication: Patients should be advised to inform their physician if they are
663
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
664
interactions.
665
Alcohol: Although PAXIL has not been shown to increase the impairment of mental and
666
motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
667
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
668
intend to become pregnant during therapy (see WARNINGS—Usage in Pregnancy: Teratogenic
669
and Nonteratogenic Effects).
670
Nursing: Patients should be advised to notify their physician if they are breast-feeding an
671
infant (see PRECAUTIONS—Nursing Mothers).
672
Laboratory Tests: There are no specific laboratory tests recommended.
673
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
674
between paroxetine and tryptophan may occur when they are coadministered. Adverse
675
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
676
reported when tryptophan was administered to patients taking PAXIL. Consequently,
677
concomitant use of PAXIL with tryptophan is not recommended (see WARNINGS—Serotonin
678
Syndrome).
679
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
680
Pimozide: In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg
681
daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in
682
pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. Due to the
683
narrow therapeutic index of pimozide and its known ability to prolong the QT interval,
684
concomitant use of pimozide and PAXIL is contraindicated (see CONTRAINDICATIONS).
685
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
686
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
687
PAXIL is coadministered with other drugs that may affect the serotonergic neurotransmitter
688
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
689
lithium, tramadol, or St. John's Wort (see WARNINGS—Serotonin Syndrome). The concomitant
690
use of PAXIL with other SSRIs, SNRIs or tryptophan is not recommended (see
691
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
PRECAUTIONS—Drug Interactions, Tryptophan).
692
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
693
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
694
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
695
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
696
of PAXIL and warfarin should be undertaken with caution (see Drugs That Interfere With
697
Hemostasis).
698
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
699
an SSRI and a triptan. If concomitant use of PAXIL with a triptan is clinically warranted, careful
700
observation of the patient is advised, particularly during treatment initiation and dose increases
701
(see WARNINGS—Serotonin Syndrome).
702
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
703
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
704
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
705
where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma
706
concentrations of paroxetine were increased by approximately 50% during coadministration with
707
oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are
708
administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be
709
guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not
710
studied.
711
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
712
single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once
713
daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
714
respectively) compared to paroxetine administered alone. The effect of paroxetine on
715
phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear
716
pharmacokinetics, the results of this study may not address the case where the 2 drugs are both
717
being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when
718
coadministered with phenobarbital; any subsequent adjustment should be guided by clinical
719
effect.
720
Phenytoin: When a single oral 30-mg dose of PAXIL was administered at phenytoin steady
721
state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of
722
50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a
723
single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once
724
daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to
725
phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above
726
studies may not address the case where the 2 drugs are both being chronically dosed. No initial
727
dosage adjustments are considered necessary when these drugs are coadministered; any
728
subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS—
729
Postmarketing Reports).
730
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are
732
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
733
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
734
(>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily
735
dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose
736
desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold,
737
respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been
738
evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to
739
8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased
740
9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the
741
active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The
742
effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs
743
were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,
744
paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This
745
resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in
746
atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.
747
Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be
748
initiated at a reduced dose when it is given with paroxetine.
749
Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not
750
been formally studied but may require lower doses than usually prescribed for either PAXIL or
751
the other drug.
752
Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme,
753
including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,
754
amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type
755
1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme
756
(e.g., quinidine), should be approached with caution.
757
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
758
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
759
coadministered (see CONTRAINDICATIONS and WARNINGS).
760
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
761
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
762
PRECAUTIONS—Tricyclic Antidepressants).
763
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
764
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
765
cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In
766
addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be
767
at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several
768
substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and
769
cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and
770
its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4
771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical
772
significance.
773
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of
774
tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism.
775
Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be
776
reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS—Drugs Metabolized by
777
Cytochrome CYP2D6).
778
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
779
protein, administration of PAXIL to a patient taking another drug that is highly protein bound
780
may cause increased free concentrations of the other drug, potentially resulting in adverse events.
781
Conversely, adverse effects could result from displacement of paroxetine by other highly bound
782
drugs.
783
Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.):
784
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
785
the case-control and cohort design that have demonstrated an association between use of
786
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
787
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated
788
the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently
789
with paroxetine.
790
Alcohol: Although PAXIL does not increase the impairment of mental and motor skills
791
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
792
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction
793
between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome,
794
caution is advised when PAXIL is coadministered with lithium.
795
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
796
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
797
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
798
paroxetine and digoxin should be undertaken with caution.
799
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
800
kinetics. The effects of paroxetine on diazepam were not evaluated.
801
Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0-
802
24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%,
803
respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen,
804
the dose of procyclidine should be reduced.
805
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
806
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
807
coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of
808
propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS—
809
Postmarketing Reports).
810
Theophylline: Reports of elevated theophylline levels associated with treatment with
811
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
PAXIL have been reported. While this interaction has not been formally studied, it is
812
recommended that theophylline levels be monitored when these drugs are concurrently
813
administered.
814
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
815
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
816
clinical effect (tolerability and efficacy).
817
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
818
ECT and PAXIL.
819
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
820
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
821
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and
822
3.9 (rat) times the maximum recommended human dose (MRHD) for major depressive disorder,
823
social anxiety disorder, GAD, and PTSD on a mg/m2 basis. Because the MRHD for major
824
depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in
825
these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD.
826
There was a significantly greater number of male rats in the high-dose group with reticulum cell
827
sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups,
828
respectively) and a significantly increased linear trend across dose groups for the occurrence of
829
lymphoreticular tumors in male rats. Female rats were not affected. Although there was a
830
dose-related increase in the number of tumors in mice, there was no drug-related increase in the
831
number of mice with tumors. The relevance of these findings to humans is unknown.
832
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
833
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
834
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
835
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
836
Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in
837
rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive
838
disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m2
839
basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity
840
studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular
841
epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with
842
arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive
843
disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a
844
mg/m2 basis).
845
Pregnancy: Pregnancy Category D. See WARNINGS—Usage in Pregnancy: Teratogenic and
846
Nonteratogenic Effects.
847
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
848
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
849
should be exercised when PAXIL is administered to a nursing woman.
850
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
851
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
(see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Three
852
placebo-controlled trials in 752 pediatric patients with MDD have been conducted with PAXIL,
853
and the data were not sufficient to support a claim for use in pediatric patients. Anyone
854
considering the use of PAXIL in a child or adolescent must balance the potential risks with the
855
clinical need.
856
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
857
events were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a
858
rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-
859
harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased
860
appetite, tremor, sweating, hyperkinesia, and agitation.
861
Events reported upon discontinuation of treatment with PAXIL in the pediatric clinical trials
862
that included a taper phase regimen, which occurred in at least 2% of patients who received
863
PAXIL and which occurred at a rate at least twice that of placebo, were: emotional lability
864
(including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness,
865
dizziness, nausea, and abdominal pain (see Discontinuation of Treatment With PAXIL).
866
Geriatric Use: In worldwide premarketing clinical trials with PAXIL, 17% of patients treated
867
with PAXIL (approximately 700) were 65 years of age or older. Pharmacokinetic studies
868
revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there
869
were, however, no overall differences in the adverse event profile between elderly and younger
870
patients, and effectiveness was similar in younger and older patients (see CLINICAL
871
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
872
ADVERSE REACTIONS
873
Associated With Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients
874
treated with PAXIL in worldwide clinical trials in major depressive disorder and 16.1%
875
(84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients
876
treated with PAXIL in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD,
877
and PTSD, respectively, discontinued treatment due to an adverse event. The most common
878
events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events
879
associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo)
880
included the following:
881
882
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Major
Depressive
Disorder
OCD
Panic Disorder
Social Anxiety
Disorder
Generalized
Anxiety Disorder
PTSD
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
CNS
Somnolence
2.3%
0.7%
—
1.9%
0.3%
3.4%
0.3%
2.0%
0.2%
2.8%
0.6%
Insomnia
—
—
1.7%
0%
1.3%
0.3%
3.1%
0%
—
—
Agitation
1.1%
0.5%
—
—
—
Tremor
1.1%
0.3%
—
1.7%
0%
1.0%
0.2%
Anxiety
—
—
—
1.1%
0%
—
—
Dizziness
—
—
1.5%
0%
1.9%
0%
1.0%
0.2%
—
—
Gastroin-
testinal
Constipation
—
1.1%
0%
—
—
Nausea
3.2%
1.1%
1.9%
0%
3.2%
1.2%
4.0%
0.3%
2.0%
0.2%
2.2%
0.6%
Diarrhea
1.0%
0.3%
—
Dry mouth
1.0%
0.3%
—
—
—
Vomiting
1.0%
0.3%
—
1.0%
0%
—
—
Flatulence
1.0%
0.3%
—
—
Other
Asthenia
1.6%
0.4%
1.9%
0.4%
2.5%
0.6%
1.8%
0.2%
1.6%
0.2%
Abnormal
ejaculation1
1.6%
0%
2.1%
0%
4.9%
0.6%
2.5%
0.5%
—
—
Sweating
1.0%
0.3%
—
1.1%
0%
1.1%
0.2%
—
—
Impotence1
—
1.5%
0%
—
—
Libido
Decreased
1.0%
0%
—
—
Where numbers are not provided the incidence of the adverse events in patients treated with PAXIL was not >1% or
883
was not greater than or equal to 2 times the incidence of placebo.
884
1. Incidence corrected for gender.
885
886
Commonly Observed Adverse Events: Major Depressive Disorder: The most
887
commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
888
greater and incidence for PAXIL at least twice that for placebo, derived from Table 2) were:
889
Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor,
890
nervousness, ejaculatory disturbance, and other male genital disorders.
891
Obsessive Compulsive Disorder: The most commonly observed adverse events
892
associated with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at
893
least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite,
894
constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
895
Panic Disorder: The most commonly observed adverse events associated with the use of
896
paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for placebo,
897
derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor,
898
abnormal ejaculation, female genital disorders, and impotence.
899
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
Social Anxiety Disorder: The most commonly observed adverse events associated with
900
the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for
901
placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased
902
appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital
903
disorders, and impotence.
904
Generalized Anxiety Disorder: The most commonly observed adverse events associated
905
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
906
that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased
907
appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal
908
ejaculation.
909
Posttraumatic Stress Disorder: The most commonly observed adverse events associated
910
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
911
that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea,
912
decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders,
913
and impotence.
914
Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in
915
the tables following cannot be used to predict the incidence of side effects in the course of usual
916
medical practice where patient characteristics and other factors differ from those that prevailed in
917
the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from
918
other clinical investigations involving different treatments, uses, and investigators. The cited
919
figures, however, do provide the prescribing physician with some basis for estimating the
920
relative contribution of drug and nondrug factors to the side effect incidence rate in the
921
populations studied.
922
Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an
923
incidence of 1% or more among paroxetine-treated patients who participated in short-term
924
(6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to
925
50 mg/day. Reported adverse events were classified using a standard COSTART-based
926
Dictionary terminology.
927
928
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
929
Clinical Trials for Major Depressive Disorder1
930
Body System
Preferred Term
PAXIL
(n = 421)
Placebo
(n = 421)
Body as a Whole
Headache
18%
17%
Asthenia
15%
6%
Cardiovascular
Palpitation
3%
1%
Vasodilation
3%
1%
Dermatologic
Sweating
11%
2%
Rash
2%
1%
Gastrointestinal
Nausea
26%
9%
Dry Mouth
18%
12%
Constipation
14%
9%
Diarrhea
12%
8%
Decreased Appetite
6%
2%
Flatulence
4%
2%
Oropharynx Disorder2
2%
0%
Dyspepsia
2%
1%
Musculoskeletal
Myopathy
2%
1%
Myalgia
2%
1%
Myasthenia
1%
0%
Nervous System
Somnolence
23%
9%
Dizziness
13%
6%
Insomnia
13%
6%
Tremor
8%
2%
Nervousness
5%
3%
Anxiety
5%
3%
Paresthesia
4%
2%
Libido Decreased
3%
0%
Drugged Feeling
2%
1%
Confusion
1%
0%
Respiration
Yawn
4%
0%
Special Senses
Blurred Vision
4%
1%
Taste Perversion
2%
0%
Urogenital System
Ejaculatory Disturbance3,4
13%
0%
Other Male Genital Disorders3,5
10%
0%
Urinary Frequency
3%
1%
Urination Disorder6
3%
0%
Female Genital Disorders3,7
2%
0%
1. Events reported by at least 1% of patients treated with PAXIL are included, except the
931
following events which had an incidence on placebo ≥ PAXIL: Abdominal pain, agitation,
932
back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis,
933
postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”),
934
trauma, and vomiting.
935
2. Includes mostly “lump in throat” and “tightness in throat.”
936
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
3. Percentage corrected for gender.
937
4. Mostly “ejaculatory delay.”
938
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual
939
dysfunction,” and “impotence.”
940
6. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
941
7. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
942
943
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:
944
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD
945
patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
946
patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on
947
PAXIL who participated in placebo-controlled trials of 10- to 12-weeks duration in which
948
patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety
949
disorder on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
950
patients were dosed in a range of 20 mg to 50 mg/day.
951
952
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
953
Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety
954
Disorder1
955
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
Body System
Preferred Term
PAXIL
(n = 542)
Placebo
(n = 265)
PAXIL
(n = 469)
Placebo
(n = 324)
PAXIL
(n = 425)
Placebo
(n = 339)
Body as a Whole
Asthenia
22%
14%
14%
5%
22%
14%
Abdominal Pain
—
—
4%
3%
—
—
Chest Pain
3%
2%
—
—
—
—
Back Pain
—
—
3%
2%
—
—
Chills
2%
1%
2%
1%
—
—
Trauma
—
—
—
—
3%
1%
Cardiovascular
Vasodilation
4%
1%
—
—
—
—
Palpitation
2%
0%
—
—
—
—
Dermatologic
Sweating
9%
3%
14%
6%
9%
2%
Rash
3%
2%
—
—
—
—
Gastrointestinal
Nausea
23%
10%
23%
17%
25%
7%
Dry Mouth
18%
9%
18%
11%
9%
3%
Constipation
16%
6%
8%
5%
5%
2%
Diarrhea
10%
10%
12%
7%
9%
6%
Decreased
Appetite
9%
3%
7%
3%
8%
2%
Dyspepsia
—
—
—
—
4%
2%
Flatulence
—
—
—
—
4%
2%
Increased
Appetite
4%
3%
2%
1%
—
—
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
Vomiting
—
—
—
—
2%
1%
Musculoskeletal
Myalgia
—
—
—
—
4%
3%
Nervous System
Insomnia
24%
13%
18%
10%
21%
16%
Somnolence
24%
7%
19%
11%
22%
5%
Dizziness
12%
6%
14%
10%
11%
7%
Tremor
11%
1%
9%
1%
9%
1%
Nervousness
9%
8%
—
—
8%
7%
Libido Decreased
7%
4%
9%
1%
12%
1%
Agitation
—
—
5%
4%
3%
1%
Anxiety
—
—
5%
4%
5%
4%
Abnormal
Dreams
4%
1%
—
—
—
—
Concentration
Impaired
3%
2%
—
—
4%
1%
Depersonalization
3%
0%
—
—
—
—
Myoclonus
3%
0%
3%
2%
2%
1%
Amnesia
2%
1%
—
—
—
—
Respiratory System
Rhinitis
—
—
3%
0%
—
—
Pharyngitis
—
—
—
—
4%
2%
Yawn
—
—
—
—
5%
1%
Special Senses
Abnormal Vision
4%
2%
—
—
4%
1%
Taste Perversion
2%
0%
—
—
—
—
Urogenital System
Abnormal
Ejaculation2
23%
1%
21%
1%
28%
1%
Dysmenorrhea
—
—
—
—
5%
4%
Female Genital
Disorder2
3%
0%
9%
1%
9%
1%
Impotence2
8%
1%
5%
0%
5%
1%
Urinary
Frequency
3%
1%
2%
0%
—
—
Urination
Impaired
3%
0%
—
—
—
—
Urinary Tract
Infection
2%
1%
2%
1%
—
—
1. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with PAXIL are
956
included, except the following events which had an incidence on placebo ≥PAXIL: [OCD]: Abdominal pain, agitation,
957
anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory
958
disorder, rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough increased,
959
depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness,
960
palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and
961
vasodilation. [social anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and
962
sinusitis.
963
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
2. Percentage corrected for gender.
964
965
Generalized Anxiety Disorder and Posttraumatic Stress Disorder: Table 4
966
enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on
967
PAXIL who participated in placebo-controlled trials of 8-weeks duration in which patients were
968
dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on PAXIL who
969
participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a
970
range of 20 mg/day to 50 mg/day.
971
972
Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
973
Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disorder1
974
Generalized
Anxiety
Disorder
Posttraumatic
Stress
Disorder
Body System
Preferred Term
PAXIL
(n = 735)
Placebo
(n = 529)
PAXIL
(n = 676)
Placebo
(n = 504)
Asthenia
14%
6%
12%
4%
Headache
17%
14%
—
—
Infection
6%
3%
5%
4%
Abdominal Pain
4%
3%
Body as a Whole
Trauma
6%
5%
Cardiovascular
Vasodilation
3%
1%
2%
1%
Dermatologic
Sweating
6%
2%
5%
1%
Nausea
20%
5%
19%
8%
Dry Mouth
11%
5%
10%
5%
Constipation
10%
2%
5%
3%
Diarrhea
9%
7%
11%
5%
Decreased Appetite
5%
1%
6%
3%
Vomiting
3%
2%
3%
2%
Gastrointestinal
Dyspepsia
—
—
5%
3%
Insomnia
11%
8%
12%
11%
Somnolence
15%
5%
16%
5%
Dizziness
6%
5%
6%
5%
Tremor
5%
1%
4%
1%
Nervousness
4%
3%
—
—
Libido Decreased
9%
2%
5%
2%
Nervous System
Abnormal Dreams
3%
2%
Respiratory Disorder
7%
5%
—
—
Sinusitis
4%
3%
—
—
Respiratory
System
Yawn
4%
—
2%
<1%
Special Senses
Abnormal Vision
2%
1%
3%
1%
Abnormal
Ejaculation
2
25%
2%
13%
2%
Female
Genital
Disorder
2
4%
1%
5%
1%
Urogenital
System
Impotence
2
4%
3%
9%
1%
1. Events reported by at least 2% of GAD and PTSD in patients treated with PAXIL are included, except the
975
following events which had an incidence on placebo ≥PAXIL [GAD]: Abdominal pain, back pain, trauma,
976
dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain, headache, anxiety, depression, nervousness, respiratory
977
disorder, pharyngitis, and sinusitis.
978
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
2. Percentage corrected for gender.
979
980
Dose Dependency of Adverse Events: A comparison of adverse event rates in a
981
fixed-dose study comparing 10, 20, 30, and 40 mg/day of PAXIL with placebo in the treatment
982
of major depressive disorder revealed a clear dose dependency for some of the more common
983
adverse events associated with use of PAXIL, as shown in the following table:
984
985
Table 5 . Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial
986
in the Treatment of Major Depressive Disorder*
987
Placebo
PAXIL
Body System/Preferred Term
n = 51
10 mg
n = 102
20 mg
n = 104
30 mg
n = 101
40 mg
n = 102
Body as a Whole
Asthenia
0.0%
2.9%
10.6%
13.9%
12.7%
Dermatology
Sweating
2.0%
1.0%
6.7%
8.9%
11.8%
Gastrointestinal
Constipation
5.9%
4.9%
7.7%
9.9%
12.7%
Decreased Appetite
2.0%
2.0%
5.8%
4.0%
4.9%
Diarrhea
7.8%
9.8%
19.2%
7.9%
14.7%
Dry Mouth
2.0%
10.8%
18.3%
15.8%
20.6%
Nausea
13.7%
14.7%
26.9%
34.7%
36.3%
Nervous System
Anxiety
0.0%
2.0%
5.8%
5.9%
5.9%
Dizziness
3.9%
6.9%
6.7%
8.9%
12.7%
Nervousness
0.0%
5.9%
5.8%
4.0%
2.9%
Paresthesia
0.0%
2.9%
1.0%
5.0%
5.9%
Somnolence
7.8%
12.7%
18.3%
20.8%
21.6%
Tremor
0.0%
0.0%
7.7%
7.9%
14.7%
Special Senses
Blurred Vision
2.0%
2.9%
2.9%
2.0%
7.8%
Urogenital System
Abnormal Ejaculation
0.0%
5.8%
6.5%
10.6%
13.0%
Impotence
0.0%
1.9%
4.3%
6.4%
1.9%
Male Genital Disorders
0.0%
3.8%
8.7%
6.4%
3.7%
* Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups
988
and ≥ twice the placebo incidence for at least 1 paroxetine group.
989
990
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
991
OCD, there was no clear relationship between adverse events and the dose of PAXIL to which
992
patients were assigned. No new adverse events were observed in the group treated with 60 mg of
993
PAXIL compared to any of the other treatment groups.
994
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of PAXIL in the treatment of
995
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
panic disorder, there was no clear relationship between adverse events and the dose of PAXIL to
996
which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor,
997
and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in
998
patients receiving 60 mg of PAXIL compared to any of the other treatment groups.
999
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
1000
social anxiety disorder, for most of the adverse events, there was no clear relationship between
1001
adverse events and the dose of PAXIL to which patients were assigned.
1002
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1003
generalized anxiety disorder, for most of the adverse events, there was no clear relationship
1004
between adverse events and the dose of PAXIL to which patients were assigned, except for the
1005
following adverse events: Asthenia, constipation, and abnormal ejaculation.
1006
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1007
posttraumatic stress disorder, for most of the adverse events, there was no clear relationship
1008
between adverse events and the dose of PAXIL to which patients were assigned, except for
1009
impotence and abnormal ejaculation.
1010
Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence
1011
of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less
1012
to other effects (e.g., dry mouth, somnolence, and asthenia).
1013
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
1014
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
1015
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
1016
evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward
1017
sexual experiences.
1018
Reliable estimates of the incidence and severity of untoward experiences involving sexual
1019
desire, performance, and satisfaction are difficult to obtain, however, in part because patients and
1020
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
1021
untoward sexual experience and performance cited in product labeling, are likely to
1022
underestimate their actual incidence.
1023
In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the
1024
reported incidence of sexual side effects in males and females with major depressive disorder,
1025
OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.
1026
1027
Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials
1028
PAXIL
Placebo
n (males)
1446
1042
Decreased Libido
6-15%
0-5%
Ejaculatory Disturbance
13-28%
0-2%
Impotence
2-9%
0-3%
n (females)
1822
1340
Decreased Libido
0-9%
0-2%
Orgasmic Disturbance
2-9%
0-1%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
1029
There are no adequate and well-controlled studies examining sexual dysfunction with
1030
paroxetine treatment.
1031
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
1032
known outcome, patients recovered without sequelae.
1033
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
1034
SSRIs, physicians should routinely inquire about such possible side effects.
1035
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
1036
treatment with PAXIL for some patients but, on average, patients in controlled trials had minimal
1037
(about 1 pound) weight loss versus smaller changes on placebo and active control. No significant
1038
changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were
1039
observed in patients treated with PAXIL in controlled clinical trials.
1040
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with PAXIL and
1041
415 patients treated with placebo in controlled clinical trials, no clinically significant changes
1042
were seen in the ECGs of either group.
1043
Liver Function Tests: In placebo-controlled clinical trials, patients treated with PAXIL
1044
exhibited abnormal values on liver function tests at no greater rate than that seen in
1045
placebo-treated patients. In particular, the PAXIL-versus-placebo comparisons for alkaline
1046
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
1047
with marked abnormalities.
1048
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
1049
hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients
1050
receiving placebo.
1051
Other Events Observed During the Premarketing Evaluation of PAXIL: During its
1052
premarketing assessment in major depressive disorder, multiple doses of PAXIL were
1053
administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure
1054
to PAXIL varied greatly and included (in overlapping categories) open and double-blind studies,
1055
uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration
1056
studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder,
1057
generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676
1058
patients, respectively, received multiple doses of PAXIL. Untoward events associated with this
1059
exposure were recorded by clinical investigators using terminology of their own choosing.
1060
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
1061
experiencing adverse events without first grouping similar types of untoward events into a
1062
smaller number of standardized event categories.
1063
In the tabulations that follow, reported adverse events were classified using a standard
1064
COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the
1065
proportion of the 9,089 patients exposed to multiple doses of PAXIL who experienced an event
1066
of the type cited on at least 1 occasion while receiving PAXIL. All reported events are included
1067
except those already listed in Tables 2 to 4, those reported in terms so general as to be
1068
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
uninformative and those events where a drug cause was remote. It is important to emphasize that
1069
although the events reported occurred during treatment with paroxetine, they were not
1070
necessarily caused by it.
1071
Events are further categorized by body system and listed in order of decreasing frequency
1072
according to the following definitions: Frequent adverse events are those occurring on 1 or more
1073
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
1074
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1075
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events
1076
of major clinical importance are also described in the PRECAUTIONS section.
1077
Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain;
1078
rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis,
1079
ulcer.
1080
Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia,
1081
hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris,
1082
arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular
1083
accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial
1084
ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis,
1085
thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
1086
Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis,
1087
gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal
1088
hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia,
1089
cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal
1090
incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction,
1091
jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis,
1092
stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
1093
Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism,
1094
thyroiditis.
1095
Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy,
1096
purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia,
1097
hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal
1098
lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia,
1099
thrombocythemia, thrombocytopenia.
1100
Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema,
1101
SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased,
1102
bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma
1103
globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia,
1104
hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic
1105
dehydrogenase increased, non-protein nitrogen (NPN) increased.
1106
Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare:
1107
Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
1108
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking,
1109
alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia,
1110
hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction,
1111
neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia,
1112
choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug
1113
dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion,
1114
hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy,
1115
nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes
1116
increased, stupor, torticollis, trismus, withdrawal syndrome.
1117
Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation,
1118
pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary
1119
edema, sputum increased, stridor, voice alteration.
1120
Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis,
1121
dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema,
1122
erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis;
1123
herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy,
1124
skin ulcer, sweating decreased, vesiculobullous rash.
1125
Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation,
1126
conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia,
1127
anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye
1128
hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia,
1129
ptosis, retinal hemorrhage, taste loss, visual field defect.
1130
Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria,
1131
menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency,
1132
vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis,
1133
female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis,
1134
metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith,
1135
vaginal hemorrhage, vaginal moniliasis.
1136
Postmarketing Reports: Voluntary reports of adverse events in patients taking PAXIL that
1137
have been received since market introduction and not listed above that may have no causal
1138
relationship with the drug include acute pancreatitis, elevated liver function tests (the most
1139
severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated
1140
with severe liver dysfunction), Guillain-Barré syndrome, toxic epidermal necrolysis, priapism,
1141
syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and
1142
galactorrhea, neuroleptic malignant syndrome–like events, serotonin syndrome; extrapyramidal
1143
symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia,
1144
oculogyric crisis which has been associated with concomitant use of pimozide; tremor and
1145
trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis,
1146
anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular
1147
tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related
1148
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and
1149
agranulocytosis), and vasculitic syndromes (such as Henoch-Schönlein purpura). There has been
1150
a case report of an elevated phenytoin level after 4 weeks of PAXIL and phenytoin
1151
coadministration. There has been a case report of severe hypotension when PAXIL was added to
1152
chronic metoprolol treatment.
1153
DRUG ABUSE AND DEPENDENCE
1154
Controlled Substance Class: PAXIL is not a controlled substance.
1155
Physical and Psychologic Dependence: PAXIL has not been systematically studied in
1156
animals or humans for its potential for abuse, tolerance or physical dependence. While the
1157
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
1158
not systematic and it is not possible to predict on the basis of this limited experience the extent to
1159
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
1160
patients should be evaluated carefully for history of drug abuse, and such patients should be
1161
observed closely for signs of misuse or abuse of PAXIL (e.g., development of tolerance,
1162
incrementations of dose, drug-seeking behavior).
1163
OVERDOSAGE
1164
Human Experience: Since the introduction of PAXIL in the United States, 342 spontaneous
1165
cases of deliberate or accidental overdosage during paroxetine treatment have been reported
1166
worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with
1167
other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve
1168
paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were
1169
generally confounded by the ingestion of other drugs or alcohol or the presence of significant
1170
comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without
1171
sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum
1172
recommended daily dose) in a patient who recovered.
1173
Commonly reported adverse events associated with paroxetine overdosage include
1174
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
1175
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
1176
substances) include mydriasis, convulsions (including status epilepticus), ventricular
1177
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
1178
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
1179
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
1180
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
1181
Overdosage Management: Treatment should consist of those general measures employed in
1182
the management of overdosage with any drugs effective in the treatment of major depressive
1183
disorder.
1184
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
1185
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
1186
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
1187
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
1188
patients.
1189
Activated charcoal should be administered. Due to the large volume of distribution of this
1190
drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of
1191
benefit. No specific antidotes for paroxetine are known.
1192
A specific caution involves patients who are taking or have recently taken paroxetine who
1193
might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
1194
parent tricyclic and/or an active metabolite may increase the possibility of clinically significant
1195
sequelae and extend the time needed for close medical observation (see PRECAUTIONS—
1196
Drugs Metabolized by Cytochrome CYP2D6).
1197
In managing overdosage, consider the possibility of multiple drug involvement. The physician
1198
should consider contacting a poison control center for additional information on the treatment of
1199
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
1200
Desk Reference (PDR).
1201
DOSAGE AND ADMINISTRATION
1202
Major Depressive Disorder: Usual Initial Dosage: PAXIL should be administered as a
1203
single daily dose with or without food, usually in the morning. The recommended initial dose is
1204
20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating
1205
the effectiveness of PAXIL in the treatment of major depressive disorder. As with all drugs
1206
effective in the treatment of major depressive disorder, the full effect may be delayed. Some
1207
patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day
1208
increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least
1209
1 week.
1210
Maintenance Therapy: There is no body of evidence available to answer the question of
1211
how long the patient treated with PAXIL should remain on it. It is generally agreed that acute
1212
episodes of major depressive disorder require several months or longer of sustained
1213
pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose
1214
needed to maintain and/or sustain euthymia is unknown.
1215
Systematic evaluation of the efficacy of PAXIL has shown that efficacy is maintained for
1216
periods of up to 1 year with doses that averaged about 30 mg.
1217
Obsessive Compulsive Disorder: Usual Initial Dosage: PAXIL should be administered
1218
as a single daily dose with or without food, usually in the morning. The recommended dose of
1219
PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the
1220
dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at
1221
least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials
1222
demonstrating the effectiveness of PAXIL in the treatment of OCD. The maximum dosage
1223
should not exceed 60 mg/day.
1224
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month
1225
relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a
1226
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—
1227
Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a
1228
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1229
effective dosage, and patients should be periodically reassessed to determine the need for
1230
continued treatment.
1231
Panic Disorder: Usual Initial Dosage: PAXIL should be administered as a single daily dose
1232
with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic
1233
disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in
1234
10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to
1235
60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL. The maximum dosage
1236
should not exceed 60 mg/day.
1237
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month
1238
relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine
1239
demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL
1240
PHARMACOLOGY—Clinical Trials). Panic disorder is a chronic condition, and it is reasonable
1241
to consider continuation for a responding patient. Dosage adjustments should be made to
1242
maintain the patient on the lowest effective dosage, and patients should be periodically
1243
reassessed to determine the need for continued treatment.
1244
Social Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a single
1245
daily dose with or without food, usually in the morning. The recommended and initial dosage is
1246
20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a
1247
range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social
1248
anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional
1249
benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY—Clinical Trials).
1250
Maintenance Therapy: There is no body of evidence available to answer the question of
1251
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1252
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety
1253
disorder is recognized as a chronic condition, and it is reasonable to consider continuation of
1254
treatment for a responding patient. Dosage adjustments should be made to maintain the patient
1255
on the lowest effective dosage, and patients should be periodically reassessed to determine the
1256
need for continued treatment.
1257
Generalized Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a
1258
single daily dose with or without food, usually in the morning. In clinical trials the effectiveness
1259
of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended
1260
starting dosage and the established effective dosage is 20 mg/day. There is not sufficient
1261
evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur
1262
in 10 mg/day increments and at intervals of at least 1 week.
1263
Maintenance Therapy: Systematic evaluation of continuing PAXIL for periods of up to
1264
24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL
1265
during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see
1266
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, patients should be periodically
1267
reassessed to determine the need for maintenance treatment.
1268
Posttraumatic Stress Disorder: Usual Initial Dosage: PAXIL should be administered as
1269
a single daily dose with or without food, usually in the morning. The recommended starting
1270
dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of
1271
PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed
1272
dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day
1273
compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at
1274
intervals of at least 1 week.
1275
Maintenance Therapy: There is no body of evidence available to answer the question of
1276
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1277
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is
1278
recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a
1279
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1280
effective dosage, and patients should be periodically reassessed to determine the need for
1281
continued treatment.
1282
Special Populations: Treatment of Pregnant Women During the Third Trimester:
1283
Neonates exposed to PAXIL and other SSRIs or SNRIs, late in the third trimester have
1284
developed complications requiring prolonged hospitalization, respiratory support, and tube
1285
feeding (see WARNINGS). When treating pregnant women with paroxetine during the third
1286
trimester, the physician should carefully consider the potential risks and benefits of treatment.
1287
The physician may consider tapering paroxetine in the third trimester.
1288
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
1289
Hepatic Impairment: The recommended initial dose is 10 mg/day for elderly patients,
1290
debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be
1291
made if indicated. Dosage should not exceed 40 mg/day.
1292
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
1293
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL.
1294
Similarly, at least 14 days should be allowed after stopping PAXIL before starting an MAOI.
1295
Discontinuation of Treatment With PAXIL: Symptoms associated with discontinuation of
1296
PAXIL have been reported (see PRECAUTIONS). Patients should be monitored for these
1297
symptoms when discontinuing treatment, regardless of the indication for which PAXIL is being
1298
prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended
1299
whenever possible. If intolerable symptoms occur following a decrease in the dose or upon
1300
discontinuation of treatment, then resuming the previously prescribed dose may be considered.
1301
Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
1302
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
1303
HOW SUPPLIED
1304
Tablets: Film-coated, modified-oval as follows:
1305
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
10-mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
1306
NDC 0029-3210-13 Bottles of 30
1307
20-mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
1308
NDC 0029-3211-13 Bottles of 30
1309
NDC 0029-3211-59 Bottles of 90
1310
NDC 0029-3211-21 SUP 100s (intended for institutional use only)
1311
30-mg blue tablets engraved on the front with PAXIL and on the back with 30.
1312
NDC 0029-3212-13 Bottles of 30
1313
40-mg green tablets engraved on the front with PAXIL and on the back with 40.
1314
NDC 0029-3213-13 Bottles of 30
1315
Store tablets between 15° and 30°C (59° and 86°F).
1316
Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.
1317
NDC 0029-3215-48
1318
Store suspension at or below 25°C (77°F).
1319
PAXIL is a registered trademark of GlaxoSmithKline.
1320
1321
1322
Medication Guide
1323
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
1324
Thoughts or Actions
1325
PAXIL® (PAX-il) (paroxetine hydrochloride) Tablets and Oral Suspension
1326
1327
Read the Medication Guide that comes with your or your family member’s antidepressant
1328
medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with
1329
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
1330
about:
1331
• All risks and benefits of treatment with antidepressant medicines
1332
• All treatment choices for depression or other serious mental illness
1333
1334
What is the most important information I should know about antidepressant medicines,
1335
depression and other serious mental illnesses, and suicidal thoughts or action?
1336
1337
1. Antidepressant medicines may increase suicidal thoughts and actions in some children,
1338
teenagers, and young adults within the first few months of treatment.
1339
1340
2. Depression and other serious mental illnesses are the most important causes of suicidal
1341
thoughts and actions. Some people may have a particularly high risk of having suicidal
1342
thoughts or actions. These include people who have (or have a family history of) bipolar
1343
illness (also called manic-depressive illness) or suicidal thoughts or actions.
1344
1345
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
1346
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
family member?
1347
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
1348
thoughts, or feelings. This is very important when an antidepressant is started or when the
1349
dose is changed.
1350
• Call the healthcare provider right away to report new or sudden changes in mood,
1351
behavior, thoughts, or feelings.
1352
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
1353
provider between visits as needed, especially if you have concerns about symptoms.
1354
1355
Call a healthcare provider right away if you or your family member hasany of the
1356
following symptoms, especially if they are new, worse, or worry you:
1357
• Thoughts about suicide or dying
1358
• Attempts to commit suicide
1359
• New or worse depression
1360
• New or worse anxiety
1361
• Feeling very agitated or restless
1362
• Panic attacks
1363
• Trouble sleeping (insomnia)
1364
• New or worse irritability
1365
• Acting aggressive, being angry, or violent
1366
• Acting on dangerous impulses
1367
• An extreme increase in activity and talking (mania)
1368
• Other unusual changes in behavior or mood
1369
1370
What else do I need to know about antidepressant medicines?
1371
1372
• Never stop an antidepressant medicine without first talking to a healthcare
1373
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
1374
1375
• Antidepressants are medicines used to treat depression and other illnesses. It is
1376
important to discuss all the risk of treating depression and also the risks of not treating it.
1377
Patients and their families or other caregivers should discuss all treatment choices with
1378
the healthcare provider, not just the use of antidepressants.
1379
1380
• Antidepressant medicines have other side effects. Talk to the healthcare provider about
1381
the side effects of the medicine prescribed for you or your family member.
1382
1383
• Antidepressant medicines can interact with other medicines. Know all of the
1384
medicines that you or your family member takes. Keep a list of all medicines to show the
1385
healthcare provider. Do not start new medicines without first checking with your
1386
healthcare provider.
1387
1388
• Not all antidepressant medicines prescribed for children are FDA approved for use
1389
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
in children. Talk to your child’s healthcare provider for more information.
1390
1391
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
1392
antidepressants.
1393
PXL:3MG
1394
1395
1396
GlaxoSmithKline
1397
Research Triangle Park, NC 27709
1398
1399
©2007, GlaxoSmithKline. All rights reserved.
1400
1401
June 2007
PXL:44PI
1402
1403
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:27.719477
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020031s053,020710s017lbl.pdf', 'application_number': 20031, 'submission_type': 'SUPPL ', 'submission_number': 53}
|
12,144
|
1
PRESCRIBING INFORMATION
2
PAXIL®
3
(paroxetine hydrochloride)
4
Tablets and Oral Suspension
5
6
Suicidality and Antidepressant Drugs
7
Antidepressants increased the risk compared to placebo of suicidal thinking and
8
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
9
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
10
use of PAXIL or any other antidepressant in a child, adolescent, or young adult must
11
balance this risk with the clinical need. Short-term studies did not show an increase in the
12
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
13
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
14
older. Depression and certain other psychiatric disorders are themselves associated with
15
increases in the risk of suicide. Patients of all ages who are started on antidepressant
16
therapy should be monitored appropriately and observed closely for clinical worsening,
17
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
18
the need for close observation and communication with the prescriber. PAXIL is not
19
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
20
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
21
DESCRIPTION
22
PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the
23
hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'
24
fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate
25
and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8
26
(329.4 as free base). The structural formula of paroxetine hydrochloride is: chemical structure of paxil
27
28
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
29
120° to 138°C and a solubility of 5.4 mg/mL in water.
30
Tablets: Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as
31
follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive
32
ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate,
33
polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C
35
Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.
36
Suspension for Oral Administration: Each 5 mL of orange-colored, orange-flavored liquid
37
contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist
38
of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol,
39
methylparaben, propylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium
40
saccharin, flavorings, FD&C Yellow No. 6 aluminum lake, and simethicone emulsion, USP.
41
CLINICAL PHARMACOLOGY
42
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
43
disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD),
44
generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be
45
linked to potentiation of serotonergic activity in the central nervous system resulting from
46
inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically
47
relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into
48
human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly
49
selective inhibitor of neuronal serotonin reuptake and has only very weak effects on
50
norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate
51
that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine
52
(D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic,
53
and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and
54
cardiovascular effects for other psychotropic drugs.
55
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
56
compound, they are essentially inactive.
57
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
58
solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours
59
(CV 32%) after oral dosing of 30 mg tablets of PAXIL daily for 30 days. Paroxetine is
60
extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in
61
pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part
62
by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the
63
feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are
64
deficient in CYP2D6 (poor metabolizers).
65
Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension
66
and tablet.
67
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
68
hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets
69
daily for 30 days, steady-state paroxetine concentrations were achieved by approximately
70
10 days for most subjects, although it may take substantially longer in an occasional patient. At
71
steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr.
72
(CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
73
and Cmin values were about 6 and 14 times what would be predicted from single-dose studies.
74
Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been
75
predicted from single-dose data in these subjects. The excess accumulation is a consequence of
76
the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.
77
The effects of food on the bioavailability of paroxetine were studied in subjects administered
78
a single dose with and without food. AUC was only slightly increased (6%) when drug was
79
administered with food but the Cmax was 29% greater, while the time to reach peak plasma
80
concentration decreased from 6.4 hours post-dosing to 4.9 hours.
81
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
82
plasma.
83
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
84
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
85
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
86
warfarin.
87
Metabolism and Excretion: The mean elimination half-life is approximately 21 hours
88
(CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose
89
proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg
90
daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was
91
observed in both populations, again reflecting a saturable metabolic pathway. In comparison to
92
Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than
93
doubled.
94
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
95
polar and conjugated products of oxidation and methylation, which are readily cleared.
96
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
97
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
98
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
99
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
100
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
101
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
102
interactions (see PRECAUTIONS).
103
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
104
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
105
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
106
1% as the parent compound over the 10-day post-dosing period.
107
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
108
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic
109
impairment. The mean plasma concentrations in patients with creatinine clearance below
110
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
111
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
112
about a 2-fold increase in plasma concentrations (AUC, Cmax).
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
113
The initial dosage should therefore be reduced in patients with severe renal or hepatic
114
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
115
AND ADMINISTRATION).
116
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20,
117
30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin
118
concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be
119
reduced (see DOSAGE AND ADMINISTRATION).
120
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
121
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
122
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
123
desipramine, risperidone, and atomoxetine (see PRECAUTIONS—Drug Interactions).
124
Clinical Trials
125
Major Depressive Disorder: The efficacy of PAXIL as a treatment for major depressive
126
disorder has been established in 6 placebo-controlled studies of patients with major depressive
127
disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective
128
than placebo in treating major depressive disorder by at least 2 of the following measures:
129
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
130
Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in
131
improvement of the HDRS sub-factor scores, including the depressed mood item, sleep
132
disturbance factor, and anxiety factor.
133
A study of outpatients with major depressive disorder who had responded to PAXIL (HDRS
134
total score <8) during an initial 8-week open-treatment phase and were then randomized to
135
continuation on PAXIL or placebo for 1 year demonstrated a significantly lower relapse rate for
136
patients taking PAXIL (15%) compared to those on placebo (39%). Effectiveness was similar for
137
male and female patients.
138
Obsessive Compulsive Disorder: The effectiveness of PAXIL in the treatment of obsessive
139
compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled
140
studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD
141
(DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale
142
(YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients
143
were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily
144
doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses
145
of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points,
146
respectively, on the YBOCS total score which was significantly greater than the approximate 4
147
point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a
148
flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg
149
daily). In this study, patients receiving paroxetine experienced a mean reduction of
150
approximately 7 points on the YBOCS total score, which was significantly greater than the mean
151
reduction of approximately 4 points in placebo-treated patients.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
152
The following table provides the outcome classification by treatment group on Global
153
Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
154
Outcome Classification (%) on CGI-Global Improvement Item
for Completers in Study 1
Outcome
Classification
Placebo
(n = 74)
PAXIL 20 mg
(n = 75)
PAXIL 40 mg
(n = 66)
PAXIL 60 mg
(n = 66)
Worse
14%
7%
7%
3%
No Change
44%
35%
22%
19%
Minimally Improved
24%
33%
29%
34%
Much Improved
11%
18%
22%
24%
Very Much Improved
7%
7%
20%
20%
155
156
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
157
function of age or gender.
158
The long-term maintenance effects of PAXIL in OCD were demonstrated in a long-term
159
extension to Study 1. Patients who were responders on paroxetine during the 3-month
160
double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were
161
randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase.
162
Patients randomized to paroxetine were significantly less likely to relapse than comparably
163
treated patients who were randomized to placebo.
164
Panic Disorder: The effectiveness of PAXIL in the treatment of panic disorder was
165
demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients
166
(Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia.
167
In these studies, PAXIL was shown to be significantly more effective than placebo in treating
168
panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical
169
Global Impression Severity of Illness score.
170
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine
171
doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed
172
only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were
173
free of panic attacks, compared to 44% of placebo-treated patients.
174
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and
175
placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of
176
placebo-treated patients.
177
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to
178
placebo in patients concurrently receiving standardized cognitive behavioral therapy. At
179
endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks
180
compared to 14% of placebo patients.
181
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was
182
approximately 40 mg/day of paroxetine.
183
Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an
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184
extension to Study 1. Patients who were responders during the 10-week double-blind phase and
185
during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or
186
40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized
187
to paroxetine were significantly less likely to relapse than comparably treated patients who were
188
randomized to placebo.
189
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
190
function of age or gender.
191
Social Anxiety Disorder: The effectiveness of PAXIL in the treatment of social anxiety
192
disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1,
193
2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the
194
effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of
195
responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very
196
much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social
197
Anxiety Scale (LSAS).
198
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and
199
placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the
200
CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In
201
Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to
202
29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI
203
Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients,
204
respectively.
205
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with
206
placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the
207
LSAS Total Score and the CGI Improvement responder criterion; there were trends for
208
superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in
209
this study of any additional benefit for doses higher than 20 mg/day.
210
Subgroup analyses generally did not indicate differences in treatment outcomes as a function
211
of age, race, or gender.
212
Generalized Anxiety Disorder: The effectiveness of PAXIL in the treatment of Generalized
213
Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled
214
studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).
215
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with
216
placebo. Doses of 20 mg or 40 mg of PAXIL were both demonstrated to be significantly superior
217
to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not
218
sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to
219
the 20 mg/day dose.
220
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo.
221
PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating
222
Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine
223
(20 mg to 50 mg daily), did not demonstrate statistically significant superiority of PAXIL over
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224
placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.
225
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or
226
gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
227
In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety
228
Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to
229
50 mg/day of PAXIL, were randomized to continuation of PAXIL at their same dose, or to
230
placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase
231
was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of
232
Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase
233
of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or
234
withdrawal due to lack of efficacy. Patients receiving continued PAXIL experienced a
235
significantly lower relapse rate over the subsequent 24 weeks compared to those receiving
236
placebo.
237
Posttraumatic Stress Disorder: The effectiveness of PAXIL in the treatment of
238
Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo
239
controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The
240
mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year
241
to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD
242
anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out
243
of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered
244
PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement
245
Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the
246
following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal.
247
The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2
248
total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were
249
defined as patients having a score of 1 (very much improved) or 2 (much improved).
250
Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to
251
placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to
252
placebo on change from baseline for the CAPS-2 total score and on proportion of responders on
253
the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the
254
40 mg/day dose compared to the 20 mg/day dose.
255
Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to
256
placebo. PAXIL was demonstrated to be significantly superior to placebo on change from
257
baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.
258
A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,
259
demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS
260
2 total score, but not on proportion of responders on the CGI-I.
261
The majority of patients in these trials were women (68% women: 377 out of 551 subjects in
262
Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not
263
indicate differences in treatment outcomes as a function of gender. There were an insufficient
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264
number of patients who were 65 years and older or were non-Caucasian to conduct subgroup
265
analyses on the basis of age or race, respectively.
266
INDICATIONS AND USAGE
267
Major Depressive Disorder: PAXIL is indicated for the treatment of major depressive
268
disorder.
269
The efficacy of PAXIL in the treatment of a major depressive episode was established in
270
6-week controlled trials of outpatients whose diagnoses corresponded most closely to the
271
DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical
272
Trials). A major depressive episode implies a prominent and relatively persistent depressed or
273
dysphoric mood that usually interferes with daily functioning (nearly every day for at least
274
2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in
275
sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in
276
sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
277
concentration, and a suicide attempt or suicidal ideation.
278
The effects of PAXIL in hospitalized depressed patients have not been adequately studied.
279
The efficacy of PAXIL in maintaining a response in major depressive disorder for up to 1 year
280
was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical
281
Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should
282
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
283
Obsessive Compulsive Disorder: PAXIL is indicated for the treatment of obsessions and
284
compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV.
285
The obsessions or compulsions cause marked distress, are time-consuming, or significantly
286
interfere with social or occupational functioning.
287
The efficacy of PAXIL was established in two 12-week trials with obsessive compulsive
288
outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive
289
compulsive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
290
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
291
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
292
intentional behaviors (compulsions) that are recognized by the person as excessive or
293
unreasonable.
294
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In
295
this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on
296
placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician
297
who elects to use PAXIL for extended periods should periodically re-evaluate the long-term
298
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
299
Panic Disorder: PAXIL is indicated for the treatment of panic disorder, with or without
300
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
301
unexpected panic attacks and associated concern about having additional attacks, worry about
302
the implications or consequences of the attacks, and/or a significant change in behavior related to
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303
the attacks.
304
The efficacy of PAXIL was established in three 10- to 12-week trials in panic disorder
305
patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
306
CLINICAL PHARMACOLOGY—Clinical Trials).
307
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
308
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
309
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
310
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
311
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
312
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
313
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
314
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
315
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In
316
this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate
317
compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials).
318
Nevertheless, the physician who prescribes PAXIL for extended periods should periodically
319
re-evaluate the long-term usefulness of the drug for the individual patient.
320
Social Anxiety Disorder: PAXIL is indicated for the treatment of social anxiety disorder,
321
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
322
characterized by a marked and persistent fear of 1 or more social or performance situations in
323
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
324
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
325
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
326
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
327
the person's normal routine, occupational or academic functioning, or social activities or
328
relationships, or there is marked distress about having the phobias. Lesser degrees of
329
performance anxiety or shyness generally do not require psychopharmacological treatment.
330
The efficacy of PAXIL was established in three 12-week trials in adult patients with social
331
anxiety disorder (DSM-IV). PAXIL has not been studied in children or adolescents with social
332
phobia (see CLINICAL PHARMACOLOGY—Clinical Trials).
333
The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more
334
than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
335
Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically
336
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
337
ADMINISTRATION).
338
Generalized Anxiety Disorder: PAXIL is indicated for the treatment of Generalized Anxiety
339
Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of
340
everyday life usually does not require treatment with an anxiolytic.
341
The efficacy of PAXIL in the treatment of GAD was established in two 8-week
342
placebo-controlled trials in adults with GAD. PAXIL has not been studied in children or
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343
adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY—Clinical
344
Trials).
345
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry
346
(apprehensive expectation) that is persistent for at least 6 months and which the person finds
347
difficult to control. It must be associated with at least 3 of the following 6 symptoms:
348
Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or
349
mind going blank, irritability, muscle tension, sleep disturbance.
350
The efficacy of PAXIL in maintaining a response in patients with Generalized Anxiety
351
Disorder, who responded during an 8-week acute treatment phase while taking PAXIL and were
352
then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo
353
controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the
354
physician who elects to use PAXIL for extended periods should periodically re-evaluate the
355
long-term usefulness of the drug for the individual patient (see DOSAGE AND
356
ADMINISTRATION).
357
Posttraumatic Stress Disorder: PAXIL is indicated for the treatment of Posttraumatic
358
Stress Disorder (PTSD).
359
The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebo
360
controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY—Clinical
361
Trials).
362
PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or
363
threatened death or serious injury, or threat to the physical integrity of self or others, and a
364
response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of
365
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
366
thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity
367
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
368
inability to recall details of the event, and/or numbing of general responsiveness manifested as
369
diminished interest in significant activities, estrangement from others, restricted range of affect,
370
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
371
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
372
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
373
and that they cause clinically significant distress or impairment in social, occupational, or other
374
important areas of functioning.
375
The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has
376
not been systematically evaluated in placebo-controlled trials. Therefore, the physician who
377
elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term
378
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
379
CONTRAINDICATIONS
380
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs), including
381
linezolid, an antibiotic which is a reversible non-selective MAOI, or thioridazine is
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382
contraindicated (see WARNINGS and PRECAUTIONS).
383
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
384
PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the
385
inactive ingredients in PAXIL.
386
WARNINGS
387
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
388
both adult and pediatric, may experience worsening of their depression and/or the emergence of
389
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
390
are taking antidepressant medications, and this risk may persist until significant remission
391
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
392
disorders themselves are the strongest predictors of suicide. There has been a long-standing
393
concern, however, that antidepressants may have a role in inducing worsening of depression and
394
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
395
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
396
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
397
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
398
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
399
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
400
antidepressants compared to placebo in adults aged 65 and older.
401
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
402
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short
403
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo
404
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short
405
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
406
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
407
increase in the younger patients for almost all drugs studied. There were differences in absolute
408
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
409
differences (drug vs placebo), however, were relatively stable within age strata and across
410
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
411
per 1,000 patients treated) are provided in Table 1.
412
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413
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
414
415
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
416
the number was not sufficient to reach any conclusion about drug effect on suicide.
417
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
418
months. However, there is substantial evidence from placebo-controlled maintenance trials in
419
adults with depression that the use of antidepressants can delay the recurrence of depression.
420
All patients being treated with antidepressants for any indication should be monitored
421
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
422
in behavior, especially during the initial few months of a course of drug therapy, or at times
423
of dose changes, either increases or decreases.
424
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
425
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
426
been reported in adult and pediatric patients being treated with antidepressants for major
427
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
428
Although a causal link between the emergence of such symptoms and either the worsening of
429
depression and/or the emergence of suicidal impulses has not been established, there is concern
430
that such symptoms may represent precursors to emerging suicidality.
431
Consideration should be given to changing the therapeutic regimen, including possibly
432
discontinuing the medication, in patients whose depression is persistently worse, or who are
433
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
434
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
435
patient’s presenting symptoms.
436
Families and caregivers of patients being treated with antidepressants for major
437
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
438
alerted about the need to monitor patients for the emergence of agitation, irritability,
439
unusual changes in behavior, and the other symptoms described above, as well as the
440
emergence of suicidality, and to report such symptoms immediately to healthcare
441
providers. Such monitoring should include daily observation by families and caregivers.
442
Prescriptions for PAXIL should be written for the smallest quantity of tablets consistent with
443
good patient management, in order to reduce the risk of overdose.
444
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
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445
presentation of bipolar disorder. It is generally believed (though not established in controlled
446
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
447
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
448
symptoms described above represent such a conversion is unknown. However, prior to initiating
449
treatment with an antidepressant, patients with depressive symptoms should be adequately
450
screened to determine if they are at risk for bipolar disorder; such screening should include a
451
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
452
depression. It should be noted that PAXIL is not approved for use in treating bipolar depression.
453
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
454
another serotonin reuptake inhibitor drug in combination with a monoamine oxidase
455
inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including
456
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of
457
vital signs, and mental status changes that include extreme agitation progressing to
458
delirium and coma. These reactions have also been reported in patients who have recently
459
discontinued that drug and have been started on an MAOI. Some cases presented with
460
features resembling neuroleptic malignant syndrome. While there are no human data
461
showing such an interaction with PAXIL, limited animal data on the effects of combined
462
use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate
463
blood pressure and evoke behavioral excitation. Therefore, it is recommended that PAXIL
464
not be used in combination with an MAOI (including linezolid, an antibiotic which is a
465
reversible non-selective MAOI), or within 14 days of discontinuing treatment with an
466
MAOI (see CONTRAINDICATIONS). At least 2 weeks should be allowed after stopping
467
PAXIL before starting an MAOI.
468
Serotonin Syndrome: The development of a potentially life-threatening serotonin
469
syndrome may occur with SNRIs and SSRIs, including PAXIL, particularly with
470
concomitant use of serotonergic drugs (including triptans) and with drugs which impair
471
metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include
472
mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
473
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g.,
474
hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting,
475
diarrhea).
476
The concomitant use of PAXIL with MAOIs intended to treat depression is
477
contraindicated (see CONTRAINDICATIONS and WARNINGS—Potential for
478
Interaction With Monoamine Oxidase Inhibitors).
479
If concomitant treatment with PAXIL with a 5-hydroxytryptamine receptor agonist
480
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
481
during treatment initiation and dose increases (see PRECAUTIONS—Drug Interactions).
482
The concomitant use of PAXIL with serotonin precursors (such as tryptophan) is not
483
recommended (see PRECAUTIONS—Drug Interactions).
484
Potential Interaction With Thioridazine: Thioridazine administration alone produces
13
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485
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
486
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
487
dose related.
488
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
489
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
490
used in combination with thioridazine (see CONTRAINDICATIONS and
491
PRECAUTIONS).
492
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
493
infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of
494
congenital malformations, particularly cardiovascular malformations. The findings from these
495
studies are summarized below:
496
• A study based on Swedish national registry data demonstrated that infants exposed to
497
paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular
498
malformations (2% risk in paroxetine-exposed infants) compared to the entire registry
499
population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8).
500
No increase in the risk of overall congenital malformations was seen in the paroxetine
501
exposed infants. The cardiac malformations in the paroxetine-exposed infants were
502
primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal
503
defects range in severity from those that resolve spontaneously to those which require
504
surgery.
505
• A separate retrospective cohort study from the United States (United Healthcare data)
506
evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester
507
(n = 815 for paroxetine). This study showed a trend towards an increased risk for
508
cardiovascular malformations for paroxetine (risk of 1.5%) compared to other
509
antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of
510
the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs.
511
This study also suggested an increased risk of overall major congenital malformations
512
including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk)
513
antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).
514
• Two large case-control studies using separate databases, each with >9,000 birth defect
515
cases and >4,000 controls, found that maternal use of paroxetine during the first
516
trimester of pregnancy was associated with a 2- to 3-fold increased risk of right
517
ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95%
518
confidence interval, 1.0 to 6.0, 7 exposed infants) and in the other study the odds ratio
519
was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).
520
Other studies have found varying results as to whether there was an increased risk of overall,
521
cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data
522
over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and
523
congenital malformations included the above-noted studies in addition to others (n = 17 studies
524
that included overall malformations and n = 14 studies that included cardiovascular
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
525
malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested
526
an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95%
527
confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1
528
to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to
529
determine the extent to which the observed prevalence of cardiovascular malformations might
530
have contributed to that of overall malformations, nor was it possible to determine whether any
531
specific types of cardiovascular malformations might have contributed to the observed
532
prevalence of all cardiovascular malformations.
533
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential
534
harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment,
535
consideration should be given to either discontinuing paroxetine therapy or switching to another
536
antidepressant (see PRECAUTIONS—Discontinuation of Treatment With PAXIL). For women
537
who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should
538
only be initiated after consideration of the other available treatment options.
539
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
540
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
541
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
542
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
543
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
544
trimester of gestation and continued throughout lactation. This effect occurred at a dose of
545
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
546
rat pup mortality was not determined. The cause of these deaths is not known.
547
Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs or serotonin and
548
norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
549
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
550
complications can arise immediately upon delivery. Reported clinical findings have included
551
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
552
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
553
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
554
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
555
clinical picture is consistent with serotonin syndrome (see WARNINGS—Potential for
556
Interaction With Monoamine Oxidase Inhibitors).
557
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
558
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
559
the general population and is associated with substantial neonatal morbidity and mortality. In a
560
retrospective case-control study of 377 women whose infants were born with PPHN and 836
561
women whose infants were born healthy, the risk for developing PPHN was approximately six
562
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
563
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
564
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
565
study that has investigated the potential risk. The study did not include enough cases with
566
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
567
There have also been postmarketing reports of premature births in pregnant women exposed
568
to paroxetine or other SSRIs.
569
When treating a pregnant woman with paroxetine during the third trimester, the physician
570
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
571
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
572
women with a history of major depression who were euthymic at the beginning of pregnancy,
573
women who discontinued antidepressant medication during pregnancy were more likely to
574
experience a relapse of major depression than women who continued antidepressant medication.
575
PRECAUTIONS
576
General: Activation of Mania/Hypomania: During premarketing testing, hypomania or
577
mania occurred in approximately 1.0% of unipolar patients treated with PAXIL compared to
578
1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients
579
classified as bipolar, the rate of manic episodes was 2.2% for PAXIL and 11.6% for the
580
combined active-control groups. As with all drugs effective in the treatment of major depressive
581
disorder, PAXIL should be used cautiously in patients with a history of mania.
582
Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with
583
PAXIL, a rate similar to that associated with other drugs effective in the treatment of major
584
depressive disorder. PAXIL should be used cautiously in patients with a history of seizures. It
585
should be discontinued in any patient who develops seizures.
586
Discontinuation of Treatment With PAXIL: Recent clinical trials supporting the various
587
approved indications for PAXIL employed a taper-phase regimen, rather than an abrupt
588
discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials
589
involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a
590
daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before
591
treatment was stopped.
592
With this regimen in those studies, the following adverse events were reported at an incidence
593
of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams,
594
paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and
595
were self-limiting and did not require medical intervention.
596
During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports
597
of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt),
598
including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances
599
(e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache,
600
lethargy, emotional lability, insomnia, and hypomania. While these events are generally self
601
limiting, there have been reports of serious discontinuation symptoms.
602
Patients should be monitored for these symptoms when discontinuing treatment with PAXIL.
603
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
604
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
605
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
606
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
607
ADMINISTRATION).
608
See also PRECAUTIONS—Pediatric Use, for adverse events reported upon discontinuation
609
of treatment with PAXIL in pediatric patients.
610
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
611
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
612
such as an inability to sit or stand still usually associated with subjective distress. This is most
613
likely to occur within the first few weeks of treatment.
614
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
615
including PAXIL. In many cases, this hyponatremia appears to be the result of the syndrome of
616
inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
617
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
618
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
619
volume depleted may be at greater risk (see Geriatric Use). Discontinuation of PAXIL should be
620
considered in patients with symptomatic hyponatremia and appropriate medical intervention
621
should be instituted.
622
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
623
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
624
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
625
seizure, coma, respiratory arrest, and death.
626
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
627
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
628
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
629
and cohort design) have demonstrated an association between use of drugs that interfere with
630
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
631
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
632
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
633
with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
634
coagulation.
635
Use in Patients With Concomitant Illness: Clinical experience with PAXIL in patients
636
with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in
637
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
638
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
639
PAXIL. A few cases of acute angle closure glaucoma associated with paroxetine therapy have
640
been reported in the literature. As mydriasis can cause acute angle closure in patients with
641
narrow angle glaucoma, caution should be used when PAXIL is prescribed for patients with
642
narrow angle glaucoma.
643
PAXIL has not been evaluated or used to any appreciable extent in patients with a recent
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
644
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
645
excluded from clinical studies during the product’s premarket testing. Evaluation of
646
electrocardiograms of 682 patients who received PAXIL in double-blind, placebo-controlled
647
trials, however, did not indicate that PAXIL is associated with the development of significant
648
ECG abnormalities. Similarly, PAXIL does not cause any clinically important changes in heart
649
rate or blood pressure.
650
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
651
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
652
be used in such patients (see DOSAGE AND ADMINISTRATION).
653
Information for Patients: PAXIL should not be chewed or crushed, and should be swallowed
654
whole.
655
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
656
PAXIL and triptans, tramadol, or other serotonergic agents.
657
Prescribers or other health professionals should inform patients, their families, and their
658
caregivers about the benefits and risks associated with treatment with PAXIL and should counsel
659
them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines,
660
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available
661
for PAXIL. The prescriber or health professional should instruct patients, their families, and their
662
caregivers to read the Medication Guide and should assist them in understanding its contents.
663
Patients should be given the opportunity to discuss the contents of the Medication Guide and to
664
obtain answers to any questions they may have. The complete text of the Medication Guide is
665
reprinted at the end of this document.
666
Patients should be advised of the following issues and asked to alert their prescriber if these
667
occur while taking PAXIL.
668
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
669
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
670
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
671
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
672
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
673
down. Families and caregivers of patients should be advised to look for the emergence of such
674
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
675
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
676
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
677
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
678
close monitoring and possibly changes in the medication.
679
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
680
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
681
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
682
interfere with serotonin reuptake and these agents has been associated with an increased risk of
683
bleeding.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
684
Interference With Cognitive and Motor Performance: Any psychoactive drug may
685
impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been
686
shown to impair psychomotor performance, patients should be cautioned about operating
687
hazardous machinery, including automobiles, until they are reasonably certain that therapy with
688
PAXIL does not affect their ability to engage in such activities.
689
Completing Course of Therapy: While patients may notice improvement with treatment
690
with PAXIL in 1 to 4 weeks, they should be advised to continue therapy as directed.
691
Concomitant Medication: Patients should be advised to inform their physician if they are
692
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
693
interactions.
694
Alcohol: Although PAXIL has not been shown to increase the impairment of mental and
695
motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
696
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
697
intend to become pregnant during therapy (see WARNINGS—Usage in Pregnancy: Teratogenic
698
and Nonteratogenic Effects).
699
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
700
infant (see PRECAUTIONS—Nursing Mothers).
701
Laboratory Tests: There are no specific laboratory tests recommended.
702
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
703
between paroxetine and tryptophan may occur when they are coadministered. Adverse
704
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
705
reported when tryptophan was administered to patients taking PAXIL. Consequently,
706
concomitant use of PAXIL with tryptophan is not recommended (see WARNINGS—Serotonin
707
Syndrome).
708
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
709
Pimozide: In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg
710
daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in
711
pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The
712
increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine.
713
Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT
714
interval, concomitant use of pimozide and PAXIL is contraindicated (see
715
CONTRAINDICATIONS).
716
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
717
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
718
PAXIL is coadministered with other drugs that may affect the serotonergic neurotransmitter
719
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
720
lithium, tramadol, or St. John's Wort (see WARNINGS—Serotonin Syndrome). The concomitant
721
use of PAXIL with MAOIs (including linezolid) is contraindicated (see
722
CONTRAINDICATIONS). The concomitant use of PAXIL with other SSRIs, SNRIs or
723
tryptophan is not recommended (see PRECAUTIONS—Drug Interactions, Tryptophan).
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
724
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
725
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
726
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
727
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
728
of PAXIL and warfarin should be undertaken with caution (see Drugs That Interfere With
729
Hemostasis).
730
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
731
an SSRI and a triptan. If concomitant use of PAXIL with a triptan is clinically warranted, careful
732
observation of the patient is advised, particularly during treatment initiation and dose increases
733
(see WARNINGS—Serotonin Syndrome).
734
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
735
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
736
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
737
where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma
738
concentrations of paroxetine were increased by approximately 50% during coadministration with
739
oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are
740
administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be
741
guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not
742
studied.
743
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
744
single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once
745
daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
746
respectively) compared to paroxetine administered alone. The effect of paroxetine on
747
phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear
748
pharmacokinetics, the results of this study may not address the case where the 2 drugs are both
749
being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when
750
coadministered with phenobarbital; any subsequent adjustment should be guided by clinical
751
effect.
752
Phenytoin: When a single oral 30-mg dose of PAXIL was administered at phenytoin steady
753
state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of
754
50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a
755
single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once
756
daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to
757
phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above
758
studies may not address the case where the 2 drugs are both being chronically dosed. No initial
759
dosage adjustments are considered necessary when these drugs are coadministered; any
760
subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS—
761
Postmarketing Reports).
762
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
763
treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
764
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
765
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
766
(>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily
767
dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose
768
desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold,
769
respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been
770
evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to
771
8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased
772
9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the
773
active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The
774
effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs
775
were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,
776
paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This
777
resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in
778
atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.
779
Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be
780
initiated at a reduced dose when it is given with paroxetine.
781
Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not
782
been formally studied but may require lower doses than usually prescribed for either PAXIL or
783
the other drug.
784
Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme,
785
including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,
786
amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type
787
1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme
788
(e.g., quinidine), should be approached with caution.
789
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
790
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
791
coadministered (see CONTRAINDICATIONS and WARNINGS).
792
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
793
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
794
PRECAUTIONS—Tricyclic Antidepressants).
795
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
796
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
797
cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In
798
addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be
799
at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several
800
substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and
801
cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and
802
its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4
803
substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
804
significance.
805
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of
806
tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism.
807
Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be
808
reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS—Drugs Metabolized by
809
Cytochrome CYP2D6).
810
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
811
protein, administration of PAXIL to a patient taking another drug that is highly protein bound
812
may cause increased free concentrations of the other drug, potentially resulting in adverse events.
813
Conversely, adverse effects could result from displacement of paroxetine by other highly bound
814
drugs.
815
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
816
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
817
the case-control and cohort design that have demonstrated an association between use of
818
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
819
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
820
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
821
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
822
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
823
Alcohol: Although PAXIL does not increase the impairment of mental and motor skills
824
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
825
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction
826
between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome,
827
caution is advised when PAXIL is coadministered with lithium.
828
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
829
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
830
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
831
paroxetine and digoxin should be undertaken with caution.
832
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
833
kinetics. The effects of paroxetine on diazepam were not evaluated.
834
Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0
835
24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%,
836
respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen,
837
the dose of procyclidine should be reduced.
838
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
839
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
840
coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of
841
propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS—
842
Postmarketing Reports).
843
Theophylline: Reports of elevated theophylline levels associated with treatment with
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
844
PAXIL have been reported. While this interaction has not been formally studied, it is
845
recommended that theophylline levels be monitored when these drugs are concurrently
846
administered.
847
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
848
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
849
clinical effect (tolerability and efficacy).
850
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
851
ECT and PAXIL.
852
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
853
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
854
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and
855
3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and
856
PTSD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than
857
that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only
858
2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of
859
male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for
860
control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
861
trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats
862
were not affected. Although there was a dose-related increase in the number of tumors in mice,
863
there was no drug-related increase in the number of mice with tumors. The relevance of these
864
findings to humans is unknown.
865
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
866
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
867
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
868
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
869
Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in
870
rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive
871
disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m2
872
basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity
873
studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular
874
epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with
875
arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive
876
disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a
877
mg/m2 basis).
878
Pregnancy: Pregnancy Category D. See WARNINGS—Usage in Pregnancy: Teratogenic and
879
Nonteratogenic Effects.
880
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
881
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
882
should be exercised when PAXIL is administered to a nursing woman.
883
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
884
(see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Three
885
placebo-controlled trials in 752 pediatric patients with MDD have been conducted with PAXIL,
886
and the data were not sufficient to support a claim for use in pediatric patients. Anyone
887
considering the use of PAXIL in a child or adolescent must balance the potential risks with the
888
clinical need.
889
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
890
events were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a
891
rate at least twice that for pediatric patients receiving placebo: emotional lability (including self
892
harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased
893
appetite, tremor, sweating, hyperkinesia, and agitation.
894
Events reported upon discontinuation of treatment with PAXIL in the pediatric clinical trials
895
that included a taper phase regimen, which occurred in at least 2% of patients who received
896
PAXIL and which occurred at a rate at least twice that of placebo, were: emotional lability
897
(including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness,
898
dizziness, nausea, and abdominal pain (see Discontinuation of Treatment With PAXIL).
899
Geriatric Use: SSRIs and SNRIs, including PAXIL, have been associated with cases of
900
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
901
event (see PRECAUTIONS, Hyponatremia).
902
In worldwide premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL
903
(approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased
904
clearance in the elderly, and a lower starting dose is recommended; there were, however, no
905
overall differences in the adverse event profile between elderly and younger patients, and
906
effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY
907
and DOSAGE AND ADMINISTRATION).
908
ADVERSE REACTIONS
909
Associated With Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients
910
treated with PAXIL in worldwide clinical trials in major depressive disorder and 16.1%
911
(84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients
912
treated with PAXIL in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD,
913
and PTSD, respectively, discontinued treatment due to an adverse event. The most common
914
events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events
915
associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo)
916
included the following:
917
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Major
Depressive
Disorder
OCD
Panic Disorder
Social Anxiety
Disorder
Generalized
Anxiety Disorder
PTSD
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
CNS
Somnolence
2.3%
0.7%
—
1.9%
0.3%
3.4%
0.3%
2.0%
0.2%
2.8%
0.6%
Insomnia
—
—
1.7%
0%
1.3%
0.3%
3.1%
0%
—
—
Agitation
1.1%
0.5%
—
—
—
Tremor
1.1%
0.3%
—
1.7%
0%
1.0%
0.2%
Anxiety
—
—
—
1.1%
0%
—
—
Dizziness
—
—
1.5%
0%
1.9%
0%
1.0%
0.2%
—
—
Gastroin
testinal
Constipation
—
1.1%
0%
—
—
Nausea
3.2%
1.1%
1.9%
0%
3.2%
1.2%
4.0%
0.3%
2.0%
0.2%
2.2%
0.6%
Diarrhea
1.0%
0.3%
—
Dry mouth
1.0%
0.3%
—
—
—
Vomiting
1.0%
0.3%
—
1.0%
0%
—
—
Flatulence
1.0%
0.3%
—
—
Other
Asthenia
Abnormal
1.6%
0.4%
1.9%
0.4%
2.5%
0.6%
1.8%
0.2%
1.6%
0.2%
ejaculation1
1.6%
0%
2.1%
0%
4.9%
0.6%
2.5%
0.5%
—
—
Sweating
1.0%
0.3%
—
1.1%
0%
1.1%
0.2%
—
—
Impotence1
Libido
—
1.5%
0%
—
—
Decreased
1.0%
0%
—
—
918
Where numbers are not provided the incidence of the adverse events in patients treated with PAXIL was not >1% or
919
was not greater than or equal to 2 times the incidence of placebo.
920
1. Incidence corrected for gender.
921
922
Commonly Observed Adverse Events: Major Depressive Disorder: The most
923
commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
924
greater and incidence for PAXIL at least twice that for placebo, derived from Table 2) were:
925
Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor,
926
nervousness, ejaculatory disturbance, and other male genital disorders.
927
Obsessive Compulsive Disorder: The most commonly observed adverse events
928
associated with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at
929
least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite,
930
constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
931
Panic Disorder: The most commonly observed adverse events associated with the use of
932
paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for placebo,
933
derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor,
934
abnormal ejaculation, female genital disorders, and impotence.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
935
Social Anxiety Disorder: The most commonly observed adverse events associated with
936
the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for
937
placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased
938
appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital
939
disorders, and impotence.
940
Generalized Anxiety Disorder: The most commonly observed adverse events associated
941
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
942
that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased
943
appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal
944
ejaculation.
945
Posttraumatic Stress Disorder: The most commonly observed adverse events associated
946
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
947
that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea,
948
decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders,
949
and impotence.
950
Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in
951
the tables following cannot be used to predict the incidence of side effects in the course of usual
952
medical practice where patient characteristics and other factors differ from those that prevailed in
953
the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from
954
other clinical investigations involving different treatments, uses, and investigators. The cited
955
figures, however, do provide the prescribing physician with some basis for estimating the
956
relative contribution of drug and nondrug factors to the side effect incidence rate in the
957
populations studied.
958
Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an
959
incidence of 1% or more among paroxetine-treated patients who participated in short-term
960
(6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to
961
50 mg/day. Reported adverse events were classified using a standard COSTART-based
962
Dictionary terminology.
963
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
964
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
965
Clinical Trials for Major Depressive Disorder1
Body System
Preferred Term
PAXIL
(n = 421)
Placebo
(n = 421)
Body as a Whole
Headache
Asthenia
18%
15%
17%
6%
Cardiovascular
Palpitation
Vasodilation
3%
3%
1%
1%
Dermatologic
Sweating
Rash
11%
2%
2%
1%
Gastrointestinal
Nausea
26%
9%
Dry Mouth
18%
12%
Constipation
14%
9%
Diarrhea
12%
8%
Decreased Appetite
6%
2%
Flatulence
4%
2%
Oropharynx Disorder2
2%
0%
Dyspepsia
2%
1%
Musculoskeletal
Myopathy
Myalgia
Myasthenia
2%
2%
1%
1%
1%
0%
Nervous System
Somnolence
23%
9%
Dizziness
13%
6%
Insomnia
13%
6%
Tremor
8%
2%
Nervousness
5%
3%
Anxiety
5%
3%
Paresthesia
4%
2%
Libido Decreased
3%
0%
Drugged Feeling
2%
1%
Confusion
1%
0%
Respiration
Yawn
4%
0%
Special Senses
Blurred Vision
Taste Perversion
4%
2%
1%
0%
Urogenital System
Ejaculatory Disturbance3,4
13%
0%
Other Male Genital Disorders3,5
10%
0%
Urinary Frequency
3%
1%
Urination Disorder6
3%
0%
Female Genital Disorders3,7
2%
0%
966
1. Events reported by at least 1% of patients treated with PAXIL are included, except the
967
following events which had an incidence on placebo ≥ PAXIL: Abdominal pain, agitation,
968
back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis,
969
postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”),
970
trauma, and vomiting.
971
2. Includes mostly “lump in throat” and “tightness in throat.”
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
972
3. Percentage corrected for gender.
973
4. Mostly “ejaculatory delay.”
974
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual
975
dysfunction,” and “impotence.”
976
6. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
977
7. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
978
979
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:
980
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD
981
patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
982
patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on
983
PAXIL who participated in placebo-controlled trials of 10- to 12-weeks duration in which
984
patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety
985
disorder on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
986
patients were dosed in a range of 20 mg to 50 mg/day.
987
988
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
989
Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety
990
Disorder1
Body System
Preferred Term
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
PAXIL
(n = 542)
Placebo
(n = 265)
PAXIL
(n = 469)
Placebo
(n = 324)
PAXIL
(n = 425)
Placebo
(n = 339)
Body as a Whole
Asthenia
Abdominal Pain
Chest Pain
Back Pain
Chills
Trauma
22%
—
3%
—
2%
—
14%
—
2%
—
1%
—
14%
4%
—
3%
2%
—
5%
3%
—
2%
1%
—
22%
—
—
—
—
3%
14%
—
—
—
—
1%
Cardiovascular
Vasodilation
Palpitation
4%
2%
1%
0%
—
—
—
—
—
—
—
—
Dermatologic
Sweating
Rash
9%
3%
3%
2%
14%
—
6%
—
9%
—
2%
—
Gastrointestinal
Nausea
Dry Mouth
Constipation
Diarrhea
Decreased
Appetite
Dyspepsia
Flatulence
Increased
Appetite
23%
18%
16%
10%
9%
—
—
4%
10%
9%
6%
10%
3%
—
—
3%
23%
18%
8%
12%
7%
—
—
2%
17%
11%
5%
7%
3%
—
—
1%
25%
9%
5%
9%
8%
4%
4%
—
7%
3%
2%
6%
2%
2%
2%
—
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
Vomiting
—
—
—
—
2%
1%
Musculoskeletal
Myalgia
—
—
—
—
4%
3%
Nervous System
Insomnia
Somnolence
Dizziness
Tremor
Nervousness
Libido Decreased
Agitation
Anxiety
Abnormal
Dreams
Concentration
Impaired
Depersonalization
Myoclonus
Amnesia
24%
24%
12%
11%
9%
7%
—
—
4%
3%
3%
3%
2%
13%
7%
6%
1%
8%
4%
—
—
1%
2%
0%
0%
1%
18%
19%
14%
9%
—
9%
5%
5%
—
—
—
3%
—
10%
11%
10%
1%
—
1%
4%
4%
—
—
—
2%
—
21%
22%
11%
9%
8%
12%
3%
5%
—
4%
—
2%
—
16%
5%
7%
1%
7%
1%
1%
4%
—
1%
—
1%
—
Respiratory System
Rhinitis
Pharyngitis
Yawn
—
—
—
—
—
—
3%
—
—
0%
—
—
—
4%
5%
—
2%
1%
Special Senses
Abnormal Vision
Taste Perversion
4%
2%
2%
0%
—
—
—
—
4%
—
1%
—
Urogenital System
Abnormal
Ejaculation2
Dysmenorrhea
Female Genital
Disorder2
Impotence2
Urinary
Frequency
Urination
Impaired
Urinary Tract
Infection
23%
—
3%
8%
3%
3%
2%
1%
—
0%
1%
1%
0%
1%
21%
—
9%
5%
2%
—
2%
1%
—
1%
0%
0%
—
1%
28%
5%
9%
5%
—
—
—
1%
4%
1%
1%
—
—
—
991
1. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with PAXIL are
992
included, except the following events which had an incidence on placebo ≥PAXIL: [OCD]: Abdominal pain, agitation,
993
anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory
994
disorder, rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough increased,
995
depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness,
996
palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and
997
vasodilation. [social anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and
998
sinusitis.
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
999
2. Percentage corrected for gender.
1000
1001
Generalized Anxiety Disorder and Posttraumatic Stress Disorder: Table 4
1002
enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on
1003
PAXIL who participated in placebo-controlled trials of 8-weeks duration in which patients were
1004
dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on PAXIL who
1005
participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a
1006
range of 20 mg/day to 50 mg/day.
1007
1008
Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
1009
Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disorder1
Body System
Preferred Term
Generalized Anxiety
Disorder
Posttraumatic Stress
Disorder
PAXIL
(n = 735)
Placebo
(n = 529)
PAXIL
(n = 676)
Placebo
(n = 504)
Body as a Whole
Asthenia
Headache
Infection
Abdominal Pain
Trauma
14%
17%
6%
6%
14%
3%
12%
—
5%
4%
6%
4%
—
4%
3%
5%
Cardiovascular
Vasodilation
3%
1%
2%
1%
Dermatologic
Sweating
6%
2%
5%
1%
Gastrointestinal
Nausea
Dry Mouth
Constipation
Diarrhea
Decreased Appetite
Vomiting
Dyspepsia
20%
11%
10%
9%
5%
3%
—
5%
5%
2%
7%
1%
2%
—
19%
10%
5%
11%
6%
3%
5%
8%
5%
3%
5%
3%
2%
3%
Nervous System
Insomnia
Somnolence
Dizziness
Tremor
Nervousness
Libido Decreased
Abnormal Dreams
11%
15%
6%
5%
4%
9%
8%
5%
5%
1%
3%
2%
12%
16%
6%
4%
—
5%
3%
11%
5%
5%
1%
—
2%
2%
Respiratory
System
Respiratory Disorder
Sinusitis
Yawn
7%
4%
4%
5%
3%
—
—
—
2%
—
—
<1%
Special Senses
Abnormal Vision
2%
1%
3%
1%
Urogenital
System
Abnormal
Ejaculation
2
Female
Genital
Disorder
2
Impotence
2
25%
4%
4%
2%
1%
3%
13%
5%
9%
2%
1%
1%
1010
1. Events reported by at least 2% of GAD and PTSD in patients treated with PAXIL are
1011
included, except the following events which had an incidence on placebo ≥PAXIL [GAD]:
1012
Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain,
1013
headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis.
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1014
2. Percentage corrected for gender.
1015
1016
Dose Dependency of Adverse Events: A comparison of adverse event rates in a
1017
fixed-dose study comparing 10, 20, 30, and 40 mg/day of PAXIL with placebo in the treatment
1018
of major depressive disorder revealed a clear dose dependency for some of the more common
1019
adverse events associated with use of PAXIL, as shown in the following table:
1020
1021
Table 5 . Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial
1022
in the Treatment of Major Depressive Disorder*
Body System/Preferred Term
Placebo
n = 51
PAXIL
10 mg
n = 102
20 mg
n = 104
30 mg
n = 101
40 mg
n = 102
Body as a Whole
Asthenia
0.0%
2.9%
10.6%
13.9%
12.7%
Dermatology
Sweating
2.0%
1.0%
6.7%
8.9%
11.8%
Gastrointestinal
Constipation
5.9%
4.9%
7.7%
9.9%
12.7%
Decreased Appetite
2.0%
2.0%
5.8%
4.0%
4.9%
Diarrhea
7.8%
9.8%
19.2%
7.9%
14.7%
Dry Mouth
2.0%
10.8%
18.3%
15.8%
20.6%
Nausea
13.7%
14.7%
26.9%
34.7%
36.3%
Nervous System
Anxiety
0.0%
2.0%
5.8%
5.9%
5.9%
Dizziness
3.9%
6.9%
6.7%
8.9%
12.7%
Nervousness
0.0%
5.9%
5.8%
4.0%
2.9%
Paresthesia
0.0%
2.9%
1.0%
5.0%
5.9%
Somnolence
7.8%
12.7%
18.3%
20.8%
21.6%
Tremor
0.0%
0.0%
7.7%
7.9%
14.7%
Special Senses
Blurred Vision
2.0%
2.9%
2.9%
2.0%
7.8%
Urogenital System
Abnormal Ejaculation
0.0%
5.8%
6.5%
10.6%
13.0%
Impotence
0.0%
1.9%
4.3%
6.4%
1.9%
Male Genital Disorders
0.0%
3.8%
8.7%
6.4%
3.7%
1023
* Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups
1024
and ≥ twice the placebo incidence for at least 1 paroxetine group.
1025
1026
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
1027
OCD, there was no clear relationship between adverse events and the dose of PAXIL to which
1028
patients were assigned. No new adverse events were observed in the group treated with 60 mg of
1029
PAXIL compared to any of the other treatment groups.
1030
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of PAXIL in the treatment of
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1031
panic disorder, there was no clear relationship between adverse events and the dose of PAXIL to
1032
which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor,
1033
and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in
1034
patients receiving 60 mg of PAXIL compared to any of the other treatment groups.
1035
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
1036
social anxiety disorder, for most of the adverse events, there was no clear relationship between
1037
adverse events and the dose of PAXIL to which patients were assigned.
1038
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1039
generalized anxiety disorder, for most of the adverse events, there was no clear relationship
1040
between adverse events and the dose of PAXIL to which patients were assigned, except for the
1041
following adverse events: Asthenia, constipation, and abnormal ejaculation.
1042
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1043
posttraumatic stress disorder, for most of the adverse events, there was no clear relationship
1044
between adverse events and the dose of PAXIL to which patients were assigned, except for
1045
impotence and abnormal ejaculation.
1046
Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence
1047
of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less
1048
to other effects (e.g., dry mouth, somnolence, and asthenia).
1049
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
1050
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
1051
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
1052
evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward
1053
sexual experiences.
1054
Reliable estimates of the incidence and severity of untoward experiences involving sexual
1055
desire, performance, and satisfaction are difficult to obtain, however, in part because patients and
1056
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
1057
untoward sexual experience and performance cited in product labeling, are likely to
1058
underestimate their actual incidence.
1059
In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the
1060
reported incidence of sexual side effects in males and females with major depressive disorder,
1061
OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.
1062
1063
Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials
PAXIL
Placebo
n (males)
1446
1042
Decreased Libido
6-15%
0-5%
Ejaculatory Disturbance
13-28%
0-2%
Impotence
2-9%
0-3%
n (females)
1822
1340
Decreased Libido
0-9%
0-2%
Orgasmic Disturbance
2-9%
0-1%
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1064
1065
There are no adequate and well-controlled studies examining sexual dysfunction with
1066
paroxetine treatment.
1067
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
1068
known outcome, patients recovered without sequelae.
1069
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
1070
SSRIs, physicians should routinely inquire about such possible side effects.
1071
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
1072
treatment with PAXIL for some patients but, on average, patients in controlled trials had minimal
1073
(about 1 pound) weight loss versus smaller changes on placebo and active control. No significant
1074
changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were
1075
observed in patients treated with PAXIL in controlled clinical trials.
1076
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with PAXIL and
1077
415 patients treated with placebo in controlled clinical trials, no clinically significant changes
1078
were seen in the ECGs of either group.
1079
Liver Function Tests: In placebo-controlled clinical trials, patients treated with PAXIL
1080
exhibited abnormal values on liver function tests at no greater rate than that seen in
1081
placebo-treated patients. In particular, the PAXIL-versus-placebo comparisons for alkaline
1082
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
1083
with marked abnormalities.
1084
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
1085
hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients
1086
receiving placebo.
1087
Other Events Observed During the Premarketing Evaluation of PAXIL: During its
1088
premarketing assessment in major depressive disorder, multiple doses of PAXIL were
1089
administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure
1090
to PAXIL varied greatly and included (in overlapping categories) open and double-blind studies,
1091
uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration
1092
studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder,
1093
generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676
1094
patients, respectively, received multiple doses of PAXIL. Untoward events associated with this
1095
exposure were recorded by clinical investigators using terminology of their own choosing.
1096
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
1097
experiencing adverse events without first grouping similar types of untoward events into a
1098
smaller number of standardized event categories.
1099
In the tabulations that follow, reported adverse events were classified using a standard
1100
COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the
1101
proportion of the 9,089 patients exposed to multiple doses of PAXIL who experienced an event
1102
of the type cited on at least 1 occasion while receiving PAXIL. All reported events are included
1103
except those already listed in Tables 2 to 4, those reported in terms so general as to be
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1104
uninformative and those events where a drug cause was remote. It is important to emphasize that
1105
although the events reported occurred during treatment with paroxetine, they were not
1106
necessarily caused by it.
1107
Events are further categorized by body system and listed in order of decreasing frequency
1108
according to the following definitions: Frequent adverse events are those occurring on 1 or more
1109
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
1110
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1111
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events
1112
of major clinical importance are also described in the PRECAUTIONS section.
1113
Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain;
1114
rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis,
1115
ulcer.
1116
Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia,
1117
hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris,
1118
arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular
1119
accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial
1120
ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis,
1121
thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
1122
Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis,
1123
gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal
1124
hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia,
1125
cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal
1126
incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction,
1127
jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis,
1128
stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
1129
Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism,
1130
thyroiditis.
1131
Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy,
1132
purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia,
1133
hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal
1134
lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia,
1135
thrombocythemia, thrombocytopenia.
1136
Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema,
1137
SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased,
1138
bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma
1139
globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia,
1140
hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic
1141
dehydrogenase increased, non-protein nitrogen (NPN) increased.
1142
Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare:
1143
Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1144
Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking,
1145
alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia,
1146
hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction,
1147
neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia,
1148
choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug
1149
dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion,
1150
hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy,
1151
nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes
1152
increased, stupor, torticollis, trismus, withdrawal syndrome.
1153
Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation,
1154
pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary
1155
edema, sputum increased, stridor, voice alteration.
1156
Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis,
1157
dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema,
1158
erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis;
1159
herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy,
1160
skin ulcer, sweating decreased, vesiculobullous rash.
1161
Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation,
1162
conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia,
1163
anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye
1164
hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia,
1165
ptosis, retinal hemorrhage, taste loss, visual field defect.
1166
Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria,
1167
menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency,
1168
vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis,
1169
female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis,
1170
metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith,
1171
vaginal hemorrhage, vaginal moniliasis.
1172
Postmarketing Reports: Voluntary reports of adverse events in patients taking PAXIL that
1173
have been received since market introduction and not listed above that may have no causal
1174
relationship with the drug include acute pancreatitis, elevated liver function tests (the most
1175
severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated
1176
with severe liver dysfunction), Guillain-Barré syndrome, toxic epidermal necrolysis, priapism,
1177
syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and
1178
galactorrhea, neuroleptic malignant syndrome–like events, serotonin syndrome; extrapyramidal
1179
symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia,
1180
oculogyric crisis which has been associated with concomitant use of pimozide; tremor and
1181
trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis,
1182
anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular
1183
tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1184
to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and
1185
agranulocytosis), and vasculitic syndromes (such as Henoch-Schönlein purpura). There has been
1186
a case report of an elevated phenytoin level after 4 weeks of PAXIL and phenytoin
1187
coadministration. There has been a case report of severe hypotension when PAXIL was added to
1188
chronic metoprolol treatment.
1189
DRUG ABUSE AND DEPENDENCE
1190
Controlled Substance Class: PAXIL is not a controlled substance.
1191
Physical and Psychologic Dependence: PAXIL has not been systematically studied in
1192
animals or humans for its potential for abuse, tolerance or physical dependence. While the
1193
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
1194
not systematic and it is not possible to predict on the basis of this limited experience the extent to
1195
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
1196
patients should be evaluated carefully for history of drug abuse, and such patients should be
1197
observed closely for signs of misuse or abuse of PAXIL (e.g., development of tolerance,
1198
incrementations of dose, drug-seeking behavior).
1199
OVERDOSAGE
1200
Human Experience: Since the introduction of PAXIL in the United States, 342 spontaneous
1201
cases of deliberate or accidental overdosage during paroxetine treatment have been reported
1202
worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with
1203
other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve
1204
paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were
1205
generally confounded by the ingestion of other drugs or alcohol or the presence of significant
1206
comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without
1207
sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum
1208
recommended daily dose) in a patient who recovered.
1209
Commonly reported adverse events associated with paroxetine overdosage include
1210
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
1211
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
1212
substances) include mydriasis, convulsions (including status epilepticus), ventricular
1213
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
1214
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
1215
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
1216
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
1217
Overdosage Management: Treatment should consist of those general measures employed in
1218
the management of overdosage with any drugs effective in the treatment of major depressive
1219
disorder.
1220
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
1221
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
1222
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
36
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1223
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
1224
patients.
1225
Activated charcoal should be administered. Due to the large volume of distribution of this
1226
drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of
1227
benefit. No specific antidotes for paroxetine are known.
1228
A specific caution involves patients who are taking or have recently taken paroxetine who
1229
might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
1230
parent tricyclic and/or an active metabolite may increase the possibility of clinically significant
1231
sequelae and extend the time needed for close medical observation (see PRECAUTIONS—
1232
Drugs Metabolized by Cytochrome CYP2D6).
1233
In managing overdosage, consider the possibility of multiple drug involvement. The physician
1234
should consider contacting a poison control center for additional information on the treatment of
1235
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
1236
Desk Reference (PDR).
1237
DOSAGE AND ADMINISTRATION
1238
Major Depressive Disorder: Usual Initial Dosage: PAXIL should be administered as a
1239
single daily dose with or without food, usually in the morning. The recommended initial dose is
1240
20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating
1241
the effectiveness of PAXIL in the treatment of major depressive disorder. As with all drugs
1242
effective in the treatment of major depressive disorder, the full effect may be delayed. Some
1243
patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day
1244
increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least
1245
1 week.
1246
Maintenance Therapy: There is no body of evidence available to answer the question of
1247
how long the patient treated with PAXIL should remain on it. It is generally agreed that acute
1248
episodes of major depressive disorder require several months or longer of sustained
1249
pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose
1250
needed to maintain and/or sustain euthymia is unknown.
1251
Systematic evaluation of the efficacy of PAXIL has shown that efficacy is maintained for
1252
periods of up to 1 year with doses that averaged about 30 mg.
1253
Obsessive Compulsive Disorder: Usual Initial Dosage: PAXIL should be administered
1254
as a single daily dose with or without food, usually in the morning. The recommended dose of
1255
PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the
1256
dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at
1257
least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials
1258
demonstrating the effectiveness of PAXIL in the treatment of OCD. The maximum dosage
1259
should not exceed 60 mg/day.
1260
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month
1261
relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1262
lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—
1263
Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a
1264
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1265
effective dosage, and patients should be periodically reassessed to determine the need for
1266
continued treatment.
1267
Panic Disorder: Usual Initial Dosage: PAXIL should be administered as a single daily dose
1268
with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic
1269
disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in
1270
10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to
1271
60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL. The maximum dosage
1272
should not exceed 60 mg/day.
1273
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month
1274
relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine
1275
demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL
1276
PHARMACOLOGY—Clinical Trials). Panic disorder is a chronic condition, and it is reasonable
1277
to consider continuation for a responding patient. Dosage adjustments should be made to
1278
maintain the patient on the lowest effective dosage, and patients should be periodically
1279
reassessed to determine the need for continued treatment.
1280
Social Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a single
1281
daily dose with or without food, usually in the morning. The recommended and initial dosage is
1282
20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a
1283
range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social
1284
anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional
1285
benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY—Clinical Trials).
1286
Maintenance Therapy: There is no body of evidence available to answer the question of
1287
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1288
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety
1289
disorder is recognized as a chronic condition, and it is reasonable to consider continuation of
1290
treatment for a responding patient. Dosage adjustments should be made to maintain the patient
1291
on the lowest effective dosage, and patients should be periodically reassessed to determine the
1292
need for continued treatment.
1293
Generalized Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a
1294
single daily dose with or without food, usually in the morning. In clinical trials the effectiveness
1295
of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended
1296
starting dosage and the established effective dosage is 20 mg/day. There is not sufficient
1297
evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur
1298
in 10 mg/day increments and at intervals of at least 1 week.
1299
Maintenance Therapy: Systematic evaluation of continuing PAXIL for periods of up to
1300
24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL
1301
during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see
38
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1302
CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, patients should be periodically
1303
reassessed to determine the need for maintenance treatment.
1304
Posttraumatic Stress Disorder: Usual Initial Dosage: PAXIL should be administered as
1305
a single daily dose with or without food, usually in the morning. The recommended starting
1306
dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of
1307
PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed
1308
dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day
1309
compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at
1310
intervals of at least 1 week.
1311
Maintenance Therapy: There is no body of evidence available to answer the question of
1312
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1313
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is
1314
recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a
1315
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1316
effective dosage, and patients should be periodically reassessed to determine the need for
1317
continued treatment.
1318
Special Populations: Treatment of Pregnant Women During the Third Trimester:
1319
Neonates exposed to PAXIL and other SSRIs or SNRIs, late in the third trimester have
1320
developed complications requiring prolonged hospitalization, respiratory support, and tube
1321
feeding (see WARNINGS). When treating pregnant women with paroxetine during the third
1322
trimester, the physician should carefully consider the potential risks and benefits of treatment.
1323
The physician may consider tapering paroxetine in the third trimester.
1324
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
1325
Hepatic Impairment: The recommended initial dose is 10 mg/day for elderly patients,
1326
debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be
1327
made if indicated. Dosage should not exceed 40 mg/day.
1328
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
1329
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL.
1330
Similarly, at least 14 days should be allowed after stopping PAXIL before starting an MAOI.
1331
Discontinuation of Treatment With PAXIL: Symptoms associated with discontinuation of
1332
PAXIL have been reported (see PRECAUTIONS). Patients should be monitored for these
1333
symptoms when discontinuing treatment, regardless of the indication for which PAXIL is being
1334
prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended
1335
whenever possible. If intolerable symptoms occur following a decrease in the dose or upon
1336
discontinuation of treatment, then resuming the previously prescribed dose may be considered.
1337
Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
1338
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
1339
HOW SUPPLIED
1340
Tablets: Film-coated, modified-oval as follows:
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1341
10-mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
1342
NDC 0029-3210-13 Bottles of 30
1343
20-mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
1344
NDC 0029-3211-13 Bottles of 30
1345
NDC 0029-3211-59 Bottles of 90
1346
NDC 0029-3211-21 SUP 100s (intended for institutional use only)
1347
30-mg blue tablets engraved on the front with PAXIL and on the back with 30.
1348
NDC 0029-3212-13 Bottles of 30
1349
40-mg green tablets engraved on the front with PAXIL and on the back with 40.
1350
NDC 0029-3213-13 Bottles of 30
1351
Store tablets between 15° and 30°C (59° and 86°F).
1352
Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.
1353
NDC 0029-3215-48
1354
Store suspension at or below 25°C (77°F).
1355
PAXIL is a registered trademark of GlaxoSmithKline.
1356
1357
1358
Medication Guide
1359
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
1360
Thoughts or Actions
1361
PAXIL® (PAX-il) (paroxetine hydrochloride) Tablets and Oral Suspension
1362
1363
Read the Medication Guide that comes with your or your family member’s antidepressant
1364
medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with
1365
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
1366
about:
1367
• All risks and benefits of treatment with antidepressant medicines
1368
• All treatment choices for depression or other serious mental illness
1369
1370
What is the most important information I should know about antidepressant medicines,
1371
depression and other serious mental illnesses, and suicidal thoughts or action?
1372
1373
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
1374
teenagers, and young adults within the first few months of treatment.
1375
1376
2. Depression and other serious mental illnesses are the most important causes of suicidal
1377
thoughts and actions. Some people may have a particularly high risk of having suicidal
1378
thoughts or actions. These include people who have (or have a family history of) bipolar
1379
illness (also called manic-depressive illness) or suicidal thoughts or actions.
1380
1381
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
40
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1382
family member?
1383
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
1384
thoughts, or feelings. This is very important when an antidepressant medicine is started or
1385
when the dose is changed.
1386
• Call the healthcare provider right away to report new or sudden changes in mood,
1387
behavior, thoughts, or feelings.
1388
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
1389
provider between visits as needed, especially if you have concerns about symptoms.
1390
1391
Call a healthcare provider right away if you or your family member has any of the
1392
following symptoms, especially if they are new, worse, or worry you:
1393
• Thoughts about suicide or dying
1394
• Attempts to commit suicide
1395
• New or worse depression
1396
• New or worse anxiety
1397
• Feeling very agitated or restless
1398
• Panic attacks
1399
• Trouble sleeping (insomnia)
1400
• New or worse irritability
1401
• Acting aggressive, being angry, or violent
1402
• Acting on dangerous impulses
1403
• An extreme increase in activity and talking (mania)
1404
• Other unusual changes in behavior or mood
1405
1406
What else do I need to know about antidepressant medicines?
1407
1408
• Never stop an antidepressant medicine without first talking to a healthcare
1409
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
1410
1411
• Antidepressants are medicines used to treat depression and other illnesses. It is
1412
important to discuss all the risks of treating depression and also the risks of not treating it.
1413
Patients and their families or other caregivers should discuss all treatment choices with
1414
the healthcare provider, not just the use of antidepressants.
1415
1416
• Antidepressant medicines have other side effects. Call your doctor for medical advice
1417
about side effects. You may report side effects to FDA at 1-800-FDA-1088.
1418
1419
• Antidepressant medicines can interact with other medicines. Know all of the
1420
medicines that you or your family member takes. Keep a list of all medicines to show the
1421
healthcare provider. Do not start new medicines without first checking with your
1422
healthcare provider.
1423
1424
• Not all antidepressant medicines prescribed for children are FDA approved for use
41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1425
in children. Talk to your child’s healthcare provider for more information.
1426
1427
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
1428
antidepressants.
1429
January 2008
PXL:4MG
1430
GSK l
ogo
1433
Research Triangle Park, NC 27709
1434
1435
©Year, GlaxoSmithKline. All rights reserved.
1436
1437
Month Year
PXL:XXPI
1438
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:27.966472
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020031s05920710s023lbl.pdf', 'application_number': 20031, 'submission_type': 'SUPPL ', 'submission_number': 59}
|
12,141
|
1
NDA 20-031/S-026
PX:Lx
PRESCRIBING INFORMATION
PAXIL®
brand of
paroxetine hydrochloride tablets and oral suspension
DESCRIPTION
Paxil (paroxetine hydrochloride) is an orally administered antidepressant with a chemical structure
unrelated to other selective serotonin reuptake inhibitors or to tricyclic, tetracyclic or other available
antidepressant agents. It is the hydrochloride salt of a phenylpiperidine compound identified
chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine
hydrochloride hemihydrate and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The
molecular weight is 374.8 (329.4 as free base). The structural formula is:
[Note: Chemical structure to be inserted]
paroxetine hydrochloride
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120º to
138ºC and a solubility of 5.4 mg/mL in water.
Tablets
Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 10 mg-
yellow (scored); 20 mg-pink (scored); 30 mg-blue, 40 mg-green. Inactive ingredients consist of dibasic
calcium phosphate dihydrate, hydroxypropyl methylcellulose, magnesium stearate, polyethylene
glycols, polysorbate 80, sodium starch glycolate, titanium dioxide and one or more of the following:
D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 2, FD&C Yellow No. 6.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Suspension for Oral Administration
Each 5 mL of orange-colored, orange-flavored liquid contains paroxetine hydrochloride equivalent to
paroxetine, 10 mg. Inactive ingredients consist of polacrilin potassium, microcrystalline cellulose,
propylene glycol, glycerin, sorbitol, methyl paraben, propyl paraben, sodium citrate dihydrate, citric
acid anhydrate, sodium saccharin, flavorings, FD&C Yellow No. 6 and simethicone emulsion, USP.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The efficacy of paroxetine in the treatment of depression, social anxiety disorder, obsessive
compulsive disorder (OCD),panic disorder (PD), and generalized anxiety disorder (GAD) is
presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting
from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at
clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin
into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly
selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine
and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has
little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-,5- HT1-, 5-HT2- and
histamine (H1)-receptors; antagonism of muscarinic, histaminergic and alpha1-adrenergic receptors
has been associated with various anticholinergic, sedative and cardiovascular effects for other
psychotropic drugs.
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
compound, they are essentially inactive.
Pharmacokinetics
Paroxetine is equally bioavailable from the oral suspension and tablet.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride
salt. In a study in which normal male subjects (n=15) received 30 mg tablets daily for 30 days, steady-
state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it
may take substantially longer in an occasional patient. At steady state, mean values of Cmax, Tmax, Cmin
and T1/2 were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%) and 21.0 hr. (CV 32%),
respectively. The steady-state Cmax and Cmin values were about 6 and 14 times what would be predicted
from single-dose studies. Steady-state drug exposure based on AUC0-24 was about 8 times greater than
would have been predicted from single-dose data in these subjects. The excess accumulation is a
consequence of the fact that one of the enzymes that metabolizes paroxetine is readily saturable.
In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 to
40 mg daily for the elderly and 20 to 50 mg daily for the nonelderly, some nonlinearity was observed in
both populations, again reflecting a saturable metabolic pathway. In comparison to Cmin values after 20
mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
The effects of food on the bioavailability of paroxetine were studied in subjects administered a single
dose with and without food. AUC was only slightly increased (6%) when drug was administered with
food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from
6.4 hours post-dosing to 4.9 hours.
Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar
and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with
glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified.
Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at
inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by cytochrome
P450IID6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of
paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme
in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS).
Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as
the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was
excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent
compound over the 10-day post-dosing period.
Distribution: Paroxetine distributes throughout the body, including the CNS, with only 1% remaining
in the plasma.
Protein Binding: Approximately 95% and 93% of paroxetine is bound to plasma protein at 100
ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would
normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
warfarin.
Renal and Liver Disease: Increased plasma concentrations of paroxetine occur in subjects with
renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance
below 30 mL/min was approximately 4 times greater than seen in normal volunteers. Patients with
creatinine clearance of 30 to 60 mL/min and patients with hepatic functional impairment had about a 2-
fold increase in plasma concentrations (AUC, Cmax).
The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and
upward titration, if necessary, should be at increased intervals (see DOSAGE AND
ADMINISTRATION).
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30 and 40
mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in
nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND
ADMINISTRATION).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Clinical Trials
Depression
The efficacy of Paxil (paroxetine hydrochloride) as a treatment for depression has been established in 6
placebo-controlled studies of patients with depression (ages 18 to 73). In these studies Paxil
(paroxetine hydrochloride) was shown to be significantly more effective than placebo in treating
depression by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the
Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paxil
(paroxetine hydrochloride) was significantly better than placebo in improvement of the HDRS sub-
factor scores, including the depressed mood item, sleep disturbance factor and anxiety factor.
A study of depressed outpatients who had responded to Paxil (HDRS total score <8) during an initial 8-
week open-treatment phase and were then randomized to continuation on Paxil or placebo for 1 year
demonstrated a significantly lower relapse rate for patients taking Paxil (15%) compared to those on
placebo (39%). Effectiveness was similar for male and female patients.
Obsessive Compulsive Disorder
The effectiveness of Paxil in the treatment of obsessive compulsive disorder (OCD) was demonstrated
in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients
in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown
Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range
finding study where patients were treated with fixed doses of 20, 40 or 60 mg of paroxetine/day
demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD.
Patients receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6
and 7 points, respectively, on the YBOCS total score which was significantly greater than the
approximate 4 point reduction at 20 mg and a 3 point reduction in the placebo-treated patients. Study 2
was a flexible dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg
daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7
points on the YBOCS total score which was significantly greater than the mean reduction of
approximately 4 points in placebo-treated patients.
The following table provides the outcome classification by treatment group on Global Improvement
items of the Clinical Global Impressions (CGI) scale for Study 1.
Outcome Classification (%) on CGI-Global Improvement Item
for Completers in Study 1
Outcome
Classification
Placebo
(N=74)
Paxil 20 mg
(N=75)
Paxil 40 mg
(N=66)
Paxil 60 mg
(N=66)
Worse
14%
7%
7%
3%
No Change
44%
35%
22%
19%
Minimally Improved
24%
33%
29%
34%
Much Improved
11%
18%
22%
24%
Very Much Improved
7%
7%
20%
20%
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function
of age or gender.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
The long-term maintenance effects of Paxil in OCD were demonstrated in a long-term extension to
Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-
month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or
placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were
significantly less likely to relapse than comparably treated patients who were randomized to placebo.
Panic Disorder
The effectiveness of Paxil in the treatment of panic disorder was demonstrated in three 10 to 12 week
multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had
panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, Paxil was shown to be
significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of
panic attack frequency and on the Clinical Global Impression Severity of Illness score.
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of
10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40
mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic
attacks, compared to 44% of placebo-treated patients.
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At
endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated
patients.
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in
patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the
paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo
patients.
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40
mg/day of paroxetine.
Long-term maintenance effects of Paxil in panic disorder were demonstrated in an extension to Study
1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-
blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-
month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly
less likely to relapse than comparably treated patients who were randomized to placebo.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function
of age or gender.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Social Anxiety Disorder
The effectiveness of Paxil in the treatment of social anxiety disorder was demonstrated in three 12-
week, multicenter, placebo-controlled studies (Studies 1-3) of adult outpatients with social anxiety
disorder (DSM-IV). In these studies, the effectiveness of Paxil compared to placebo was evaluated on
the basis of (1) the proportion of responders, as defined by a Clinical Global Impressions (CGI)
Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in
the Liebowitz Social Anxiety Scale (LSAS).
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo.
Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement
responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who
completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients
were CGI Improvement responders. In study 2, CGI Improvement responders were 77% and 42% for
the paroxetine and placebo treated patients, respectively.
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40 or 60 mg/day with placebo.
Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total
Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for
the 40 and 60 mg/day dose groups. There was no indication in this study of any additional benefit for
doses higher than 20 mg/day.
Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age,
race, or gender.
Generalized Anxiety Disorder
The effectiveness of Paxil in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated
in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with
Generalized Anxiety Disorder (DSM-IV).
Study 1 was a 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo.
Paxil 20 mg or 40 mg were both demonstrated to be significantly superior to placebo on the Hamilton
Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to
suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose.
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paxil
demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for
Anxiety (HAM-A) total score.
A third study, also flexible dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate
statistically significant superiority of Paxil over placebo on the Hamilton Rating Scale for Anxiety
(HAM-A) total score, the primary outcome.
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender.
There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
INDICATIONS AND USAGE
Depression
Paxil (paroxetine hydrochloride) is indicated for the treatment of depression.
The efficacy of Paxil in the treatment of a major depressive episode was established in 6-week
controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of
major depressive disorder (see CLINICAL PHARMACOLOGY). A major depressive episode implies
a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily
functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8
symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in
usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed
thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of Paxil in hospitalized depressed patients has not been adequately studied.
The efficacy of Paxil in maintaining an antidepressant response for up to 1 year was demonstrated in a
placebo-controlled trial (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
to use Paxil for extended periods should periodically re-evaluate the long-term usefulness of the drug
for the individual patient.
Obsessive Compulsive Disorder
Paxil is indicated for the treatment of obsessions and compulsions in patients with obsessive
compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked
distress, are time-consuming, or significantly interfere with social or occupational functioning.
The efficacy of Paxil was established in two 12 week trials with obsessive compulsive outpatients
whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive
disorder (see CLINICAL PHARMACOLOGY-Clinical Trials).
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or
images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors
(compulsions) that are recognized by the person as excessive or unreasonable.
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this
trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see
CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use Paxil for extended
periods should periodically reevaluate the long-term usefulness of the drug for the individual patient
(see DOSAGE AND ADMINISTRATION).
Panic Disorder
Paxil is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-
IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated
concern about having additional attacks, worry about the implications or consequences of the attacks,
and/or a significant change in behavior related to the attacks.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
The efficacy of Paxil (paroxetine hydrochloride) was established in three 10 to 12 week trials in panic
disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
Clinical Pharmacology-Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period
of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and
reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating;
(3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6)
chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or
faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10)
fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13)
chills or hot flushes.
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this
trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to
patients on placebo (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who prescribes
Paxil for extended periods should periodically reevaluate the long-term usefulness of the drug for the
individual patient.
Social Anxiety Disorder
Paxil is indicated for the treatment of social anxiety disorder, also known as social phobia, as defined
in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of one or
more social or performance situations in which the person is exposed to unfamiliar people or to
possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which
may approach the intensity of a panic attack. The feared situations are avoided or endured with intense
anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes
significantly with the person's normal routine, occupational or academic functioning, or social activities
or relationships, or there is marked distress about having the phobias. Lesser degrees of performance
anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of Paxil (paroxetine hydrochloride) was established in three 12-week trials in adult
patients with social anxiety disorder (DSM-IV). Paxil has not been studied in children or adolescents
with social phobia. (see Clinical Pharmacology-Clinical Trials).
The effectiveness of Paxil in long-term treatment of social anxiety disorder, i.e., for more than 12
weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the
physician who elects to prescribe Paxil for extended periods should periodically reevaluate the long-
term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Generalized Anxiety Disorder
Paxil is indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV.
Anxiety or tension associated with the stress of everyday life usually does not require treatment with
an anxiolytic.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
The efficacy of Paxil in the treatment of GAD was established in two 8-week placebo-controlled trials
in adults with GAD. Paxil has not been studied in children or adolescents with Generalized Anxiety
Disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry
(apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult
to control. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling
keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability,
muscle tension, sleep disturbance.
The effectiveness of Paxil in the long-term treatment of GAD, that is, for more than 8 weeks, has not
been systematically evaluated in controlled trials. The physician who elects to use Paxil for extended
periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient
(see “DOSAGE AND ADMINISTRATION”).
CONTRAINDICATIONS
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or thioridazine is
contraindicated (see WARNINGS and PRECAUTIONS).
Paxil is contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive
ingredients in Paxil.
WARNINGS
Potential for Interaction with Monoamine Oxidase Inhibitors
In patients receiving another serotonin reuptake inhibitor drug in combination with a
monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal,
reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that include extreme agitation progressing
to delirium and coma. These reactions have also been reported in patients who have recently
discontinued that drug and have been started on a MAOI. Some cases presented with features
resembling neuroleptic malignant syndrome. While there are no human data showing such an
interaction with Paxil, limited animal data on the effects of combined use of paroxetine and
MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke
behavioral excitation. Therefore, it is recommended that Paxil (paroxetine hydrochloride) not be
used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI.
At least 2 weeks should be allowed after stopping Paxil before starting a MAOI.
Potential Interaction with Thioridazine
Thioridazine administration alone produces prolongation of the QTc interval, which is
associated with serious ventricular arrhythmias, such as torsade de pointes-type arrythmias, and
sudden death. This effect appears to be dose related.
An in vivo study suggests that drugs which inhibit P450IID6, such as paroxetine, will elevate
plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in
combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).
This label may not be the latest approved by FDA.
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PRECAUTIONS
General
Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in
approximately 1.0% of Paxil-treated unipolar patients compared to 1.1% of active-control and 0.3% of
placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic
episodes was 2.2% for Paxil and 11.6% for the combined active-control groups. As with all
antidepressants, Paxil should be used cautiously in patients with a history of mania.
Seizures: During premarketing testing, seizures occurred in 0.1% of Paxil-treated patients, a rate
similar to that associated with other antidepressants. Paxil should be used cautiously in patients with a
history of seizures. It should be discontinued in any patient who develops seizures.
Suicide: The possibility of a suicide attempt is inherent in depression and may persist until
significant remission occurs. Close supervision of high-risk patients should accompany initial drug
therapy. Prescriptions for Paxil should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose.
Hyponatremia: Several cases of hyponatremia have been reported. The hyponatremia appeared to
be reversible when Paxil was discontinued. The majority of these occurrences have been in elderly
individuals, some in patients taking diuretics or who were otherwise volume depleted.
Abnormal Bleeding: There have been several reports of abnormal bleeding (mostly ecchymosis and
purpura) associated with paroxetine treatment, including a report of impaired platelet aggregation.
While a causal relationship to paroxetine is unclear, impaired platelet aggregation may result from
platelet serotonin depletion and contribute to such occurrences.
Use in Patients with Concomitant Illness: Clinical experience with Paxil in patients with
certain concomitant systemic illness is limited. Caution is advisable in using Paxil in patients with
diseases or conditions that could affect metabolism or hemodynamic responses.
Paxil has not been evaluated or used to any appreciable extent in patients with a recent history of
myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from
clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682
patients who received Paxil in double-blind, placebo-controlled trials, however, did not indicate that
Paxil is associated with the development of significant ECG abnormalities. Similarly, Paxil
(paroxetine hydrochloride) does not cause any clinically important changes in heart rate or blood
pressure.
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should be
used in such patients (see DOSAGE AND ADMINISTRATION).
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Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe Paxil:
Interference with Cognitive and Motor Performance: Any psychoactive drug may impair
judgment, thinking or motor skills. Although in controlled studies Paxil has not been shown to impair
psychomotor performance, patients should be cautioned about operating hazardous machinery,
including automobiles, until they are reasonably certain that Paxil therapy does not affect their ability
to engage in such activities.
Completing Course of Therapy: While patients may notice improvement with Paxil therapy in 1
to 4 weeks, they should be advised to continue therapy as directed.
Concomitant Medication: Patients should be advised to inform their physician if they are taking,
or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol: Although Paxil has not been shown to increase the impairment of mental and motor skills
caused by alcohol, patients should be advised to avoid alcohol while taking Paxil.
Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to
become pregnant during therapy.
Nursing: Patients should be advised to notify their physician if they are breast-feeding an infant (see
PRECAUTIONS-Nursing Mothers).
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
Tryptophan: As with other serotonin reuptake inhibitors, an interaction between paroxetine and
tryptophan may occur when they are co-administered. Adverse experiences, consisting primarily of
headache, nausea, sweating and dizziness, have been reported when tryptophan was administered to
patients taking Paxil (paroxetine hydrochloride). Consequently, concomitant use of Paxil with
tryptophan is not recommended.
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an
increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and
warfarin. Since there is little clinical experience, the concomitant administration of Paxil and warfarin
should be undertaken with caution.
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Sumatriptan: There have been rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI)
and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine,
fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is
advised.
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of paroxetine may be
affected by the induction or inhibition of drug-metabolizing enzymes.
Cimetidine - Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where Paxil
(30 mg q.d.) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were
increased by approximately 50% during co-administration with oral cimetidine (300 mg t.i.d.) for the
final week. Therefore, when these drugs are administered concurrently, dosage adjustment of Paxil
(paroxetine hydrochloride) after the 20 mg starting dose should be guided by clinical effect. The effect
of paroxetine on cimetidine’s pharmacokinetics was not studied.
Phenobarbital - Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral
30 mg dose of Paxil was administered at phenobarbital steady state (100 mg q.d. for 14 days),
paroxetine AUC and T1/2 were reduced (by an average of 25% and 38%, respectively) compared to
paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not
studied. Since Paxil exhibits nonlinear pharmacokinetics, the results of this study may not address the
case where the 2 drugs are both being chronically dosed. No initial Paxil dosage adjustment is
considered necessary when co-administered with phenobarbital; any subsequent adjustment should be
guided by clinical effect.
Phenytoin - When a single oral 30 mg dose of Paxil was administered at phenytoin steady state (300
mg q.d. for 14 days), paroxetine AUC and T1/2 were reduced (by an average of 50% and 35%,
respectively) compared to Paxil administered alone. In a separate study, when a single oral 300 mg
dose of phenytoin was administered at paroxetine steady state (30 mg q.d. for 14 days), phenytoin AUC
was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs
exhibit nonlinear pharmacokinetics, the above studies may not address the case where the two drugs
are both being chronically dosed. No initial dosage adjustments are considered necessary when these
drugs are co-administered; any subsequent adjustments should be guided by clinical effect (see
ADVERSE REACTIONS-Postmarketing Reports).
Drugs Metabolized by Cytochrome P450IID6: Many drugs, including most antidepressants
(paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P450 isozyme
P450IID6. Like other agents that are metabolized by P450IID6, paroxetine may significantly inhibit the
activity of this isozyme. In most patients (>90%), this P450IID6 isozyme is saturated early during Paxil
dosing. In one study, daily dosing of Paxil (20 mg q.d.) under steady-state conditions increased single
dose desipramine (100 mg) Cmax, AUC and T½ by an average of approximately two-, five- and three-
fold, respectively. Concomitant use of Paxil with other drugs metabolized by cytochrome P450IID6 has
not been formally studied but may require lower doses than usually prescribed for either Paxil or the
other drug.
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Therefore, co-administration of Paxil with other drugs that are metabolized by this isozyme, including
certain antidepressants (e.g., nortriptyline, amitriptyline, imipramine, desipramine and fluoxetine),
phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that
inhibit this enzyme (e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrythmias and sudden death potentially associated with
elevated plasma levels of thioridazine, paroxetine and thioridazine should not be co-administered (see
CONTRAINDICATIONS and WARNINGS).
At steady state, when the P450IID6 pathway is essentially saturated, paroxetine clearance is governed by
alternative P450 isozymes which, unlike P450IID6, show no evidence of saturation (see
PRECAUTIONS-Tricyclic Antidepressants).
Drugs Metabolized by Cytochrome P450IIIA4: An in vivo interaction study involving the co-
administration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome
P450IIIA4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro
studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more
potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme,
including terfenadine, astemizole, cisapride, triazolam, and cyclosporin. Based on the assumption that
the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance
predicts its effect on other IIIA4 substrates, paroxetine’s extent of inhibition of IIIA4 activity is not
likely to be of clinical significance.
Tricyclic Antidepressants (TCA): Caution is indicated in the co-administration of tricyclic
antidepressants (TCAs) with Paxil, because paroxetine may inhibit TCA metabolism. Plasma TCA
concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is
co-administered with Paxil (see PRECAUTIONS-Drugs Metabolized by Cytochrome P450IID6).
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein,
administration of Paxil to a patient taking another drug that is highly protein bound may cause
increased free concentrations of the other drug, potentially resulting in adverse events. Conversely,
adverse effects could result from displacement of paroxetine by other highly bound drugs.
Alcohol: Although Paxil does not increase the impairment of mental and motor skills caused by
alcohol, patients should be advised to avoid alcohol while taking Paxil (paroxetine hydrochloride).
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction between Paxil
and lithium carbonate. However, since there is little clinical experience, the concurrent administration
of paroxetine and lithium should be undertaken with caution.
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with
digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of
paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and
digoxin should be undertaken with caution.
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The
effects of paroxetine on diazepam were not evaluated.
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Procyclidine: Daily oral dosing of Paxil (30 mg q.d.) increased steady-state AUC0-24, Cmax and Cmin
values of procyclidine (5 mg oral q.d.) by 35%, 37% and 67%, respectively, compared to procyclidine
alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.
Beta-Blockers: In a study where propranolol (80 mg b.i.d.) was dosed orally for 18 days, the
established steady-state plasma concentrations of propranolol were unaltered during co-administration
with Paxil (30 mg q.d.) for the final 10 days. The effects of propranolol on paroxetine have not been
evaluated (see ADVERSE REACTIONS-Postmarketing Reports).
Theophylline: Reports of elevated theophylline levels associated with Paxil treatment have been
reported. While this interaction has not been formally studied, it is recommended that theophylline
levels be monitored when these drugs are concurrently administered.
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and
Paxil.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Two-year carcinogenicity studies were conducted in rodents given paroxetine in
the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4
(mouse) and 3.9 (rat) times the maximum recommended human dose (MRHD) for depression, social
anxiety disorder and GAD on a mg/m2 basis. Because the MRHD for depression is slightly less than
that for OCD (50 mg vs. 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse)
and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the
high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50 and 4/50 for control, low-, middle-
and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the
occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was
a dose-related increase in the number of tumors in mice, there was no drug-related increase in the
number of mice with tumors. The relevance of these findings to humans is unknown.
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo
assays that included the following: bacterial mutation assay, mouse lymphoma mutation assay,
unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow
and in vitro in human lymphocytes and in a dominant lethal test in rats.
Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in rats at a
dose of paroxetine of 15 mg/kg/day which is 2.9 times the MRHD for depression, social anxiety
disorder and GAD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible lesions occurred in
the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions
consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the
seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the
MRHD for depression, social anxiety disorder and GAD; 8.2 and 4.1 times the MRHD for OCD and
PD on a mg/m2 basis).
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Pregnancy
Teratogenic Effects - Pregnancy Category C
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits
administered during organogenesis. These doses are equivalent to 9.7 (rat) and 2.2 (rabbit) times the
maximum recommended human dose (MRHD) for depression, social anxiety disorder and GAD (50
mg) and 8.1 (rat) and 1.9 (rabbit) times the MRHD for OCD, on a mg/m2 basis. These studies have
revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths
during the first 4 days of lactation when dosing occurred during the last trimester of gestation and
continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or 0.19 times (mg/m2)
the MRHD for depression, social anxiety disorder and GAD, and at 0.16 times (mg/m2) the MRHD for
OCD. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not
known. There are no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of paroxetine on labor and delivery in humans is unknown.
Nursing Mothers
Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when
Paxil (paroxetine hydrochloride) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established.
Geriatric Use
In worldwide premarketing Paxil clinical trials, 17% of Paxil-treated patients (approximately 700)
were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly,
and a lower starting dose is recommended; there were, however, no overall differences in the adverse
event profile between elderly and younger patients, and effectiveness was similar in younger and older
patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
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16
ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Twenty percent (1,199/6,145) of Paxil patients in worldwide clinical trials in depression and 16.1%
(84/522), 11.8% (64/542), 9.4% (44/469) and 10.7% (79/735) of Paxil patients in worldwide trials in
social anxiety disorder, OCD, panic disorder, and GAD respectively, discontinued treatment due to an
adverse event. The most common events (≥1%) associated with discontinuation and considered to be
drug related (i.e., those events associated with dropout at a rate approximately twice or greater for Paxil
compared to placebo) included the following:
Depression
OCD
Panic Disorder
Social Anxiety
Disorder
Generalized Anxiety
Disorder
Paxil
Placebo
Paxil
Placebo
Paxil
Placebo
Paxil
Placebo
Paxil
Placebo
CNS
Somnolence
2.3%
0.7%
-
1.9%
0.3%
3.4%
0.3%
2.0%
0.2%
Insomnia
-
-
1.7%
0%
1.3%
0.3%
3.1%
0%
Agitation
1.1%
0.5%
-
Tremor
1.1%
0.3%
-
1.7%
0%
Anxiety
-
-
-
1.1%
0%
Dizziness
-
-
1.5%
0%
1.9%
0%
1.0%
0.2%
Gastrointestinal
Constipation
-
1.1%
0%
Nausea
3.2%
1.1%
1.9%
0%
3.2%
1.2%
4.0%
0.3%
2.0%
0.2%
Diarrhea
1.0%
0.3%
-
Dry mouth
1.0%
0.3%
-
Vomiting
1.0%
0.3%
-
1.0%
0%
Flatulence
1.0%
0.3%
Other
Asthenia
1.6%
0.4%
1.9%
0.4%
2.5%
0.6%
1.8%
0.2%
Abnormal
ejaculation1
1.6%
0%
2.1%
0%
4.9%
0.6%
2.5%
0.5%
Sweating
1.0%
0.3%
-
1.1%
0%
1.1%
0.2%
Impotence1
-
1.5%
0%
Libido Decreased
1.0%
0%
Where numbers are not provided the incidence of the adverse events in Paxil (paroxetine hydrochloride) patients was not >1% or was not greater
than or equal to two times the incidence of placebo.
1. Incidence corrected for gender.
Commonly Observed Adverse Events
Depression
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
greater and incidence for Paxil at least twice that for placebo, derived from Table 1 below) were:
asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness,
ejaculatory disturbance and other male genital disorders.
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Obsessive Compulsive Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
greater and incidence for Paxil at least twice that of placebo, derived from Table 2 below) were:
nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating,
impotence and abnormal ejaculation.
Panic Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
greater and incidence for Paxil at least twice that for placebo, derived from Table 2 below) were:
asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital
disorders and impotence.
Social Anxiety Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
greater and incidence for Paxil at least twice that for placebo, derived from Table 2 below) were:
sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased,
yawn, abnormal ejaculation, female genital disorders and impotence.
Generalized Anxiety Disorder
The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
greater and incidence for Paxil at least twice that for placebo, derived from Table 3 below) were:
asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence,
tremor, sweating, abnormal ejaculation.
Incidence in Controlled Clinical Trials
The prescriber should be aware that the figures in the tables following cannot be used to predict the
incidence of side effects in the course of usual medical practice where patient characteristics and other
factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot
be compared with figures obtained from other clinical investigations involving different treatments,
uses and investigators. The cited figures, however, do provide the prescribing physician with some
basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence
rate in the populations studied.
Depression
Table 1 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-
treated patients who participated in short term (6-week) placebo-controlled trials in which patients
were dosed in a range of 20 to 50 mg/day. Reported adverse events were classified using a standard
COSTART-based Dictionary terminology.
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Table 1. Treatment-Emergent Adverse
Experience Incidence in Placebo-Controlled
Clinical Trials for Depression1
Body System
Preferred Term
Paxil
(n=421)
Placebo
(n=421)
Body as a Whole
Headache
18%
17%
Asthenia
15%
6%
Cardiovascular
Palpitation
3%
1%
Vasodilation
3%
1%
Dermatologic
Sweating
11%
2%
Rash
2%
1%
Gastrointestinal
Nausea
26%
9%
Dry Mouth
18%
12%
Constipation
14%
9%
Diarrhea
12%
8%
Decreased Appetite
6%
2%
Flatulence
4%
2%
Oropharynx Disorder2
2%
0%
Dyspepsia
2%
1%
Musculoskeletal
Myopathy
2%
1%
Myalgia
2%
1%
Myasthenia
1%
0%
Nervous System
Somnolence
23%
9%
Dizziness
13%
6%
Insomnia
13%
6%
Tremor
8%
2%
Nervousness
5%
3%
Anxiety
5%
3%
Paresthesia
4%
2%
Libido Decreased
3%
0%
Drugged Feeling
2%
1%
Confusion
1%
0%
Respiration
Yawn
4%
0%
Special Senses
Blurred Vision
4%
1%
Taste Perversion
2%
0%
Urogenital System
Ejaculatory
Disturbance3,4
13%
0%
Other Male Genital
Disorders3,5
10%
0%
Urinary Frequency
3%
1%
Urination Disorder6
3%
0%
Female Genital Disorders3,7
2%
0%
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19
1.
Events reported by at least 1% of patients treated with Paxil (paroxetine hydrochloride) are included, except the following events which had an
incidence on placebo ≥ Paxil: abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus,
pharyngitis, postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”), trauma and vomiting.
2.
Includes mostly “lump in throat” and “tightness in throat.”
3.
Percentage corrected for gender.
4.
Mostly “ejaculatory delay.”
5.
Includes "anorgasmia,” "erectile difficulties,” "delayed ejaculation/orgasm,”
and “sexual dysfunction,” and “impotence.”
6.
Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7.
Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
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Obsessive Compulsive Disorder, Panic Disorder
and Social Anxiety Disorder
Table 2 enumerates adverse events that occurred at a frequency of 2% or more among OCD
patients on Paxil who participated in placebo-controlled trials of 12-weeks duration in which
patients were dosed in a range of 20 to 60 mg/day or among patients with panic disorder on
Paxil who participated in placebo-controlled trials of 10 to 12 weeks duration in which patients
were dosed in a range of 10 to 60 mg/day or among patients with social anxiety disorder on
Paxil who participated in placebo-controlled trials of 12 weeks duration in which patients were
dosed in a range of 20 to 50 mg/day.
Table 2. Treatment-Emergent Adverse Experience
Incidence in Placebo-Controlled Clinical Trials for
Obsessive Compulsive Disorder, Panic Disorder and Social Anxiety Disorder1
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
Paxil
Placebo
Paxil
Placebo
Paxil
Placebo
Body System
Preferred Term
(n=542)
(n=265)
(n=469)
(n=324)
(n=425)
(n=339)
Body as a Whole
Asthenia
22%
14%
14%
5%
22%
14%
Abdominal Pain
-
-
4%
3%
-
-
Chest Pain
3%
2%
-
-
-
-
Back Pain
-
-
3%
2%
-
-
Chills
2%
1%
2%
1%
-
-
Trauma
-
-
-
-
3%
1%
Cardiovascular
Vasodilation
4%
1%
-
-
-
-
Palpitation
2%
0%
-
-
-
-
Dermatologic
Sweating
9%
3%
14%
6%
9%
2%
Rash
3%
2%
-
-
-
-
Gastrointestinal
Nausea
23%
10%
23%
17%
25%
7%
Dry Mouth
18%
9%
18%
11%
9%
3%
Constipation
16%
6%
8%
5%
5%
2%
Diarrhea
10%
10%
12%
7%
9%
6%
Decreased Appetite
9%
3%
7%
3%
8%
2%
Dyspepsia
-
-
-
-
4%
2%
Flatulence
-
-
-
-
4%
2%
Increased Appetite
4%
3%
2%
1%
-
-
Vomiting
-
-
-
-
2%
1%
Musculoskeletal
Myalgia
-
-
-
-
4%
3%
Nervous System
Insomnia
24%
13%
18%
10%
21%
16%
Somnolence
24%
7%
19%
11%
22%
5%
Dizziness
12%
6%
14%
10%
11%
7%
Tremor
11%
1%
9%
1%
9%
1%
Nervousness
9%
8%
-
-
8%
7%
Libido Decreased
7%
4%
9%
1%
12%
1%
Agitation
-
-
5%
4%
3%
1%
Anxiety
-
-
5%
4%
5%
4%
Abnormal Dreams
4%
1%
-
-
-
-
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21
Concentration Impaired
3%
2%
-
-
4%
1%
Depersonalization
3%
0%
-
-
-
-
Myoclonus
3%
0%
3%
2%
2%
1%
Amnesia
2%
1%
-
-
-
-
Respiratory System
Rhinitis
-
-
3%
0%
-
-
Pharyngitis
-
-
-
-
4%
2%
Yawn
-
-
-
-
5%
1%
Special Senses
Abnormal Vision
4%
2%
-
-
4%
1%
Taste Perversion
2%
0%
-
-
-
-
Urogenital System
Abnormal Ejaculation2
23%
1%
21%
1%
28%
1%
Dysmenorrhea
-
-
-
-
5%
4%
Female Genital Disorder2
3%
0%
9%
1%
9%
1%
Impotence2
8%
1%
5%
0%
5%
1%
Urinary Frequency
3%
1%
2%
0%
-
-
Urination Impaired
3%
0%
-
-
-
-
Urinary Tract Infection
2%
1%
2%
1%
-
-
1. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder Paxil- treated patients are included, except the following
events which had an incidence on placebo ≥Paxil: [OCD]: abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache,
hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis and sinusitis. [panic disorder]: abnormal dreams, abnormal
vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia,
nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired and
vasodilation. [social anxiety disorder]: abdominal pain, depression, headache, infection, respiratory disorder, sinusitis.
2. Percentage corrected for gender.
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Generalized Anxiety Disorder
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among GAD
patients on Paxil who participated in placebo-controlled trials of 8 weeks duration in which
patients were dosed in a range of 10 mg/day to 50 mg/day.
Table 3. Treatment-Emergent Adverse Experience
Incidence in Placebo-Controlled Clinical Trials for
Generalized Anxiety Disorder1
Generalized
Anxiety Disorder
Paxil
Placebo
Body System
Preferred Term
(n=735)
(n=529)
Body as a Whole
Asthenia
14%
6%
Headache
17%
14%
Infection
6%
3%
Cardiovascular
Vasodilation
3%
1%
Dermatologic
Sweating
6%
2%
Gastrointestinal
Nausea
20%
5%
Dry Mouth
11%
5%
Constipation
10%
2%
Diarrhea
9%
7%
Decreased Appetite
5%
1%
Vomiting
3%
2%
Nervous System
Insomnia
11%
8%
Somnolence
15%
5%
Dizziness
6%
5%
Tremor
5%
1%
Nervousness
4%
3%
Libido Decreased
9%
2%
Respiratory System
Respiratory Disorder
7%
5%
Sinusitis
4%
3%
Yawn
4%
-
Special Senses
Abnormal Vision
2%
1%
Urogenital System
Abnormal Ejaculation2
25%
2%
Female Genital Disorder2
4%
1%
Impotence2
4%
3%
1. Events reported by at least 2% of Paxil- treated patients are included, except the following events which had an incidence on placebo ≥Paxil:
abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis.
2. Percentage corrected for gender.
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Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose
study comparing Paxil 10, 20, 30 and 40 mg/day with placebo in the treatment of depression revealed a
clear dose dependency for some of the more common adverse events associated with Paxil use, as
shown in the following table:
Table 4 . Treatment-Emergent Adverse Experience Incidence
in a Depression Dose-Comparison Trial*
Placebo
Paxil
Body System/
Preferred Term
n=51
10 mg
n=102
20 mg
n=104
30 mg
n=101
40 mg
n=102
Body as a Whole
Asthenia
0.0%
2.9%
10.6%
13.9%
12.7%
Dermatology
Sweating
2.0%
1.0%
6.7%
8.9%
11.8%
Gastrointestinal
Constipation
5.9%
4.9%
7.7%
9.9%
12.7%
Decreased Appetite
2.0%
2.0%
5.8%
4.0%
4.9%
Diarrhea
7.8%
9.8%
19.2%
7.9%
14.7%
Dry Mouth
2.0%
10.8%
18.3%
15.8%
20.6%
Nausea
13.7%
14.7%
26.9%
34.7%
36.3%
Nervous System
Anxiety
0.0%
2.0%
5.8%
5.9%
5.9%
Dizziness
3.9%
6.9%
6.7%
8.9%
12.7%
Nervousness
0.0%
5.9%
5.8%
4.0%
2.9%
Paresthesia
0.0%
2.9%
1.0%
5.0%
5.9%
Somnolence
7.8%
12.7%
18.3%
20.8%
21.6%
Tremor
0.0%
0.0%
7.7%
7.9%
14.7%
Special Senses
Blurred Vision
2.0%
2.9%
2.9%
2.0%
7.8%
Urogenital System
Abnormal Ejaculation
0.0%
5.8%
6.5%
10.6%
13.0%
Impotence
0.0%
1.9%
4.3%
6.4%
1.9%
Male Genital Disorders
0.0%
3.8%
8.7%
6.4%
3.7%
*Rule for including adverse events in table: incidence at least 5% for one of paroxetine groups and ≥ twice the placebo incidence for at least one paroxetine
group.
In a fixed-dose study comparing placebo and Paxil 20, 40 and 60 mg in the treatment of OCD, there
was no clear relationship between adverse events and the dose of Paxil (paroxetine hydrochloride) to
which patients were assigned. No new adverse events were observed in the Paxil 60 mg dose group
compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and Paxil 10, 20 and 40 mg in the treatment of panic disorder,
there was no clear relationship between adverse events and the dose of Paxil to which patients were
assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor and abnormal ejaculation.
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In flexible dose studies, no new adverse events were observed in patients receiving Paxil 60 mg
compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and Paxil 20, 40 and 60 mg in the treatment of social anxiety
disorder, for most of the adverse events, there was no clear relationship between adverse events and the
dose of Paxil (paroxetine hydrochloride) to which patients were assigned.
In a fixed-dose study comparing placebo and Paxil 20 and 40 mg in the treatment of generalized
anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events
and the dose of Paxil (paroxetine hydrochloride) to which patients were assigned, except for the
following adverse events: asthenia, constipation, and abnormal ejaculation.
Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence of
adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other
effects (e.g., dry mouth, somnolence and asthenia).
Male and Female Sexual Dysfunction with SSRIs: Although changes in sexual desire, sexual
performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may
also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective
serotonin reuptake inhibitors (SSRI's) can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual desire,
performance and satisfaction are difficult to obtain, however, in part because patients and physicians
may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual
experience and performance cited in product labeling, are likely to underestimate their actual incidence.
In placebo-controlled clinical trials involving more than 2,500 patients, the ranges for the reported
incidence of sexual side effects in males and females with depression, OCD, panic disorder, social
anxiety disorder, and GAD are displayed in Table 5 below.
Table 5. Incidence of Sexual Adverse Events in Controlled Clinical Trials
Paxil
Placebo
n (males)
1208
852
Decreased Libido
6-15%
0-5%
Ejaculatory Disturbance
13-28%
0-2%
Impotence
2-8%
0-3 %
n (females)
1384
1026
Decreased Libido
0-9%
0-2%
Orgasmic Disturbance
2-9%
0-1%
There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine
treatment.
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Paroxetine treatment has been associated with several cases of priapism. In those cases with a known
outcome, patients recovered without sequelae.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs,
physicians should routinely inquire about such possible side effects.
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
treatment with Paxil for some patients but, on average, patients in controlled trials had minimal (about
1 pound) weight loss vs. smaller changes on placebo and active control. No significant changes in vital
signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated
with Paxil in controlled clinical trials.
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with Paxil and 415 patients
treated with placebo in controlled clinical trials, no clinically significant changes were seen in the
ECGs of either group.
Liver Function Tests: In placebo-controlled clinical trials, patients treated with Paxil exhibited
abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In
particular, the Paxil-vs.-placebo comparisons for alkaline phosphatase, SGOT, SGPT and bilirubin
revealed no differences in the percentage of patients with marked abnormalities.
Other Events Observed During the Premarketing Evaluation of Paxil (paroxetine
hydrochloride)
During its premarketing assessment in depression, multiple doses of Paxil were administered to 6,145
patients in phase 2 and 3 studies. The conditions and duration of exposure to Paxil varied greatly and
included (in overlapping categories) open and double-blind studies, uncontrolled and controlled
studies, inpatient and outpatient studies, and fixed-dose and titration studies. During premarketing
clinical trials in OCD, panic disorder, social anxiety disorder, and generalized anxiety disorder, 542,
469, 522, and 735 patients, respectively, received multiple doses of Paxil. Untoward events associated
with this exposure were recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
experiencing adverse events without first grouping similar types of untoward events into a smaller
number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a standard COSTART-
based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the
8,413 patients exposed to multiple doses of Paxil (paroxetine hydrochloride) who experienced an event
of the type cited on at least one occasion while receiving Paxil. All reported events are included except
those already listed in Tables 1 – 3 , those reported in terms so general as to be uninformative and those
events where a drug cause was remote. It is important to emphasize that although the events reported
occurred during treatment with paroxetine, they were not necessarily caused by it.
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Events are further categorized by body system and listed in order of decreasing frequency according to
the following definitions: frequent adverse events are those occurring on one or more occasions in at
least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials
appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare
events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also
described in the PRECAUTIONS section.
Body as a Whole: frequent: chills, malaise; infrequent: allergic reaction, face edema, moniliasis,
neck pain; rare: adrenergic syndrome, cellulitis, neck rigidity, pelvic pain, peritonitis, ulcer.
Cardiovascular System: frequent: hypertension, tachycardia; infrequent: bradycardia, hematoma,
hypotension, migraine, syncope; rare: angina pectoris, arrhythmia nodal, atrial fibrillation, bundle
branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low
cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus,
supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache,
ventricular extrasystoles.
Digestive System: infrequent: bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis,
gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative
stomatitis; rare: aphthous stomatitis, bloody diarrhea, bulimia, cholelithiasis, duodenitis, enteritis,
esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileus,
intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement,
stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
Endocrine System: rare: diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis.
Hemic and Lymphatic Systems: infrequent: anemia, eosinophilia, leukocytosis, leukopenia,
lymphadenopathy, purpura; rare: abnormal erythrocytes, basophilia, bleeding time increased,
hypochromic anemia, iron deficiency anemia, lymphedema, abnormal lymphocytes, lymphocytosis,
microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia.
Metabolic and Nutritional: frequent: weight gain, weight loss; infrequent: alkaline phosphatase
increased, edema, peripheral edema, SGOT increased, SGPT increased, thirst; rare: bilirubinemia,
BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout,
hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia,
hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein
nitrogen (NPN) increased.
Musculoskeletal System: frequent: arthralgia; infrequent: arthritis, arthrosis; rare: bursitis,
myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
Nervous System: frequent: emotional lability, vertigo; infrequent: abnormal thinking, alcohol
abuse, ataxia, delirium, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia,
hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis,
paralysis, paranoid reaction, psychosis; rare: abnormal gait, akinesia, antisocial reaction, aphasia,
choreoathetosis, circumoral paresthesias, convulsion, delusions, diplopia, drug dependence, dysarthria,
extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-
depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis,
psychotic depression, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal
syndrome.
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Respiratory System: infrequent: asthma, bronchitis, dyspnea, epistaxis, hyperventilation,
pneumonia, respiratory flu; rare: emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema,
sputum increased, voice alteration.
Skin and Appendages: frequent: pruritus; infrequent: acne, alopecia, contact dermatitis, dry skin,
ecchymosis, eczema, furunculosis, herpes simplex, maculopapular rash, photosensitivity, urticaria;
rare: angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, ,
herpes zoster, hirsutism, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating
decreased, vesiculobullous rash.
Special Senses: frequent: tinnitus; infrequent: abnormality of accommodation, conjunctivitis, ear
pain, eye pain, mydriasis, otitis media, photophobia, ; rare: amblyopia, anisocoria, blepharitis, cataract,
conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis,
keratoconjunctivitis, night blindness, otitis externa, parosmia, ptosis, retinal hemorrhage, taste loss,
visual field defect.
Urogenital System: infrequent: abortion, amenorrhea, breast pain, cystitis, dysuria, hematuria,
menorrhagia, nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal
moniliasis, vaginitis; rare: breast atrophy, breast enlargement, endometrial disorder, epididymitis,
female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia,
nephritis, oliguria, pyuria, urethritis, uterine spasm, urolith, vaginal hemorrhage.
Postmarketing Reports
Voluntary reports of adverse events in patients taking Paxil (paroxetine hydrochloride) that have been
received since market introduction and not listed above that may have no causal relationship with the
drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to
liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-
Barré syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion,
symptoms suggestive of prolactinemia and galactorrhea, neuroleptic malignant syndrome-like events;
extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia,
hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide, tremor and
trismus; serotonin syndrome, associated in some cases with concomitant use of serotonergic drugs and
with drugs which may have impaired Paxil metabolism (symptoms have included agitation, confusion,
diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor), status
epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia,
laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including
torsade de pointes), thrombocytopenia, hemolytic anemia, and events related to impaired hematopoiesis
(including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis). There have been
spontaneous reports that discontinuation (particularly when abrupt) may lead to symptoms such as
dizziness, sensory disturbances, agitation or anxiety, nausea and sweating; these events are generally
self-limiting. There has been a case report of an elevated phenytoin level after 4 weeks of Paxil and
phenytoin co-administration. There has been a case report of severe hypotension when Paxil was added
to chronic metoprolol treatment.
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DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Paxil (paroxetine hydrochloride) is not a controlled substance.
Physical and Psychologic Dependence: Paxil has not been systematically studied in animals or
humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not
reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not
possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be
misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully
for history of drug abuse, and such patients should be observed closely for signs of Paxil misuse or
abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience
Since the introduction of Paxil in the U.S., 342 spontaneous cases of deliberate or accidental
overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include
overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were
fatal and, of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases which documented
the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol
or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most
recovered without sequelae. The largest known ingestion involved 2,000mg of paroxetine (33 times the
maximum recommended daily dose) in a patient who recovered.
Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma,
nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms
observed with overdoses involving paroxetine (alone or with other substances) include mydriasis,
convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes),
hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia,
rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis,
jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal
failure, and urinary retention.
Overdosage Management:
Treatment should consist of those general measures employed in the management of overdosage with
any antidepressant.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if
needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced
diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific
antidotes for paroxetine are known.
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A specific caution involves patients who are taking or have recently taken paroxetine who might ingest
excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic
and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the
time needed for close medical observation (see Drugs Metabolized by Cytochrome P450IID6 under
Precautions).
In managing overdosage, consider the possibility of multiple drug involvement. The physician should
consider contacting a poison control center for additional information on the treatment of any overdose.
Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference
(PDR).
DOSAGE AND ADMINISTRATION
Depression
Usual Initial Dosage: Paxil (paroxetine hydrochloride) should be administered as a single daily
dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day.
Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the antidepressant
effectiveness of Paxil. As with all antidepressants, the full antidepressant effect may be delayed.
Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day
increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of how long
the patient treated with Paxil should remain on it. It is generally agreed that acute episodes of
depression require several months or longer of sustained pharmacologic therapy. Whether the dose of
an antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain
euthymia is unknown.
Systematic evaluation of the efficacy of Paxil (paroxetine hydrochloride) has shown that efficacy is
maintained for periods of up to 1 year with doses that averaged about 30 mg.
Obsessive Compulsive Disorder
Usual Initial Dosage: Paxil (paroxetine hydrochloride) should be administered as a single daily
dose with or without food, usually in the morning. The recommended dose of Paxil in the treatment of
OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10
mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in
a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of Paxil in the
treatment of OCD. The maximum dosage should not exceed 60 mg/day.
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month
relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower
relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY). OCD is a chronic
condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments
should be made to maintain the patient on the lowest effective dosage, and patients should be
periodically reassessed to determine the need for continued treatment.
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30
Panic Disorder
Usual Initial Dosage: Paxil should be administered as a single daily dose with or without food,
usually in the morning. The target dose of Paxil in the treatment of panic disorder is 40 mg/day.
Patients should be started on 10 mg/day. Dose changes should occur in 10 mg/day increments and at
intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials
demonstrating the effectiveness of Paxil. The maximum dosage should not exceed 60 mg/day.
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month
relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a
lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY). Panic
disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient.
Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients
should be periodically reassessed to determine the need for continued treatment.
Social Anxiety Disorder
Usual Initial Dosage: Paxil should be administered as a single daily dose with or without food,
usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the
effectiveness of Paxil was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the
safety of Paxil has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day,
available information does not suggest any additional benefit for doses above 20 mg/day. (See Clinical
Pharmacology).
Maintenance Therapy: There is no body of evidence available to answer the question of how long the
patient treated with Paxil should remain on it. Although the efficacy of Paxil beyond 12 weeks of
dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a
chronic condition, and it is reasonable to consider continuation of treatment for a responding patient.
Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients
should be periodically reassessed to determine the need for continued treatment.
Generalized Anxiety Disorder
Usual Initial Dosage: Paxil should be administered as a single daily dose with or without food,
usually in the morning. In clinical trials the effectiveness of Paxil was demonstrated in patients dosed
in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage
is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20
mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of how long the
patient treated with Paxil should remain on it. Although the efficacy of Paxil beyond 8 weeks of
dosing has not been demonstrated in controlled clinical trials, generalized anxiety disorder is
recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a
responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective
dosage, and patients should be periodically reassessed to determine the need for continued treatment.
This label may not be the latest approved by FDA.
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31
Dosage for Elderly or Debilitated, and Patients with Severe Renal or Hepatic
Impairment: The recommended initial dose is 10 mg/day for elderly patients, debilitated patients,
and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage
should not exceed 40 mg/day.
Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should
elapse between discontinuation of a MAOI and initiation of Paxil therapy. Similarly, at least 14 days
should be allowed after stopping Paxil (paroxetine hydrochloride) before starting a MAOI.
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
HOW SUPPLIED
Tablets: Film-coated, modified-oval as follows:
10 mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
NDC 0029-3210-13 Bottles of 30
20 mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
NDC 0029-3211-13 Bottles of 30
NDC 0029-3211-20 Bottles of 100
NDC 0029-3211-21 SUP 100's (intended for institutional use only)
30 mg blue tablets engraved on the front with PAXIL and on the back with 30.
NDC 0029-3212-13 Bottles of 30
40 mg green tablets engraved on the front with PAXIL and on the back with 40.
NDC 0029-3213-13 Bottles of 30
Store tablets between 15º and 30ºC (59º and 86ºF).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.
NDC 0029-3215-48
Store suspension at or below 25oC (77oF).
DATE OF ISSUANCE xxxxx
SmithKline Beecham,
SmithKline Beecham Pharmaceuticals
Philadelphia, PA 19101
Rx only
PX:Lx
Printed in U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:46:28.107144
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20031S26lbl.pdf', 'application_number': 20031, 'submission_type': 'SUPPL ', 'submission_number': 26}
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PRESCRIBING INFORMATION
PAXIL®
(paroxetine hydrochloride)
Tablets and Oral Suspension
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
use of PAXIL or any other antidepressant in a child, adolescent, or young adult must
balance this risk with the clinical need. Short-term studies did not show an increase in the
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
older. Depression and certain other psychiatric disorders are themselves associated with
increases in the risk of suicide. Patients of all ages who are started on antidepressant
therapy should be monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
the need for close observation and communication with the prescriber. PAXIL is not
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
DESCRIPTION
PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the
hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'
fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate
and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8
(329.4 as free base). The structural formula of paroxetine hydrochloride is: Chemical Structure
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
120° to 138°C and a solubility of 5.4 mg/mL in water.
Tablets: Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as
follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive
ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate,
polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of
1
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the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C
Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.
Suspension for Oral Administration: Each 5 mL of orange-colored, orange-flavored liquid
contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist
of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol,
methylparaben, propylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium
saccharin, flavorings, FD&C Yellow No. 6 aluminum lake, and simethicone emulsion, USP.
CLINICAL PHARMACOLOGY
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD),
generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be
linked to potentiation of serotonergic activity in the central nervous system resulting from
inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically
relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into
human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly
selective inhibitor of neuronal serotonin reuptake and has only very weak effects on
norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate
that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine
(D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic,
and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and
cardiovascular effects for other psychotropic drugs.
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
compound, they are essentially inactive.
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours
(CV 32%) after oral dosing of 30 mg tablets of PAXIL daily for 30 days. Paroxetine is
extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in
pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part
by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the
feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are
deficient in CYP2D6 (poor metabolizers).
Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension
and tablet.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets
daily for 30 days, steady-state paroxetine concentrations were achieved by approximately
10 days for most subjects, although it may take substantially longer in an occasional patient. At
steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr.
(CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax
2
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and Cmin values were about 6 and 14 times what would be predicted from single-dose studies.
Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been
predicted from single-dose data in these subjects. The excess accumulation is a consequence of
the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.
The effects of food on the bioavailability of paroxetine were studied in subjects administered
a single dose with and without food. AUC was only slightly increased (6%) when drug was
administered with food but the Cmax was 29% greater, while the time to reach peak plasma
concentration decreased from 6.4 hours post-dosing to 4.9 hours.
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
plasma.
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
warfarin.
Metabolism and Excretion: The mean elimination half-life is approximately 21 hours
(CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose
proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg
daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was
observed in both populations, again reflecting a saturable metabolic pathway. In comparison to
Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than
doubled.
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
polar and conjugated products of oxidation and methylation, which are readily cleared.
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
interactions (see PRECAUTIONS).
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
1% as the parent compound over the 10-day post-dosing period.
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and
hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
about a 2-fold increase in plasma concentrations (AUC, Cmax).
3
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The initial dosage should therefore be reduced in patients with severe renal or hepatic
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
AND ADMINISTRATION).
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20,
30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin
concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be
reduced (see DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
desipramine, risperidone, and atomoxetine (see PRECAUTIONS—Drug Interactions).
Clinical Trials
Major Depressive Disorder: The efficacy of PAXIL as a treatment for major depressive
disorder has been established in 6 placebo-controlled studies of patients with major depressive
disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective
than placebo in treating major depressive disorder by at least 2 of the following measures:
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in
improvement of the HDRS sub-factor scores, including the depressed mood item, sleep
disturbance factor, and anxiety factor.
A study of outpatients with major depressive disorder who had responded to PAXIL (HDRS
total score <8) during an initial 8-week open-treatment phase and were then randomized to
continuation on PAXIL or placebo for 1 year demonstrated a significantly lower relapse rate for
patients taking PAXIL (15%) compared to those on placebo (39%). Effectiveness was similar for
male and female patients.
Obsessive Compulsive Disorder: The effectiveness of PAXIL in the treatment of obsessive
compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled
studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD
(DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale
(YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients
were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily
doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses
of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points,
respectively, on the YBOCS total score which was significantly greater than the approximate 4
point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a
flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg
daily). In this study, patients receiving paroxetine experienced a mean reduction of
approximately 7 points on the YBOCS total score, which was significantly greater than the mean
reduction of approximately 4 points in placebo-treated patients.
4
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The following table provides the outcome classification by treatment group on Global
Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
Outcome Classification (%) on CGI-Global Improvement Item
for Completers in Study 1
Outcome
Classification
Placebo
(n = 74)
PAXIL 20 mg
(n = 75)
PAXIL 40 mg
(n = 66)
PAXIL 60 mg
(n = 66)
Worse
14%
7%
7%
3%
No Change
44%
35%
22%
19%
Minimally Improved
24%
33%
29%
34%
Much Improved
11%
18%
22%
24%
Very Much Improved
7%
7%
20%
20%
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age or gender.
The long-term maintenance effects of PAXIL in OCD were demonstrated in a long-term
extension to Study 1. Patients who were responders on paroxetine during the 3-month
double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were
randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase.
Patients randomized to paroxetine were significantly less likely to relapse than comparably
treated patients who were randomized to placebo.
Panic Disorder: The effectiveness of PAXIL in the treatment of panic disorder was
demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia.
In these studies, PAXIL was shown to be significantly more effective than placebo in treating
panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical
Global Impression Severity of Illness score.
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine
doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed
only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were
free of panic attacks, compared to 44% of placebo-treated patients.
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and
placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of
placebo-treated patients.
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to
placebo in patients concurrently receiving standardized cognitive behavioral therapy. At
endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks
compared to 14% of placebo patients.
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was
approximately 40 mg/day of paroxetine.
Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an
5
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extension to Study 1. Patients who were responders during the 10-week double-blind phase and
during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or
40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized
to paroxetine were significantly less likely to relapse than comparably treated patients who were
randomized to placebo.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age or gender.
Social Anxiety Disorder: The effectiveness of PAXIL in the treatment of social anxiety
disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1,
2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the
effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of
responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very
much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social
Anxiety Scale (LSAS).
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and
placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the
CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In
Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to
29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI
Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients,
respectively.
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with
placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the
LSAS Total Score and the CGI Improvement responder criterion; there were trends for
superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in
this study of any additional benefit for doses higher than 20 mg/day.
Subgroup analyses generally did not indicate differences in treatment outcomes as a function
of age, race, or gender.
Generalized Anxiety Disorder: The effectiveness of PAXIL in the treatment of Generalized
Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled
studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with
placebo. Doses of 20 mg or 40 mg of PAXIL were both demonstrated to be significantly superior
to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not
sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to
the 20 mg/day dose.
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo.
PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating
Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine
(20 mg to 50 mg daily), did not demonstrate statistically significant superiority of PAXIL over
6
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placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or
gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety
Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to
50 mg/day of PAXIL, were randomized to continuation of PAXIL at their same dose, or to
placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase
was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of
Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase
of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or
withdrawal due to lack of efficacy. Patients receiving continued PAXIL experienced a
significantly lower relapse rate over the subsequent 24 weeks compared to those receiving
placebo.
Posttraumatic Stress Disorder: The effectiveness of PAXIL in the treatment of
Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-
controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The
mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year
to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD
anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out
of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered
PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement
Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the
following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal.
The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2
total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were
defined as patients having a score of 1 (very much improved) or 2 (much improved).
Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to
placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to
placebo on change from baseline for the CAPS-2 total score and on proportion of responders on
the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the
40 mg/day dose compared to the 20 mg/day dose.
Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to
placebo. PAXIL was demonstrated to be significantly superior to placebo on change from
baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.
A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,
demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS
2 total score, but not on proportion of responders on the CGI-I.
The majority of patients in these trials were women (68% women: 377 out of 551 subjects in
Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not
indicate differences in treatment outcomes as a function of gender. There were an insufficient
7
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number of patients who were 65 years and older or were non-Caucasian to conduct subgroup
analyses on the basis of age or race, respectively.
INDICATIONS AND USAGE
Major Depressive Disorder: PAXIL is indicated for the treatment of major depressive
disorder.
The efficacy of PAXIL in the treatment of a major depressive episode was established in
6-week controlled trials of outpatients whose diagnoses corresponded most closely to the
DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical
Trials). A major depressive episode implies a prominent and relatively persistent depressed or
dysphoric mood that usually interferes with daily functioning (nearly every day for at least
2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in
sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in
sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The effects of PAXIL in hospitalized depressed patients have not been adequately studied.
The efficacy of PAXIL in maintaining a response in major depressive disorder for up to 1 year
was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical
Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Obsessive Compulsive Disorder: PAXIL is indicated for the treatment of obsessions and
compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV.
The obsessions or compulsions cause marked distress, are time-consuming, or significantly
interfere with social or occupational functioning.
The efficacy of PAXIL was established in two 12-week trials with obsessive compulsive
outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive
compulsive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In
this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on
placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician
who elects to use PAXIL for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder: PAXIL is indicated for the treatment of panic disorder, with or without
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
8
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the attacks.
The efficacy of PAXIL was established in three 10- to 12-week trials in panic disorder
patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
CLINICAL PHARMACOLOGY—Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In
this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate
compared to patients on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials).
Nevertheless, the physician who prescribes PAXIL for extended periods should periodically
re-evaluate the long-term usefulness of the drug for the individual patient.
Social Anxiety Disorder: PAXIL is indicated for the treatment of social anxiety disorder,
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
characterized by a marked and persistent fear of 1 or more social or performance situations in
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
the person's normal routine, occupational or academic functioning, or social activities or
relationships, or there is marked distress about having the phobias. Lesser degrees of
performance anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of PAXIL was established in three 12-week trials in adult patients with social
anxiety disorder (DSM-IV). PAXIL has not been studied in children or adolescents with social
phobia (see CLINICAL PHARMACOLOGY—Clinical Trials).
The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more
than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Generalized Anxiety Disorder: PAXIL is indicated for the treatment of Generalized Anxiety
Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of
everyday life usually does not require treatment with an anxiolytic.
The efficacy of PAXIL in the treatment of GAD was established in two 8-week
placebo-controlled trials in adults with GAD. PAXIL has not been studied in children or
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adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY—Clinical
Trials).
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry
(apprehensive expectation) that is persistent for at least 6 months and which the person finds
difficult to control. It must be associated with at least 3 of the following 6 symptoms:
Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or
mind going blank, irritability, muscle tension, sleep disturbance.
The efficacy of PAXIL in maintaining a response in patients with Generalized Anxiety
Disorder, who responded during an 8-week acute treatment phase while taking PAXIL and were
then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-
controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the
physician who elects to use PAXIL for extended periods should periodically re-evaluate the
long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Posttraumatic Stress Disorder: PAXIL is indicated for the treatment of Posttraumatic
Stress Disorder (PTSD).
The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebo-
controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY—Clinical
Trials).
PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or
threatened death or serious injury, or threat to the physical integrity of self or others, and a
response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has
not been systematically evaluated in placebo-controlled trials. Therefore, the physician who
elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs), including
linezolid, an antibiotic which is a reversible non-selective MAOI, or thioridazine is
10
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For current labeling information, please visit https://www.fda.gov/drugsatfda
contraindicated (see WARNINGS and PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the
inactive ingredients in PAXIL.
WARNINGS
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
both adult and pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
are taking antidepressant medications, and this risk may persist until significant remission
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-standing
concern, however, that antidepressants may have a role in inducing worsening of depression and
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
increase in the younger patients for almost all drugs studied. There were differences in absolute
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1,000 patients treated) are provided in Table 1.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of
Treatment with PAXIL), for a description of the risks of discontinuation of PAXIL.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to healthcare
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providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for PAXIL should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that PAXIL is not approved for use in treating bipolar depression.
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
another serotonin reuptake inhibitor drug in combination with a monoamine oxidase
inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of
vital signs, and mental status changes that include extreme agitation progressing to
delirium and coma. These reactions have also been reported in patients who have recently
discontinued that drug and have been started on an MAOI. Some cases presented with
features resembling neuroleptic malignant syndrome. While there are no human data
showing such an interaction with PAXIL, limited animal data on the effects of combined
use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate
blood pressure and evoke behavioral excitation. Therefore, it is recommended that PAXIL
not be used in combination with an MAOI (including linezolid, an antibiotic which is a
reversible non-selective MAOI), or within 14 days of discontinuing treatment with an
MAOI (see CONTRAINDICATIONS). At least 2 weeks should be allowed after stopping
PAXIL before starting an MAOI.
Serotonin Syndrome: The development of a potentially life-threatening serotonin
syndrome may occur with SNRIs and SSRIs, including PAXIL, particularly with
concomitant use of serotonergic drugs (including triptans) and with drugs which impair
metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include
mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g.,
hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting,
diarrhea).
The concomitant use of PAXIL with MAOIs intended to treat depression is
contraindicated (see CONTRAINDICATIONS and WARNINGS—Potential for
Interaction With Monoamine Oxidase Inhibitors).
If concomitant treatment with PAXIL with a 5-hydroxytryptamine receptor agonist
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
13
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during treatment initiation and dose increases (see PRECAUTIONS—Drug Interactions).
The concomitant use of PAXIL with serotonin precursors (such as tryptophan) is not
recommended (see PRECAUTIONS—Drug Interactions).
Potential Interaction With Thioridazine: Thioridazine administration alone produces
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
dose related.
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
used in combination with thioridazine (see CONTRAINDICATIONS and
PRECAUTIONS).
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
infants born to women who had first trimester paroxetine exposure had an increased risk of
cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs).
In general, septal defects range from those that are symptomatic and may require surgery to those
that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while
taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of
paroxetine to the mother justify continuing treatment, consideration should be given to either
discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS—
Discontinuation of Treatment with PAXIL). For women who intend to become pregnant or are in
their first trimester of pregnancy, paroxetine should only be initiated after consideration of the
other available treatment options.
A study based on Swedish national registry data evaluated infants of 6,896 women exposed to
antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for
paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of
cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry
population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations
following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population.
Among the same paroxetine exposed infants, an examination of the data showed no increase in
the overall risk for congenital malformations.
A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants
of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815 for
paroxetine). This study showed a trend towards an increased risk for cardiovascular
malformations for paroxetine compared to other antidepressants (OR 1.5; 95% confidence
interval 0.8-2.9). The prevalence of cardiovascular malformations following first trimester
dispensing was 1.5% for paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with
cardiovascular malformations whose mothers were dispensed paroxetine in the first trimester had
VSDs. This study also suggested an increased risk of overall major congenital malformations
(inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR
1.8; 95% confidence interval 1.2-2.8). The prevalence of all congenital malformations following
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first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants.
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
trimester of gestation and continued throughout lactation. This effect occurred at a dose of
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
rat pup mortality was not determined. The cause of these deaths is not known.
Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs or serotonin and
norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS—Potential for
Interaction With Monoamine Oxidase Inhibitors).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
the general population and is associated with substantial neonatal morbidity and mortality. In a
retrospective case-control study of 377 women whose infants were born with PPHN and 836
women whose infants were born healthy, the risk for developing PPHN was approximately six
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
study that has investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
There have also been postmarketing reports of premature births in pregnant women exposed
to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester, the physician
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
women with a history of major depression who were euthymic at the beginning of pregnancy,
women who discontinued antidepressant medication during pregnancy were more likely to
experience a relapse of major depression than women who continued antidepressant medication.
PRECAUTIONS
General: Activation of Mania/Hypomania: During premarketing testing, hypomania or
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mania occurred in approximately 1.0% of unipolar patients treated with PAXIL compared to
1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients
classified as bipolar, the rate of manic episodes was 2.2% for PAXIL and 11.6% for the
combined active-control groups. As with all drugs effective in the treatment of major depressive
disorder, PAXIL should be used cautiously in patients with a history of mania.
Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with
PAXIL, a rate similar to that associated with other drugs effective in the treatment of major
depressive disorder. PAXIL should be used cautiously in patients with a history of seizures. It
should be discontinued in any patient who develops seizures.
Discontinuation of Treatment With PAXIL: Recent clinical trials supporting the various
approved indications for PAXIL employed a taper-phase regimen, rather than an abrupt
discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials
involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a
daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before
treatment was stopped.
With this regimen in those studies, the following adverse events were reported at an incidence
of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams,
paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and
were self-limiting and did not require medical intervention.
During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports
of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt),
including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances
(e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache,
lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-
limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with PAXIL.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
See also PRECAUTIONS—Pediatric Use, for adverse events reported upon discontinuation
of treatment with PAXIL in pediatric patients.
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
such as an inability to sit or stand still usually associated with subjective distress. This is most
likely to occur within the first few weeks of treatment.
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
including PAXIL. In many cases, this hyponatremia appears to be the result of the syndrome of
inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
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For current labeling information, please visit https://www.fda.gov/drugsatfda
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk (see Geriatric Use). Discontinuation of PAXIL should be
considered in patients with symptomatic hyponatremia and appropriate medical intervention
should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
and cohort design) have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
coagulation.
Use in Patients With Concomitant Illness: Clinical experience with PAXIL in patients
with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
PAXIL. A few cases of acute angle closure glaucoma associated with paroxetine therapy have
been reported in the literature. As mydriasis can cause acute angle closure in patients with
narrow angle glaucoma, caution should be used when PAXIL is prescribed for patients with
narrow angle glaucoma.
PAXIL has not been evaluated or used to any appreciable extent in patients with a recent
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
excluded from clinical studies during the product’s premarket testing. Evaluation of
electrocardiograms of 682 patients who received PAXIL in double-blind, placebo-controlled
trials, however, did not indicate that PAXIL is associated with the development of significant
ECG abnormalities. Similarly, PAXIL does not cause any clinically important changes in heart
rate or blood pressure.
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients: PAXIL should not be chewed or crushed, and should be swallowed
whole.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
PAXIL and triptans, tramadol, or other serotonergic agents.
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Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with PAXIL and should counsel
them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines,
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available
for PAXIL. The prescriber or health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of the Medication Guide and to
obtain answers to any questions they may have. The complete text of the Medication Guide is
reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking PAXIL.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of such
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
close monitoring and possibly changes in the medication.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
interfere with serotonin reuptake and these agents has been associated with an increased risk of
bleeding.
Interference With Cognitive and Motor Performance: Any psychoactive drug may
impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been
shown to impair psychomotor performance, patients should be cautioned about operating
hazardous machinery, including automobiles, until they are reasonably certain that therapy with
PAXIL does not affect their ability to engage in such activities.
Completing Course of Therapy: While patients may notice improvement with treatment
with PAXIL in 1 to 4 weeks, they should be advised to continue therapy as directed.
Concomitant Medication: Patients should be advised to inform their physician if they are
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
interactions.
Alcohol: Although PAXIL has not been shown to increase the impairment of mental and
motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
intend to become pregnant during therapy (see WARNINGS—Usage in Pregnancy: Teratogenic
and Nonteratogenic Effects).
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
infant (see PRECAUTIONS—Nursing Mothers).
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
between paroxetine and tryptophan may occur when they are coadministered. Adverse
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
reported when tryptophan was administered to patients taking PAXIL. Consequently,
concomitant use of PAXIL with tryptophan is not recommended (see WARNINGS—Serotonin
Syndrome).
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
Pimozide: In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg
daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in
pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The
increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine.
Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT
interval, concomitant use of pimozide and PAXIL is contraindicated (see
CONTRAINDICATIONS).
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
PAXIL is coadministered with other drugs that may affect the serotonergic neurotransmitter
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
lithium, tramadol, or St. John's Wort (see WARNINGS—Serotonin Syndrome). The concomitant
use of PAXIL with MAOIs (including linezolid) is contraindicated (see
CONTRAINDICATIONS). The concomitant use of PAXIL with other SSRIs, SNRIs or
tryptophan is not recommended (see PRECAUTIONS—Drug Interactions, Tryptophan).
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
of PAXIL and warfarin should be undertaken with caution (see Drugs That Interfere With
Hemostasis).
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
an SSRI and a triptan. If concomitant use of PAXIL with a triptan is clinically warranted, careful
observation of the patient is advised, particularly during treatment initiation and dose increases
(see WARNINGS—Serotonin Syndrome).
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
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For current labeling information, please visit https://www.fda.gov/drugsatfda
where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma
concentrations of paroxetine were increased by approximately 50% during coadministration with
oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are
administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be
guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not
studied.
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once
daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
respectively) compared to paroxetine administered alone. The effect of paroxetine on
phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear
pharmacokinetics, the results of this study may not address the case where the 2 drugs are both
being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when
coadministered with phenobarbital; any subsequent adjustment should be guided by clinical
effect.
Phenytoin: When a single oral 30-mg dose of PAXIL was administered at phenytoin steady
state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of
50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a
single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once
daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to
phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above
studies may not address the case where the 2 drugs are both being chronically dosed. No initial
dosage adjustments are considered necessary when these drugs are coadministered; any
subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS—
Postmarketing Reports).
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
(>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily
dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose
desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold,
respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been
evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to
8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased
9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the
active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The
effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs
were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,
paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This
20
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For current labeling information, please visit https://www.fda.gov/drugsatfda
resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in
atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.
Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be
initiated at a reduced dose when it is given with paroxetine.
Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not
been formally studied but may require lower doses than usually prescribed for either PAXIL or
the other drug.
Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme,
including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,
amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, tamoxifen,
and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this
enzyme (e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
coadministered (see CONTRAINDICATIONS and WARNINGS).
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6
by paroxetine may lead to reduced plasma concentrations of an active metabolite and hence
reduced efficacy of tamoxifen.
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
PRECAUTIONS—Tricyclic Antidepressants).
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In
addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be
at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several
substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and
cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and
its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4
substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical
significance.
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of
tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism.
Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be
reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS—Drugs Metabolized by
Cytochrome CYP2D6).
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
protein, administration of PAXIL to a patient taking another drug that is highly protein bound
may cause increased free concentrations of the other drug, potentially resulting in adverse events.
Conversely, adverse effects could result from displacement of paroxetine by other highly bound
21
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For current labeling information, please visit https://www.fda.gov/drugsatfda
drugs.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
Alcohol: Although PAXIL does not increase the impairment of mental and motor skills
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction
between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome,
caution is advised when PAXIL is coadministered with lithium.
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
paroxetine and digoxin should be undertaken with caution.
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
kinetics. The effects of paroxetine on diazepam were not evaluated.
Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0
24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%,
respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen,
the dose of procyclidine should be reduced.
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of
propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS—
Postmarketing Reports).
Theophylline: Reports of elevated theophylline levels associated with treatment with
PAXIL have been reported. While this interaction has not been formally studied, it is
recommended that theophylline levels be monitored when these drugs are concurrently
administered.
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
clinical effect (tolerability and efficacy).
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
ECT and PAXIL.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
22
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For current labeling information, please visit https://www.fda.gov/drugsatfda
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and
3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and
PTSD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than
that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only
2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of
male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for
control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats
were not affected. Although there was a dose-related increase in the number of tumors in mice,
there was no drug-related increase in the number of mice with tumors. The relevance of these
findings to humans is unknown.
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in
rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive
disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m2
basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity
studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular
epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with
arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive
disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a
mg/m2 basis).
Pregnancy: Pregnancy Category D. See WARNINGS—Usage in Pregnancy: Teratogenic and
Nonteratogenic Effects.
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
should be exercised when PAXIL is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
(see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Three
placebo-controlled trials in 752 pediatric patients with MDD have been conducted with PAXIL,
and the data were not sufficient to support a claim for use in pediatric patients. Anyone
considering the use of PAXIL in a child or adolescent must balance the potential risks with the
clinical need.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
events were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a
rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-
harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased
appetite, tremor, sweating, hyperkinesia, and agitation.
23
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Events reported upon discontinuation of treatment with PAXIL in the pediatric clinical trials
that included a taper phase regimen, which occurred in at least 2% of patients who received
PAXIL and which occurred at a rate at least twice that of placebo, were: emotional lability
(including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness,
dizziness, nausea, and abdominal pain (see Discontinuation of Treatment With PAXIL).
Geriatric Use: SSRIs and SNRIs, including PAXIL, have been associated with cases of
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
event (see PRECAUTIONS, Hyponatremia).
In worldwide premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL
(approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased
clearance in the elderly, and a lower starting dose is recommended; there were, however, no
overall differences in the adverse event profile between elderly and younger patients, and
effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Associated With Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients
treated with PAXIL in worldwide clinical trials in major depressive disorder and 16.1%
(84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients
treated with PAXIL in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD,
and PTSD, respectively, discontinued treatment due to an adverse event. The most common
events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events
associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo)
included the following:
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Major
Depressive
Disorder
OCD
Panic Disorder
Social Anxiety
Disorder
Generalized
Anxiety Disorder
PTSD
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
CNS
Somnolence
2.3%
0.7%
—
1.9%
0.3%
3.4%
0.3%
2.0%
0.2%
2.8%
0.6%
Insomnia
—
—
1.7%
0%
1.3%
0.3%
3.1%
0%
—
—
Agitation
1.1%
0.5%
—
—
—
Tremor
1.1%
0.3%
—
1.7%
0%
1.0%
0.2%
Anxiety
—
—
—
1.1%
0%
—
—
Dizziness
—
—
1.5%
0%
1.9%
0%
1.0%
0.2%
—
—
Gastroin
testinal
Constipation
—
1.1%
0%
—
—
Nausea
3.2%
1.1%
1.9%
0%
3.2%
1.2%
4.0%
0.3%
2.0%
0.2%
2.2%
0.6%
Diarrhea
1.0%
0.3%
—
Dry mouth
1.0%
0.3%
—
—
—
Vomiting
1.0%
0.3%
—
1.0%
0%
—
—
Flatulence
1.0%
0.3%
—
—
Other
Asthenia
Abnormal
1.6%
0.4%
1.9%
0.4%
2.5%
0.6%
1.8%
0.2%
1.6%
0.2%
ejaculation1
1.6%
0%
2.1%
0%
4.9%
0.6%
2.5%
0.5%
—
—
Sweating
1.0%
0.3%
—
1.1%
0%
1.1%
0.2%
—
—
Impotence1
Libido
—
1.5%
0%
—
—
Decreased
1.0%
0%
—
—
Where numbers are not provided the incidence of the adverse events in patients treated with PAXIL was not >1% or
was not greater than or equal to 2 times the incidence of placebo.
1. Incidence corrected for gender.
Commonly Observed Adverse Events: Major Depressive Disorder: The most
commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
greater and incidence for PAXIL at least twice that for placebo, derived from Table 2) were:
Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor,
nervousness, ejaculatory disturbance, and other male genital disorders.
Obsessive Compulsive Disorder: The most commonly observed adverse events
associated with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at
least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite,
constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
Panic Disorder: The most commonly observed adverse events associated with the use of
paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for placebo,
derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor,
abnormal ejaculation, female genital disorders, and impotence.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Social Anxiety Disorder: The most commonly observed adverse events associated with
the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for
placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased
appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital
disorders, and impotence.
Generalized Anxiety Disorder: The most commonly observed adverse events associated
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased
appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal
ejaculation.
Posttraumatic Stress Disorder: The most commonly observed adverse events associated
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea,
decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders,
and impotence.
Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in
the tables following cannot be used to predict the incidence of side effects in the course of usual
medical practice where patient characteristics and other factors differ from those that prevailed in
the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from
other clinical investigations involving different treatments, uses, and investigators. The cited
figures, however, do provide the prescribing physician with some basis for estimating the
relative contribution of drug and nondrug factors to the side effect incidence rate in the
populations studied.
Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an
incidence of 1% or more among paroxetine-treated patients who participated in short-term
(6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to
50 mg/day. Reported adverse events were classified using a standard COSTART-based
Dictionary terminology.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Major Depressive Disorder1
Body System
Preferred Term
PAXIL
(n = 421)
Placebo
(n = 421)
Body as a Whole
Headache
Asthenia
18%
15%
17%
6%
Cardiovascular
Palpitation
Vasodilation
3%
3%
1%
1%
Dermatologic
Sweating
Rash
11%
2%
2%
1%
Gastrointestinal
Nausea
26%
9%
Dry Mouth
18%
12%
Constipation
14%
9%
Diarrhea
12%
8%
Decreased Appetite
6%
2%
Flatulence
4%
2%
Oropharynx Disorder2
2%
0%
Dyspepsia
2%
1%
Musculoskeletal
Myopathy
Myalgia
Myasthenia
2%
2%
1%
1%
1%
0%
Nervous System
Somnolence
23%
9%
Dizziness
13%
6%
Insomnia
13%
6%
Tremor
8%
2%
Nervousness
5%
3%
Anxiety
5%
3%
Paresthesia
4%
2%
Libido Decreased
3%
0%
Drugged Feeling
2%
1%
Confusion
1%
0%
Respiration
Yawn
4%
0%
Special Senses
Blurred Vision
Taste Perversion
4%
2%
1%
0%
Urogenital System
Ejaculatory Disturbance3,4
13%
0%
Other Male Genital Disorders3,5
10%
0%
Urinary Frequency
3%
1%
Urination Disorder6
3%
0%
Female Genital Disorders3,7
2%
0%
1. Events reported by at least 1% of patients treated with PAXIL are included, except the
following events which had an incidence on placebo ≥ PAXIL: Abdominal pain, agitation,
back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis,
postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”),
trauma, and vomiting.
2. Includes mostly “lump in throat” and “tightness in throat.”
27
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3. Percentage corrected for gender.
4. Mostly “ejaculatory delay.”
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual
dysfunction,” and “impotence.”
6. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD
patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on
PAXIL who participated in placebo-controlled trials of 10- to 12-weeks duration in which
patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety
disorder on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
patients were dosed in a range of 20 mg to 50 mg/day.
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety
Disorder1
Body System
Preferred Term
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
PAXIL
(n = 542)
Placebo
(n = 265)
PAXIL
(n = 469)
Placebo
(n = 324)
PAXIL
(n = 425)
Placebo
(n = 339)
Body as a Whole
Asthenia
Abdominal Pain
Chest Pain
Back Pain
Chills
Trauma
22%
—
3%
—
2%
—
14%
—
2%
—
1%
—
14%
4%
—
3%
2%
—
5%
3%
—
2%
1%
—
22%
—
—
—
—
3%
14%
—
—
—
—
1%
Cardiovascular
Vasodilation
Palpitation
4%
2%
1%
0%
—
—
—
—
—
—
—
—
Dermatologic
Sweating
Rash
9%
3%
3%
2%
14%
—
6%
—
9%
—
2%
—
Gastrointestinal
Nausea
23%
10%
23%
17%
25%
7%
Dry Mouth
18%
9%
18%
11%
9%
3%
Constipation
16%
6%
8%
5%
5%
2%
Diarrhea
Decreased
10%
10%
12%
7%
9%
6%
Appetite
9%
3%
7%
3%
8%
2%
Dyspepsia
—
—
—
—
4%
2%
Flatulence
Increased
—
—
—
—
4%
2%
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Appetite
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
4%
3%
2%
1%
—
—
Vomiting
—
—
—
—
2%
1%
Musculoskeletal
Myalgia
—
—
—
—
4%
3%
Nervous System
Insomnia
Somnolence
Dizziness
Tremor
Nervousness
Libido Decreased
Agitation
Anxiety
Abnormal
Dreams
Concentration
Impaired
Depersonalization
Myoclonus
Amnesia
24%
24%
12%
11%
9%
7%
—
—
4%
3%
3%
3%
2%
13%
7%
6%
1%
8%
4%
—
—
1%
2%
0%
0%
1%
18%
19%
14%
9%
—
9%
5%
5%
—
—
—
3%
—
10%
11%
10%
1%
—
1%
4%
4%
—
—
—
2%
—
21%
22%
11%
9%
8%
12%
3%
5%
—
4%
—
2%
—
16%
5%
7%
1%
7%
1%
1%
4%
—
1%
—
1%
—
Respiratory System
Rhinitis
Pharyngitis
Yawn
—
—
—
—
—
—
3%
—
—
0%
—
—
—
4%
5%
—
2%
1%
Special Senses
Abnormal Vision
Taste Perversion
4%
2%
2%
0%
—
—
—
—
4%
—
1%
—
Urogenital System
Abnormal
Ejaculation2
Dysmenorrhea
Female Genital
Disorder2
Impotence2
Urinary
Frequency
Urination
Impaired
Urinary Tract
Infection
23%
—
3%
8%
3%
3%
2%
1%
—
0%
1%
1%
0%
1%
21%
—
9%
5%
2%
—
2%
1%
—
1%
0%
0%
—
1%
28%
5%
9%
5%
—
—
—
1%
4%
1%
1%
—
—
—
1. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients
treated with PAXIL are included, except the following events which had an incidence on
placebo ≥PAXIL: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased,
depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder,
rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough
increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache,
29
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infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory
disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social
anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and
sinusitis.
2. Percentage corrected for gender.
Generalized Anxiety Disorder and Posttraumatic Stress Disorder: Table 4
enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on
PAXIL who participated in placebo-controlled trials of 8-weeks duration in which patients were
dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on PAXIL who
participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a
range of 20 mg/day to 50 mg/day.
30
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Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disorder1
Body System
Preferred Term
Generalized Anxiety
Disorder
Posttraumatic Stress
Disorder
PAXIL
(n = 735)
Placebo
(n = 529)
PAXIL
(n = 676)
Placebo
(n = 504)
Body as a Whole
Asthenia
Headache
Infection
Abdominal Pain
Trauma
14%
17%
6%
6%
14%
3%
12%
—
5%
4%
6%
4%
—
4%
3%
5%
Cardiovascular
Vasodilation
3%
1%
2%
1%
Dermatologic
Sweating
6%
2%
5%
1%
Gastrointestinal
Nausea
Dry Mouth
Constipation
Diarrhea
Decreased Appetite
Vomiting
Dyspepsia
20%
11%
10%
9%
5%
3%
—
5%
5%
2%
7%
1%
2%
—
19%
10%
5%
11%
6%
3%
5%
8%
5%
3%
5%
3%
2%
3%
Nervous System
Insomnia
Somnolence
Dizziness
Tremor
Nervousness
Libido Decreased
Abnormal Dreams
11%
15%
6%
5%
4%
9%
8%
5%
5%
1%
3%
2%
12%
16%
6%
4%
—
5%
3%
11%
5%
5%
1%
—
2%
2%
Respiratory
System
Respiratory Disorder
Sinusitis
Yawn
7%
4%
4%
5%
3%
—
—
—
2%
—
—
<1%
Special Senses
Abnormal Vision
2%
1%
3%
1%
Urogenital
System
Abnormal
Ejaculation
2
Female Genital
Disorder
2
Impotence
2
25%
4%
4%
2%
1%
3%
13%
5%
9%
2%
1%
1%
1. Events reported by at least 2% of GAD and PTSD in patients treated with PAXIL are
included, except the following events which had an incidence on placebo ≥PAXIL [GAD]:
Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain,
headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis.
2. Percentage corrected for gender.
Dose Dependency of Adverse Events: A comparison of adverse event rates in a
fixed-dose study comparing 10, 20, 30, and 40 mg/day of PAXIL with placebo in the treatment
of major depressive disorder revealed a clear dose dependency for some of the more common
adverse events associated with use of PAXIL, as shown in the following table:
31
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Table 5 . Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial
in the Treatment of Major Depressive Disorder*
Body System/Preferred Term
Placebo
n = 51
PAXIL
10 mg
n = 102
20 mg
n = 104
30 mg
n = 101
40 mg
n = 102
Body as a Whole
Asthenia
0.0%
2.9%
10.6%
13.9%
12.7%
Dermatology
Sweating
2.0%
1.0%
6.7%
8.9%
11.8%
Gastrointestinal
Constipation
5.9%
4.9%
7.7%
9.9%
12.7%
Decreased Appetite
2.0%
2.0%
5.8%
4.0%
4.9%
Diarrhea
7.8%
9.8%
19.2%
7.9%
14.7%
Dry Mouth
2.0%
10.8%
18.3%
15.8%
20.6%
Nausea
13.7%
14.7%
26.9%
34.7%
36.3%
Nervous System
Anxiety
0.0%
2.0%
5.8%
5.9%
5.9%
Dizziness
3.9%
6.9%
6.7%
8.9%
12.7%
Nervousness
0.0%
5.9%
5.8%
4.0%
2.9%
Paresthesia
0.0%
2.9%
1.0%
5.0%
5.9%
Somnolence
7.8%
12.7%
18.3%
20.8%
21.6%
Tremor
0.0%
0.0%
7.7%
7.9%
14.7%
Special Senses
Blurred Vision
2.0%
2.9%
2.9%
2.0%
7.8%
Urogenital System
Abnormal Ejaculation
0.0%
5.8%
6.5%
10.6%
13.0%
Impotence
0.0%
1.9%
4.3%
6.4%
1.9%
Male Genital Disorders
0.0%
3.8%
8.7%
6.4%
3.7%
* Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups
and ≥ twice the placebo incidence for at least 1 paroxetine group.
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
OCD, there was no clear relationship between adverse events and the dose of PAXIL to which
patients were assigned. No new adverse events were observed in the group treated with 60 mg of
PAXIL compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of PAXIL in the treatment of
panic disorder, there was no clear relationship between adverse events and the dose of PAXIL to
which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor,
and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in
patients receiving 60 mg of PAXIL compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
social anxiety disorder, for most of the adverse events, there was no clear relationship between
32
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adverse events and the dose of PAXIL to which patients were assigned.
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
generalized anxiety disorder, for most of the adverse events, there was no clear relationship
between adverse events and the dose of PAXIL to which patients were assigned, except for the
following adverse events: Asthenia, constipation, and abnormal ejaculation.
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
posttraumatic stress disorder, for most of the adverse events, there was no clear relationship
between adverse events and the dose of PAXIL to which patients were assigned, except for
impotence and abnormal ejaculation.
Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence
of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less
to other effects (e.g., dry mouth, somnolence, and asthenia).
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward
sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual
desire, performance, and satisfaction are difficult to obtain, however, in part because patients and
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
untoward sexual experience and performance cited in product labeling, are likely to
underestimate their actual incidence.
In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the
reported incidence of sexual side effects in males and females with major depressive disorder,
OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.
Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials
PAXIL
Placebo
n (males)
1446
1042
Decreased Libido
6-15%
0-5%
Ejaculatory Disturbance
13-28%
0-2%
Impotence
2-9%
0-3%
n (females)
1822
1340
Decreased Libido
0-9%
0-2%
Orgasmic Disturbance
2-9%
0-1%
There are no adequate and well-controlled studies examining sexual dysfunction with
paroxetine treatment.
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
known outcome, patients recovered without sequelae.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
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SSRIs, physicians should routinely inquire about such possible side effects.
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
treatment with PAXIL for some patients but, on average, patients in controlled trials had minimal
(about 1 pound) weight loss versus smaller changes on placebo and active control. No significant
changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were
observed in patients treated with PAXIL in controlled clinical trials.
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with PAXIL and
415 patients treated with placebo in controlled clinical trials, no clinically significant changes
were seen in the ECGs of either group.
Liver Function Tests: In placebo-controlled clinical trials, patients treated with PAXIL
exhibited abnormal values on liver function tests at no greater rate than that seen in
placebo-treated patients. In particular, the PAXIL-versus-placebo comparisons for alkaline
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
with marked abnormalities.
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients
receiving placebo.
Other Events Observed During the Premarketing Evaluation of PAXIL: During its
premarketing assessment in major depressive disorder, multiple doses of PAXIL were
administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure
to PAXIL varied greatly and included (in overlapping categories) open and double-blind studies,
uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration
studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder,
generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676
patients, respectively, received multiple doses of PAXIL. Untoward events associated with this
exposure were recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
experiencing adverse events without first grouping similar types of untoward events into a
smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a standard
COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the
proportion of the 9,089 patients exposed to multiple doses of PAXIL who experienced an event
of the type cited on at least 1 occasion while receiving PAXIL. All reported events are included
except those already listed in Tables 2 to 4, those reported in terms so general as to be
uninformative and those events where a drug cause was remote. It is important to emphasize that
although the events reported occurred during treatment with paroxetine, they were not
necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: Frequent adverse events are those occurring on 1 or more
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
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placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events
of major clinical importance are also described in the PRECAUTIONS section.
Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain;
rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis,
ulcer.
Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia,
hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris,
arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular
accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial
ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis,
thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis,
gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal
hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia,
cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal
incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction,
jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis,
stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism,
thyroiditis.
Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy,
purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia,
hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal
lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia,
thrombocythemia, thrombocytopenia.
Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema,
SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased,
bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma
globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia,
hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic
dehydrogenase increased, non-protein nitrogen (NPN) increased.
Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare:
Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking,
alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia,
hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction,
neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia,
choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug
dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion,
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hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy,
nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes
increased, stupor, torticollis, trismus, withdrawal syndrome.
Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation,
pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary
edema, sputum increased, stridor, voice alteration.
Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis,
dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema,
erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis;
herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy,
skin ulcer, sweating decreased, vesiculobullous rash.
Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation,
conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia,
anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye
hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia,
ptosis, retinal hemorrhage, taste loss, visual field defect.
Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria,
menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency,
vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis,
female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis,
metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith,
vaginal hemorrhage, vaginal moniliasis.
Postmarketing Reports: Voluntary reports of adverse events in patients taking PAXIL that
have been received since market introduction and not listed above that may have no causal
relationship with the drug include acute pancreatitis, elevated liver function tests (the most
severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated
with severe liver dysfunction), Guillain-Barré syndrome, toxic epidermal necrolysis, priapism,
syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and
galactorrhea, neuroleptic malignant syndrome–like events, serotonin syndrome; extrapyramidal
symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia,
oculogyric crisis which has been associated with concomitant use of pimozide; tremor and
trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis,
anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular
tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related
to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and
agranulocytosis), and vasculitic syndromes (such as Henoch-Schönlein purpura). There has been
a case report of an elevated phenytoin level after 4 weeks of PAXIL and phenytoin
coadministration. There has been a case report of severe hypotension when PAXIL was added to
chronic metoprolol treatment.
36
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DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: PAXIL is not a controlled substance.
Physical and Psychologic Dependence: PAXIL has not been systematically studied in
animals or humans for its potential for abuse, tolerance or physical dependence. While the
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
not systematic and it is not possible to predict on the basis of this limited experience the extent to
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
patients should be evaluated carefully for history of drug abuse, and such patients should be
observed closely for signs of misuse or abuse of PAXIL (e.g., development of tolerance,
incrementations of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience: Since the introduction of PAXIL in the United States, 342 spontaneous
cases of deliberate or accidental overdosage during paroxetine treatment have been reported
worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with
other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve
paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were
generally confounded by the ingestion of other drugs or alcohol or the presence of significant
comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without
sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum
recommended daily dose) in a patient who recovered.
Commonly reported adverse events associated with paroxetine overdosage include
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
substances) include mydriasis, convulsions (including status epilepticus), ventricular
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
Overdosage Management: Treatment should consist of those general measures employed in
the management of overdosage with any drugs effective in the treatment of major depressive
disorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to the large volume of distribution of this
drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of
benefit. No specific antidotes for paroxetine are known.
37
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A specific caution involves patients who are taking or have recently taken paroxetine who
might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
parent tricyclic and/or an active metabolite may increase the possibility of clinically significant
sequelae and extend the time needed for close medical observation (see PRECAUTIONS—
Drugs Metabolized by Cytochrome CYP2D6).
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center for additional information on the treatment of
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
Major Depressive Disorder: Usual Initial Dosage: PAXIL should be administered as a
single daily dose with or without food, usually in the morning. The recommended initial dose is
20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating
the effectiveness of PAXIL in the treatment of major depressive disorder. As with all drugs
effective in the treatment of major depressive disorder, the full effect may be delayed. Some
patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day
increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least
1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL should remain on it. It is generally agreed that acute
episodes of major depressive disorder require several months or longer of sustained
pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose
needed to maintain and/or sustain euthymia is unknown.
Systematic evaluation of the efficacy of PAXIL has shown that efficacy is maintained for
periods of up to 1 year with doses that averaged about 30 mg.
Obsessive Compulsive Disorder: Usual Initial Dosage: PAXIL should be administered
as a single daily dose with or without food, usually in the morning. The recommended dose of
PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the
dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at
least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials
demonstrating the effectiveness of PAXIL in the treatment of OCD. The maximum dosage
should not exceed 60 mg/day.
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month
relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a
lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY—
Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
effective dosage, and patients should be periodically reassessed to determine the need for
continued treatment.
38
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Panic Disorder: Usual Initial Dosage: PAXIL should be administered as a single daily dose
with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic
disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in
10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to
60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL. The maximum dosage
should not exceed 60 mg/day.
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month
relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine
demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL
PHARMACOLOGY—Clinical Trials). Panic disorder is a chronic condition, and it is reasonable
to consider continuation for a responding patient. Dosage adjustments should be made to
maintain the patient on the lowest effective dosage, and patients should be periodically
reassessed to determine the need for continued treatment.
Social Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a single
daily dose with or without food, usually in the morning. The recommended and initial dosage is
20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a
range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social
anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional
benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY—Clinical Trials).
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety
disorder is recognized as a chronic condition, and it is reasonable to consider continuation of
treatment for a responding patient. Dosage adjustments should be made to maintain the patient
on the lowest effective dosage, and patients should be periodically reassessed to determine the
need for continued treatment.
Generalized Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a
single daily dose with or without food, usually in the morning. In clinical trials the effectiveness
of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended
starting dosage and the established effective dosage is 20 mg/day. There is not sufficient
evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur
in 10 mg/day increments and at intervals of at least 1 week.
Maintenance Therapy: Systematic evaluation of continuing PAXIL for periods of up to
24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL
during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see
CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, patients should be periodically
reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder: Usual Initial Dosage: PAXIL should be administered as
a single daily dose with or without food, usually in the morning. The recommended starting
dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of
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PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed
dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day
compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at
intervals of at least 1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is
recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
effective dosage, and patients should be periodically reassessed to determine the need for
continued treatment.
Special Populations: Treatment of Pregnant Women During the Third Trimester:
Neonates exposed to PAXIL and other SSRIs or SNRIs, late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding (see WARNINGS). When treating pregnant women with paroxetine during the third
trimester, the physician should carefully consider the potential risks and benefits of treatment.
The physician may consider tapering paroxetine in the third trimester.
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
Hepatic Impairment: The recommended initial dose is 10 mg/day for elderly patients,
debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be
made if indicated. Dosage should not exceed 40 mg/day.
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL.
Similarly, at least 14 days should be allowed after stopping PAXIL before starting an MAOI.
Discontinuation of Treatment With PAXIL: Symptoms associated with discontinuation of
PAXIL have been reported (see PRECAUTIONS). Patients should be monitored for these
symptoms when discontinuing treatment, regardless of the indication for which PAXIL is being
prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended
whenever possible. If intolerable symptoms occur following a decrease in the dose or upon
discontinuation of treatment, then resuming the previously prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
HOW SUPPLIED
Tablets: Film-coated, modified-oval as follows:
10-mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
NDC 0029-3210-13 Bottles of 30
20-mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
NDC 0029-3211-13 Bottles of 30
NDC 0029-3211-59 Bottles of 90
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NDC 0029-3211-21 SUP 100s (intended for institutional use only)
30-mg blue tablets engraved on the front with PAXIL and on the back with 30.
NDC 0029-3212-13 Bottles of 30
40-mg green tablets engraved on the front with PAXIL and on the back with 40.
NDC 0029-3213-13 Bottles of 30
Store tablets between 15° and 30°C (59° and 86°F).
Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.
NDC 0029-3215-48
Store suspension at or below 25°C (77°F).
PAXIL is a registered trademark of GlaxoSmithKline.
Medication Guide
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions
PAXIL® (PAX-il) (paroxetine hydrochloride) Tablets and Oral Suspension
Read the Medication Guide that comes with your or your family member’s antidepressant
medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
about:
• All risks and benefits of treatment with antidepressant medicines
• All treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or action?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started or
when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
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• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the
following symptoms, especially if they are new, worse, or worry you:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Trouble sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking (mania)
• Other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating it.
Patients and their families or other caregivers should discuss all treatment choices with
the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Call your doctor for medical advice
about side effects. You may report side effects to FDA at 1-800-FDA-1088.
• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show the
healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use
in children. Talk to your child’s healthcare provider for more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
January 2008
PXL:4MG
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For current labeling information, please visit https://www.fda.gov/drugsatfda
logo
Research Triangle Park, NC 27709
©2008, GlaxoSmithKline. All rights reserved.
June 2008
PXL:48PI
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PRESCRIBING INFORMATION
PAXIL CR®
(paroxetine hydrochloride)
Controlled-Release Tablets
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
use of PAXIL CR or any other antidepressant in a child, adolescent, or young adult must
balance this risk with the clinical need. Short-term studies did not show an increase in the
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
older. Depression and certain other psychiatric disorders are themselves associated with
increases in the risk of suicide. Patients of all ages who are started on antidepressant
therapy should be monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
the need for close observation and communication with the prescriber. PAXIL CR is not
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
DESCRIPTION
PAXIL CR (paroxetine hydrochloride) is an orally administered psychotropic drug with a
chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic,
tetracyclic, or other available antidepressant or antipanic agents. It is the hydrochloride salt of a
phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'
methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical
formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The
structural formula of paroxetine hydrochloride is: Chemical Structure
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
120° to 138°C and a solubility of 5.4 mg/mL in water.
Each enteric, film-coated, controlled-release tablet contains paroxetine hydrochloride
equivalent to paroxetine as follows: 12.5 mg–yellow, 25 mg–pink, 37.5 mg–blue. One layer of
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the tablet consists of a degradable barrier layer and the other contains the active material in a
hydrophilic matrix.
Inactive ingredients consist of hypromellose, polyvinylpyrrolidone, lactose monohydrate,
magnesium stearate, silicon dioxide, glyceryl behenate, methacrylic acid copolymer type C,
sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate, titanium dioxide, polyethylene
glycols, and 1 or more of the following colorants: Yellow ferric oxide, red ferric oxide, D&C
Red No. 30 aluminum lake, FD&C Yellow No. 6 aluminum lake, D&C Yellow No. 10
aluminum lake, FD&C Blue No. 2 aluminum lake.
CLINICAL PHARMACOLOGY
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder (PMDD) is
presumed to be linked to potentiation of serotonergic activity in the central nervous system
resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT).
Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the
uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine
is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak
effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies
indicate that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-,
dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic,
histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic,
sedative, and cardiovascular effects for other psychotropic drugs.
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
compound, they are essentially inactive.
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
solution of the hydrochloride salt. The elimination half-life is approximately 15 to 20 hours after
a single dose of PAXIL CR. Paroxetine is extensively metabolized and the metabolites are
considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses.
Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily
excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has
not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).
Absorption and Distribution: Tablets of PAXIL CR contain a degradable polymeric
matrix (GEOMATRIX™) designed to control the dissolution rate of paroxetine over a period of
approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric
coat delays the start of drug release until tablets of PAXIL CR have left the stomach.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
hydrochloride salt. In a study in which normal male and female subjects (n = 23) received single
oral doses of PAXIL CR at 4 dosage strengths (12.5 mg, 25 mg, 37.5 mg, and 50 mg), paroxetine
Cmax and AUC0-inf increased disproportionately with dose (as seen also with immediate-release
formulations). Mean Cmax and AUC0-inf values at these doses were 2.0, 5.5, 9.0, and 12.5 ng/mL,
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and 121, 261, 338, and 540 ng•hr./mL, respectively. Tmax was observed typically between 6 and
10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release
formulations. The bioavailability of 25 mg PAXIL CR is not affected by food.
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
plasma.
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
warfarin.
Metabolism and Excretion: The mean elimination half-life of paroxetine was 15 to
20 hours throughout a range of single doses of PAXIL CR (12.5 mg, 25 mg, 37.5 mg, and
50 mg). During repeated administration of PAXIL CR (25 mg once daily), steady state was
reached within 2 weeks (i.e., comparable to immediate-release formulations). In a repeat-dose
study in which normal male and female subjects (n = 23) received PAXIL CR (25 mg daily),
mean steady state Cmax, Cmin, and AUC0-24 values were 30 ng/mL, 20 ng/mL, and 550 ng•hr./mL,
respectively.
Based on studies using immediate-release formulations, steady-state drug exposure based on
AUC0-24 was several-fold greater than would have been predicted from single-dose data. The
excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes
paroxetine is readily saturable.
In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses
of the immediate-release formulation of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg
daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a
saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg
daily were only about 2 to 3 times greater than doubled.
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
polar and conjugated products of oxidation and methylation, which are readily cleared.
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
interactions (see PRECAUTIONS).
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
1% as the parent compound over the 10-day post-dosing period.
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic
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impairment. The mean plasma concentrations in patients with creatinine clearance below
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
about a 2-fold increase in plasma concentrations (AUC, Cmax).
The initial dosage should therefore be reduced in patients with severe renal or hepatic
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
AND ADMINISTRATION).
Elderly Patients: In a multiple-dose study in the elderly at daily doses of 20, 30, and
40 mg of the immediate-release formulation, Cmin concentrations were about 70% to 80% greater
than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the
elderly should be reduced (see DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
desipramine, risperidone, and atomoxetine (see PRECAUTIONS—Drug Interactions).
Clinical Trials
Major Depressive Disorder: The efficacy of PAXIL CR controlled-release tablets as a
treatment for major depressive disorder has been established in two 12-week, flexible-dose,
placebo-controlled studies of patients with DSM-IV Major Depressive Disorder. One study
included patients in the age range 18 to 65 years, and a second study included elderly patients,
ranging in age from 60 to 88. In both studies, PAXIL CR was shown to be significantly more
effective than placebo in treating major depressive disorder as measured by the following:
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
Global Impression (CGI)–Severity of Illness score.
A study of outpatients with major depressive disorder who had responded to
immediate-release paroxetine tablets (HDRS total score <8) during an initial 8-week
open-treatment phase and were then randomized to continuation on immediate-release paroxetine
tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking
immediate-release paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness
was similar for male and female patients.
Panic Disorder: The effectiveness of PAXIL CR in the treatment of panic disorder was
evaluated in three 10-week, multicenter, flexible-dose studies (Studies 1, 2, and 3) comparing
paroxetine controlled-release (12.5 to 75 mg daily) to placebo in adult outpatients who had panic
disorder (DSM-IV), with or without agoraphobia. These trials were assessed on the basis of their
outcomes on 3 variables: (1) the proportions of patients free of full panic attacks at endpoint; (2)
change from baseline to endpoint in the median number of full panic attacks; and (3) change
from baseline to endpoint in the median Clinical Global Impression Severity score. For Studies 1
and 2, PAXIL CR was consistently superior to placebo on 2 of these 3 variables. Study 3 failed
to consistently demonstrate a significant difference between PAXIL CR and placebo on any of
these variables.
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For all 3 studies, the mean dose of PAXIL CR for completers at endpoint was approximately
50 mg/day. Subgroup analyses did not indicate that there were any differences in treatment
outcomes as a function of age or gender.
Long-term maintenance effects of the immediate-release formulation of paroxetine in panic
disorder were demonstrated in an extension study. Patients who were responders during a
10-week double-blind phase with immediate-release paroxetine and during a 3-month
double-blind extension phase were randomized to either immediate-release paroxetine or placebo
in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were
significantly less likely to relapse than comparably treated patients who were randomized to
placebo.
Social Anxiety Disorder: The efficacy of PAXIL CR as a treatment for social anxiety
disorder has been established, in part, on the basis of extrapolation from the established
effectiveness of the immediate-release formulation of paroxetine. In addition, the effectiveness
of PAXIL CR in the treatment of social anxiety disorder was demonstrated in a 12-week,
multicenter, double-blind, flexible-dose, placebo-controlled study of adult outpatients with a
primary diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness of
PAXIL CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1)
change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and (2) the
proportion of responders who scored 1 or 2 (very much improved or much improved) on the
Clinical Global Impression (CGI) Global Improvement score.
PAXIL CR demonstrated statistically significant superiority over placebo on both the LSAS
total score and the CGI Improvement responder criterion. For patients who completed the trial,
64% of patients treated with PAXIL CR compared to 34.7% of patients treated with placebo
were CGI Improvement responders.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of gender. Subgroup analyses of studies utilizing the immediate-release formulation of
paroxetine generally did not indicate differences in treatment outcomes as a function of age, race,
or gender.
Premenstrual Dysphoric Disorder: The effectiveness of PAXIL CR for the treatment of
PMDD utilizing a continuous dosing regimen has been established in 2 placebo-controlled trials.
Patients in these trials met DSM-IV criteria for PMDD. In a pool of 1,030 patients, treated with
daily doses of PAXIL CR 12.5 or 25 mg/day, or placebo the mean duration of the PMDD
symptoms was approximately 11 ± 7 years. Patients on systemic hormonal contraceptives were
excluded from these trials. Therefore, the efficacy of PAXIL CR in combination with systemic
(including oral) hormonal contraceptives for the continuous daily treatment of PMDD is
unknown. In both positive studies, patients (N = 672) were treated with 12.5 mg/day or
25 mg/day of PAXIL CR or placebo continuously throughout the menstrual cycle for a period of
3 menstrual cycles. The VAS-Total score is a patient-rated instrument that mirrors the diagnostic
criteria of PMDD as identified in the DSM-IV, and includes assessments for mood, physical
symptoms, and other symptoms. 12.5 mg/day and 25 mg/day of PAXIL CR were significantly
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more effective than placebo as measured by change from baseline to the endpoint on the luteal
phase VAS-Total score.
In a third study employing intermittent dosing, patients (N = 366) were treated for the 2 weeks
prior to the onset of menses (luteal phase dosing, also known as intermittent dosing) with
12.5 mg/day or 25 mg/day of PAXIL CR or placebo for a period of 3 months. 12.5 mg/day and
25 mg/day of PAXIL CR, as luteal phase dosing, was significantly more effective than placebo
as measured by change from baseline luteal phase VAS total score.
There is insufficient information to determine the effect of race or age on outcome in
these studies.
INDICATIONS AND USAGE
Major Depressive Disorder: PAXIL CR is indicated for the treatment of major depressive
disorder.
The efficacy of PAXIL CR in the treatment of a major depressive episode was established in
two 12-week controlled trials of outpatients whose diagnoses corresponded to the DSM-IV
category of major depressive disorder (see CLINICAL PHARMACOLOGY—Clinical Trials).
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly
every day for at least 2 weeks) depressed mood or loss of interest or pleasure in nearly all
activities, representing a change from previous functioning, and includes the presence of at least
5 of the following 9 symptoms during the same 2-week period: Depressed mood, markedly
diminished interest or pleasure in usual activities, significant change in weight and/or appetite,
insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of
guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal
ideation.
The antidepressant action of paroxetine in hospitalized depressed patients has not been
adequately studied.
PAXIL CR has not been systematically evaluated beyond 12 weeks in controlled clinical
trials; however, the effectiveness of immediate-release paroxetine hydrochloride in maintaining a
response in major depressive disorder for up to 1 year has been demonstrated in a
placebo-controlled trial (see CLINICAL PHARMACOLOGY—Clinical Trials). The physician
who elects to use PAXIL CR for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
Panic Disorder: PAXIL CR is indicated for the treatment of panic disorder, with or without
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of PAXIL CR controlled-release tablets was established in two 10-week trials in
panic disorder patients whose diagnoses corresponded to the DSM-IV category of panic disorder
(see CLINICAL PHARMACOLOGY—Clinical Trials).
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Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11)
fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
Long-term maintenance of efficacy with the immediate-release formulation of paroxetine was
demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder
assigned to immediate-release paroxetine demonstrated a lower relapse rate compared to patients
on placebo (see CLINICAL PHARMACOLOGY—Clinical Trials). Nevertheless, the physician
who prescribes PAXIL CR for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
Social Anxiety Disorder: PAXIL CR is indicated for the treatment of social anxiety disorder,
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
characterized by a marked and persistent fear of 1 or more social or performance situations in
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
the person's normal routine, occupational or academic functioning, or social activities or
relationships, or there is marked distress about having the phobias. Lesser degrees of
performance anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of PAXIL CR as a treatment for social anxiety disorder has been established, in
part, on the basis of extrapolation from the established effectiveness of the immediate-release
formulation of paroxetine. In addition, the efficacy of PAXIL CR was established in a 12-week
trial, in adult outpatients with social anxiety disorder (DSM-IV). PAXIL CR has not been studied
in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY—Clinical
Trials).
The effectiveness of PAXIL CR in long-term treatment of social anxiety disorder, i.e., for
more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
Therefore, the physician who elects to prescribe PAXIL CR for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder: PAXIL CR is indicated for the treatment of PMDD.
The efficacy of PAXIL CR in the treatment of PMDD has been established in 3
placebo-controlled trials (see CLINICAL PHARMACOLOGY—Clinical Trials).
The essential features of PMDD, according to DSM-IV, include markedly depressed mood,
anxiety or tension, affective lability, and persistent anger or irritability. Other features include
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decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite
or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast
tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur
regularly during the luteal phase and remit within a few days following the onset of menses; the
disturbance markedly interferes with work or school or with usual social activities and
relationships with others. In making the diagnosis, care should be taken to rule out other cyclical
mood disorders that may be exacerbated by treatment with an antidepressant.
The effectiveness of PAXIL CR in long-term use, that is, for more than 3 menstrual cycles,
has not been systematically evaluated in controlled trials. Therefore, the physician who elects to
use PAXIL CR for extended periods should periodically re-evaluate the long-term usefulness of
the drug for the individual patient.
CONTRAINDICATIONS
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs), including
linezolid, an antibiotic which is a reversible non-selective MAOI, or thioridazine is
contraindicated (see WARNINGS and PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
PAXIL CR is contraindicated in patients with a hypersensitivity to paroxetine or to any of the
inactive ingredients in PAXIL CR.
WARNINGS
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
both adult and pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
are taking antidepressant medications, and this risk may persist until significant remission
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-standing
concern, however, that antidepressants may have a role in inducing worsening of depression and
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
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For current labeling information, please visit https://www.fda.gov/drugsatfda
increase in the younger patients for almost all drugs studied. There were differences in absolute
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1,000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as
rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—
Discontinuation of Treatment With PAXIL CR), for a description of the risks of discontinuation
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of PAXIL CR.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to healthcare
providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for PAXIL CR should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that PAXIL CR is not approved for use in treating bipolar
depression.
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
another serotonin reuptake inhibitor drug in combination with an MAOI, there have been
reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus,
autonomic instability with possible rapid fluctuations of vital signs, and mental status
changes that include extreme agitation progressing to delirium and coma. These reactions
have also been reported in patients who have recently discontinued that drug and have
been started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. While there are no human data showing such an interaction with
paroxetine hydrochloride, limited animal data on the effects of combined use of paroxetine
and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and
evoke behavioral excitation. Therefore, it is recommended that PAXIL CR not be used in
combination with an MAOI (including linezolid, an antibiotic which is a reversible non
selective MAOI), or within 14 days of discontinuing treatment with an MAOI (see
CONTRAINDICATIONS). At least 2 weeks should be allowed after stopping PAXIL CR
before starting an MAOI.
Serotonin Syndrome: The development of a potentially life-threatening serotonin
syndrome may occur with SNRIs and SSRIs, including PAXIL CR, particularly with
concomitant use of serotonergic drugs (including triptans) and with drugs which impair
metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include
mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g.,
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hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting,
diarrhea).
The concomitant use of PAXIL CR with MAOIs intended to treat depression is
contraindicated (see CONTRAINDICATIONS and WARNINGS—Potential for
Interaction With Monoamine Oxidase Inhibitors).
If concomitant treatment with PAXIL CR with a 5-hydroxytryptamine receptor agonist
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
during treatment initiation and dose increases (see PRECAUTIONS—Drug Interactions).
The concomitant use of PAXIL CR with serotonin precursors (such as tryptophan) is
not recommended (see PRECAUTIONS—Drug Interactions).
Potential Interaction With Thioridazine: Thioridazine administration alone produces
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
dose related.
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
used in combination with thioridazine (see CONTRAINDICATIONS and
PRECAUTIONS).
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
infants born to women who had first trimester paroxetine exposure had an increased risk of
cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs).
In general, septal defects range from those that are symptomatic and may require surgery to those
that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while
taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of
paroxetine to the mother justify continuing treatment, consideration should be given to either
discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS—
Discontinuation of Treatment with PAXIL CR). For women who intend to become pregnant or
are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of
the other available treatment options.
A study based on Swedish national registry data evaluated infants of 6,896 women exposed to
antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for
paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of
cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry
population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations
following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population.
Among the same paroxetine exposed infants, an examination of the data showed no increase in
the overall risk for congenital malformations.
A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants
of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815 for
paroxetine). This study showed a trend towards an increased risk for cardiovascular
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malformations for paroxetine compared to other antidepressants (OR 1.5; 95% confidence
interval 0.8-2.9). The prevalence of cardiovascular malformations following first trimester
dispensing was 1.5% for paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with
cardiovascular malformations whose mothers were dispensed paroxetine in the first trimester had
VSDs. This study also suggested an increased risk of overall major congenital malformations
(inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR
1.8; 95% confidence interval 1.2-2.8). The prevalence of all congenital malformations following
first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants.
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
trimester of gestation and continued throughout lactation. This effect occurred at a dose of
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
rat pup mortality was not determined. The cause of these deaths is not known.
Nonteratogenic Effects: Neonates exposed to PAXIL CR and other SSRIs or serotonin
and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
clinical picture is consistent with serotonin syndrome (see WARNINGS—Potential for
Interaction With Monoamine Oxidase Inhibitors).
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
the general population and is associated with substantial neonatal morbidity and mortality. In a
retrospective case-control study of 377 women whose infants were born with PPHN and 836
women whose infants were born healthy, the risk for developing PPHN was approximately six
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
study that has investigated the potential risk. The study did not include enough cases with
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
There have also been postmarketing reports of premature births in pregnant women exposed
to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester, the physician
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
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ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
women with a history of major depression who were euthymic at the beginning of pregnancy,
women who discontinued antidepressant medication during pregnancy were more likely to
experience a relapse of major depression than women who continued antidepressant medication.
PRECAUTIONS
General: Activation of Mania/Hypomania: During premarketing testing of
immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately
1.0% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of
placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic
episodes was 2.2% for immediate-release paroxetine and 11.6% for the combined active-control
groups. Among 1,627 patients with major depressive disorder, panic disorder, social anxiety
disorder, or PMDD treated with PAXIL CR in controlled clinical studies, there were no reports
of mania or hypomania. As with all drugs effective in the treatment of major depressive disorder,
PAXIL CR should be used cautiously in patients with a history of mania.
Seizures: During premarketing testing of immediate-release paroxetine hydrochloride,
seizures occurred in 0.1% of paroxetine-treated patients, a rate similar to that associated with
other drugs effective in the treatment of major depressive disorder. Among 1,627 patients who
received PAXIL CR in controlled clinical trials in major depressive disorder, panic disorder,
social anxiety disorder, or PMDD, 1 patient (0.1%) experienced a seizure. PAXIL CR should be
used cautiously in patients with a history of seizures. It should be discontinued in any patient
who develops seizures.
Discontinuation of Treatment With PAXIL CR: Adverse events while discontinuing
therapy with PAXIL CR were not systematically evaluated in most clinical trials; however, in
recent placebo-controlled clinical trials utilizing daily doses of PAXIL CR up to 37.5 mg/day,
spontaneously reported adverse events while discontinuing therapy with PAXIL CR were
evaluated. Patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose
by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients
receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in
dose. With this regimen in those studies, the following adverse events were reported for
PAXIL CR, at an incidence of 2% or greater for PAXIL CR and were at least twice that reported
for placebo: Dizziness, nausea, nervousness, and additional symptoms described by the
investigator as associated with tapering or discontinuing PAXIL CR (e.g., emotional lability,
headache, agitation, electric shock sensations, fatigue, and sleep disturbances). These events
were reported as serious in 0.3% of patients who discontinued therapy with PAXIL CR.
During marketing of PAXIL CR and other SSRIs and SNRIs, there have been spontaneous
reports of adverse events occurring upon discontinuation of these drugs, (particularly when
abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory
disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety,
confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events
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are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with
PAXIL CR. A gradual reduction in the dose rather than abrupt cessation is recommended
whenever possible. If intolerable symptoms occur following a decrease in the dose or upon
discontinuation of treatment, then resuming the previously prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see
DOSAGE AND ADMINISTRATION).
See also PRECAUTIONS—Pediatric Use, for adverse events reported upon discontinuation
of treatment with paroxetine in pediatric patients.
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
such as an inability to sit or stand still usually associated with subjective distress. This is most
likely to occur within the first few weeks of treatment.
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
including PAXIL CR. In many cases, this hyponatremia appears to be the result of the syndrome
of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk (see Geriatric Use). Discontinuation of PAXIL CR
should be considered in patients with symptomatic hyponatremia and appropriate medical
intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
and cohort design) have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
coagulation.
Use in Patients With Concomitant Illness: Clinical experience with immediate-release
paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution
is advisable in using PAXIL CR in patients with diseases or conditions that could affect
metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with therapy
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with immediate-release paroxetine have been reported in the literature. As mydriasis can cause
acute angle closure in patients with narrow angle glaucoma, caution should be used when
PAXIL CR is prescribed for patients with narrow angle glaucoma.
PAXIL CR or the immediate-release formulation has not been evaluated or used to any
appreciable extent in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during premarket
testing. Evaluation of electrocardiograms of 682 patients who received immediate-release
paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate
that paroxetine is associated with the development of significant ECG abnormalities. Similarly,
paroxetine hydrochloride does not cause any clinically important changes in heart rate or blood
pressure.
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients: PAXIL CR should not be chewed or crushed, and should be
swallowed whole.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
PAXIL CR and triptans, tramadol, or other serotonergic agents.
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with PAXIL CR and should
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is
available for PAXIL CR. The prescriber or health professional should instruct patients, their
families, and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss the contents of the
Medication Guide and to obtain answers to any questions they may have. The complete text of
the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking PAXIL CR.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of such
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
close monitoring and possibly changes in the medication.
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Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
interfere with serotonin reuptake and these agents has been associated with an increased risk of
bleeding.
Interference With Cognitive and Motor Performance: Any psychoactive drug may
impair judgment, thinking, or motor skills. Although in controlled studies immediate-release
paroxetine hydrochloride has not been shown to impair psychomotor performance, patients
should be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that therapy with PAXIL CR does not affect their ability to engage in such
activities.
Completing Course of Therapy: While patients may notice improvement with use of
PAXIL CR in 1 to 4 weeks, they should be advised to continue therapy as directed.
Concomitant Medications: Patients should be advised to inform their physician if they are
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
interactions.
Alcohol: Although immediate-release paroxetine hydrochloride has not been shown to
increase the impairment of mental and motor skills caused by alcohol, patients should be advised
to avoid alcohol while taking PAXIL CR.
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
intend to become pregnant during therapy (see WARNINGS—Usage in Pregnancy: Teratogenic
and Nonteratogenic Effects).
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
infant (see PRECAUTIONS—Nursing Mothers).
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
between paroxetine and tryptophan may occur when they are coadministered. Adverse
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
reported when tryptophan was administered to patients taking immediate-release paroxetine.
Consequently, concomitant use of PAXIL CR with tryptophan is not recommended (see
WARNINGS—Serotonin Syndrome).
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
Pimozide: In a controlled study of healthy volunteers, after immediate-release paroxetine
hydrochloride was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide
was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to
pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6
inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its
known ability to prolong the QT interval, concomitant use of pimozide and PAXIL CR is
contraindicated (see CONTRAINDICATIONS).
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
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paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
PAXIL CR is coadministered with other drugs that may affect the serotonergic neurotransmitter
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI),
lithium, tramadol, or St. John's Wort (see WARNINGS—Serotonin Syndrome). The concomitant
use of PAXIL CR with MAOIs (including linezolid) is contraindicated (see
CONTRAINDICATIONS). The concomitant use of PAXIL CR with other SSRIs, SNRIs or
tryptophan is not recommended (see PRECAUTIONS—Drug Interactions, Tryptophan).
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
of PAXIL CR and warfarin should be undertaken with caution (see Drugs That Interfere With
Hemostasis).
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
an SSRI and a triptan. If concomitant use of PAXIL CR with a triptan is clinically warranted,
careful observation of the patient is advised, particularly during treatment initiation and dose
increases (see WARNINGS—Serotonin Syndrome).
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
where immediate-release paroxetine (30 mg once daily) was dosed orally for 4 weeks,
steady-state plasma concentrations of paroxetine were increased by approximately 50% during
coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore,
when these drugs are administered concurrently, dosage adjustment of PAXIL CR after the
starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s
pharmacokinetics was not studied.
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
single oral 30-mg dose of immediate-release paroxetine was administered at phenobarbital
steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an
average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of
paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits
nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs
are both being chronically dosed. No initial dosage adjustment with PAXIL CR is considered
necessary when coadministered with phenobarbital; any subsequent adjustment should be guided
by clinical effect.
Phenytoin: When a single oral 30-mg dose of immediate-release paroxetine was
administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T½
were reduced (by an average of 50% and 35%, respectively) compared to immediate-release
paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin
was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was
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slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs
exhibit nonlinear pharmacokinetics, the above studies may not address the case where the
2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary
when PAXIL CR is coadministered with phenytoin; any subsequent adjustments should be
guided by clinical effect (see ADVERSE REACTIONS—Postmarketing Reports).
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
treatment of major depressive disorder (paroxetine, other SSRIs, and many tricyclics), are
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
(>90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In 1 study, daily
dosing of immediate-release paroxetine (20 mg once daily) under steady-state conditions
increased single-dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately
2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6
substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients
stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone
approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and
increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone)
approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has
been evaluated when both drugs were at steady state. In healthy volunteers who were extensive
metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg
atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values
that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than
when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it
is recommended that atomoxetine be initiated at a reduced dose when given with paroxetine.
Concomitant use of PAXIL CR with other drugs metabolized by cytochrome CYP2D6 has not
been formally studied but may require lower doses than usually prescribed for either PAXIL CR
or the other drug.
Therefore, coadministration of PAXIL CR with other drugs that are metabolized by this
isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g.,
nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines,
risperidone, tamoxifen, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and
encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
coadministered (see CONTRAINDICATIONS and WARNINGS).
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6
by paroxetine may lead to reduced plasma concentrations of an active metabolite and hence
reduced efficacy of tamoxifen.
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
18
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS—Tricyclic Antidepressants).
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro
studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times
more potent than paroxetine as an inhibitor of the metabolism of several substrates for this
enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the
assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on
terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s
extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of TCAs
with PAXIL CR, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations
may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is
coadministered with PAXIL CR (see PRECAUTIONS—Drugs Metabolized by Cytochrome
CYP2D6).
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
protein, administration of PAXIL CR to a patient taking another drug that is highly protein
bound may cause increased free concentrations of the other drug, potentially resulting in adverse
events. Conversely, adverse effects could result from displacement of paroxetine by other highly
bound drugs.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
Alcohol: Although paroxetine does not increase the impairment of mental and motor skills
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL CR.
Lithium: A multiple-dose study with immediate-release paroxetine hydrochloride has shown
that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However,
due to the potential for serotonin syndrome, caution is advised when immediate-release
paroxetine hydrochloride is coadministered with lithium.
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
PAXIL CR and digoxin should be undertaken with caution.
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
kinetics. The effects of paroxetine on diazepam were not evaluated.
19
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Procyclidine: Daily oral dosing of immediate-release paroxetine (30 mg once daily)
increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by
35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If
anticholinergic effects are seen, the dose of procyclidine should be reduced.
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
coadministration with immediate-release paroxetine (30 mg once daily) for the final 10 days. The
effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS—
Postmarketing Reports).
Theophylline: Reports of elevated theophylline levels associated with immediate-release
paroxetine treatment have been reported. While this interaction has not been formally studied, it
is recommended that theophylline levels be monitored when these drugs are concurrently
administered.
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
clinical effect (tolerability and efficacy).
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
ECT and PAXIL CR.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to approximately 2
(mouse) and 3 (rat) times the (MRHD on a mg/m2 basis. There was a significantly greater
number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and
4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased
linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats.
Female rats were not affected. Although there was a dose-related increase in the number of
tumors in mice, there was no drug-related increase in the number of mice with tumors. The
relevance of these findings to humans is unknown.
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
Impairment of Fertility: A reduced pregnancy rate was found in reproduction studies in
rats at a dose of paroxetine of 15 mg/kg/day, which is approximately twice the MRHD on a
mg/m2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in
toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular
epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with
arrested spermatogenesis at 25 mg/kg/day (approximately 8 and 4 times the MRHD on a mg/m2
basis).
Pregnancy: Pregnancy Category D. See WARNINGS—Usage in Pregnancy: Teratogenic and
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nonteratogenic Effects.
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
should be exercised when PAXIL CR is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
(see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Three
placebo-controlled trials in 752 pediatric patients with MDD have been conducted with PAXIL,
and the data were not sufficient to support a claim for use in pediatric patients. Anyone
considering the use of PAXIL CR in a child or adolescent must balance the potential risks with
the clinical need.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
events were reported in at least 2% of pediatric patients treated with immediate-release
paroxetine hydrochloride and occurred at a rate at least twice that for pediatric patients receiving
placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and
mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.
Events reported upon discontinuation of treatment with immediate-release paroxetine
hydrochloride in the pediatric clinical trials that included a taper phase regimen, which occurred
in at least 2% of patients who received immediate-release paroxetine hydrochloride and which
occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal
ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and
abdominal pain (see Discontinuation of Treatment With PAXIL CR).
Geriatric Use: SSRIs and SNRIs, including PAXIL CR, have been associated with cases of
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
event (see PRECAUTIONS, Hyponatremia).
In worldwide premarketing clinical trials with immediate-release paroxetine hydrochloride,
17% of paroxetine-treated patients (approximately 700) were 65 years or older. Pharmacokinetic
studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended;
there were, however, no overall differences in the adverse event profile between elderly and
younger patients, and effectiveness was similar in younger and older patients (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
In a controlled study focusing specifically on elderly patients with major depressive disorder,
PAXIL CR was demonstrated to be safe and effective in the treatment of elderly patients (>60
years) with major depressive disorder. (See CLINICAL PHARMACOLOGY—Clinical Trials
and ADVERSE REACTIONS—Table 2.)
ADVERSE REACTIONS
The information included under the “Adverse Findings Observed in Short-Term,
Placebo-Controlled Trials With PAXIL CR” subsection of ADVERSE REACTIONS is based on
data from 11 placebo-controlled clinical trials. Three of these studies were conducted in patients
with major depressive disorder, 3 studies were done in patients with panic disorder, 1 study was
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
conducted in patients with social anxiety disorder, and 4 studies were done in female patients
with PMDD. Two of the studies in major depressive disorder, which enrolled patients in the age
range 18 to 65 years, are pooled. Information from a third study of major depressive disorder,
which focused on elderly patients (60 to 88 years), is presented separately as is the information
from the panic disorder studies and the information from the PMDD studies. Information on
additional adverse events associated with PAXIL CR and the immediate-release formulation of
paroxetine hydrochloride is included in a separate subsection (see Other Events).
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With PAXIL
CR:
Adverse Events Associated With Discontinuation of Treatment: Major Depressive
Disorder: Ten percent (21/212) of patients treated with PAXIL CR discontinued treatment due
to an adverse event in a pool of 2 studies of patients with major depressive disorder. The most
common events (≥1%) associated with discontinuation and considered to be drug related (i.e.,
those events associated with dropout at a rate approximately twice or greater for PAXIL CR
compared to placebo) included the following:
PAXIL CR
(n = 212)
Placebo
(n = 211)
Nausea
3.7%
0.5%
Asthenia
1.9%
0.5%
Dizziness
1.4%
0.0%
Somnolence
1.4%
0.0%
In a placebo-controlled study of elderly patients with major depressive disorder, 13% (13/104)
of patients treated with PAXIL CR discontinued due to an adverse event. Events meeting the
above criteria included the following:
PAXIL CR
Placebo
(n = 104)
(n = 109)
Nausea
2.9%
0.0%
Headache
1.9%
0.9%
Depression
1.9%
0.0%
LFT’s abnormal
1.9%
0.0%
Panic Disorder: Eleven percent (50/444) of patients treated with PAXIL CR in panic
disorder studies discontinued treatment due to an adverse event. Events meeting the above
criteria included the following:
22
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PAXIL CR
Placebo
(n = 444)
(n = 445)
Nausea
2.9%
0.4%
Insomnia
1.8%
0.0%
Headache
1.4%
0.2%
Asthenia
1.1%
0.0%
Social Anxiety Disorder: Three percent (5/186) of patients treated with PAXIL CR in the
social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the
above criteria included the following:
PAXIL CR
Placebo
(n = 186)
(n = 184)
Nausea
2.2%
0.5%
Headache
1.6%
0.5%
Diarrhea
1.1%
0.5%
Premenstrual Dysphoric Disorder: Spontaneously reported adverse events were
monitored in studies of both continuous and intermittent dosing of PAXIL CR in the treatment of
PMDD. Generally, there were few differences in the adverse event profiles of the 2 dosing
regimens. Thirteen percent (88/681) of patients treated with PAXIL CR in PMDD studies of
continuous dosing discontinued treatment due to an adverse event.
The most common events (≥1%) associated with discontinuation in either group treated with
PAXIL CR with an incidence rate that is at least twice that of placebo in PMDD trials that
employed a continuous dosing regimen are shown in the following table. This table also shows
those events that were dose dependent (indicated with an asterisk) as defined as events having an
incidence rate with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR
(as well as the placebo group).
23
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PAXIL CR
25 mg
(n = 348)
PAXIL CR
12.5 mg
(n = 333)
Placebo
(n = 349)
TOTAL
15%
9.9%
6.3%
Nausea∗
6.0%
2.4%
0.9%
Asthenia
4.9%
3.0%
1.4%
Somnolence∗
4.3%
1.8%
0.3%
Insomnia
2.3%
1.5%
0.0%
Concentration Impaired∗
2.0%
0.6%
0.3%
Dry mouth∗
2.0%
0.6%
0.3%
Dizziness∗
1.7%
0.6%
0.6%
Decreased Appetite∗
1.4%
0.6%
0.0%
Sweating∗
1.4%
0.0%
0.3%
Tremor∗
1.4%
0.3%
0.0%
Yawn∗
1.1%
0.0%
0.0%
Diarrhea
0.9%
1.2%
0.0%
* Events considered to be dose dependent are defined as events having an incidence rate with
25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the
placebo group).
Commonly Observed Adverse Events: Major Depressive Disorder: The most
commonly observed adverse events associated with the use of PAXIL CR in a pool of 2 trials
(incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo,
derived from Table 2) were: Abnormal ejaculation, abnormal vision, constipation, decreased
libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma,
tremor, and yawning.
Using the same criteria, the adverse events associated with the use of PAXIL CR in a study of
elderly patients with major depressive disorder were: Abnormal ejaculation, constipation,
decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.
Panic Disorder: In the pool of panic disorder studies, the adverse events meeting these
criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating,
and female genital disorders (generally anorgasmia or difficulty achieving orgasm).
Social Anxiety Disorder: In the social anxiety disorder study, the adverse events meeting
these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence,
insomnia, and libido decreased.
Premenstrual Dysphoric Disorder: The most commonly observed adverse events
associated with the use of PAXIL CR either during continuous dosing or luteal phase dosing
(incidence of 5% or greater and incidence for PAXIL CR at least twice that for placebo, derived
from Table 6) were: Nausea, asthenia, libido decreased, somnolence, insomnia, female genital
disorders, sweating, dizziness, diarrhea, and constipation.
24
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day
of PAXIL CR limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual
cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the
3 off-drug phases were combined, the following adverse events were reported at an incidence of
2% or greater for PAXIL CR and were at least twice the rate of that reported for placebo:
Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%),
sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).
Incidence in Controlled Clinical Trials: Table 2 enumerates adverse events that occurred at
an incidence of 1% or more among patients treated with PAXIL CR, aged 18 to 65, who
participated in 2 short-term (12-week) placebo-controlled trials in major depressive disorder in
which patients were dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse
events reported at an incidence of 5% or greater among elderly patients (ages 60 to 88) treated
with PAXIL CR who participated in a short-term (12-week) placebo-controlled trial in major
depressive disorder in which patients were dosed in a range of 12.5 mg to 50 mg/day. Table 4
enumerates adverse events reported at an incidence of 1% or greater among patients (19 to 72
years) treated with PAXIL CR who participated in short-term (10-week) placebo-controlled trials
in panic disorder in which patients were dosed in a range of 12.5 mg to 75 mg/day. Table 5
enumerates adverse events reported at an incidence of 1% or greater among adult patients treated
with PAXIL CR who participated in a short-term (12-week), double-blind, placebo-controlled
trial in social anxiety disorder in which patients were dosed in a range of 12.5 to 37.5 mg/day.
Table 6 enumerates adverse events that occurred at an incidence of 1% or more among patients
treated with PAXIL CR who participated in three, 12-week, placebo-controlled trials in PMDD
in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week
placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses
(luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified
using a standard COSTART-based Dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of
side effects in the course of usual medical practice where patient characteristics and other factors
differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving different treatments,
uses, and investigators. The cited figures, however, do provide the prescribing physician with
some basis for estimating the relative contribution of drug and nondrug factors to the side effect
incidence rate in the population studied.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
PAXIL CR in a Pool of 2 Studies in Major Depressive Disorder1,2
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 212)
Placebo
(n = 211)
Body as a Whole
Headache
27%
20%
Asthenia
14%
9%
Infection3
8%
5%
Abdominal Pain
7%
4%
Back Pain
5%
3%
Trauma4
5%
1%
Pain5
3%
1%
Allergic Reaction6
2%
1%
Cardiovascular System
Tachycardia
Vasodilatation7
1%
2%
0%
0%
Digestive System
Nausea
22%
10%
Diarrhea
18%
7%
Dry Mouth
15%
8%
Constipation
10%
4%
Flatulence
6%
4%
Decreased Appetite
4%
2%
Vomiting
2%
1%
Nervous System
Somnolence
22%
8%
Insomnia
17%
9%
Dizziness
14%
4%
Libido Decreased
7%
3%
Tremor
7%
1%
Hypertonia
3%
1%
Paresthesia
3%
1%
Agitation
2%
1%
Confusion
1%
0%
Respiratory System
Yawn
5%
0%
Rhinitis
4%
1%
Cough Increased
2%
1%
Bronchitis
1%
0%
26
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Skin and Appendages
Sweating
Photosensitivity
6%
2%
2%
0%
Special Senses
Abnormal Vision8
Taste Perversion
5%
2%
1%
0%
Urogenital System
Abnormal Ejaculation9,10
Female Genital Disorder9,11
Impotence9
Urinary Tract Infection
Menstrual Disorder9
Vaginitis9
26%
10%
5%
3%
2%
2%
1%
<1%
3%
1%
<1%
0%
1. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the
placebo incidence are not included. These events are: Abnormal dreams, anxiety, arthralgia,
depersonalization, dysmenorrhea, dyspepsia, hyperkinesia, increased appetite, myalgia,
nervousness, pharyngitis, purpura, rash, respiratory disorder, sinusitis, urinary frequency, and
weight gain.
2. <1% means greater than zero and less than 1%.
3. Mostly flu.
4. A wide variety of injuries with no obvious pattern.
5. Pain in a variety of locations with no obvious pattern.
6. Most frequently seasonal allergic symptoms.
7. Usually flushing.
8. Mostly blurred vision.
9. Based on the number of males or females.
10. Mostly anorgasmia or delayed ejaculation.
11. Mostly anorgasmia or delayed orgasm.
27
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. Treatment-Emergent Adverse Events Occurring in ≥5% of
Patients Treated With PAXIL CR in a Study of Elderly Patients With Major Depressive
Disorder1,2
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 104)
Placebo
(n = 109)
Body as a Whole
Headache
17%
13%
Asthenia
15%
14%
Trauma
8%
5%
Infection
6%
2%
Digestive System
Dry Mouth
18%
7%
Diarrhea
15%
9%
Constipation
13%
5%
Dyspepsia
13%
10%
Decreased Appetite
12%
5%
Flatulence
8%
7%
Nervous System
Somnolence
21%
12%
Insomnia
10%
8%
Dizziness
9%
5%
Libido Decreased
8%
<1%
Tremor
7%
0%
Skin and Appendages
Sweating
10%
<1%
Urogenital System
Abnormal Ejaculation3,4
Impotence3
17%
9%
3%
3%
1. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the
placebo incidence are not included. These events are nausea and respiratory disorder.
2. <1% means greater than zero and less than 1%.
3. Based on the number of males.
4. Mostly anorgasmia or delayed ejaculation.
28
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Table 4. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
PAXIL CR in a Pool of 3 Panic Disorder Studies1,2
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 444)
Placebo
(n = 445)
Body as a Whole
Asthenia
15%
10%
Abdominal Pain
6%
4%
Trauma3
5%
4%
Cardiovascular System
Vasodilation4
3%
2%
Digestive System
Nausea
23%
17%
Dry Mouth
13%
9%
Diarrhea
12%
9%
Constipation
9%
6%
Decreased Appetite
8%
6%
Metabolic/Nutritional
Disorders
Weight Loss
1%
0%
Musculoskeletal System
Myalgia
5%
3%
Nervous System
Insomnia
20%
11%
Somnolence
20%
9%
Libido Decreased
9%
4%
Nervousness
8%
7%
Tremor
8%
2%
Anxiety
5%
4%
Agitation
3%
2%
Hypertonia5
2%
<1%
Myoclonus
2%
<1%
Respiratory System
Sinusitis
Yawn
8%
3%
5%
0%
Skin and Appendages
Sweating
7%
2%
Special Senses
Abnormal Vision6
3%
<1%
Urogenital System
Abnormal Ejaculation7,8
27%
3%
Impotence7
10%
1%
Female Genital Disorders9,10
7%
1%
Urinary Frequency
2%
<1%
Urination Impaired
2%
<1%
Vaginitis9
1%
<1%
29
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the
placebo rate are not included. These events are: Abnormal dreams, allergic reaction, back
pain, bronchitis, chest pain, concentration impaired, confusion, cough increased, depression,
dizziness, dysmenorrhea, dyspepsia, fever, flatulence, headache, increased appetite, infection,
menstrual disorder, migraine, pain, paresthesia, pharyngitis, respiratory disorder, rhinitis,
tachycardia, taste perversion, thinking abnormal, urinary tract infection, and vomiting.
2. <1% means greater than zero and less than 1%.
3. Various physical injuries.
4. Mostly flushing.
5. Mostly muscle tightness or stiffness.
6. Mostly blurred vision.
7. Based on the number of male patients.
8. Mostly anorgasmia or delayed ejaculation.
9. Based on the number of female patients.
10. Mostly anorgasmia or difficulty achieving orgasm.
Table 5. Treatment-Emergent Adverse Effects Occurring in ≥1% of Patients Treated
With PAXIL CR in a Social Anxiety Disorder Study1,2
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 186)
Placebo
(n = 184)
Body as a Whole
Headache
23%
17%
Asthenia
18%
7%
Abdominal Pain
5%
4%
Back Pain
4%
1%
Trauma3
3%
<1%
Allergic Reaction4
2%
<1%
Chest Pain
1%
<1%
Cardiovascular System
Hypertension
2%
0%
Migraine
2%
1%
Tachycardia
2%
1%
Digestive System
Nausea
22%
6%
Diarrhea
9%
8%
Constipation
5%
2%
Dry Mouth
3%
2%
Dyspepsia
2%
<1%
Decreased Appetite
1%
<1%
30
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Tooth Disorder
1%
0%
Metabolic/Nutritional
Disorders
Weight Gain
3%
1%
Weight Loss
1%
0%
Nervous System
Insomnia
9%
4%
Somnolence
9%
4%
Libido Decreased
8%
1%
Dizziness
7%
4%
Tremor
4%
2%
Anxiety
2%
1%
Concentration Impaired
2%
0%
Depression
2%
1%
Myoclonus
1%
<1%
Paresthesia
1%
<1%
Respiratory System
Yawn
2%
0%
Skin and Appendages
Sweating
Eczema
14%
1%
3%
0%
Special Senses
Abnormal Vision5
2%
0%
Abnormality
of
Accommodation
2%
0%
Urogenital System
Abnormal Ejaculation6,7
15%
1%
Impotence6
9%
0%
Female Genital Disorders8,9
3%
0%
1. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the
placebo rate are not included. These events are: Dysmenorrhea, flatulence, gastroenteritis,
hypertonia, infection, pain, pharyngitis, rash, respiratory disorder, rhinitis, and vomiting.
2. <1% means greater than zero and less than 1%.
3. Various physical injuries.
4. Most frequently seasonal allergic symptoms.
5. Mostly blurred vision.
6. Based on the number of male patients.
7. Mostly anorgasmia or delayed ejaculation.
8. Based on the number of female patients.
9. Mostly anorgasmia or difficulty achieving orgasm.
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Table 6. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
PAXIL CR in a Pool of 3 Premenstrual Dysphoric Disorder Studies with Continuous
Dosing or in 1 Premenstrual Dysphoric Disorder Study with Luteal Phase Dosing1,2,3
Body System/Adverse
Event
% Reporting Event
Continuous Dosing
Luteal Phase Dosing
PAXIL CR
(n = 681)
Placebo
(n = 349)
PAXIL CR
(n = 246)
Placebo
(n = 120)
Body as a Whole
Asthenia
Headache
Infection
Abdominal pain
17%
6%
15%
12%
6%
4%
-
-
15%
4%
-
-
-
-
3%
0%
Cardiovascular System
Migraine
1%
<1%
-
-
Digestive System
Nausea
Diarrhea
Constipation
Dry Mouth
Increased Appetite
Decreased Appetite
Dyspepsia
Gingivitis
17%
7%
6%
2%
5%
1%
4%
2%
3%
<1%
2%
<1%
2%
1%
-
-
18%
2%
6%
0%
2%
<1%
2%
<1%
-
-
2%
0%
2%
2%
1%
0%
Metabolic and
Nutritional Disorders
Generalized Edema
-
-
1%
<1%
Weight Gain
-
-
1%
<1%
Musculoskeletal
System
Arthralgia
2%
1%
-
-
Nervous System
Libido Decreased
12%
5%
9%
6%
Somnolence
9%
2%
3%
<1%
Insomnia
8%
2%
7%
3%
Dizziness
7%
3%
6%
3%
Tremor
4%
<1%
5%
0%
Concentration Impaired
3%
<1%
1%
0%
Nervousness
2%
<1%
3%
2%
Anxiety
2%
1%
-
-
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Lack of Emotion
Depression
Vertigo
Abnormal Dreams
Amnesia
2%
-
-
1%
-
<1%
-
-
<1%
-
-
2%
2%
-
1%
-
<1%
<1%
-
0%
Respiratory System
Sinusitis
Yawn
Bronchitis
Cough Increased
-
2%
-
1%
-
<1%
-
<1%
4%
-
2%
-
2%
-
0%
-
Skin and Appendages
Sweating
7%
<1%
6%
<1%
Special Senses
Abnormal Vision
-
-
1%
0%
Urogenital System
Female Genital
Disorders4
Menorrhagia
Vaginal Moniliasis
Menstrual Disorder
8%
1%
1%
-
1%
<1%
<1%
-
2%
-
-
1%
0%
-
-
0%
1. Adverse events for which the reporting rate of PAXIL CR was less than or equal to the
placebo rate are not included. These events for continuous dosing are: Abdominal pain, back
pain, pain, trauma, weight gain, myalgia, pharyngitis, respiratory disorder, rhinitis, sinusitis,
pruritis, dysmenorrhea, menstrual disorder, urinary tract infection, and vomiting. The events
for luteal phase dosing are: Allergic reaction, back pain, headache, infection, pain, trauma,
myalgia, anxiety, pharyngitis, respiratory disorder, cystitis, and dysmenorrhea.
2. <1% means greater than zero and less than 1%.
3. The luteal phase and continuous dosing PMDD trials were not designed for making direct
comparisons between the 2 dosing regimens. Therefore, a comparison between the 2 dosing
regimens of the PMDD trials of incidence rates shown in Table 5 should be avoided.
4. Mostly anorgasmia or difficulty achieving orgasm.
Dose Dependency of Adverse Events: The following table shows results in PMDD
trials of common adverse events, defined as events with an incidence of ≥1% with 25 mg of
PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR and with placebo.
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Incidence of Common Adverse Events in Placebo, 12.5 mg and 25 mg of PAXIL CR in a
Pool of 3 Fixed-Dose PMDD Trials
PAXIL CR
PAXIL CR
Placebo
25 mg
12.5 mg
(n = 349)
(n = 348)
(n = 333)
Common Adverse Event
Sweating
8.9%
4.2%
0.9%
Tremor
6.0%
1.5%
0.3%
Concentration Impaired
4.3%
1.5%
0.6%
Yawn
3.2%
0.9%
0.3%
Paresthesia
1.4%
0.3%
0.3%
Hyperkinesia
1.1%
0.3%
0.0%
Vaginitis
1.1%
0.3%
0.3%
A comparison of adverse event rates in a fixed-dose study comparing immediate-release
paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose
dependency for some of the more common adverse events associated with the use of
immediate-release paroxetine.
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
evidence suggests that SSRIs can cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual
desire, performance, and satisfaction are difficult to obtain; however, in part because patients and
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
untoward sexual experience and performance cited in product labeling, are likely to
underestimate their actual incidence.
The percentage of patients reporting symptoms of sexual dysfunction in the pool of 2
placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of 3
placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients
with social anxiety disorder, and in the intermittent dosing and the pool of 3 placebo-controlled
continuous dosing trials in female patients with PMDD are as follows:
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Major Depressive
Panic Disorder
Social Anxiety
PMDD
PMDD
Disorder
Disorder
Continuous Dosing
Luteal Phase
Dosing
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
CR
CR
CR
CR
CR
n (males)
78
78
162
194
88
97
n/a
n/a
n/a
n/a
Decreased
10%
5%
9%
6%
13%
1%
n/a
n/a
n/a
n/a
Libido
Ejaculatory
Disturbance
26%
1%
27%
3%
15%
1%
n/a
n/a
n/a
n/a
Impotence
5%
3%
10%
1%
9%
0%
n/a
n/a
n/a
n/a
n (females)
134
133
282
251
98
87
681
349
246
120
Decreased
4%
2%
8%
2%
4%
1%
12%
5%
9%
6%
Libido
Orgasmic
Disturbance
10%
<1%
7%
1%
3%
0%
8%
1%
2%
0%
There are no adequate, controlled studies examining sexual dysfunction with paroxetine
treatment.
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
known outcome, patients recovered without sequelae.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
treatment with paroxetine for some patients but, on average, patients in controlled trials with
PAXIL CR or the immediate-release formulation, had minimal weight loss (about 1 pound). No
significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature)
were observed in patients treated with PAXIL CR, or immediate-release paroxetine
hydrochloride, in controlled clinical trials.
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with
immediate-release paroxetine and 415 patients treated with placebo in controlled clinical trials,
no clinically significant changes were seen in the ECGs of either group.
Liver Function Tests: In a pool of 2 placebo-controlled clinical trials, patients treated with
PAXIL CR or placebo exhibited abnormal values on liver function tests at comparable rates. In
particular, the controlled-release paroxetine-versus-placebo comparisons for alkaline
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
with marked abnormalities.
In a study of elderly patients with major depressive disorder, 3 of 104 patients treated with
PAXIL CR and none of 109 placebo patients experienced liver transaminase elevations of
potential clinical concern.
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Two of the patients treated with PAXIL CR dropped out of the study due to abnormal liver
function tests; the third patient experienced normalization of transaminase levels with continued
treatment. Also, in the pool of 3 studies of patients with panic disorder, 4 of 444 patients treated
with PAXIL CR and none of 445 placebo patients experienced liver transaminase elevations of
potential clinical concern. Elevations in all 4 patients decreased substantially after
discontinuation of PAXIL CR. The clinical significance of these findings is unknown.
In placebo-controlled clinical trials with the immediate-release formulation of paroxetine,
patients exhibited abnormal values on liver function tests at no greater rate than that seen in
placebo-treated patients.
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
hallucinations were observed in 22 of 9,089 patients receiving drug and in 4 of 3,187 patients
receiving placebo.
Other Events Observed During the Clinical Development of Paroxetine: The
following adverse events were reported during the clinical development of PAXIL CR and/or the
clinical development of the immediate-release formulation of paroxetine.
Adverse events for which frequencies are provided below occurred in clinical trials with the
controlled-release formulation of paroxetine. During its premarketing assessment in major
depressive disorder, panic disorder, social anxiety disorder, and PMDD, multiple doses of
PAXIL CR were administered to 1,627 patients in phase 3 double-blind, controlled, outpatient
studies. Untoward events associated with this exposure were recorded by clinical investigators
using terminology of their own choosing. Consequently, it is not possible to provide a
meaningful estimate of the proportion of individuals experiencing adverse events without first
grouping similar types of untoward events into a smaller number of standardized event
categories.
In the tabulations that follow, reported adverse events were classified using a
COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of
the 1,627 patients exposed to PAXIL CR who experienced an event of the type cited on at least 1
occasion while receiving PAXIL CR. All reported events are included except those already listed
in Tables 2 through 6 and those events where a drug cause was remote. If the COSTART term
for an event was so general as to be uninformative, it was deleted or, when possible, replaced
with a more informative term. It is important to emphasize that although the events reported
occurred during treatment with paroxetine, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: Frequent adverse events are those occurring on 1 or more
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.
Adverse events for which frequencies are not provided occurred during the premarketing
assessment of immediate-release paroxetine in phase 2 and 3 studies of major depressive
disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized
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anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to
immediate-release paroxetine varied greatly and included (in overlapping categories) open and
double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and
fixed-dose and titration studies. Only those events not previously listed for controlled-release
paroxetine are included. The extent to which these events may be associated with PAXIL CR is
unknown.
Events are listed alphabetically within the respective body system. Events of major clinical
importance are also described in the PRECAUTIONS section.
Body as a Whole: Infrequent were chills, face edema, fever, flu syndrome, malaise; rare
were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed
were adrenergic syndrome, neck rigidity, sepsis.
Cardiovascular System: Infrequent were angina pectoris, bradycardia, hematoma,
hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia,
syncope; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation,
cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct,
myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles,
thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.
Digestive System: Infrequent were bruxism, dysphagia, eructation, gastritis,
gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function test abnormal,
melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis,
glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction,
peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody
diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions,
fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth
ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue
edema.
Endocrine System: Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus,
hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis.
Hemic and Lymphatic System: Infrequent were anemia, eosinophilia, hypochromic
anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also
observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis,
lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.
Metabolic and Nutritional Disorders: Infrequent were generalized edema,
hyperglycemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare
were bilirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase
increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased,
gout, hypercalcemia, hypercholesteremia, hyperphosphatemia, hypocalcemia, hypoglycemia,
hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.
Musculoskeletal System: Infrequent were arthritis, bursitis, tendonitis; rare were
myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis,
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tenosynovitis, tetany.
Nervous System: Frequent were depression; infrequent were amnesia, convulsion,
depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia,
hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis,
vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis,
withdrawal syndrome; also observed were abnormal gait, akathisia, akinesia, aphasia,
choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal
syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction,
manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic
depression, reflexes decreased, reflexes increased, stupor, trismus.
Respiratory System: Frequent were pharyngitis; infrequent were asthma, dyspnea,
epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema,
hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum
increased.
Skin and Appendages: Frequent were rash; infrequent were acne, alopecia, dry skin,
eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash,
seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema
nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer,
sweating decreased, vesiculobullous rash.
Special Senses: Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis,
photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed
were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness,
exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss.
Urogenital System: Frequent were dysmenorrhea*; infrequent were albuminuria,
amenorrhea*, breast pain*, cystitis, dysuria, prostatitis*, urinary retention; rare were breast
enlargement*, breast neoplasm*, female lactation, hematuria, kidney calculus, metrorrhagia*,
nephritis, nocturia, pregnancy and puerperal disorders*, salpingitis, urinary incontinence, uterine
fibroids enlarged*; also observed were breast atrophy, ejaculatory disturbance, endometrial
disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria,
urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage.
*Based on the number of men and women as appropriate.
Postmarketing Reports: Voluntary reports of adverse events in patients taking
immediate-release paroxetine hydrochloride that have been received since market introduction
and not listed above that may have no causal relationship with the drug include acute
pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis,
and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré
syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion,
symptoms suggestive of prolactinemia and galactorrhea, neuroleptic malignant syndrome–like
events, serotonin syndrome; extrapyramidal symptoms which have included akathisia,
bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been
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associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal
failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic
neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including torsade de pointes),
thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including
aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic
syndromes (such as Henoch-Schönlein purpura). There has been a case report of an elevated
phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin coadministration.
There has been a case report of severe hypotension when immediate-release paroxetine was
added to chronic metoprolol treatment.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: PAXIL CR is not a controlled substance.
Physical and Psychologic Dependence: PAXIL CR has not been systematically studied
in animals or humans for its potential for abuse, tolerance or physical dependence. While the
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
not systematic and it is not possible to predict on the basis of this limited experience the extent to
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
patients should be evaluated carefully for history of drug abuse, and such patients should be
observed closely for signs of misuse or abuse of PAXIL CR (e.g., development of tolerance,
incrementations of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience: Since the introduction of immediate-release paroxetine hydrochloride in
the United States, 342 spontaneous cases of deliberate or accidental overdosage during
paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with
paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of
the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the
amount of paroxetine ingested were generally confounded by the ingestion of other drugs or
alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known
outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of
paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.
Commonly reported adverse events associated with paroxetine overdosage include
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
substances) include mydriasis, convulsions (including status epilepticus), ventricular
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
Overdosage Management: Treatment should consist of those general measures employed in
the management of overdosage with any drugs effective in the treatment of major depressive
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disorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway
protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to the large volume of distribution of this
drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of
benefit. No specific antidotes for paroxetine are known.
A specific caution involves patients taking or recently having taken paroxetine who might
ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
parent tricyclic and an active metabolite may increase the possibility of clinically significant
sequelae and extend the time needed for close medical observation (see PRECAUTIONS—
Drugs Metabolized by Cytochrome CYP2D6).
In managing overdosage, consider the possibility of multiple-drug involvement. The physician
should consider contacting a poison control center for additional information on the treatment of
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
Major Depressive Disorder: Usual Initial Dosage: PAXIL CR should be administered as
a single daily dose, usually in the morning, with or without food. The recommended initial dose
is 25 mg/day. Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials
demonstrating the effectiveness of PAXIL CR in the treatment of major depressive disorder. As
with all drugs effective in the treatment of major depressive disorder, the full effect may be
delayed. Some patients not responding to a 25-mg dose may benefit from dose increases, in
12.5-mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at
intervals of at least 1 week.
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
swallowed whole.
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL CR should remain on it. It is generally agreed that acute
episodes of major depressive disorder require several months or longer of sustained
pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission is
identical to the dose needed to maintain and/or sustain euthymia is unknown.
Systematic evaluation of the efficacy of immediate-release paroxetine hydrochloride has
shown that efficacy is maintained for periods of up to 1 year with doses that averaged about
30 mg, which corresponds to a 37.5-mg dose of PAXIL CR, based on relative bioavailability
considerations (see CLINICAL PHARMACOLOGY—Pharmacokinetics).
40
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Panic Disorder: Usual Initial Dosage: PAXIL CR should be administered as a single daily
dose, usually in the morning. Patients should be started on 12.5 mg/day. Dose changes should
occur in 12.5-mg/day increments and at intervals of at least 1 week. Patients were dosed in a
range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of PAXIL CR.
The maximum dosage should not exceed 75 mg/day.
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
swallowed whole.
Maintenance Therapy: Long-term maintenance of efficacy with the immediate-release
formulation of paroxetine was demonstrated in a 3-month relapse prevention trial. In this trial,
patients with panic disorder assigned to immediate-release paroxetine demonstrated a lower
relapse rate compared to patients on placebo. Panic disorder is a chronic condition, and it is
reasonable to consider continuation for a responding patient. Dosage adjustments should be
made to maintain the patient on the lowest effective dosage, and patients should be periodically
reassessed to determine the need for continued treatment.
Social Anxiety Disorder: Usual Initial Dosage: PAXIL CR should be administered as a
single daily dose, usually in the morning, with or without food. The recommended initial dose is
12.5 mg/day. Patients were dosed in a range of 12.5 mg to 37.5 mg/day in the clinical trial
demonstrating the effectiveness of PAXIL CR in the treatment of social anxiety disorder. If the
dose is increased, this should occur at intervals of at least 1 week, in increments of 12.5 mg/day,
up to a maximum of 37.5 mg/day.
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
swallowed whole.
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL CR should remain on it. Although the efficacy of
PAXIL CR beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials,
social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider
continuation of treatment for a responding patient. Dosage adjustments should be made to
maintain the patient on the lowest effective dosage, and patients should be periodically
reassessed to determine the need for continued treatment.
Premenstrual Dysphoric Disorder: Usual Initial Dosage: PAXIL CR should be
administered as a single daily dose, usually in the morning, with or without food. PAXIL CR
may be administered either daily throughout the menstrual cycle or limited to the luteal phase of
the menstrual cycle, depending on physician assessment. The recommended initial dose is
12.5 mg/day. In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective.
Dose changes should occur at intervals of at least 1 week.
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
swallowed whole.
Maintenance/Continuation Therapy: The effectiveness of PAXIL CR for a period
exceeding 3 menstrual cycles has not been systematically evaluated in controlled trials.
However, women commonly report that symptoms worsen with age until relieved by the onset of
41
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For current labeling information, please visit https://www.fda.gov/drugsatfda
menopause. Therefore, it is reasonable to consider continuation of a responding patient. Patients
should be periodically reassessed to determine the need for continued treatment.
Special Populations: Treatment of Pregnant Women During the Third Trimester:
Neonates exposed to PAXIL CR and other SSRIs or SNRIs, late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding (see WARNINGS). When treating pregnant women with paroxetine during the third
trimester, the physician should carefully consider the potential risks and benefits of treatment.
The physician may consider tapering paroxetine in the third trimester.
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
Hepatic Impairment: The recommended initial dose of PAXIL CR is 12.5 mg/day for elderly
patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases
may be made if indicated. Dosage should not exceed 50 mg/day.
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL CR.
Similarly, at least 14 days should be allowed after stopping PAXIL CR before starting an MAOI.
Discontinuation of Treatment With PAXIL CR: Symptoms associated with discontinuation
of immediate-release paroxetine hydrochloride or PAXIL CR have been reported (see
PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing
treatment, regardless of the indication for which PAXIL CR is being prescribed. A gradual
reduction in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate.
HOW SUPPLIED
PAXIL CR is supplied as an enteric film-coated, controlled-release, round tablet, as follows:
12.5-mg yellow tablets, engraved with PAXIL CR and 12.5
NDC 0029-3206-13 Bottles of 30
25-mg pink tablets, engraved with PAXIL CR and 25
NDC 0029-3207-13 Bottles of 30
37.5 mg blue tablets, engraved with PAXIL CR and 37.5
NDC 0029-3208-13 Bottles of 30
Store at or below 25°C (77°F) [see USP].
PAXIL CR is a registered trademark of GlaxoSmithKline.
GEOMATRIX is a trademark of Jago Pharma, Muttenz, Switzerland.
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions
PAXIL CR® (PAX-il) (paroxetine hydrochloride) Controlled-Release Tablets
Read the Medication Guide that comes with your or your family member’s antidepressant
medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
about:
• All risks and benefits of treatment with antidepressant medicines
• All treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or action?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started or
when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the
following symptoms, especially if they are new, worse, or worry you:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
43
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Trouble sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking (mania)
• Other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare
provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating it.
Patients and their families or other caregivers should discuss all treatment choices with
the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Call your doctor for medical advice
about side effects. You may report side effects to FDA at 1-800-FDA-1088.
• Antidepressant medicines can interact with other medicines. Know all of the
medicines that you or your family member takes. Keep a list of all medicines to show the
healthcare provider. Do not start new medicines without first checking with your
healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use
in children. Talk to your child’s healthcare provider for more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
January 2008
PCR:3MG logo
GlaxoSmithKline
44
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Research Triangle Park, NC 27709
©2008, GlaxoSmithKline. All rights reserved.
June 2008
PCR:29PI
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:29.455414
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020031s060,020936s037,020710s024lbl.pdf', 'application_number': 20031, 'submission_type': 'SUPPL ', 'submission_number': 60}
|
12,146
|
structural formula
1
PRESCRIBING INFORMATION
2
PAXIL®
3
(paroxetine hydrochloride)
4
Tablets and Oral Suspension
5
6
Suicidality and Antidepressant Drugs
7
Antidepressants increased the risk compared to placebo of suicidal thinking and
8
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
9
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
10
use of PAXIL or any other antidepressant in a child, adolescent, or young adult must
11
balance this risk with the clinical need. Short-term studies did not show an increase in the
12
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
13
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
14
older. Depression and certain other psychiatric disorders are themselves associated with
15
increases in the risk of suicide. Patients of all ages who are started on antidepressant
16
therapy should be monitored appropriately and observed closely for clinical worsening,
17
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
18
the need for close observation and communication with the prescriber. PAXIL is not
19
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
20
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
21
DESCRIPTION
22
PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the
23
hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'
24
fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate
25
and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8
26
(329.4 as free base). The structural formula of paroxetine hydrochloride is:
27
28
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
29
120° to 138°C and a solubility of 5.4 mg/mL in water.
30
Tablets: Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as
31
follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive
32
ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate,
33
polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of
1
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
34
the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C
35
Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.
36
Suspension for Oral Administration: Each 5 mL of orange-colored, orange-flavored liquid
37
contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist
38
of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol,
39
methylparaben, propylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium
40
saccharin, flavorings, FD&C Yellow No. 6 aluminum lake, and simethicone emulsion, USP.
41
CLINICAL PHARMACOLOGY
42
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
43
disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD),
44
generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be
45
linked to potentiation of serotonergic activity in the central nervous system resulting from
46
inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically
47
relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into
48
human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly
49
selective inhibitor of neuronal serotonin reuptake and has only very weak effects on
50
norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate
51
that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine
52
(D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic,
53
and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and
54
cardiovascular effects for other psychotropic drugs.
55
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
56
compound, they are essentially inactive.
57
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
58
solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours
59
(CV 32%) after oral dosing of 30 mg tablets of PAXIL daily for 30 days. Paroxetine is
60
extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in
61
pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part
62
by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the
63
feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are
64
deficient in CYP2D6 (poor metabolizers).
65
In a meta analysis of paroxetine from 4 studies done in healthy volunteers following
66
multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower
67
Cmax or AUC than females.
68
Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension
69
and tablet.
70
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
71
hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets
72
daily for 30 days, steady-state paroxetine concentrations were achieved by approximately
73
10 days for most subjects, although it may take substantially longer in an occasional patient. At
2
Reference ID: 2920253
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74
steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr.
75
(CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax
76
and Cmin values were about 6 and 14 times what would be predicted from single-dose studies.
77
Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been
78
predicted from single-dose data in these subjects. The excess accumulation is a consequence of
79
the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.
80
The effects of food on the bioavailability of paroxetine were studied in subjects administered
81
a single dose with and without food. AUC was only slightly increased (6%) when drug was
82
administered with food but the Cmax was 29% greater, while the time to reach peak plasma
83
concentration decreased from 6.4 hours post-dosing to 4.9 hours.
84
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
85
plasma.
86
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
87
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
88
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
89
warfarin.
90
Metabolism and Excretion: The mean elimination half-life is approximately 21 hours
91
(CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose
92
proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg
93
daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was
94
observed in both populations, again reflecting a saturable metabolic pathway. In comparison to
95
Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than
96
doubled.
97
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
98
polar and conjugated products of oxidation and methylation, which are readily cleared.
99
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
100
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
101
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
102
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
103
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
104
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
105
interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6).
106
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
107
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
108
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
109
1% as the parent compound over the 10-day post-dosing period.
110
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
111
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and
112
hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below
113
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
3
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114
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
115
about a 2-fold increase in plasma concentrations (AUC, Cmax).
116
The initial dosage should therefore be reduced in patients with severe renal or hepatic
117
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
118
AND ADMINISTRATION).
119
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20,
120
30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin
121
concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be
122
reduced (see DOSAGE AND ADMINISTRATION).
123
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
124
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
125
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
126
desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions).
127
Clinical Trials
128
Major Depressive Disorder: The efficacy of PAXIL as a treatment for major depressive
129
disorder has been established in 6 placebo-controlled studies of patients with major depressive
130
disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective
131
than placebo in treating major depressive disorder by at least 2 of the following measures:
132
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
133
Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in
134
improvement of the HDRS sub-factor scores, including the depressed mood item, sleep
135
disturbance factor, and anxiety factor.
136
A study of outpatients with major depressive disorder who had responded to PAXIL (HDRS
137
total score <8) during an initial 8-week open-treatment phase and were then randomized to
138
continuation on PAXIL or placebo for 1 year demonstrated a significantly lower relapse rate for
139
patients taking PAXIL (15%) compared to those on placebo (39%). Effectiveness was similar for
140
male and female patients.
141
Obsessive Compulsive Disorder: The effectiveness of PAXIL in the treatment of obsessive
142
compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled
143
studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD
144
(DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale
145
(YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients
146
were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily
147
doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses
148
of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points,
149
respectively, on the YBOCS total score which was significantly greater than the approximate 4
150
point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a
151
flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg
152
daily). In this study, patients receiving paroxetine experienced a mean reduction of
4
Reference ID: 2920253
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153
approximately 7 points on the YBOCS total score, which was significantly greater than the mean
154
reduction of approximately 4 points in placebo-treated patients.
155
The following table provides the outcome classification by treatment group on Global
156
Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
157
Outcome Classification (%) on CGI-Global Improvement Item
for Completers in Study 1
Outcome
Classification
Placebo
(n = 74)
PAXIL 20 mg
(n = 75)
PAXIL 40 mg
(n = 66)
PAXIL 60 mg
(n = 66)
Worse
14%
7%
7%
3%
No Change
44%
35%
22%
19%
Minimally Improved
24%
33%
29%
34%
Much Improved
11%
18%
22%
24%
Very Much Improved
7%
7%
20%
20%
158
159
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
160
function of age or gender.
161
The long-term maintenance effects of PAXIL in OCD were demonstrated in a long-term
162
extension to Study 1. Patients who were responders on paroxetine during the 3-month
163
double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were
164
randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase.
165
Patients randomized to paroxetine were significantly less likely to relapse than comparably
166
treated patients who were randomized to placebo.
167
Panic Disorder: The effectiveness of PAXIL in the treatment of panic disorder was
168
demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients
169
(Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia.
170
In these studies, PAXIL was shown to be significantly more effective than placebo in treating
171
panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical
172
Global Impression Severity of Illness score.
173
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine
174
doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed
175
only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were
176
free of panic attacks, compared to 44% of placebo-treated patients.
177
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and
178
placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of
179
placebo-treated patients.
180
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to
181
placebo in patients concurrently receiving standardized cognitive behavioral therapy. At
182
endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks
183
compared to 14% of placebo patients.
184
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was
5
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185
approximately 40 mg/day of paroxetine.
186
Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an
187
extension to Study 1. Patients who were responders during the 10-week double-blind phase and
188
during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or
189
40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized
190
to paroxetine were significantly less likely to relapse than comparably treated patients who were
191
randomized to placebo.
192
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
193
function of age or gender.
194
Social Anxiety Disorder: The effectiveness of PAXIL in the treatment of social anxiety
195
disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1,
196
2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the
197
effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of
198
responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very
199
much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social
200
Anxiety Scale (LSAS).
201
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and
202
placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the
203
CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In
204
Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to
205
29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI
206
Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients,
207
respectively.
208
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with
209
placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the
210
LSAS Total Score and the CGI Improvement responder criterion; there were trends for
211
superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in
212
this study of any additional benefit for doses higher than 20 mg/day.
213
Subgroup analyses generally did not indicate differences in treatment outcomes as a function
214
of age, race, or gender.
215
Generalized Anxiety Disorder: The effectiveness of PAXIL in the treatment of Generalized
216
Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled
217
studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).
218
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with
219
placebo. Doses of 20 mg or 40 mg of PAXIL were both demonstrated to be significantly superior
220
to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not
221
sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to
222
the 20 mg/day dose.
223
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo.
224
PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating
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225
Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine
226
(20 mg to 50 mg daily), did not demonstrate statistically significant superiority of PAXIL over
227
placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.
228
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or
229
gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
230
In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety
231
Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to
232
50 mg/day of PAXIL, were randomized to continuation of PAXIL at their same dose, or to
233
placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase
234
was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of
235
Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase
236
of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or
237
withdrawal due to lack of efficacy. Patients receiving continued PAXIL experienced a
238
significantly lower relapse rate over the subsequent 24 weeks compared to those receiving
239
placebo.
240
Posttraumatic Stress Disorder: The effectiveness of PAXIL in the treatment of
241
Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo
242
controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The
243
mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year
244
to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD
245
anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out
246
of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered
247
PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement
248
Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the
249
following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal.
250
The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2
251
total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were
252
defined as patients having a score of 1 (very much improved) or 2 (much improved).
253
Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to
254
placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to
255
placebo on change from baseline for the CAPS-2 total score and on proportion of responders on
256
the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the
257
40 mg/day dose compared to the 20 mg/day dose.
258
Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to
259
placebo. PAXIL was demonstrated to be significantly superior to placebo on change from
260
baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.
261
A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,
262
demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS
263
2 total score, but not on proportion of responders on the CGI-I.
264
The majority of patients in these trials were women (68% women: 377 out of 551 subjects in
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Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not
266
indicate differences in treatment outcomes as a function of gender. There were an insufficient
267
number of patients who were 65 years and older or were non-Caucasian to conduct subgroup
268
analyses on the basis of age or race, respectively.
269
INDICATIONS AND USAGE
270
Major Depressive Disorder: PAXIL is indicated for the treatment of major depressive
271
disorder.
272
The efficacy of PAXIL in the treatment of a major depressive episode was established in
273
6-week controlled trials of outpatients whose diagnoses corresponded most closely to the
274
DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical
275
Trials). A major depressive episode implies a prominent and relatively persistent depressed or
276
dysphoric mood that usually interferes with daily functioning (nearly every day for at least
277
2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in
278
sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in
279
sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
280
concentration, and a suicide attempt or suicidal ideation.
281
The effects of PAXIL in hospitalized depressed patients have not been adequately studied.
282
The efficacy of PAXIL in maintaining a response in major depressive disorder for up to 1 year
283
was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical
284
Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should
285
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
286
Obsessive Compulsive Disorder: PAXIL is indicated for the treatment of obsessions and
287
compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV.
288
The obsessions or compulsions cause marked distress, are time-consuming, or significantly
289
interfere with social or occupational functioning.
290
The efficacy of PAXIL was established in two 12-week trials with obsessive compulsive
291
outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive
292
compulsive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
293
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
294
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
295
intentional behaviors (compulsions) that are recognized by the person as excessive or
296
unreasonable.
297
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In
298
this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on
299
placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who
300
elects to use PAXIL for extended periods should periodically re-evaluate the long-term
301
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
302
Panic Disorder: PAXIL is indicated for the treatment of panic disorder, with or without
303
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
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unexpected panic attacks and associated concern about having additional attacks, worry about
305
the implications or consequences of the attacks, and/or a significant change in behavior related to
306
the attacks.
307
The efficacy of PAXIL was established in three 10- to 12-week trials in panic disorder
308
patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
309
CLINICAL PHARMACOLOGY: Clinical Trials).
310
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
311
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
312
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
313
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
314
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
315
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
316
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
317
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
318
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In
319
this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate
320
compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials).
321
Nevertheless, the physician who prescribes PAXIL for extended periods should periodically
322
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
323
ADMINISTRATION).
324
Social Anxiety Disorder: PAXIL is indicated for the treatment of social anxiety disorder,
325
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
326
characterized by a marked and persistent fear of 1 or more social or performance situations in
327
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
328
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
329
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
330
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
331
the person's normal routine, occupational or academic functioning, or social activities or
332
relationships, or there is marked distress about having the phobias. Lesser degrees of
333
performance anxiety or shyness generally do not require psychopharmacological treatment.
334
The efficacy of PAXIL was established in three 12-week trials in adult patients with social
335
anxiety disorder (DSM-IV). PAXIL has not been studied in children or adolescents with social
336
phobia (see CLINICAL PHARMACOLOGY: Clinical Trials).
337
The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more
338
than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
339
Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically
340
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
341
ADMINISTRATION).
342
Generalized Anxiety Disorder: PAXIL is indicated for the treatment of Generalized Anxiety
343
Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of
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everyday life usually does not require treatment with an anxiolytic.
345
The efficacy of PAXIL in the treatment of GAD was established in two 8-week
346
placebo-controlled trials in adults with GAD. PAXIL has not been studied in children or
347
adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY: Clinical
348
Trials).
349
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry
350
(apprehensive expectation) that is persistent for at least 6 months and which the person finds
351
difficult to control. It must be associated with at least 3 of the following 6 symptoms:
352
Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or
353
mind going blank, irritability, muscle tension, sleep disturbance.
354
The efficacy of PAXIL in maintaining a response in patients with Generalized Anxiety
355
Disorder, who responded during an 8-week acute treatment phase while taking PAXIL and were
356
then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo
357
controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the
358
physician who elects to use PAXIL for extended periods should periodically re-evaluate the
359
long-term usefulness of the drug for the individual patient (see DOSAGE AND
360
ADMINISTRATION).
361
Posttraumatic Stress Disorder: PAXIL is indicated for the treatment of Posttraumatic
362
Stress Disorder (PTSD).
363
The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebo
364
controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY: Clinical
365
Trials).
366
PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or
367
threatened death or serious injury, or threat to the physical integrity of self or others, and a
368
response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of
369
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
370
thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity
371
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
372
inability to recall details of the event, and/or numbing of general responsiveness manifested as
373
diminished interest in significant activities, estrangement from others, restricted range of affect,
374
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
375
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
376
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
377
and that they cause clinically significant distress or impairment in social, occupational, or other
378
important areas of functioning.
379
The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has
380
not been systematically evaluated in placebo-controlled trials. Therefore, the physician who
381
elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term
382
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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CONTRAINDICATIONS
384
PAXIL should not be used in patients taking monoamine oxidase inhibitors (MAOIs),
385
including linezolid (an antibiotic which is a reversible non-selective MAOI) and
386
methylthioninium chloride (methylene blue), or within 2 weeks of stopping treatment with
387
MAOIs (see WARNINGS).
388
Concomitant use with thioridazine is contraindicated (see WARNINGS and
389
PRECAUTIONS).
390
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
391
PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the
392
inactive ingredients in PAXIL.
393
WARNINGS
394
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
395
both adult and pediatric, may experience worsening of their depression and/or the emergence of
396
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
397
are taking antidepressant medications, and this risk may persist until significant remission
398
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
399
disorders themselves are the strongest predictors of suicide. There has been a long-standing
400
concern, however, that antidepressants may have a role in inducing worsening of depression and
401
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
402
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
403
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
404
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
405
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
406
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
407
antidepressants compared to placebo in adults aged 65 and older.
408
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
409
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short
410
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo
411
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short
412
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
413
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
414
increase in the younger patients for almost all drugs studied. There were differences in absolute
415
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
416
differences (drug vs placebo), however, were relatively stable within age strata and across
417
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
418
per 1,000 patients treated) are provided in Table 1.
419
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420
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
421
422
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
423
the number was not sufficient to reach any conclusion about drug effect on suicide.
424
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
425
months. However, there is substantial evidence from placebo-controlled maintenance trials in
426
adults with depression that the use of antidepressants can delay the recurrence of depression.
427
All patients being treated with antidepressants for any indication should be monitored
428
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
429
in behavior, especially during the initial few months of a course of drug therapy, or at times
430
of dose changes, either increases or decreases.
431
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
432
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
433
been reported in adult and pediatric patients being treated with antidepressants for major
434
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
435
Although a causal link between the emergence of such symptoms and either the worsening of
436
depression and/or the emergence of suicidal impulses has not been established, there is concern
437
that such symptoms may represent precursors to emerging suicidality.
438
Consideration should be given to changing the therapeutic regimen, including possibly
439
discontinuing the medication, in patients whose depression is persistently worse, or who are
440
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
441
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
442
patient’s presenting symptoms.
443
If the decision has been made to discontinue treatment, medication should be tapered, as
444
rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
445
certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION:
446
Discontinuation of Treatment With PAXIL, for a description of the risks of discontinuation of
447
PAXIL).
448
Families and caregivers of patients being treated with antidepressants for major
449
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
450
alerted about the need to monitor patients for the emergence of agitation, irritability,
451
unusual changes in behavior, and the other symptoms described above, as well as the
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452
emergence of suicidality, and to report such symptoms immediately to healthcare
453
providers. Such monitoring should include daily observation by families and caregivers.
454
Prescriptions for PAXIL should be written for the smallest quantity of tablets consistent with
455
good patient management, in order to reduce the risk of overdose.
456
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
457
presentation of bipolar disorder. It is generally believed (though not established in controlled
458
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
459
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
460
symptoms described above represent such a conversion is unknown. However, prior to initiating
461
treatment with an antidepressant, patients with depressive symptoms should be adequately
462
screened to determine if they are at risk for bipolar disorder; such screening should include a
463
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
464
depression. It should be noted that PAXIL is not approved for use in treating bipolar depression.
465
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
466
another serotonin reuptake inhibitor drug in combination with a monoamine oxidase
467
inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including
468
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of
469
vital signs, and mental status changes that include extreme agitation progressing to
470
delirium and coma. These reactions have also been reported in patients who have recently
471
discontinued that drug and have been started on an MAOI. Some cases presented with
472
features resembling neuroleptic malignant syndrome. While there are no human data
473
showing such an interaction with PAXIL, limited animal data on the effects of combined
474
use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate
475
blood pressure and evoke behavioral excitation. Therefore, it is recommended that PAXIL
476
not be used in combination with an MAOI (including linezolid, an antibiotic which is a
477
reversible non-selective MAOI), and methylthioninium chloride [methylene blue]), or
478
within 14 days of discontinuing treatment with an MAOI (see CONTRAINDICATIONS).
479
At least 2 weeks should be allowed after stopping PAXIL before starting an MAOI.
480
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions:
481
The development of a potentially life-threatening serotonin syndrome or Neuroleptic
482
Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs
483
alone, including treatment with PAXIL, but particularly with concomitant use of
484
serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin
485
(including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin
486
syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
487
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
488
neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal
489
symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form
490
can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle
491
rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental
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492
status changes. Patients should be monitored for the emergence of serotonin syndrome or
493
NMS-like signs and symptoms.
494
The concomitant use of PAXIL with MAOIs intended to treat depression is
495
contraindicated.
496
If concomitant treatment of PAXIL with a 5-hydroxytryptamine receptor agonist
497
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
498
during treatment initiation and dose increases.
499
The concomitant use of PAXIL with serotonin precursors (such as tryptophan) is not
500
recommended.
501
Treatment with PAXIL and any concomitant serotonergic or antidopaminergic agents,
502
including antipsychotics, should be discontinued immediately if the above events occur and
503
supportive symptomatic treatment should be initiated.
504
Potential Interaction With Thioridazine: Thioridazine administration alone produces
505
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
506
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
507
dose related.
508
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
509
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
510
used in combination with thioridazine (see CONTRAINDICATIONS and
511
PRECAUTIONS).
512
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
513
infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of
514
congenital malformations, particularly cardiovascular malformations. The findings from these
515
studies are summarized below:
516
•
A study based on Swedish national registry data demonstrated that infants exposed to
517
paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular
518
malformations (2% risk in paroxetine-exposed infants) compared to the entire registry
519
population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No
520
increase in the risk of overall congenital malformations was seen in the paroxetine-exposed
521
infants. The cardiac malformations in the paroxetine-exposed infants were primarily
522
ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in
523
severity from those that resolve spontaneously to those which require surgery.
524
•
A separate retrospective cohort study from the United States (United Healthcare data)
525
evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester
526
(n = 815 for paroxetine). This study showed a trend towards an increased risk for
527
cardiovascular malformations for paroxetine (risk of 1.5%) compared to other
528
antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the
529
12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study
530
also suggested an increased risk of overall major congenital malformations including
531
cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants
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(OR 1.8; 95% confidence interval 1.2 to 2.8).
533
•
Two large case-control studies using separate databases, each with >9,000 birth defect
534
cases and >4,000 controls, found that maternal use of paroxetine during the first trimester
535
of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow
536
tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1.0 to 6.0,
537
7 exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval,
538
1.3 to 8.8, 6 exposed infants).
539
Other studies have found varying results as to whether there was an increased risk of overall,
540
cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data
541
over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and
542
congenital malformations included the above-noted studies in addition to others (n = 17 studies
543
that included overall malformations and n = 14 studies that included cardiovascular
544
malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested
545
an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95%
546
confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1
547
to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to
548
determine the extent to which the observed prevalence of cardiovascular malformations might
549
have contributed to that of overall malformations, nor was it possible to determine whether any
550
specific types of cardiovascular malformations might have contributed to the observed
551
prevalence of all cardiovascular malformations.
552
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential
553
harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment,
554
consideration should be given to either discontinuing paroxetine therapy or switching to another
555
antidepressant (see PRECAUTIONS: Discontinuation of Treatment With PAXIL). For women
556
who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should
557
only be initiated after consideration of the other available treatment options.
558
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
559
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
560
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
561
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
562
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
563
trimester of gestation and continued throughout lactation. This effect occurred at a dose of
564
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
565
rat pup mortality was not determined. The cause of these deaths is not known.
566
Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs or serotonin and
567
norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
568
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
569
complications can arise immediately upon delivery. Reported clinical findings have included
570
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
571
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
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572
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
573
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
574
clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome or
575
Neuroleptic Malignant Syndrome (NMS)-like Reactions).
576
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
577
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
578
the general population and is associated with substantial neonatal morbidity and mortality. In a
579
retrospective case-control study of 377 women whose infants were born with PPHN and 836
580
women whose infants were born healthy, the risk for developing PPHN was approximately six
581
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
582
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
583
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
584
study that has investigated the potential risk. The study did not include enough cases with
585
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
586
There have also been postmarketing reports of premature births in pregnant women exposed
587
to paroxetine or other SSRIs.
588
When treating a pregnant woman with paroxetine during the third trimester, the physician
589
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
590
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
591
women with a history of major depression who were euthymic at the beginning of pregnancy,
592
women who discontinued antidepressant medication during pregnancy were more likely to
593
experience a relapse of major depression than women who continued antidepressant medication.
594
PRECAUTIONS
595
General: Activation of Mania/Hypomania: During premarketing testing, hypomania or
596
mania occurred in approximately 1.0% of unipolar patients treated with PAXIL compared to
597
1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients
598
classified as bipolar, the rate of manic episodes was 2.2% for PAXIL and 11.6% for the
599
combined active-control groups. As with all drugs effective in the treatment of major depressive
600
disorder, PAXIL should be used cautiously in patients with a history of mania.
601
Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with
602
PAXIL, a rate similar to that associated with other drugs effective in the treatment of major
603
depressive disorder. PAXIL should be used cautiously in patients with a history of seizures. It
604
should be discontinued in any patient who develops seizures.
605
Discontinuation of Treatment With PAXIL: Recent clinical trials supporting the various
606
approved indications for PAXIL employed a taper-phase regimen, rather than an abrupt
607
discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials
608
involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a
609
daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before
610
treatment was stopped.
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611
With this regimen in those studies, the following adverse events were reported at an incidence
612
of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams,
613
paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and
614
were self-limiting and did not require medical intervention.
615
During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports
616
of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt),
617
including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances
618
(e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache,
619
lethargy, emotional lability, insomnia, and hypomania. While these events are generally self
620
limiting, there have been reports of serious discontinuation symptoms.
621
Patients should be monitored for these symptoms when discontinuing treatment with PAXIL.
622
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
623
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
624
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
625
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
626
ADMINISTRATION).
627
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of
628
treatment with PAXIL in pediatric patients.
629
Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk
630
of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a
631
result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other
632
studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of
633
paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study
634
suggests that the risk may increase with longer duration of coadministration. When tamoxifen is
635
used for the treatment or prevention of breast cancer, prescribers should consider using an
636
alternative antidepressant with little or no CYP2D6 inhibition.
637
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
638
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
639
such as an inability to sit or stand still usually associated with subjective distress. This is most
640
likely to occur within the first few weeks of treatment.
641
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
642
including PAXIL. In many cases, this hyponatremia appears to be the result of the syndrome of
643
inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
644
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
645
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
646
volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of
647
PAXIL should be considered in patients with symptomatic hyponatremia and appropriate
648
medical intervention should be instituted.
649
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
650
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
17
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651
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
652
seizure, coma, respiratory arrest, and death.
653
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
654
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
655
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
656
and cohort design) have demonstrated an association between use of drugs that interfere with
657
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
658
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
659
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
660
with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
661
coagulation.
662
Bone Fracture: Epidemiological studies on bone fracture risk following exposure to some
663
antidepressants, including SSRIs, have reported an association between antidepressant treatment
664
and fractures. There are multiple possible causes for this observation and it is unknown to what
665
extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological
666
fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral
667
density, should be considered in patients treated with paroxetine who present with unexplained
668
bone pain, point tenderness, swelling, or bruising.
669
Use in Patients With Concomitant Illness: Clinical experience with PAXIL in patients
670
with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in
671
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
672
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
673
PAXIL. A few cases of acute angle closure glaucoma associated with paroxetine therapy have
674
been reported in the literature. As mydriasis can cause acute angle closure in patients with
675
narrow angle glaucoma, caution should be used when PAXIL is prescribed for patients with
676
narrow angle glaucoma.
677
PAXIL has not been evaluated or used to any appreciable extent in patients with a recent
678
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
679
excluded from clinical studies during the product’s premarket testing. Evaluation of
680
electrocardiograms of 682 patients who received PAXIL in double-blind, placebo-controlled
681
trials, however, did not indicate that PAXIL is associated with the development of significant
682
ECG abnormalities. Similarly, PAXIL does not cause any clinically important changes in heart
683
rate or blood pressure.
684
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
685
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
686
be used in such patients (see DOSAGE AND ADMINISTRATION).
687
Information for Patients: PAXIL should not be chewed or crushed, and should be swallowed
688
whole.
689
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
690
PAXIL and triptans, tramadol, or other serotonergic agents.
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Reference ID: 2920253
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691
Prescribers or other health professionals should inform patients, their families, and their
692
caregivers about the benefits and risks associated with treatment with PAXIL and should counsel
693
them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines,
694
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available
695
for PAXIL. The prescriber or health professional should instruct patients, their families, and their
696
caregivers to read the Medication Guide and should assist them in understanding its contents.
697
Patients should be given the opportunity to discuss the contents of the Medication Guide and to
698
obtain answers to any questions they may have. The complete text of the Medication Guide is
699
reprinted at the end of this document.
700
Patients should be advised of the following issues and asked to alert their prescriber if these
701
occur while taking PAXIL.
702
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
703
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
704
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
705
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
706
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
707
down. Families and caregivers of patients should be advised to look for the emergence of such
708
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
709
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
710
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
711
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
712
close monitoring and possibly changes in the medication.
713
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
714
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
715
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
716
interfere with serotonin reuptake and these agents has been associated with an increased risk of
717
bleeding.
718
Interference With Cognitive and Motor Performance: Any psychoactive drug may
719
impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been
720
shown to impair psychomotor performance, patients should be cautioned about operating
721
hazardous machinery, including automobiles, until they are reasonably certain that therapy with
722
PAXIL does not affect their ability to engage in such activities.
723
Completing Course of Therapy: While patients may notice improvement with treatment
724
with PAXIL in 1 to 4 weeks, they should be advised to continue therapy as directed.
725
Concomitant Medication: Patients should be advised to inform their physician if they are
726
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
727
interactions.
728
Alcohol: Although PAXIL has not been shown to increase the impairment of mental and
729
motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
730
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
19
Reference ID: 2920253
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731
intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic
732
and Nonteratogenic Effects).
733
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
734
infant (see PRECAUTIONS: Nursing Mothers).
735
Laboratory Tests: There are no specific laboratory tests recommended.
736
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
737
between paroxetine and tryptophan may occur when they are coadministered. Adverse
738
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
739
reported when tryptophan was administered to patients taking PAXIL. Consequently,
740
concomitant use of PAXIL with tryptophan is not recommended (see WARNINGS: Serotonin
741
Syndrome or Neuroleptic Malignant Syndrom (NMS)-like Reactions).
742
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
743
Pimozide: In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg
744
daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in
745
pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The
746
increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine.
747
Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT
748
interval, concomitant use of pimozide and PAXIL is contraindicated (see
749
CONTRAINDICATIONS).
750
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
751
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
752
PAXIL is coadministered with other drugs that may affect the serotonergic neurotransmitter
753
systems, such as triptans, lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS:
754
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions).
755
The concomitant use of PAXIL with MAOIs (including linezolid and methylene blue) is
756
contraindicated (see CONTRAINDICATIONS). The concomitant use of PAXIL with other
757
SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions:
758
Tryptophan).
759
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
760
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
761
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
762
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
763
of PAXIL and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That
764
Interfere With Hemostasis).
765
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
766
an SSRI and a triptan. If concomitant use of PAXIL with a triptan is clinically warranted, careful
767
observation of the patient is advised, particularly during treatment initiation and dose increases
768
(see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like
769
Reactions).
770
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
20
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
771
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
772
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
773
where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma
774
concentrations of paroxetine were increased by approximately 50% during coadministration with
775
oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are
776
administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be
777
guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not
778
studied.
779
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
780
single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once
781
daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
782
respectively) compared to paroxetine administered alone. The effect of paroxetine on
783
phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear
784
pharmacokinetics, the results of this study may not address the case where the 2 drugs are both
785
being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when
786
coadministered with phenobarbital; any subsequent adjustment should be guided by clinical
787
effect.
788
Phenytoin: When a single oral 30-mg dose of PAXIL was administered at phenytoin steady
789
state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of
790
50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a
791
single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once
792
daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to
793
phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above
794
studies may not address the case where the 2 drugs are both being chronically dosed. No initial
795
dosage adjustments are considered necessary when these drugs are coadministered; any
796
subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS:
797
Postmarketing Reports).
798
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
799
treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are
800
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
801
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
802
(>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily
803
dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose
804
desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold,
805
respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been
806
evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to
807
8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased
808
9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the
809
active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The
810
effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs
21
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
811
were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,
812
paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This
813
resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in
814
atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.
815
Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be
816
initiated at a reduced dose when it is given with paroxetine.
817
Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not
818
been formally studied but may require lower doses than usually prescribed for either PAXIL or
819
the other drug.
820
Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme,
821
including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,
822
amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type
823
1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme
824
(e.g., quinidine), should be approached with caution.
825
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
826
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
827
coadministered (see CONTRAINDICATIONS and WARNINGS).
828
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6
829
by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and
830
hence reduced efficacy of tamoxifen (see PRECAUTIONS).
831
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
832
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
833
PRECAUTIONS: Tricyclic Antidepressants [TCAs]).
834
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
835
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
836
cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In
837
addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be
838
at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several
839
substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and
840
cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and
841
its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4
842
substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical
843
significance.
844
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of
845
tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism.
846
Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be
847
reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS: Drugs Metabolized by
848
Cytochrome CYP2D6).
849
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
850
protein, administration of PAXIL to a patient taking another drug that is highly protein bound
22
Reference ID: 2920253
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851
may cause increased free concentrations of the other drug, potentially resulting in adverse events.
852
Conversely, adverse effects could result from displacement of paroxetine by other highly bound
853
drugs.
854
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
855
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
856
the case-control and cohort design that have demonstrated an association between use of
857
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
858
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
859
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
860
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
861
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
862
Alcohol: Although PAXIL does not increase the impairment of mental and motor skills
863
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
864
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction
865
between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome,
866
caution is advised when PAXIL is coadministered with lithium.
867
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
868
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
869
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
870
paroxetine and digoxin should be undertaken with caution.
871
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
872
kinetics. The effects of paroxetine on diazepam were not evaluated.
873
Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0
874
24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%,
875
respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen,
876
the dose of procyclidine should be reduced.
877
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
878
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
879
coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of
880
propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS:
881
Postmarketing Reports).
882
Theophylline: Reports of elevated theophylline levels associated with treatment with
883
PAXIL have been reported. While this interaction has not been formally studied, it is
884
recommended that theophylline levels be monitored when these drugs are concurrently
885
administered.
886
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
887
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
888
clinical effect (tolerability and efficacy).
889
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
890
ECT and PAXIL.
23
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
891
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
892
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
893
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and
894
3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and
895
PTSD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than
896
that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only
897
2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of
898
male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for
899
control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
900
trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats
901
were not affected. Although there was a dose-related increase in the number of tumors in mice,
902
there was no drug-related increase in the number of mice with tumors. The relevance of these
903
findings to humans is unknown.
904
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
905
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
906
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
907
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
908
Impairment of Fertility: Some clinical studies have shown that SSRIs (including
909
paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some
910
men.
911
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of
912
15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety
913
disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible
914
lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to
915
52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at
916
50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested
917
spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder,
918
social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2
919
basis).
920
Pregnancy: Pregnancy Category D. See WARNINGS: Usage in Pregnancy: Teratogenic and
921
Nonteratogenic Effects.
922
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
923
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
924
should be exercised when PAXIL is administered to a nursing woman.
925
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
926
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Three placebo
927
controlled trials in 752 pediatric patients with MDD have been conducted with PAXIL, and the
928
data were not sufficient to support a claim for use in pediatric patients. Anyone considering the
929
use of PAXIL in a child or adolescent must balance the potential risks with the clinical need.
930
Decreased appetite and weight loss have been observed in association with the use of SSRIs.
24
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
931
Consequently, regular monitoring of weight and growth should be performed in children and
932
adolescents treated with an SSRI such as Paxil.
933
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
934
events were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a
935
rate at least twice that for pediatric patients receiving placebo: emotional lability (including self
936
harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased
937
appetite, tremor, sweating, hyperkinesia, and agitation.
938
Events reported upon discontinuation of treatment with PAXIL in the pediatric clinical trials
939
that included a taper phase regimen, which occurred in at least 2% of patients who received
940
PAXIL and which occurred at a rate at least twice that of placebo, were: emotional lability
941
(including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness,
942
dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION:
943
Discontinuation of Treatment With PAXIL).
944
Geriatric Use: SSRIs and SNRIs, including PAXIL, have been associated with cases of
945
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
946
event (see PRECAUTIONS: Hyponatremia).
947
In worldwide premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL
948
(approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased
949
clearance in the elderly, and a lower starting dose is recommended; there were, however, no
950
overall differences in the adverse event profile between elderly and younger patients, and
951
effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY
952
and DOSAGE AND ADMINISTRATION).
953
ADVERSE REACTIONS
954
Associated With Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients
955
treated with PAXIL in worldwide clinical trials in major depressive disorder and 16.1%
956
(84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients
957
treated with PAXIL in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD,
958
and PTSD, respectively, discontinued treatment due to an adverse event. The most common
959
events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events
960
associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo)
961
included the following:
962
25
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Major
Depressive
Disorder
OCD
Panic Disorder
Social Anxiety
Disorder
Generalized
Anxiety Disorder
PTSD
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
CNS
Somnolence
2.3%
0.7%
—
1.9%
0.3%
3.4%
0.3%
2.0%
0.2%
2.8%
0.6%
Insomnia
—
—
1.7%
0%
1.3%
0.3%
3.1%
0%
—
—
Agitation
1.1%
0.5%
—
—
—
Tremor
1.1%
0.3%
—
1.7%
0%
1.0%
0.2%
Anxiety
—
—
—
1.1%
0%
—
—
Dizziness
—
—
1.5%
0%
1.9%
0%
1.0%
0.2%
—
—
Gastroin
testinal
Constipation
—
1.1%
0%
—
—
Nausea
3.2%
1.1%
1.9%
0%
3.2%
1.2%
4.0%
0.3%
2.0%
0.2%
2.2%
0.6%
Diarrhea
1.0%
0.3%
—
Dry mouth
1.0%
0.3%
—
—
—
Vomiting
1.0%
0.3%
—
1.0%
0%
—
—
Flatulence
1.0%
0.3%
—
—
Other
Asthenia
Abnormal
1.6%
0.4%
1.9%
0.4%
2.5%
0.6%
1.8%
0.2%
1.6%
0.2%
Ejaculationa
1.6%
0%
2.1%
0%
4.9%
0.6%
2.5%
0.5%
—
—
Sweating
1.0%
0.3%
—
1.1%
0%
1.1%
0.2%
—
—
Impotencea
Libido
—
1.5%
0%
—
—
Decreased
1.0%
0%
—
—
963
Where numbers are not provided the incidence of the adverse events in patients treated with
964
PAXIL was not >1% or was not greater than or equal to 2 times the incidence of placebo.
965
a. Incidence corrected for gender.
966
967
Commonly Observed Adverse Events: Major Depressive Disorder: The most
968
commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
969
greater and incidence for PAXIL at least twice that for placebo, derived from Table 2) were:
970
Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor,
971
nervousness, ejaculatory disturbance, and other male genital disorders.
972
Obsessive Compulsive Disorder: The most commonly observed adverse events
973
associated with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at
974
least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite,
975
constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
976
Panic Disorder: The most commonly observed adverse events associated with the use of
977
paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for placebo,
978
derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor,
26
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
979
abnormal ejaculation, female genital disorders, and impotence.
980
Social Anxiety Disorder: The most commonly observed adverse events associated with
981
the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for
982
placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased
983
appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital
984
disorders, and impotence.
985
Generalized Anxiety Disorder: The most commonly observed adverse events associated
986
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
987
that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased
988
appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal
989
ejaculation.
990
Posttraumatic Stress Disorder: The most commonly observed adverse events associated
991
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
992
that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea,
993
decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders,
994
and impotence.
995
Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in
996
the tables following cannot be used to predict the incidence of side effects in the course of usual
997
medical practice where patient characteristics and other factors differ from those that prevailed in
998
the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from
999
other clinical investigations involving different treatments, uses, and investigators. The cited
1000
figures, however, do provide the prescribing physician with some basis for estimating the
1001
relative contribution of drug and nondrug factors to the side effect incidence rate in the
1002
populations studied.
1003
Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an
1004
incidence of 1% or more among paroxetine-treated patients who participated in short-term
1005
(6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to
1006
50 mg/day. Reported adverse events were classified using a standard COSTART-based
1007
Dictionary terminology.
1008
27
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1009
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
1010
Clinical Trials for Major Depressive Disordera
Body System
Preferred Term
PAXIL
(n = 421)
Placebo
(n = 421)
Body as a Whole
Headache
Asthenia
18%
15%
17%
6%
Cardiovascular
Palpitation
Vasodilation
3%
3%
1%
1%
Dermatologic
Sweating
Rash
11%
2%
2%
1%
Gastrointestinal
Nausea
26%
9%
Dry Mouth
18%
12%
Constipation
14%
9%
Diarrhea
12%
8%
Decreased Appetite
6%
2%
Flatulence
4%
2%
Oropharynx Disorderb
2%
0%
Dyspepsia
2%
1%
Musculoskeletal
Myopathy
Myalgia
Myasthenia
2%
2%
1%
1%
1%
0%
Nervous System
Somnolence
23%
9%
Dizziness
13%
6%
Insomnia
13%
6%
Tremor
8%
2%
Nervousness
5%
3%
Anxiety
5%
3%
Paresthesia
4%
2%
Libido Decreased
3%
0%
Drugged Feeling
2%
1%
Confusion
1%
0%
Respiration
Yawn
4%
0%
Special Senses
Blurred Vision
Taste Perversion
4%
2%
1%
0%
Urogenital System
Ejaculatory Disturbancec,d
13%
0%
Other Male Genital Disordersc,e
10%
0%
Urinary Frequency
3%
1%
Urination Disorderf
3%
0%
Female Genital Disordersc,g
2%
0%
1011
a. Events reported by at least 1% of patients treated with PAXIL are included, except the
1012
following events which had an incidence on placebo ≥ PAXIL: Abdominal pain, agitation,
1013
back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis,
1014
postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”),
1015
trauma, and vomiting.
1016
b. Includes mostly “lump in throat” and “tightness in throat.”
28
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1017
c. Percentage corrected for gender.
1018
d. Mostly “ejaculatory delay.”
1019
e. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual
1020
dysfunction,” and “impotence.”
1021
f. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
1022
g. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
1023
1024
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:
1025
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD
1026
patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
1027
patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on
1028
PAXIL who participated in placebo-controlled trials of 10- to 12-weeks duration in which
1029
patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety
1030
disorder on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
1031
patients were dosed in a range of 20 mg to 50 mg/day.
1032
1033
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
1034
Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety
1035
Disordera
Body System
Preferred Term
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
PAXIL
(n = 542)
Placebo
(n = 265)
PAXIL
(n = 469)
Placebo
(n = 324)
PAXIL
(n = 425)
Placebo
(n = 339)
Body as a Whole
Asthenia
Abdominal Pain
Chest Pain
Back Pain
Chills
Trauma
22%
—
3%
—
2%
—
14%
—
2%
—
1%
—
14%
4%
—
3%
2%
—
5%
3%
—
2%
1%
—
22%
—
—
—
—
3%
14%
—
—
—
—
1%
Cardiovascular
Vasodilation
Palpitation
4%
2%
1%
0%
—
—
—
—
—
—
—
—
Dermatologic
Sweating
Rash
9%
3%
3%
2%
14%
—
6%
—
9%
—
2%
—
Gastrointestinal
Nausea
23%
10%
23%
17%
25%
7%
Dry Mouth
18%
9%
18%
11%
9%
3%
Constipation
16%
6%
8%
5%
5%
2%
Diarrhea
Decreased
10%
10%
12%
7%
9%
6%
Appetite
9%
3%
7%
3%
8%
2%
Dyspepsia
—
—
—
—
4%
2%
Flatulence
Increased
—
—
—
—
4%
2%
29
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
Appetite
4%
3%
2%
1%
—
—
Vomiting
—
—
—
—
2%
1%
Musculoskeletal
Myalgia
—
—
—
—
4%
3%
Nervous System
Insomnia
Somnolence
24%
24%
13%
7%
18%
19%
10%
11%
21%
22%
16%
5%
Dizziness
12%
6%
14%
10%
11%
7%
Tremor
11%
1%
9%
1%
9%
1%
Nervousness
9%
8%
—
—
8%
7%
Libido Decreased
7%
4%
9%
1%
12%
1%
Agitation
Anxiety
Abnormal
—
—
—
—
5%
5%
4%
4%
3%
5%
1%
4%
Dreams
4%
1%
—
—
—
—
Concentration
Impaired
Depersonalization
Myoclonus
Amnesia
3%
3%
3%
2%
2%
0%
0%
1%
—
—
3%
—
—
—
2%
—
4%
—
2%
—
1%
—
1%
—
Respiratory System
Rhinitis
Pharyngitis
Yawn
—
—
—
—
—
—
3%
—
—
0%
—
—
—
4%
5%
—
2%
1%
Special Senses
Abnormal Vision
Taste Perversion
4%
2%
2%
0%
—
—
—
—
4%
—
1%
—
Urogenital System
Abnormal
Ejaculationb
Dysmenorrhea
Female Genital
23%
—
1%
—
21%
—
1%
—
28%
5%
1%
4%
Disorderb
3%
0%
9%
1%
9%
1%
Impotenceb
Urinary
Frequency
Urination
8%
3%
1%
1%
5%
2%
0%
0%
5%
—
1%
—
Impaired
Urinary Tract
Infection
3%
2%
0%
1%
—
2%
—
1%
—
—
—
—
1036
a. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients
1037
treated with PAXIL are included, except the following events which had an incidence on
1038
placebo ≥PAXIL: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased,
1039
depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder,
1040
rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough
1041
increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache,
30
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1042
infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory
1043
disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social
1044
anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and
1045
sinusitis.
1046
b. Percentage corrected for gender.
1047
1048
Generalized Anxiety Disorder and Posttraumatic Stress Disorder: Table 4
1049
enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on
1050
PAXIL who participated in placebo-controlled trials of 8-weeks duration in which patients were
1051
dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on PAXIL who
1052
participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a
1053
range of 20 mg/day to 50 mg/day.
1054
31
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1055
Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
1056
Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disordera
Body System
Preferred Term
Generalized Anxiety
Disorder
Posttraumatic Stress
Disorder
PAXIL
(n = 735)
Placebo
(n = 529)
PAXIL
(n = 676)
Placebo
(n = 504)
Body as a Whole
Asthenia
Headache
Infection
Abdominal Pain
Trauma
14%
17%
6%
6%
14%
3%
12%
—
5%
4%
6%
4%
—
4%
3%
5%
Cardiovascular
Vasodilation
3%
1%
2%
1%
Dermatologic
Sweating
6%
2%
5%
1%
Gastrointestinal
Nausea
Dry Mouth
Constipation
Diarrhea
Decreased Appetite
Vomiting
Dyspepsia
20%
11%
10%
9%
5%
3%
—
5%
5%
2%
7%
1%
2%
—
19%
10%
5%
11%
6%
3%
5%
8%
5%
3%
5%
3%
2%
3%
Nervous System
Insomnia
Somnolence
Dizziness
Tremor
Nervousness
Libido Decreased
Abnormal Dreams
11%
15%
6%
5%
4%
9%
8%
5%
5%
1%
3%
2%
12%
16%
6%
4%
—
5%
3%
11%
5%
5%
1%
—
2%
2%
Respiratory
System
Respiratory Disorder
Sinusitis
Yawn
7%
4%
4%
5%
3%
—
—
—
2%
—
—
<1%
Special Senses
Abnormal Vision
2%
1%
3%
1%
Urogenital
System
Abnormal
Ejaculation
b
Female Genital
Disorder
b
Impotence
b
25%
4%
4%
2%
1%
3%
13%
5%
9%
2%
1%
1%
1057
a. Events reported by at least 2% of GAD and PTSD in patients treated with PAXIL are
1058
included, except the following events which had an incidence on placebo ≥PAXIL [GAD]:
1059
Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain,
1060
headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis.
1061
b. Percentage corrected for gender.
1062
1063
Dose Dependency of Adverse Events: A comparison of adverse event rates in a
1064
fixed-dose study comparing 10, 20, 30, and 40 mg/day of PAXIL with placebo in the treatment
1065
of major depressive disorder revealed a clear dose dependency for some of the more common
1066
adverse events associated with use of PAXIL, as shown in Table 5:
32
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1067
1068
Table 5 . Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial
1069
in the Treatment of Major Depressive Disordera
Body System/Preferred Term
Placebo
n = 51
PAXIL
10 mg
n = 102
20 mg
n = 104
30 mg
n = 101
40 mg
n = 102
Body as a Whole
Asthenia
0.0%
2.9%
10.6%
13.9%
12.7%
Dermatology
Sweating
2.0%
1.0%
6.7%
8.9%
11.8%
Gastrointestinal
Constipation
5.9%
4.9%
7.7%
9.9%
12.7%
Decreased Appetite
2.0%
2.0%
5.8%
4.0%
4.9%
Diarrhea
7.8%
9.8%
19.2%
7.9%
14.7%
Dry Mouth
2.0%
10.8%
18.3%
15.8%
20.6%
Nausea
13.7%
14.7%
26.9%
34.7%
36.3%
Nervous System
Anxiety
0.0%
2.0%
5.8%
5.9%
5.9%
Dizziness
3.9%
6.9%
6.7%
8.9%
12.7%
Nervousness
0.0%
5.9%
5.8%
4.0%
2.9%
Paresthesia
0.0%
2.9%
1.0%
5.0%
5.9%
Somnolence
7.8%
12.7%
18.3%
20.8%
21.6%
Tremor
0.0%
0.0%
7.7%
7.9%
14.7%
Special Senses
Blurred Vision
2.0%
2.9%
2.9%
2.0%
7.8%
Urogenital System
Abnormal Ejaculation
0.0%
5.8%
6.5%
10.6%
13.0%
Impotence
0.0%
1.9%
4.3%
6.4%
1.9%
Male Genital Disorders
0.0%
3.8%
8.7%
6.4%
3.7%
1070
a. Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups
1071
and ≥ twice the placebo incidence for at least 1 paroxetine group.
1072
1073
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
1074
OCD, there was no clear relationship between adverse events and the dose of PAXIL to which
1075
patients were assigned. No new adverse events were observed in the group treated with 60 mg of
1076
PAXIL compared to any of the other treatment groups.
1077
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of PAXIL in the treatment of
1078
panic disorder, there was no clear relationship between adverse events and the dose of PAXIL to
1079
which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor,
1080
and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in
1081
patients receiving 60 mg of PAXIL compared to any of the other treatment groups.
1082
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
1083
social anxiety disorder, for most of the adverse events, there was no clear relationship between
33
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1084
adverse events and the dose of PAXIL to which patients were assigned.
1085
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1086
generalized anxiety disorder, for most of the adverse events, there was no clear relationship
1087
between adverse events and the dose of PAXIL to which patients were assigned, except for the
1088
following adverse events: Asthenia, constipation, and abnormal ejaculation.
1089
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1090
posttraumatic stress disorder, for most of the adverse events, there was no clear relationship
1091
between adverse events and the dose of PAXIL to which patients were assigned, except for
1092
impotence and abnormal ejaculation.
1093
Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence
1094
of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less
1095
to other effects (e.g., dry mouth, somnolence, and asthenia).
1096
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
1097
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
1098
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
1099
evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward
1100
sexual experiences.
1101
Reliable estimates of the incidence and severity of untoward experiences involving sexual
1102
desire, performance, and satisfaction are difficult to obtain, however, in part because patients and
1103
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
1104
untoward sexual experience and performance cited in product labeling, are likely to
1105
underestimate their actual incidence.
1106
In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the
1107
reported incidence of sexual side effects in males and females with major depressive disorder,
1108
OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.
1109
1110
Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials
PAXIL
Placebo
n (males)
1446
1042
Decreased Libido
6-15%
0-5%
Ejaculatory Disturbance
13-28%
0-2%
Impotence
2-9%
0-3%
n (females)
1822
1340
Decreased Libido
0-9%
0-2%
Orgasmic Disturbance
2-9%
0-1%
1111
1112
There are no adequate and well-controlled studies examining sexual dysfunction with
1113
paroxetine treatment.
1114
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
1115
known outcome, patients recovered without sequelae.
1116
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
34
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1117
SSRIs, physicians should routinely inquire about such possible side effects.
1118
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
1119
treatment with PAXIL for some patients but, on average, patients in controlled trials had minimal
1120
(about 1 pound) weight loss versus smaller changes on placebo and active control. No significant
1121
changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were
1122
observed in patients treated with PAXIL in controlled clinical trials.
1123
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with PAXIL and
1124
415 patients treated with placebo in controlled clinical trials, no clinically significant changes
1125
were seen in the ECGs of either group.
1126
Liver Function Tests: In placebo-controlled clinical trials, patients treated with PAXIL
1127
exhibited abnormal values on liver function tests at no greater rate than that seen in
1128
placebo-treated patients. In particular, the PAXIL-versus-placebo comparisons for alkaline
1129
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
1130
with marked abnormalities.
1131
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
1132
hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients
1133
receiving placebo.
1134
Other Events Observed During the Premarketing Evaluation of PAXIL: During its
1135
premarketing assessment in major depressive disorder, multiple doses of PAXIL were
1136
administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure
1137
to PAXIL varied greatly and included (in overlapping categories) open and double-blind studies,
1138
uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration
1139
studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder,
1140
generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676
1141
patients, respectively, received multiple doses of PAXIL. Untoward events associated with this
1142
exposure were recorded by clinical investigators using terminology of their own choosing.
1143
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
1144
experiencing adverse events without first grouping similar types of untoward events into a
1145
smaller number of standardized event categories.
1146
In the tabulations that follow, reported adverse events were classified using a standard
1147
COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the
1148
proportion of the 9,089 patients exposed to multiple doses of PAXIL who experienced an event
1149
of the type cited on at least 1 occasion while receiving PAXIL. All reported events are included
1150
except those already listed in Tables 2 to 5, those reported in terms so general as to be
1151
uninformative and those events where a drug cause was remote. It is important to emphasize that
1152
although the events reported occurred during treatment with paroxetine, they were not
1153
necessarily caused by it.
1154
Events are further categorized by body system and listed in order of decreasing frequency
1155
according to the following definitions: Frequent adverse events are those occurring on 1 or more
1156
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
35
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1157
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1158
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events
1159
of major clinical importance are also described in the PRECAUTIONS section.
1160
Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain;
1161
rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis,
1162
ulcer.
1163
Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia,
1164
hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris,
1165
arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular
1166
accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial
1167
ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis,
1168
thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
1169
Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis,
1170
gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal
1171
hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia,
1172
cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal
1173
incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction,
1174
jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis,
1175
stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
1176
Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism,
1177
thyroiditis.
1178
Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy,
1179
purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia,
1180
hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal
1181
lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia,
1182
thrombocythemia, thrombocytopenia.
1183
Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema,
1184
SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased,
1185
bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma
1186
globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia,
1187
hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic
1188
dehydrogenase increased, non-protein nitrogen (NPN) increased.
1189
Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare:
1190
Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
1191
Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking,
1192
alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia,
1193
hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction,
1194
neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia,
1195
choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug
1196
dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion,
36
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1197
hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy,
1198
nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes
1199
increased, stupor, torticollis, trismus, withdrawal syndrome.
1200
Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation,
1201
pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary
1202
edema, sputum increased, stridor, voice alteration.
1203
Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis,
1204
dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema,
1205
erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis;
1206
herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy,
1207
skin ulcer, sweating decreased, vesiculobullous rash.
1208
Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation,
1209
conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia,
1210
anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye
1211
hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia,
1212
ptosis, retinal hemorrhage, taste loss, visual field defect.
1213
Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria,
1214
menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency,
1215
vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis,
1216
female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis,
1217
metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith,
1218
vaginal hemorrhage, vaginal moniliasis.
1219
Postmarketing Reports: Voluntary reports of adverse events in patients taking PAXIL that
1220
have been received since market introduction and not listed above that may have no causal
1221
relationship with the drug include acute pancreatitis, elevated liver function tests (the most
1222
severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated
1223
with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic
1224
epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive
1225
of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia,
1226
bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been
1227
associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal
1228
failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic
1229
neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia
1230
(including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired
1231
hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and
1232
agranulocytosis), and vasculitic syndromes (such as Henoch-Schönlein purpura). There has been
1233
a case report of an elevated phenytoin level after 4 weeks of PAXIL and phenytoin
1234
coadministration. There has been a case report of severe hypotension when PAXIL was added to
1235
chronic metoprolol treatment.
37
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1236
DRUG ABUSE AND DEPENDENCE
1237
Controlled Substance Class: PAXIL is not a controlled substance.
1238
Physical and Psychologic Dependence: PAXIL has not been systematically studied in
1239
animals or humans for its potential for abuse, tolerance or physical dependence. While the
1240
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
1241
not systematic and it is not possible to predict on the basis of this limited experience the extent to
1242
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
1243
patients should be evaluated carefully for history of drug abuse, and such patients should be
1244
observed closely for signs of misuse or abuse of PAXIL (e.g., development of tolerance,
1245
incrementations of dose, drug-seeking behavior).
1246
OVERDOSAGE
1247
Human Experience: Since the introduction of PAXIL in the United States, 342 spontaneous
1248
cases of deliberate or accidental overdosage during paroxetine treatment have been reported
1249
worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with
1250
other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve
1251
paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were
1252
generally confounded by the ingestion of other drugs or alcohol or the presence of significant
1253
comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without
1254
sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum
1255
recommended daily dose) in a patient who recovered.
1256
Commonly reported adverse events associated with paroxetine overdosage include
1257
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
1258
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
1259
substances) include mydriasis, convulsions (including status epilepticus), ventricular
1260
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
1261
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
1262
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
1263
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
1264
Overdosage Management: No specific antidotes for paroxetine are known. Treatment
1265
should consist of those general measures employed in the management of overdosage with any
1266
drugs effective in the treatment of major depressive disorder.
1267
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
1268
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
1269
is not recommended. Due to the large volume of distribution of this drug, forced diuresis,
1270
dialysis, hemoperfusion, or exchange transfusion are unlikely to be of benefit.
1271
A specific caution involves patients who are taking or have recently taken paroxetine who
1272
might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
1273
parent tricyclic and/or an active metabolite may increase the possibility of clinically significant
1274
sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drugs
38
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1275
Metabolized by Cytochrome CYP2D6).
1276
In managing overdosage, consider the possibility of multiple drug involvement. The physician
1277
should consider contacting a poison control center for additional information on the treatment of
1278
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
1279
Desk Reference (PDR).
1280
DOSAGE AND ADMINISTRATION
1281
Major Depressive Disorder: Usual Initial Dosage: PAXIL should be administered as a
1282
single daily dose with or without food, usually in the morning. The recommended initial dose is
1283
20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating
1284
the effectiveness of PAXIL in the treatment of major depressive disorder. As with all drugs
1285
effective in the treatment of major depressive disorder, the full effect may be delayed. Some
1286
patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day
1287
increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least
1288
1 week.
1289
Maintenance Therapy: There is no body of evidence available to answer the question of
1290
how long the patient treated with PAXIL should remain on it. It is generally agreed that acute
1291
episodes of major depressive disorder require several months or longer of sustained
1292
pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose
1293
needed to maintain and/or sustain euthymia is unknown.
1294
Systematic evaluation of the efficacy of PAXIL has shown that efficacy is maintained for
1295
periods of up to 1 year with doses that averaged about 30 mg.
1296
Obsessive Compulsive Disorder: Usual Initial Dosage: PAXIL should be administered
1297
as a single daily dose with or without food, usually in the morning. The recommended dose of
1298
PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the
1299
dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at
1300
least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials
1301
demonstrating the effectiveness of PAXIL in the treatment of OCD. The maximum dosage
1302
should not exceed 60 mg/day.
1303
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month
1304
relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a
1305
lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY:
1306
Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a
1307
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1308
effective dosage, and patients should be periodically reassessed to determine the need for
1309
continued treatment.
1310
Panic Disorder: Usual Initial Dosage: PAXIL should be administered as a single daily dose
1311
with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic
1312
disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in
1313
10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to
39
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1314
60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL. The maximum dosage
1315
should not exceed 60 mg/day.
1316
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month
1317
relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine
1318
demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL
1319
PHARMACOLOGY: Clinical Trials). Panic disorder is a chronic condition, and it is reasonable
1320
to consider continuation for a responding patient. Dosage adjustments should be made to
1321
maintain the patient on the lowest effective dosage, and patients should be periodically
1322
reassessed to determine the need for continued treatment.
1323
Social Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a single
1324
daily dose with or without food, usually in the morning. The recommended and initial dosage is
1325
20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a
1326
range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social
1327
anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional
1328
benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials).
1329
Maintenance Therapy: There is no body of evidence available to answer the question of
1330
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1331
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety
1332
disorder is recognized as a chronic condition, and it is reasonable to consider continuation of
1333
treatment for a responding patient. Dosage adjustments should be made to maintain the patient
1334
on the lowest effective dosage, and patients should be periodically reassessed to determine the
1335
need for continued treatment.
1336
Generalized Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a
1337
single daily dose with or without food, usually in the morning. In clinical trials the effectiveness
1338
of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended
1339
starting dosage and the established effective dosage is 20 mg/day. There is not sufficient
1340
evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur
1341
in 10 mg/day increments and at intervals of at least 1 week.
1342
Maintenance Therapy: Systematic evaluation of continuing PAXIL for periods of up to
1343
24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL
1344
during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see
1345
CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically
1346
reassessed to determine the need for maintenance treatment.
1347
Posttraumatic Stress Disorder: Usual Initial Dosage: PAXIL should be administered as
1348
a single daily dose with or without food, usually in the morning. The recommended starting
1349
dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of
1350
PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed
1351
dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day
1352
compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at
1353
intervals of at least 1 week.
40
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1354
Maintenance Therapy: There is no body of evidence available to answer the question of
1355
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1356
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is
1357
recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a
1358
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1359
effective dosage, and patients should be periodically reassessed to determine the need for
1360
continued treatment.
1361
Special Populations: Treatment of Pregnant Women During the Third Trimester:
1362
Neonates exposed to PAXIL and other SSRIs or SNRIs, late in the third trimester have
1363
developed complications requiring prolonged hospitalization, respiratory support, and tube
1364
feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine
1365
during the third trimester, the physician should carefully consider the potential risks and benefits
1366
of treatment. The physician may consider tapering paroxetine in the third trimester.
1367
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
1368
Hepatic Impairment: The recommended initial dose is 10 mg/day for elderly patients,
1369
debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be
1370
made if indicated. Dosage should not exceed 40 mg/day.
1371
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
1372
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL.
1373
Similarly, at least 14 days should be allowed after stopping PAXIL before starting an MAOI.
1374
Discontinuation of Treatment With PAXIL: Symptoms associated with discontinuation of
1375
PAXIL have been reported (see PRECAUTIONS: Discontinuation of Treatment With PAXIL).
1376
Patients should be monitored for these symptoms when discontinuing treatment, regardless of the
1377
indication for which PAXIL is being prescribed. A gradual reduction in the dose rather than
1378
abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a
1379
decrease in the dose or upon discontinuation of treatment, then resuming the previously
1380
prescribed dose may be considered. Subsequently, the physician may continue decreasing the
1381
dose but at a more gradual rate.
1382
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
1383
HOW SUPPLIED
1384
Tablets: Film-coated, modified-oval as follows:
1385
10-mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
1386
NDC 0029-3210-13 Bottles of 30
1387
20-mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
1388
NDC 0029-3211-13 Bottles of 30
1389
30-mg blue tablets engraved on the front with PAXIL and on the back with 30.
1390
NDC 0029-3212-13 Bottles of 30
1391
40-mg green tablets engraved on the front with PAXIL and on the back with 40.
1392
NDC 0029-3213-13 Bottles of 30
41
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1393
Store tablets between 15° and 30°C (59° and 86°F).
1394
Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.
1395
NDC 0029-3215-48
1396
Store suspension at or below 25°C (77°F).
1397
PAXIL is a registered trademark of GlaxoSmithKline.
1398
1399
1400
1401
42
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1402
1403
Medication Guide
1404
PAXIL® (PAX-il)
1405
(paroxetine hydrochloride)
1406
Tablets and Oral Suspension
1407
1408
Read the Medication Guide that comes with PAXIL before you start taking it and each time you
1409
get a refill. There may be new information. This Medication Guide does not take the place of
1410
talking to your healthcare provider about your medical condition or treatment. Talk with your
1411
healthcare provider if there is something you do not understand or want to learn more about.
1412
What is the most important information I
should know about PAXIL?
PAXIL and other antidepressant medicines
may cause serious side effects, including:
1.
Suicidal thoughts or actions:
• PAXIL and other antidepressant
medicines may increase suicidal
thoughts or actions in some
children, teenagers, or young adults
within the first few months of
treatment or when the dose is
changed.
• Depression or other serious mental
illnesses are the most important
causes of suicidal thoughts or
actions.
• Watch for these changes and call
your healthcare provider right away
if you notice:
• New or sudden changes in mood,
behavior, actions, thoughts, or
feelings, especially if severe.
• Pay particular attention to such
changes when PAXIL is started
or when the dose is changed.
Keep all follow-up visits with your
healthcare provider and call between
visits if you are worried about
symptoms.
Call your healthcare provider right
away if you have any of the following
symptoms, or call 911 if an
emergency, especially if they are new,
worse, or worry you:
• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic
attacks
• feeling agitated, restless, angry,
or irritable
• trouble sleeping
• an increase in activity or talking
more than what is normal for you
• other unusual changes in
behavior or mood
Call your healthcare provider right away
if you have any of the following
symptoms, or call 911 if an emergency.
PAXIL may be associated with these
serious side effects:
2.
Serotonin Syndrome or Neuroleptic
Malignant Syndrome-like reactions.
This condition can be life-
threatening and may include:
• agitation, hallucinations, coma, or
43
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For current labeling information, please visit https://www.fda.gov/drugsatfda
other changes in mental status
• coordination problems or muscle
twitching (overactive reflexes)
• racing heartbeat, high or low blood
pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity
3.
Severe allergic reactions:
• trouble breathing
• swelling of the face, tongue, eyes,
or mouth
• rash, itchy welts (hives), or blisters,
alone or with fever or joint pain
4.
Abnormal bleeding: PAXIL and
other antidepressant medicines may
increase your risk of bleeding or
bruising, especially if you take the
blood thinner warfarin (Coumadin®,
Jantoven®), a non-steroidal anti
inflammatory drug (NSAIDs, like
ibuprofen or naproxen), or aspirin.
5.
Seizures or convulsions
6.
Manic episodes:
• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual
7.
Changes in appetite or weight.
Children and adolescents should have
height and weight monitored during
treatment.
8.
Low salt (sodium) levels in the
blood. Elderly people may be at
greater risk for this. Symptoms may
include:
• headache
• weakness or feeling unsteady
• confusion, problems concentrating
or thinking, or memory problems
Do not stop PAXIL without first talking
to your healthcare provider. Stopping
PAXIL too quickly may cause serious
symptoms including:
• anxiety, irritability, high or low mood,
feeling restless, or changes in sleep
habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking,
confusion
What is PAXIL?
PAXIL is a prescription medicine used to
treat depression. It is important to talk with
your healthcare provider about the risks of
treating depression and also the risks of not
treating it. You should discuss all treatment
choices with your healthcare provider.
PAXIL is also used to treat:
• Major Depressive Disorder (MDD)
• Obsessive Compulsive Disorder (OCD)
• Panic Disorder
• Social Anxiety Disorder
• Generalized Anxiety Disorder (GAD)
• Post Traumatic Stress Disorder (PTSD)
Talk to your healthcare provider if you do
not think that your condition is getting better
with treatment using PAXIL.
Who should not take PAXIL?
Do not take PAXIL if you:
• are allergic to paroxetine hydrochloride
or any of the ingredients in PAXIL. See
the end of this Medication Guide for a
complete list of ingredients in PAXIL.
2
Reference ID: 2920253
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• take a Monoamine Oxidase Inhibitor
(MAOI), such as PARNATE®
(tranylcypromine), NARDIL®
(phenelzine), or the antibiotic ZYVOX®
(linezolid). Ask your healthcare provider
or pharmacist if you are not sure if you
take an MAOI.
•
Do not take an MAOI within 2
weeks of stopping PAXIL.
•
Do not start PAXIL if you stopped
taking an MAOI in the last 2 weeks.
•
People who take PAXIL close in
time to an MAOI may have serious
or even life-threatening side
effects. Get medical help right
away if you have any of these
symptoms:
• high fever
• uncontrolled muscle spasms
• stiff muscles
• rapid changes in heart rate or
blood pressure
• confusion
• loss of consciousness (pass out)
• take MELLARIL® (thioridazine). Do
not take MELLARIL® together with
PAXIL because this can cause serious
heart rhythm problems or sudden
death.
• take the antipsychotic medicine
pimozide (ORAP®) because this can
cause serious heart problems.
What should I tell my healthcare provider
before taking PAXIL? Ask if you are not
sure.
Before starting PAXIL, tell your healthcare
provider if you:
• are pregnant, may be pregnant, or
plan to become pregnant. There is a
possibility that PAXIL may harm your
unborn baby, including an increased risk
of birth defects, particularly heart
defects. Other risks may include a
serious condition in which there is not
enough oxygen in the baby’s blood.
Your baby may also have certain other
symptoms shortly after birth. Premature
births have also been reported in some
women who used PAXIL during
pregnancy.
• are breastfeeding. PAXIL passes into
your milk. Talk to your healthcare
provider about the best way to feed your
baby while taking PAXIL.
• are taking certain drugs such as:
• triptans used to treat migraine
headache
• other antidepressants (SSRIs, SNRIs,
tricyclics, or lithium) or
antipsychotics
• drugs that affect serotonin, such as
lithium, tramadol, tryptophan, St.
John’s wort
• certain drugs used to treat irregular
heart beats
• certain drugs used to treat
schizophrenia
• certain drugs used to treat HIV
infection
• certain drugs that affect the blood,
such as warfarin, aspirin, and
ibuprofen
• certain drugs used to treat epilepsy
• atomoxetine
• cimetidine
• fentanyl
• metoprolol
• pimozide
• procyclidine
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• tamoxifen
• have liver problems
• have kidney problems
• have heart problems
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have a history of a stroke
• have high blood pressure
• have or had bleeding problems
• have glaucoma (high pressure in the eye)
Tell your healthcare provider about all
the medicines you take, including
prescription and non-prescription medicines,
vitamins, and herbal supplements. PAXIL
and some medicines may interact with each
other, may not work as well, or may cause
serious side effects.
Your healthcare provider or pharmacist can
tell you if it is safe to take PAXIL with your
other medicines. Do not start or stop any
medicine while taking PAXIL without
talking to your healthcare provider first.
If you take PAXIL, you should not take any
other medicines that contain paroxetine
hydrochloride, including PAXIL CR and
PEXEVA® (paroxetine mesylate).
How should I take PAXIL?
• Take PAXIL exactly as prescribed. Your
healthcare provider may need to change
the dose of PAXIL until it is the right
dose for you.
• PAXIL may be taken with or without
food.
• If you are taking PAXIL Oral
Suspension, shake the suspension well
before use.
• If you miss a dose of PAXIL, take the
missed dose as soon as you remember. If
it is almost time for the next dose, skip
the missed dose and take your next dose
at the regular time. Do not take two
doses of PAXIL at the same time.
• If you take too much PAXIL, call your
healthcare provider or poison control
center right away, or get emergency
treatment.
• Do not stop taking PAXIL suddenly
without talking to your doctor (unless
you have symptoms of a severe allergic
reaction). If you need to stop taking
PAXIL, your healthcare provider can tell
you how to safely stop taking it.
What should I avoid while taking
PAXIL?
PAXIL can cause sleepiness or may affect
your ability to make decisions, think clearly,
or react quickly. You should not drive,
operate heavy machinery, or do other
dangerous activities until you know how
PAXIL affects you. Do not drink alcohol
while using PAXIL.
What are possible side effects of PAXIL?
PAXIL may cause serious side effects,
including all of those described in the
section entitled “What is the most important
information I should know about PAXIL?”
Common possible side effects in people who
take PAXIL include:
• nausea
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• sleepiness
• weakness
• dizziness
• feeling anxious or trouble sleeping
• sexual problems
• sweating
• shaking
• not feeling hungry
• dry mouth
• constipation
• infection
• yawning
Tell your healthcare provider if you have
any side effect that bothers you or that does
not go away. These are not all the possible
side effects of PAXIL. For more
information, ask your healthcare provider or
pharmacist.
CALL YOUR DOCTOR FOR
MEDICAL ADVICE ABOUT SIDE
EFFECTS. YOU MAY REPORT SIDE
EFFECTS TO THE FDA AT 1-800-FDA
1088 or 1-800-332-1088.
How should I store PAXIL?
• Store PAXIL Tablets at room
temperature between 59º and 86ºF (15º
and 30ºC).
• Store PAXIL Oral Suspension at or
below 77ºF (25ºC).
• Keep PAXIL away from light.
• Keep bottle of PAXIL closed tightly.
Keep PAXIL and all medicines out of the
reach of children.
General information about PAXIL
Medicines are sometimes prescribed for
purposes other than those listed in a
Medication Guide. Do not use PAXIL for a
condition for which it was not prescribed.
Do not give PAXIL to other people, even if
they have the same condition. It may harm
them.
This Medication Guide summarizes the most
important information about PAXIL. If you
would like more information, talk with your
healthcare provider. You may ask your
healthcare provider or pharmacist for
information about PAXIL that is written for
healthcare professionals.
For more information about PAXIL call 1
888-825-5249 or go to www.us.gsk.com.
What are the ingredients in PAXIL?
Active ingredient: paroxetine
hydrochloride
Inactive ingredients in tablets: dibasic
calcium phosphate dihydrate, hypromellose,
magnesium stearate, polyethylene glycols,
polysorbate 80, sodium starch glycolate,
titanium dioxide, and 1 or more of the
following: D&C Red No. 30 aluminum lake,
D&C Yellow No. 10 aluminum lake, FD&C
Blue No. 2 aluminum lake, FD&C Yellow
No. 6 aluminum lake.
Inactive ingredients in suspension for oral
administration: polacrilin potassium,
microcrystalline cellulose, propylene glycol,
glycerin, sorbitol, methylparaben,
propylparaben, sodium citrate dihydrate,
citric acid anhydrous, sodium saccharin,
flavorings, FD&C Yellow No. 6 aluminum
lake, and simethicone emulsion, USP.
PAXIL is a registered trademark of
GlaxoSmithKline. The other brands listed
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
are trademarks of their respective owners
its products.
and are not trademarks of GlaxoSmithKline.
The makers of these brands are not affiliated
This Medication Guide has been approved
with and do not endorse GlaxoSmithKline or
by the U.S. Food and Drug Administration.
Month Year
PXL:XMG company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
©2010, GlaxoSmithKline. All rights reserved.
October 2010
PXL:55PI
6
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1
PRESCRIBING INFORMATION
2
PAXIL CR®
3
(paroxetine hydrochloride)
4
Controlled-Release Tablets
5
6
Suicidality and Antidepressant Drugs
7
Antidepressants increased the risk compared to placebo of suicidal thinking and
8
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
9
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
10
use of PAXIL CR or any other antidepressant in a child, adolescent, or young adult must
11
balance this risk with the clinical need. Short-term studies did not show an increase in the
12
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
13
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
14
older. Depression and certain other psychiatric disorders are themselves associated with
15
increases in the risk of suicide. Patients of all ages who are started on antidepressant
16
therapy should be monitored appropriately and observed closely for clinical worsening,
17
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
18
the need for close observation and communication with the prescriber. PAXIL CR is not
19
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
20
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
21
DESCRIPTION
22
PAXIL CR (paroxetine hydrochloride) is an orally administered psychotropic drug with a
23
chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic,
24
tetracyclic, or other available antidepressant or antipanic agents. It is the hydrochloride salt of a
25
phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'
26
methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical
27
formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The
28
structural formula of paroxetine hydrochloride is:
29
30
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
31
120° to 138°C and a solubility of 5.4 mg/mL in water.
32
Each enteric, film-coated, controlled-release tablet contains paroxetine hydrochloride
33
equivalent to paroxetine as follows: 12.5 mg–yellow, 25 mg–pink, 37.5 mg–blue. One layer of structural formula
1
Reference ID: 2920253
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34
the tablet consists of a degradable barrier layer and the other contains the active material in a
35
hydrophilic matrix.
36
Inactive ingredients consist of hypromellose, polyvinylpyrrolidone, lactose monohydrate,
37
magnesium stearate, silicon dioxide, glyceryl behenate, methacrylic acid copolymer type C,
38
sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate, titanium dioxide, polyethylene
39
glycols, and 1 or more of the following colorants: Yellow ferric oxide, red ferric oxide, D&C
40
Red No. 30 aluminum lake, FD&C Yellow No. 6 aluminum lake, D&C Yellow No. 10
41
aluminum lake, FD&C Blue No. 2 aluminum lake.
42
CLINICAL PHARMACOLOGY
43
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
44
disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder (PMDD) is
45
presumed to be linked to potentiation of serotonergic activity in the central nervous system
46
resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT).
47
Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the
48
uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine
49
is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak
50
effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies
51
indicate that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-,
52
dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic,
53
histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic,
54
sedative, and cardiovascular effects for other psychotropic drugs.
55
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
56
compound, they are essentially inactive.
57
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
58
solution of the hydrochloride salt. The elimination half-life is approximately 15 to 20 hours after
59
a single dose of PAXIL CR. Paroxetine is extensively metabolized and the metabolites are
60
considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses.
61
Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily
62
excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has
63
not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).
64
Absorption and Distribution: Tablets of PAXIL CR contain a degradable polymeric
65
matrix (GEOMATRIX™) designed to control the dissolution rate of paroxetine over a period of
66
approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric
67
coat delays the start of drug release until tablets of PAXIL CR have left the stomach.
68
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
69
hydrochloride salt. In a study in which normal male and female subjects (n = 23) received single
70
oral doses of PAXIL CR at 4 dosage strengths (12.5 mg, 25 mg, 37.5 mg, and 50 mg), paroxetine
71
Cmax and AUC0-inf increased disproportionately with dose (as seen also with immediate-release
72
formulations). Mean Cmax and AUC0-inf values at these doses were 2.0, 5.5, 9.0, and 12.5 ng/mL,
2
Reference ID: 2920253
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73
and 121, 261, 338, and 540 ng•hr./mL, respectively. Tmax was observed typically between 6 and
74
10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release
75
formulations. The bioavailability of 25 mg PAXIL CR is not affected by food.
76
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
77
plasma.
78
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
79
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
80
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
81
warfarin.
82
Metabolism and Excretion: The mean elimination half-life of paroxetine was 15 to
83
20 hours throughout a range of single doses of PAXIL CR (12.5 mg, 25 mg, 37.5 mg, and
84
50 mg). During repeated administration of PAXIL CR (25 mg once daily), steady state was
85
reached within 2 weeks (i.e., comparable to immediate-release formulations). In a repeat-dose
86
study in which normal male and female subjects (n = 23) received PAXIL CR (25 mg daily),
87
mean steady state Cmax, Cmin, and AUC0-24 values were 30 ng/mL, 20 ng/mL, and 550 ng•hr./mL,
88
respectively.
89
Based on studies using immediate-release formulations, steady-state drug exposure based on
90
AUC0-24 was several-fold greater than would have been predicted from single-dose data. The
91
excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes
92
paroxetine is readily saturable.
93
In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses
94
of the immediate-release formulation of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg
95
daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a
96
saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg
97
daily were only about 2 to 3 times greater than doubled.
98
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
99
polar and conjugated products of oxidation and methylation, which are readily cleared.
100
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
101
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
102
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
103
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
104
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
105
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
106
interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6).
107
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
108
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
109
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
110
1% as the parent compound over the 10-day post-dosing period.
111
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
112
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic
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113
impairment. The mean plasma concentrations in patients with creatinine clearance below
114
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
115
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
116
about a 2-fold increase in plasma concentrations (AUC, Cmax).
117
The initial dosage should therefore be reduced in patients with severe renal or hepatic
118
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
119
AND ADMINISTRATION).
120
Elderly Patients: In a multiple-dose study in the elderly at daily doses of 20, 30, and
121
40 mg of the immediate-release formulation, Cmin concentrations were about 70% to 80% greater
122
than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the
123
elderly should be reduced (see DOSAGE AND ADMINISTRATION).
124
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
125
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
126
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
127
desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions).
128
Clinical Trials
129
Major Depressive Disorder: The efficacy of PAXIL CR controlled-release tablets as a
130
treatment for major depressive disorder has been established in two 12-week, flexible-dose,
131
placebo-controlled studies of patients with DSM-IV Major Depressive Disorder. One study
132
included patients in the age range 18 to 65 years, and a second study included elderly patients,
133
ranging in age from 60 to 88. In both studies, PAXIL CR was shown to be significantly more
134
effective than placebo in treating major depressive disorder as measured by the following:
135
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
136
Global Impression (CGI)–Severity of Illness score.
137
A study of outpatients with major depressive disorder who had responded to
138
immediate-release paroxetine tablets (HDRS total score <8) during an initial 8-week
139
open-treatment phase and were then randomized to continuation on immediate-release paroxetine
140
tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking
141
immediate-release paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness
142
was similar for male and female patients.
143
Panic Disorder: The effectiveness of PAXIL CR in the treatment of panic disorder was
144
evaluated in three 10-week, multicenter, flexible-dose studies (Studies 1, 2, and 3) comparing
145
paroxetine controlled-release (12.5 to 75 mg daily) to placebo in adult outpatients who had panic
146
disorder (DSM-IV), with or without agoraphobia. These trials were assessed on the basis of their
147
outcomes on 3 variables: (1) the proportions of patients free of full panic attacks at endpoint; (2)
148
change from baseline to endpoint in the median number of full panic attacks; and (3) change
149
from baseline to endpoint in the median Clinical Global Impression Severity score. For Studies 1
150
and 2, PAXIL CR was consistently superior to placebo on 2 of these 3 variables. Study 3 failed
151
to consistently demonstrate a significant difference between PAXIL CR and placebo on any of
152
these variables.
4
Reference ID: 2920253
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153
For all 3 studies, the mean dose of PAXIL CR for completers at endpoint was approximately
154
50 mg/day. Subgroup analyses did not indicate that there were any differences in treatment
155
outcomes as a function of age or gender.
156
Long-term maintenance effects of the immediate-release formulation of paroxetine in panic
157
disorder were demonstrated in an extension study. Patients who were responders during a
158
10-week double-blind phase with immediate-release paroxetine and during a 3-month
159
double-blind extension phase were randomized to either immediate-release paroxetine or placebo
160
in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were
161
significantly less likely to relapse than comparably treated patients who were randomized to
162
placebo.
163
Social Anxiety Disorder: The efficacy of PAXIL CR as a treatment for social anxiety
164
disorder has been established, in part, on the basis of extrapolation from the established
165
effectiveness of the immediate-release formulation of paroxetine. In addition, the effectiveness
166
of PAXIL CR in the treatment of social anxiety disorder was demonstrated in a 12-week,
167
multicenter, double-blind, flexible-dose, placebo-controlled study of adult outpatients with a
168
primary diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness of
169
PAXIL CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1)
170
change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and (2) the
171
proportion of responders who scored 1 or 2 (very much improved or much improved) on the
172
Clinical Global Impression (CGI) Global Improvement score.
173
PAXIL CR demonstrated statistically significant superiority over placebo on both the LSAS
174
total score and the CGI Improvement responder criterion. For patients who completed the trial,
175
64% of patients treated with PAXIL CR compared to 34.7% of patients treated with placebo
176
were CGI Improvement responders.
177
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
178
function of gender. Subgroup analyses of studies utilizing the immediate-release formulation of
179
paroxetine generally did not indicate differences in treatment outcomes as a function of age, race,
180
or gender.
181
Premenstrual Dysphoric Disorder: The effectiveness of PAXIL CR for the treatment of
182
PMDD utilizing a continuous dosing regimen has been established in 2 placebo-controlled trials.
183
Patients in these trials met DSM-IV criteria for PMDD. In a pool of 1,030 patients, treated with
184
daily doses of PAXIL CR 12.5 or 25 mg/day, or placebo the mean duration of the PMDD
185
symptoms was approximately 11 ± 7 years. Patients on systemic hormonal contraceptives were
186
excluded from these trials. Therefore, the efficacy of PAXIL CR in combination with systemic
187
(including oral) hormonal contraceptives for the continuous daily treatment of PMDD is
188
unknown. In both positive studies, patients (N = 672) were treated with 12.5 mg/day or
189
25 mg/day of PAXIL CR or placebo continuously throughout the menstrual cycle for a period of
190
3 menstrual cycles. The VAS-Total score is a patient-rated instrument that mirrors the diagnostic
191
criteria of PMDD as identified in the DSM-IV, and includes assessments for mood, physical
192
symptoms, and other symptoms. 12.5 mg/day and 25 mg/day of PAXIL CR were significantly
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more effective than placebo as measured by change from baseline to the endpoint on the luteal
194
phase VAS-Total score.
195
In a third study employing intermittent dosing, patients (N = 366) were treated for the 2 weeks
196
prior to the onset of menses (luteal phase dosing, also known as intermittent dosing) with
197
12.5 mg/day or 25 mg/day of PAXIL CR or placebo for a period of 3 months. 12.5 mg/day and
198
25 mg/day of PAXIL CR, as luteal phase dosing, was significantly more effective than placebo
199
as measured by change from baseline luteal phase VAS total score.
200
There is insufficient information to determine the effect of race or age on outcome in
201
these studies.
202
INDICATIONS AND USAGE
203
Major Depressive Disorder: PAXIL CR is indicated for the treatment of major depressive
204
disorder.
205
The efficacy of PAXIL CR in the treatment of a major depressive episode was established in
206
two 12-week controlled trials of outpatients whose diagnoses corresponded to the DSM-IV
207
category of major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
208
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly
209
every day for at least 2 weeks) depressed mood or loss of interest or pleasure in nearly all
210
activities, representing a change from previous functioning, and includes the presence of at least
211
5 of the following 9 symptoms during the same 2-week period: Depressed mood, markedly
212
diminished interest or pleasure in usual activities, significant change in weight and/or appetite,
213
insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of
214
guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal
215
ideation.
216
The antidepressant action of paroxetine in hospitalized depressed patients has not been
217
adequately studied.
218
PAXIL CR has not been systematically evaluated beyond 12 weeks in controlled clinical
219
trials; however, the effectiveness of immediate-release paroxetine hydrochloride in maintaining a
220
response in major depressive disorder for up to 1 year has been demonstrated in a
221
placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials). The physician
222
who elects to use PAXIL CR for extended periods should periodically re-evaluate the long-term
223
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
224
Panic Disorder: PAXIL CR is indicated for the treatment of panic disorder, with or without
225
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
226
unexpected panic attacks and associated concern about having additional attacks, worry about
227
the implications or consequences of the attacks, and/or a significant change in behavior related to
228
the attacks.
229
The efficacy of PAXIL CR controlled-release tablets was established in two 10-week trials in
230
panic disorder patients whose diagnoses corresponded to the DSM-IV category of panic disorder
231
(see CLINICAL PHARMACOLOGY: Clinical Trials).
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Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
233
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
234
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
235
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
236
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
237
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
238
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11)
239
fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
240
Long-term maintenance of efficacy with the immediate-release formulation of paroxetine was
241
demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder
242
assigned to immediate-release paroxetine demonstrated a lower relapse rate compared to patients
243
on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician
244
who prescribes PAXIL CR for extended periods should periodically re-evaluate the long-term
245
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
246
Social Anxiety Disorder: PAXIL CR is indicated for the treatment of social anxiety disorder,
247
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
248
characterized by a marked and persistent fear of 1 or more social or performance situations in
249
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
250
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
251
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
252
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
253
the person's normal routine, occupational or academic functioning, or social activities or
254
relationships, or there is marked distress about having the phobias. Lesser degrees of
255
performance anxiety or shyness generally do not require psychopharmacological treatment.
256
The efficacy of PAXIL CR as a treatment for social anxiety disorder has been established, in
257
part, on the basis of extrapolation from the established effectiveness of the immediate-release
258
formulation of paroxetine. In addition, the efficacy of PAXIL CR was established in a 12-week
259
trial, in adult outpatients with social anxiety disorder (DSM-IV). PAXIL CR has not been studied
260
in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY: Clinical
261
Trials).
262
The effectiveness of PAXIL CR in long-term treatment of social anxiety disorder, i.e., for
263
more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
264
Therefore, the physician who elects to prescribe PAXIL CR for extended periods should
265
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
266
DOSAGE AND ADMINISTRATION).
267
Premenstrual Dysphoric Disorder: PAXIL CR is indicated for the treatment of PMDD.
268
The efficacy of PAXIL CR in the treatment of PMDD has been established in 3
269
placebo-controlled trials (see CLINICAL PHARMACOLOGY: Clinical Trials).
270
The essential features of PMDD, according to DSM-IV, include markedly depressed mood,
271
anxiety or tension, affective lability, and persistent anger or irritability. Other features include
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decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite
273
or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast
274
tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur
275
regularly during the luteal phase and remit within a few days following the onset of menses; the
276
disturbance markedly interferes with work or school or with usual social activities and
277
relationships with others. In making the diagnosis, care should be taken to rule out other cyclical
278
mood disorders that may be exacerbated by treatment with an antidepressant.
279
The effectiveness of PAXIL CR in long-term use, that is, for more than 3 menstrual cycles,
280
has not been systematically evaluated in controlled trials. Therefore, the physician who elects to
281
use PAXIL CR for extended periods should periodically re-evaluate the long-term usefulness of
282
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
283
CONTRAINDICATIONS
284
PAXIL CR should not be used in patients taking monoamine oxidase inhibitors (MAOIs),
285
including linezolid (an antibiotic which is a reversible non-selective MAOI) and
286
methylthioninium chloride (methylene blue), or within 2 weeks of stopping treatment with
287
MAOIs (see WARNINGS).
288
Concomitant use with thioridazine is contraindicated (see WARNINGS and
289
PRECAUTIONS).
290
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
291
PAXIL CR is contraindicated in patients with a hypersensitivity to paroxetine or to any of the
292
inactive ingredients in PAXIL CR.
293
WARNINGS
294
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
295
both adult and pediatric, may experience worsening of their depression and/or the emergence of
296
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
297
are taking antidepressant medications, and this risk may persist until significant remission
298
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
299
disorders themselves are the strongest predictors of suicide. There has been a long-standing
300
concern, however, that antidepressants may have a role in inducing worsening of depression and
301
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
302
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
303
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
304
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
305
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
306
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
307
antidepressants compared to placebo in adults aged 65 and older.
308
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
309
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short
310
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo
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controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short
312
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
313
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
314
increase in the younger patients for almost all drugs studied. There were differences in absolute
315
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
316
differences (drug vs placebo), however, were relatively stable within age strata and across
317
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
318
per 1,000 patients treated) are provided in Table 1.
319
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
320
321
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
322
the number was not sufficient to reach any conclusion about drug effect on suicide.
323
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
324
months. However, there is substantial evidence from placebo-controlled maintenance trials in
325
adults with depression that the use of antidepressants can delay the recurrence of depression.
326
All patients being treated with antidepressants for any indication should be monitored
327
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
328
in behavior, especially during the initial few months of a course of drug therapy, or at times
329
of dose changes, either increases or decreases.
330
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
331
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
332
been reported in adult and pediatric patients being treated with antidepressants for major
333
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
334
Although a causal link between the emergence of such symptoms and either the worsening of
335
depression and/or the emergence of suicidal impulses has not been established, there is concern
336
that such symptoms may represent precursors to emerging suicidality.
337
Consideration should be given to changing the therapeutic regimen, including possibly
338
discontinuing the medication, in patients whose depression is persistently worse, or who are
339
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
340
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
341
patient’s presenting symptoms.
342
If the decision has been made to discontinue treatment, medication should be tapered, as
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rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
344
certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION:
345
Discontinuation of Treatment With PAXIL CR, for a description of the risks of discontinuation of
346
PAXIL CR).
347
Families and caregivers of patients being treated with antidepressants for major
348
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
349
alerted about the need to monitor patients for the emergence of agitation, irritability,
350
unusual changes in behavior, and the other symptoms described above, as well as the
351
emergence of suicidality, and to report such symptoms immediately to healthcare
352
providers. Such monitoring should include daily observation by families and caregivers.
353
Prescriptions for PAXIL CR should be written for the smallest quantity of tablets consistent with
354
good patient management, in order to reduce the risk of overdose.
355
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
356
presentation of bipolar disorder. It is generally believed (though not established in controlled
357
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
358
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
359
symptoms described above represent such a conversion is unknown. However, prior to initiating
360
treatment with an antidepressant, patients with depressive symptoms should be adequately
361
screened to determine if they are at risk for bipolar disorder; such screening should include a
362
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
363
depression. It should be noted that PAXIL CR is not approved for use in treating bipolar
364
depression.
365
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
366
another serotonin reuptake inhibitor drug in combination with an MAOI, there have been
367
reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus,
368
autonomic instability with possible rapid fluctuations of vital signs, and mental status
369
changes that include extreme agitation progressing to delirium and coma. These reactions
370
have also been reported in patients who have recently discontinued that drug and have
371
been started on an MAOI. Some cases presented with features resembling neuroleptic
372
malignant syndrome. While there are no human data showing such an interaction with
373
paroxetine hydrochloride, limited animal data on the effects of combined use of paroxetine
374
and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and
375
evoke behavioral excitation. Therefore, it is recommended that PAXIL CR not be used in
376
combination with an MAOI (including linezolid, an antibiotic which is a reversible non
377
selective MAOI, and methylthioninium chloride [methylene blue]), or within 14 days of
378
discontinuing treatment with an MAOI (see CONTRAINDICATIONS). At least 2 weeks
379
should be allowed after stopping PAXIL CR before starting an MAOI.
380
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions:
381
The development of a potentially life-threatening serotonin syndrome or Neuroleptic
382
Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs
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alone, including treatment with PAXIL CR, but particularly with concomitant use of
384
serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin
385
(including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin
386
syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
387
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
388
neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal
389
symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form
390
can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle
391
rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental
392
status changes. Patients should be monitored for the emergence of serotonin syndrome or
393
NMS-like signs and symptoms.
394
The concomitant use of PAXIL CR with MAOIs intended to treat depression is
395
contraindicated.
396
If concomitant treatment of PAXIL CR with a 5-hydroxytryptamine receptor agonist
397
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
398
during treatment initiation and dose increases.
399
The concomitant use of PAXIL CR with serotonin precursors (such as tryptophan) is
400
not recommended.
401
Treatment with PAXIL CR and any concomitant serotonergic or antidopaminergic
402
agents, including antipsychotics, should be discontinued immediately if the above events
403
occur and supportive symptomatic treatment should be initiated.
404
Potential Interaction With Thioridazine: Thioridazine administration alone produces
405
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
406
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
407
dose related.
408
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
409
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
410
used in combination with thioridazine (see CONTRAINDICATIONS and
411
PRECAUTIONS).
412
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
413
infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of
414
congenital malformations, particularly cardiovascular malformations. The findings from these
415
studies are summarized below:
416
•
A study based on Swedish national registry data demonstrated that infants exposed to
417
paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular
418
malformations (2% risk in paroxetine-exposed infants) compared to the entire registry
419
population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No
420
increase in the risk of overall congenital malformations was seen in the paroxetine-exposed
421
infants. The cardiac malformations in the paroxetine-exposed infants were primarily
422
ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in
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severity from those that resolve spontaneously to those which require surgery.
424
•
A separate retrospective cohort study from the United States (United Healthcare data)
425
evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester
426
(n = 815 for paroxetine). This study showed a trend towards an increased risk for
427
cardiovascular malformations for paroxetine (risk of 1.5%) compared to other
428
antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the
429
12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study
430
also suggested an increased risk of overall major congenital malformations including
431
cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants
432
(OR 1.8; 95% confidence interval 1.2 to 2.8).
433
•
Two large case-control studies using separate databases, each with >9,000 birth defect
434
cases and >4,000 controls, found that maternal use of paroxetine during the first trimester
435
of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow
436
tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, 7
437
exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to
438
8.8, 6 exposed infants).
439
Other studies have found varying results as to whether there was an increased risk of overall,
440
cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data
441
over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and
442
congenital malformations included the above-noted studies in addition to others (n = 17 studies
443
that included overall malformations and n = 14 studies that included cardiovascular
444
malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested
445
an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95%
446
confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1
447
to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to
448
determine the extent to which the observed prevalence of cardiovascular malformations might
449
have contributed to that of overall malformations, nor was it possible to determine whether any
450
specific types of cardiovascular malformations might have contributed to the observed
451
prevalence of all cardiovascular malformations.
452
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential
453
harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment,
454
consideration should be given to either discontinuing paroxetine therapy or switching to another
455
antidepressant (see PRECAUTIONS: Discontinuation of Treatment With PAXIL CR). For
456
women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine
457
should only be initiated after consideration of the other available treatment options.
458
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
459
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
460
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
461
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
462
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
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trimester of gestation and continued throughout lactation. This effect occurred at a dose of
464
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
465
rat pup mortality was not determined. The cause of these deaths is not known.
466
Nonteratogenic Effects: Neonates exposed to PAXIL CR and other SSRIs or serotonin
467
and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
468
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
469
complications can arise immediately upon delivery. Reported clinical findings have included
470
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
471
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
472
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
473
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
474
clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome or
475
Neuroleptic Malignant Syndrome (NMS)-like Reactions).
476
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
477
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
478
the general population and is associated with substantial neonatal morbidity and mortality. In a
479
retrospective case-control study of 377 women whose infants were born with PPHN and 836
480
women whose infants were born healthy, the risk for developing PPHN was approximately six
481
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
482
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
483
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
484
study that has investigated the potential risk. The study did not include enough cases with
485
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
486
There have also been postmarketing reports of premature births in pregnant women exposed
487
to paroxetine or other SSRIs.
488
When treating a pregnant woman with paroxetine during the third trimester, the physician
489
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
490
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
491
women with a history of major depression who were euthymic at the beginning of pregnancy,
492
women who discontinued antidepressant medication during pregnancy were more likely to
493
experience a relapse of major depression than women who continued antidepressant medication.
494
PRECAUTIONS
495
General: Activation of Mania/Hypomania: During premarketing testing of
496
immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately
497
1.0% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of
498
placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic
499
episodes was 2.2% for immediate-release paroxetine and 11.6% for the combined active-control
500
groups. Among 1,627 patients with major depressive disorder, panic disorder, social anxiety
501
disorder, or PMDD treated with PAXIL CR in controlled clinical studies, there were no reports
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of mania or hypomania. As with all drugs effective in the treatment of major depressive disorder,
503
PAXIL CR should be used cautiously in patients with a history of mania.
504
Seizures: During premarketing testing of immediate-release paroxetine hydrochloride,
505
seizures occurred in 0.1% of paroxetine-treated patients, a rate similar to that associated with
506
other drugs effective in the treatment of major depressive disorder. Among 1,627 patients who
507
received PAXIL CR in controlled clinical trials in major depressive disorder, panic disorder,
508
social anxiety disorder, or PMDD, 1 patient (0.1%) experienced a seizure. PAXIL CR should be
509
used cautiously in patients with a history of seizures. It should be discontinued in any patient
510
who develops seizures.
511
Discontinuation of Treatment With PAXIL CR: Adverse events while discontinuing
512
therapy with PAXIL CR were not systematically evaluated in most clinical trials; however, in
513
recent placebo-controlled clinical trials utilizing daily doses of PAXIL CR up to 37.5 mg/day,
514
spontaneously reported adverse events while discontinuing therapy with PAXIL CR were
515
evaluated. Patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose
516
by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients
517
receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in
518
dose. With this regimen in those studies, the following adverse events were reported for
519
PAXIL CR, at an incidence of 2% or greater for PAXIL CR and were at least twice that reported
520
for placebo: Dizziness, nausea, nervousness, and additional symptoms described by the
521
investigator as associated with tapering or discontinuing PAXIL CR (e.g., emotional lability,
522
headache, agitation, electric shock sensations, fatigue, and sleep disturbances). These events
523
were reported as serious in 0.3% of patients who discontinued therapy with PAXIL CR.
524
During marketing of PAXIL CR and other SSRIs and SNRIs, there have been spontaneous
525
reports of adverse events occurring upon discontinuation of these drugs, (particularly when
526
abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory
527
disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety,
528
confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events
529
are generally self-limiting, there have been reports of serious discontinuation symptoms.
530
Patients should be monitored for these symptoms when discontinuing treatment with
531
PAXIL CR. A gradual reduction in the dose rather than abrupt cessation is recommended
532
whenever possible. If intolerable symptoms occur following a decrease in the dose or upon
533
discontinuation of treatment, then resuming the previously prescribed dose may be considered.
534
Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see
535
DOSAGE AND ADMINISTRATION).
536
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of
537
treatment with paroxetine in pediatric patients.
538
Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk
539
of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a
540
result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other
541
studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of
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542
paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study
543
suggests that the risk may increase with longer duration of coadministration. When tamoxifen is
544
used for the treatment or prevention of breast cancer, prescribers should consider using an
545
alternative antidepressant with little or no CYP2D6 inhibition.
546
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
547
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
548
such as an inability to sit or stand still usually associated with subjective distress. This is most
549
likely to occur within the first few weeks of treatment.
550
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
551
including PAXIL CR. In many cases, this hyponatremia appears to be the result of the syndrome
552
of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
553
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
554
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
555
volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of
556
PAXIL CR should be considered in patients with symptomatic hyponatremia and appropriate
557
medical intervention should be instituted.
558
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
559
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
560
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
561
seizure, coma, respiratory arrest, and death.
562
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
563
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
564
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
565
and cohort design) have demonstrated an association between use of drugs that interfere with
566
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
567
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
568
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
569
with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
570
coagulation.
571
Bone Fracture: Epidemiological studies on bone fracture risk following exposure to some
572
antidepressants, including SSRIs, have reported an association between antidepressant treatment
573
and fractures. There are multiple possible causes for this observation and it is unknown to what
574
extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological
575
fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral
576
density, should be considered in patients treated with paroxetine who present with unexplained
577
bone pain, point tenderness, swelling, or bruising.
578
Use in Patients With Concomitant Illness: Clinical experience with immediate-release
579
paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution
580
is advisable in using PAXIL CR in patients with diseases or conditions that could affect
581
metabolism or hemodynamic responses.
15
Reference ID: 2920253
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582
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
583
paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with therapy
584
with immediate-release paroxetine have been reported in the literature. As mydriasis can cause
585
acute angle closure in patients with narrow angle glaucoma, caution should be used when
586
PAXIL CR is prescribed for patients with narrow angle glaucoma.
587
PAXIL CR or the immediate-release formulation has not been evaluated or used to any
588
appreciable extent in patients with a recent history of myocardial infarction or unstable heart
589
disease. Patients with these diagnoses were excluded from clinical studies during premarket
590
testing. Evaluation of electrocardiograms of 682 patients who received immediate-release
591
paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate
592
that paroxetine is associated with the development of significant ECG abnormalities. Similarly,
593
paroxetine hydrochloride does not cause any clinically important changes in heart rate or blood
594
pressure.
595
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
596
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
597
be used in such patients (see DOSAGE AND ADMINISTRATION).
598
Information for Patients: PAXIL CR should not be chewed or crushed, and should be
599
swallowed whole.
600
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
601
PAXIL CR and triptans, tramadol, or other serotonergic agents.
602
Prescribers or other health professionals should inform patients, their families, and their
603
caregivers about the benefits and risks associated with treatment with PAXIL CR and should
604
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
605
Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is
606
available for PAXIL CR. The prescriber or health professional should instruct patients, their
607
families, and their caregivers to read the Medication Guide and should assist them in
608
understanding its contents. Patients should be given the opportunity to discuss the contents of the
609
Medication Guide and to obtain answers to any questions they may have. The complete text of
610
the Medication Guide is reprinted at the end of this document.
611
Patients should be advised of the following issues and asked to alert their prescriber if these
612
occur while taking PAXIL CR.
613
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
614
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
615
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
616
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
617
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
618
down. Families and caregivers of patients should be advised to look for the emergence of such
619
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
620
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
621
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
16
Reference ID: 2920253
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622
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
623
close monitoring and possibly changes in the medication.
624
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
625
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
626
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
627
interfere with serotonin reuptake and these agents has been associated with an increased risk of
628
bleeding.
629
Interference With Cognitive and Motor Performance: Any psychoactive drug may
630
impair judgment, thinking, or motor skills. Although in controlled studies immediate-release
631
paroxetine hydrochloride has not been shown to impair psychomotor performance, patients
632
should be cautioned about operating hazardous machinery, including automobiles, until they are
633
reasonably certain that therapy with PAXIL CR does not affect their ability to engage in such
634
activities.
635
Completing Course of Therapy: While patients may notice improvement with use of
636
PAXIL CR in 1 to 4 weeks, they should be advised to continue therapy as directed.
637
Concomitant Medications: Patients should be advised to inform their physician if they are
638
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
639
interactions.
640
Alcohol: Although immediate-release paroxetine hydrochloride has not been shown to
641
increase the impairment of mental and motor skills caused by alcohol, patients should be advised
642
to avoid alcohol while taking PAXIL CR.
643
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
644
intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic
645
and Nonteratogenic Effects).
646
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
647
infant (see PRECAUTIONS: Nursing Mothers).
648
Laboratory Tests: There are no specific laboratory tests recommended.
649
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
650
between paroxetine and tryptophan may occur when they are coadministered. Adverse
651
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
652
reported when tryptophan was administered to patients taking immediate-release paroxetine.
653
Consequently, concomitant use of PAXIL CR with tryptophan is not recommended (see
654
WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions).
655
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
656
Pimozide: In a controlled study of healthy volunteers, after immediate-release paroxetine
657
hydrochloride was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide
658
was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to
659
pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6
660
inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its
661
known ability to prolong the QT interval, concomitant use of pimozide and PAXIL CR is
17
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
662
contraindicated (see CONTRAINDICATIONS).
663
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
664
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
665
PAXIL CR is coadministered with other drugs that may affect the serotonergic neurotransmitter
666
systems, such as triptans, lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS:
667
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions). The
668
concomitant use of PAXIL CR with MAOIs (including linezolid and methylene blue) is
669
contraindicated (see CONTRAINDICATIONS). The concomitant use of PAXIL CR with other
670
SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions,
671
Tryptophan).
672
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
673
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
674
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
675
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
676
of PAXIL CR and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs
677
That Interfere With Hemostasis).
678
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
679
an SSRI and a triptan. If concomitant use of PAXIL CR with a triptan is clinically warranted,
680
careful observation of the patient is advised, particularly during treatment initiation and dose
681
increases (see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)
682
like Reactions).
683
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
684
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
685
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
686
where immediate-release paroxetine (30 mg once daily) was dosed orally for 4 weeks,
687
steady-state plasma concentrations of paroxetine were increased by approximately 50% during
688
coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore,
689
when these drugs are administered concurrently, dosage adjustment of PAXIL CR after the
690
starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s
691
pharmacokinetics was not studied.
692
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
693
single oral 30-mg dose of immediate-release paroxetine was administered at phenobarbital
694
steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an
695
average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of
696
paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits
697
nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs
698
are both being chronically dosed. No initial dosage adjustment with PAXIL CR is considered
699
necessary when coadministered with phenobarbital; any subsequent adjustment should be guided
700
by clinical effect.
701
Phenytoin: When a single oral 30-mg dose of immediate-release paroxetine was
18
Reference ID: 2920253
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702
administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T½
703
were reduced (by an average of 50% and 35%, respectively) compared to immediate-release
704
paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin
705
was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was
706
slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs
707
exhibit nonlinear pharmacokinetics, the above studies may not address the case where the
708
2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary
709
when PAXIL CR is coadministered with phenytoin; any subsequent adjustments should be
710
guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports).
711
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
712
treatment of major depressive disorder (paroxetine, other SSRIs, and many tricyclics), are
713
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
714
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
715
(>90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In 1 study, daily
716
dosing of immediate-release paroxetine (20 mg once daily) under steady-state conditions
717
increased single-dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately
718
2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6
719
substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients
720
stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone
721
approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and
722
increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone)
723
approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has
724
been evaluated when both drugs were at steady state. In healthy volunteers who were extensive
725
metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg
726
atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values
727
that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than
728
when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it
729
is recommended that atomoxetine be initiated at a reduced dose when given with paroxetine.
730
Concomitant use of PAXIL CR with other drugs metabolized by cytochrome CYP2D6 has not
731
been formally studied but may require lower doses than usually prescribed for either PAXIL CR
732
or the other drug.
733
Therefore, coadministration of PAXIL CR with other drugs that are metabolized by this
734
isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g.,
735
nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines,
736
risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that
737
inhibit this enzyme (e.g., quinidine), should be approached with caution.
738
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
739
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
740
coadministered (see CONTRAINDICATIONS and WARNINGS).
741
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6
19
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
742
by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and
743
hence reduced efficacy of tamoxifen (see PRECAUTIONS).
744
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
745
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
746
PRECAUTIONS: Tricyclic Antidepressants [TCAs]).
747
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
748
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
749
CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro
750
studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times
751
more potent than paroxetine as an inhibitor of the metabolism of several substrates for this
752
enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the
753
assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on
754
terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s
755
extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
756
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of TCAs
757
with PAXIL CR, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations
758
may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is
759
coadministered with PAXIL CR (see PRECAUTIONS: Drugs Metabolized by Cytochrome
760
CYP2D6).
761
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
762
protein, administration of PAXIL CR to a patient taking another drug that is highly protein
763
bound may cause increased free concentrations of the other drug, potentially resulting in adverse
764
events. Conversely, adverse effects could result from displacement of paroxetine by other highly
765
bound drugs.
766
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
767
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
768
the case-control and cohort design that have demonstrated an association between use of
769
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
770
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
771
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
772
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
773
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
774
Alcohol: Although paroxetine does not increase the impairment of mental and motor skills
775
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL CR.
776
Lithium: A multiple-dose study with immediate-release paroxetine hydrochloride has shown
777
that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However,
778
due to the potential for serotonin syndrome, caution is advised when immediate-release
779
paroxetine hydrochloride is coadministered with lithium.
780
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
781
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
20
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
782
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
783
PAXIL CR and digoxin should be undertaken with caution.
784
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
785
kinetics. The effects of paroxetine on diazepam were not evaluated.
786
Procyclidine: Daily oral dosing of immediate-release paroxetine (30 mg once daily)
787
increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by
788
35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If
789
anticholinergic effects are seen, the dose of procyclidine should be reduced.
790
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
791
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
792
coadministration with immediate-release paroxetine (30 mg once daily) for the final 10 days. The
793
effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS:
794
Postmarketing Reports).
795
Theophylline: Reports of elevated theophylline levels associated with immediate-release
796
paroxetine treatment have been reported. While this interaction has not been formally studied, it
797
is recommended that theophylline levels be monitored when these drugs are concurrently
798
administered.
799
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
800
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
801
clinical effect (tolerability and efficacy).
802
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
803
ECT and PAXIL CR.
804
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
805
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
806
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to approximately 2
807
(mouse) and 3 (rat) times the MRHD on a mg/m2 basis. There was a significantly greater number
808
of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for
809
control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
810
trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats
811
were not affected. Although there was a dose-related increase in the number of tumors in mice,
812
there was no drug-related increase in the number of mice with tumors. The relevance of these
813
findings to humans is unknown.
814
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
815
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
816
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
817
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
818
Impairment of Fertility: Some clinical studies have shown that SSRIs (including
819
paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some
820
men.
821
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of
21
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
822
15 mg/kg/day, which is approximately twice the MRHD on a mg/m2 basis. Irreversible lesions
823
occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks.
824
These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and
825
atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at
826
25 mg/kg/day (approximately 8 and 4 times the MRHD on a mg/m2 basis).
827
Pregnancy: Pregnancy Category D. See WARNINGS: Usage in Pregnancy: Teratogenic and
828
Nonteratogenic Effects.
829
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
830
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
831
should be exercised when PAXIL CR is administered to a nursing woman.
832
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
833
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Three placebo
834
controlled trials in 752 pediatric patients with MDD have been conducted with immediate
835
release PAXIL, and the data were not sufficient to support a claim for use in pediatric patients.
836
Anyone considering the use of PAXIL CR in a child or adolescent must balance the potential
837
risks with the clinical need. Decreased appetite and weight loss have been observed in association
838
with the use of SSRIs. Consequently, regular monitoring of weight and growth should be
839
performed in children and adolescents treated with an SSRI such as PAXIL CR.
840
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
841
events were reported in at least 2% of pediatric patients treated with immediate-release
842
paroxetine hydrochloride and occurred at a rate at least twice that for pediatric patients receiving
843
placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and
844
mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.
845
Events reported upon discontinuation of treatment with immediate-release paroxetine
846
hydrochloride in the pediatric clinical trials that included a taper phase regimen, which occurred
847
in at least 2% of patients who received immediate-release paroxetine hydrochloride and which
848
occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal
849
ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and
850
abdominal pain (see DOSAGE AND ADMINISTRATIONS: Discontinuation of Treatment With
851
PAXIL CR).
852
Geriatric Use: SSRIs and SNRIs, including PAXIL CR, have been associated with cases of
853
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
854
event (see PRECAUTIONS: Hyponatremia).
855
In worldwide premarketing clinical trials with immediate-release paroxetine hydrochloride,
856
17% of paroxetine-treated patients (approximately 700) were 65 years or older. Pharmacokinetic
857
studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended;
858
there were, however, no overall differences in the adverse event profile between elderly and
859
younger patients, and effectiveness was similar in younger and older patients (see CLINICAL
860
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
861
In a controlled study focusing specifically on elderly patients with major depressive disorder,
22
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
862
PAXIL CR was demonstrated to be safe and effective in the treatment of elderly patients (>60
863
years) with major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials and
864
ADVERSE REACTIONS: Table 3.)
865
ADVERSE REACTIONS
866
The information included under the “Adverse Findings Observed in Short-Term,
867
Placebo-Controlled Trials With PAXIL CR” subsection of ADVERSE REACTIONS is based on
868
data from 11 placebo-controlled clinical trials. Three of these studies were conducted in patients
869
with major depressive disorder, 3 studies were done in patients with panic disorder, 1 study was
870
conducted in patients with social anxiety disorder, and 4 studies were done in female patients
871
with PMDD. Two of the studies in major depressive disorder, which enrolled patients in the age
872
range 18 to 65 years, are pooled. Information from a third study of major depressive disorder,
873
which focused on elderly patients (60 to 88 years), is presented separately as is the information
874
from the panic disorder studies and the information from the PMDD studies. Information on
875
additional adverse events associated with PAXIL CR and the immediate-release formulation of
876
paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During
877
the Clinical Development of Paroxetine).
878
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With PAXIL
879
CR:
880
Adverse Events Associated With Discontinuation of Treatment: Major Depressive
881
Disorder: Ten percent (21/212) of patients treated with PAXIL CR discontinued treatment due
882
to an adverse event in a pool of 2 studies of patients with major depressive disorder. The most
883
common events (≥1%) associated with discontinuation and considered to be drug related (i.e.,
884
those events associated with dropout at a rate approximately twice or greater for PAXIL CR
885
compared to placebo) included the following:
PAXIL CR
(n = 212)
Placebo
(n = 211)
Nausea
3.7%
0.5%
Asthenia
1.9%
0.5%
Dizziness
1.4%
0.0%
Somnolence
1.4%
0.0%
886
887
In a placebo-controlled study of elderly patients with major depressive disorder, 13% (13/104)
888
of patients treated with PAXIL CR discontinued due to an adverse event. Events meeting the
889
above criteria included the following:
23
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nausea
Headache
Depression
LFT’s abnormal
890
PAXIL CR
Placebo
(n = 104)
(n = 109)
2.9%
0.0%
1.9%
0.9%
1.9%
0.0%
1.9%
0.0%
891
Panic Disorder: Eleven percent (50/444) of patients treated with PAXIL CR in panic
892
disorder studies discontinued treatment due to an adverse event. Events meeting the above
893
criteria included the following:
PAXIL CR
Placebo
(n = 444)
(n = 445)
Nausea
2.9%
0.4%
Insomnia
1.8%
0.0%
Headache
1.4%
0.2%
Asthenia
1.1%
0.0%
894
895
Social Anxiety Disorder: Three percent (5/186) of patients treated with PAXIL CR in the
896
social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the
897
above criteria included the following:
PAXIL CR
Placebo
(n = 186)
(n = 184)
Nausea
2.2%
0.5%
Headache
1.6%
0.5%
Diarrhea
1.1%
0.5%
898
899
Premenstrual Dysphoric Disorder: Spontaneously reported adverse events were
900
monitored in studies of both continuous and intermittent dosing of PAXIL CR in the treatment of
901
PMDD. Generally, there were few differences in the adverse event profiles of the 2 dosing
902
regimens. Thirteen percent (88/681) of patients treated with PAXIL CR in PMDD studies of
903
continuous dosing discontinued treatment due to an adverse event.
904
The most common events (≥1%) associated with discontinuation in either group treated with
905
PAXIL CR with an incidence rate that is at least twice that of placebo in PMDD trials that
906
employed a continuous dosing regimen are shown in the following table. This table also shows
907
those events that were dose dependent (indicated with an asterisk) as defined as events having an
908
incidence rate with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR
909
(as well as the placebo group).
24
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PAXIL CR
25 mg
(n = 348)
PAXIL CR
12.5 mg
(n = 333)
Placebo
(n = 349)
TOTAL
15%
9.9%
6.3%
Nauseaa
6.0%
2.4%
0.9%
Asthenia
4.9%
3.0%
1.4%
Somnolencea
4.3%
1.8%
0.3%
Insomnia
2.3%
1.5%
0.0%
Concentration Impaireda
2.0%
0.6%
0.3%
Dry moutha
2.0%
0.6%
0.3%
Dizzinessa
1.7%
0.6%
0.6%
Decreased Appetitea
1.4%
0.6%
0.0%
Sweatinga
1.4%
0.0%
0.3%
Tremora
1.4%
0.3%
0.0%
Yawna
1.1%
0.0%
0.0%
Diarrhea
0.9%
1.2%
0.0%
910
a. Events considered to be dose dependent are defined as events having an incidence rate with
911
25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the
912
placebo group).
913
914
Commonly Observed Adverse Events: Major Depressive Disorder: The most
915
commonly observed adverse events associated with the use of PAXIL CR in a pool of 2 trials
916
(incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo,
917
derived from Table 2) were: Abnormal ejaculation, abnormal vision, constipation, decreased
918
libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma,
919
tremor, and yawning.
920
Using the same criteria, the adverse events associated with the use of PAXIL CR in a study of
921
elderly patients with major depressive disorder were: Abnormal ejaculation, constipation,
922
decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.
923
Panic Disorder: In the pool of panic disorder studies, the adverse events meeting these
924
criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating,
925
and female genital disorders (generally anorgasmia or difficulty achieving orgasm).
926
Social Anxiety Disorder: In the social anxiety disorder study, the adverse events meeting
927
these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence,
928
insomnia, and libido decreased.
929
Premenstrual Dysphoric Disorder: The most commonly observed adverse events
930
associated with the use of PAXIL CR either during continuous dosing or luteal phase dosing
931
(incidence of 5% or greater and incidence for PAXIL CR at least twice that for placebo, derived
932
from Table 6) were: Nausea, asthenia, libido decreased, somnolence, insomnia, female genital
933
disorders, sweating, dizziness, diarrhea, and constipation.
934
In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day
25
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
935
of PAXIL CR limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual
936
cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the
937
3 off-drug phases were combined, the following adverse events were reported at an incidence of
938
2% or greater for PAXIL CR and were at least twice the rate of that reported for placebo:
939
Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%),
940
sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).
941
Incidence in Controlled Clinical Trials: Table 2 enumerates adverse events that occurred at
942
an incidence of 1% or more among patients treated with PAXIL CR, aged 18 to 65, who
943
participated in 2 short-term (12-week) placebo-controlled trials in major depressive disorder in
944
which patients were dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse
945
events reported at an incidence of 5% or greater among elderly patients (ages 60 to 88) treated
946
with PAXIL CR who participated in a short-term (12-week) placebo-controlled trial in major
947
depressive disorder in which patients were dosed in a range of 12.5 mg to 50 mg/day. Table 4
948
enumerates adverse events reported at an incidence of 1% or greater among patients (19 to 72
949
years) treated with PAXIL CR who participated in short-term (10-week) placebo-controlled trials
950
in panic disorder in which patients were dosed in a range of 12.5 mg to 75 mg/day. Table 5
951
enumerates adverse events reported at an incidence of 1% or greater among adult patients treated
952
with PAXIL CR who participated in a short-term (12-week), double-blind, placebo-controlled
953
trial in social anxiety disorder in which patients were dosed in a range of 12.5 to 37.5 mg/day.
954
Table 6 enumerates adverse events that occurred at an incidence of 1% or more among patients
955
treated with PAXIL CR who participated in three, 12-week, placebo-controlled trials in PMDD
956
in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week
957
placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses
958
(luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified
959
using a standard COSTART-based Dictionary terminology.
960
The prescriber should be aware that these figures cannot be used to predict the incidence of
961
side effects in the course of usual medical practice where patient characteristics and other factors
962
differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be
963
compared with figures obtained from other clinical investigations involving different treatments,
964
uses, and investigators. The cited figures, however, do provide the prescribing physician with
965
some basis for estimating the relative contribution of drug and nondrug factors to the side effect
966
incidence rate in the population studied.
26
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
967
968
Table 2. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
969
PAXIL CR in a Pool of 2 Studies in Major Depressive Disordera,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 212)
Placebo
(n = 211)
Body as a Whole
Headache
27%
20%
Asthenia
14%
9%
Infectionc
8%
5%
Abdominal Pain
7%
4%
Back Pain
5%
3%
Traumad
5%
1%
Paine
3%
1%
Allergic Reactionf
2%
1%
Cardiovascular System
Tachycardia
Vasodilatationg
1%
2%
0%
0%
Digestive System
Nausea
22%
10%
Diarrhea
18%
7%
Dry Mouth
15%
8%
Constipation
10%
4%
Flatulence
6%
4%
Decreased Appetite
4%
2%
Vomiting
2%
1%
Nervous System
Somnolence
22%
8%
Insomnia
17%
9%
Dizziness
14%
4%
Libido Decreased
7%
3%
Tremor
7%
1%
Hypertonia
3%
1%
Paresthesia
3%
1%
Agitation
2%
1%
Confusion
1%
0%
Respiratory System
Yawn
5%
0%
Rhinitis
4%
1%
Cough Increased
2%
1%
Bronchitis
1%
0%
27
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
970
Skin and Appendages
Sweating
Photosensitivity
6%
2%
2%
0%
Special Senses
Abnormal Visionh
Taste Perversion
5%
2%
1%
0%
Urogenital System
Abnormal Ejaculationi,j
Female Genital Disorderi,k
Impotencei
Urinary Tract Infection
Menstrual Disorderi
Vaginitisi
26%
10%
5%
3%
2%
2%
1%
<1%
3%
1%
<1%
0%
971
a. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the
972
placebo incidence are not included. These events are: Abnormal dreams, anxiety, arthralgia,
973
depersonalization, dysmenorrhea, dyspepsia, hyperkinesia, increased appetite, myalgia,
974
nervousness, pharyngitis, purpura, rash, respiratory disorder, sinusitis, urinary frequency, and
975
weight gain.
976
b. <1% means greater than zero and less than 1%.
977
c. Mostly flu.
978
d. A wide variety of injuries with no obvious pattern.
979
e. Pain in a variety of locations with no obvious pattern.
980
f. Most frequently seasonal allergic symptoms.
981
g. Usually flushing.
982
h. Mostly blurred vision.
983
i. Based on the number of males or females.
984
j. Mostly anorgasmia or delayed ejaculation.
985
k. Mostly anorgasmia or delayed orgasm.
28
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
986
987
Table 3. Treatment-Emergent Adverse Events Occurring in ≥5% of
988
Patients Treated With PAXIL CR in a Study of Elderly Patients With Major Depressive
989
Disordera,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 104)
Placebo
(n = 109)
Body as a Whole
Headache
17%
13%
Asthenia
15%
14%
Trauma
8%
5%
Infection
6%
2%
Digestive System
Dry Mouth
18%
7%
Diarrhea
15%
9%
Constipation
13%
5%
Dyspepsia
13%
10%
Decreased Appetite
12%
5%
Flatulence
8%
7%
Nervous System
Somnolence
21%
12%
Insomnia
10%
8%
Dizziness
9%
5%
Libido Decreased
8%
<1%
Tremor
7%
0%
Skin and Appendages
Sweating
10%
<1%
Urogenital System
Abnormal Ejaculationc,d
Impotencec
17%
9%
3%
3%
990
a. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the
991
placebo incidence are not included. These events are nausea and respiratory disorder.
992
b. <1% means greater than zero and less than 1%.
993
c. Based on the number of males.
994
d. Mostly anorgasmia or delayed ejaculation.
995
29
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
996
Table 4. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
997
PAXIL CR in a Pool of 3 Panic Disorder Studiesa,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 444)
Placebo
(n = 445)
Body as a Whole
Asthenia
15%
10%
Abdominal Pain
6%
4%
Traumac
5%
4%
Cardiovascular System
Vasodilationd
3%
2%
Digestive System
Nausea
23%
17%
Dry Mouth
13%
9%
Diarrhea
12%
9%
Constipation
9%
6%
Decreased Appetite
8%
6%
Metabolic/Nutritional
Disorders
Weight Loss
1%
0%
Musculoskeletal System
Myalgia
5%
3%
Nervous System
Insomnia
20%
11%
Somnolence
20%
9%
Libido Decreased
9%
4%
Nervousness
8%
7%
Tremor
8%
2%
Anxiety
5%
4%
Agitation
3%
2%
Hypertoniae
2%
<1%
Myoclonus
2%
<1%
Respiratory System
Sinusitis
Yawn
8%
3%
5%
0%
Skin and Appendages
Sweating
7%
2%
Special Senses
Abnormal Visionf
3%
<1%
Urogenital System
Abnormal Ejaculationg,h
27%
3%
Impotenceg
10%
1%
Female Genital Disordersi,j
7%
1%
Urinary Frequency
2%
<1%
Urination Impaired
2%
<1%
Vaginitisi
1%
<1%
30
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
998
a. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the
999
placebo rate are not included. These events are: Abnormal dreams, allergic reaction, back
1000
pain, bronchitis, chest pain, concentration impaired, confusion, cough increased, depression,
1001
dizziness, dysmenorrhea, dyspepsia, fever, flatulence, headache, increased appetite, infection,
1002
menstrual disorder, migraine, pain, paresthesia, pharyngitis, respiratory disorder, rhinitis,
1003
tachycardia, taste perversion, thinking abnormal, urinary tract infection, and vomiting.
1004
b. <1% means greater than zero and less than 1%.
1005
c. Various physical injuries.
1006
d. Mostly flushing.
1007
e. Mostly muscle tightness or stiffness.
1008
f. Mostly blurred vision.
1009
g. Based on the number of male patients.
1010
h. Mostly anorgasmia or delayed ejaculation.
1011
i. Based on the number of female patients.
1012
j. Mostly anorgasmia or difficulty achieving orgasm.
1013
1014
Table 5. Treatment-Emergent Adverse Effects Occurring in ≥1% of Patients Treated
1015
With PAXIL CR in a Social Anxiety Disorder Studya,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 186)
Placebo
(n = 184)
Body as a Whole
Headache
23%
17%
Asthenia
18%
7%
Abdominal Pain
5%
4%
Back Pain
4%
1%
Traumac
3%
<1%
Allergic Reactiond
2%
<1%
Chest Pain
1%
<1%
Cardiovascular System
Hypertension
2%
0%
Migraine
2%
1%
Tachycardia
2%
1%
Digestive System
Nausea
22%
6%
Diarrhea
9%
8%
Constipation
5%
2%
Dry Mouth
3%
2%
Dyspepsia
2%
<1%
Decreased Appetite
1%
<1%
31
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tooth Disorder
1%
0%
Metabolic/Nutritional
Disorders
Weight Gain
3%
1%
Weight Loss
1%
0%
Nervous System
Insomnia
9%
4%
Somnolence
9%
4%
Libido Decreased
8%
1%
Dizziness
7%
4%
Tremor
4%
2%
Anxiety
2%
1%
Concentration Impaired
2%
0%
Depression
2%
1%
Myoclonus
1%
<1%
Paresthesia
1%
<1%
Respiratory System
Yawn
2%
0%
Skin and Appendages
Sweating
Eczema
14%
1%
3%
0%
Special Senses
Abnormal Visione
2%
0%
Abnormality of
Accommodation
2%
0%
Urogenital System
Abnormal Ejaculationf,g
15%
1%
Impotencef
9%
0%
Female Genital Disordersh,i
3%
0%
1016
a. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the
1017
placebo rate are not included. These events are: Dysmenorrhea, flatulence, gastroenteritis,
1018
hypertonia, infection, pain, pharyngitis, rash, respiratory disorder, rhinitis, and vomiting.
1019
b. <1% means greater than zero and less than 1%.
1020
c. Various physical injuries.
1021
d. Most frequently seasonal allergic symptoms.
1022
e. Mostly blurred vision.
1023
f. Based on the number of male patients.
1024
g. Mostly anorgasmia or delayed ejaculation.
1025
h. Based on the number of female patients.
1026
i. Mostly anorgasmia or difficulty achieving orgasm.
32
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1027
1028
Table 6. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
1029
PAXIL CR in a Pool of 3 Premenstrual Dysphoric Disorder Studies With Continuous
1030
Dosing or in 1 Premenstrual Dysphoric Disorder Study With Luteal Phase Dosinga,b,c
Body System/Adverse
Event
% Reporting Event
Continuous Dosing
Luteal Phase Dosing
PAXIL CR
(n = 681)
Placebo
(n = 349)
PAXIL CR
(n = 246)
Placebo
(n = 120)
Body as a Whole
Asthenia
Headache
Infection
Abdominal pain
17%
6%
15%
12%
6%
4%
-
-
15%
4%
-
-
-
-
3%
0%
Cardiovascular System
Migraine
1%
<1%
-
-
Digestive System
Nausea
Diarrhea
Constipation
Dry Mouth
Increased Appetite
Decreased Appetite
Dyspepsia
Gingivitis
17%
7%
6%
2%
5%
1%
4%
2%
3%
<1%
2%
<1%
2%
1%
-
-
18%
2%
6%
0%
2%
<1%
2%
<1%
-
-
2%
0%
2%
2%
1%
0%
Metabolic and
Nutritional Disorders
Generalized Edema
-
-
1%
<1%
Weight Gain
-
-
1%
<1%
Musculoskeletal
System
Arthralgia
2%
1%
-
-
Nervous System
Libido Decreased
12%
5%
9%
6%
Somnolence
9%
2%
3%
<1%
Insomnia
8%
2%
7%
3%
Dizziness
7%
3%
6%
3%
Tremor
4%
<1%
5%
0%
Concentration Impaired
3%
<1%
1%
0%
Nervousness
2%
<1%
3%
2%
Anxiety
2%
1%
-
-
33
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lack of Emotion
Depression
Vertigo
Abnormal Dreams
Amnesia
2%
-
-
1%
-
<1%
-
-
<1%
-
-
2%
2%
-
1%
-
<1%
<1%
-
0%
Respiratory System
Sinusitis
Yawn
Bronchitis
Cough Increased
-
2%
-
1%
-
<1%
-
<1%
4%
-
2%
-
2%
-
0%
-
Skin and Appendages
Sweating
7%
<1%
6%
<1%
Special Senses
Abnormal Vision
-
-
1%
0%
Urogenital System
Female Genital
Disordersd
Menorrhagia
Vaginal Moniliasis
Menstrual Disorder
8%
1%
1%
-
1%
<1%
<1%
-
2%
-
-
1%
0%
-
-
0%
1031
a. Adverse events for which the reporting rate of PAXIL CR was less than or equal to the
1032
placebo rate are not included. These events for continuous dosing are: Abdominal pain, back
1033
pain, pain, trauma, weight gain, myalgia, pharyngitis, respiratory disorder, rhinitis, sinusitis,
1034
pruritis, dysmenorrhea, menstrual disorder, urinary tract infection, and vomiting. The events
1035
for luteal phase dosing are: Allergic reaction, back pain, headache, infection, pain, trauma,
1036
myalgia, anxiety, pharyngitis, respiratory disorder, cystitis, and dysmenorrhea.
1037
b. <1% means greater than zero and less than 1%.
1038
c. The luteal phase and continuous dosing PMDD trials were not designed for making direct
1039
comparisons between the 2 dosing regimens. Therefore, a comparison between the 2 dosing
1040
regimens of the PMDD trials of incidence rates shown in Table 6 should be avoided.
1041
d. Mostly anorgasmia or difficulty achieving orgasm.
1042
1043
Dose Dependency of Adverse Events: Table 7 shows results in PMDD trials of
1044
common adverse events, defined as events with an incidence of ≥1% with 25 mg of PAXIL CR
1045
that was at least twice that with 12.5 mg of PAXIL CR and with placebo.
1046
1047
Table 7. Incidence of Common Adverse Events in Placebo, 12.5 mg, and 25 mg of
1048
PAXIL CR in a Pool of 3 Fixed-Dose PMDD Trials
34
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PAXIL CR
25 mg
(n = 348)
PAXIL CR
12.5 mg
(n = 333)
Placebo
(n = 349)
Common Adverse Event
Sweating
Tremor
Concentration Impaired
Yawn
Paresthesia
Hyperkinesia
Vaginitis
8.9%
6.0%
4.3%
3.2%
1.4%
1.1%
1.1%
4.2%
1.5%
1.5%
0.9%
0.3%
0.3%
0.3%
0.9%
0.3%
0.6%
0.3%
0.3%
0.0%
0.3%
1049
1050
A comparison of adverse event rates in a fixed-dose study comparing immediate-release
1051
paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose
1052
dependency for some of the more common adverse events associated with the use of
1053
immediate-release paroxetine.
1054
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
1055
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
1056
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
1057
evidence suggests that SSRIs can cause such untoward sexual experiences.
1058
Reliable estimates of the incidence and severity of untoward experiences involving sexual
1059
desire, performance, and satisfaction are difficult to obtain; however, in part because patients and
1060
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
1061
untoward sexual experience and performance cited in product labeling, are likely to
1062
underestimate their actual incidence.
1063
The percentage of patients reporting symptoms of sexual dysfunction in the pool of 2
1064
placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of 3
1065
placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients
1066
with social anxiety disorder, and in the intermittent dosing and the pool of 3 placebo-controlled
1067
continuous dosing trials in female patients with PMDD are as follows:
1068
35
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Major Depressive
Disorder
Panic Disorder
Social Anxiety
Disorder
PMDD
Continuous Dosing
PMDD
Luteal Phase
Dosing
PAXIL
CR
Placebo
PAXIL
CR
Placebo
PAXIL
CR
Placebo
PAXIL
CR
Placebo
PAXIL
CR
Placebo
n (males)
78
78
162
194
88
97
n/a
n/a
n/a
n/a
Decreased
Libido
10%
5%
9%
6%
13%
1%
n/a
n/a
n/a
n/a
Ejaculatory
Disturbance
26%
1%
27%
3%
15%
1%
n/a
n/a
n/a
n/a
Impotence
5%
3%
10%
1%
9%
0%
n/a
n/a
n/a
n/a
n (females)
134
133
282
251
98
87
681
349
246
120
Decreased
Libido
4%
2%
8%
2%
4%
1%
12%
5%
9%
6%
Orgasmic
Disturbance
10%
<1%
7%
1%
3%
0%
8%
1%
2%
0%
1069
1070
There are no adequate, controlled studies examining sexual dysfunction with paroxetine
1071
treatment.
1072
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
1073
known outcome, patients recovered without sequelae.
1074
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
1075
SSRIs, physicians should routinely inquire about such possible side effects.
1076
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
1077
treatment with paroxetine for some patients but, on average, patients in controlled trials with
1078
PAXIL CR or the immediate-release formulation, had minimal weight loss (about 1 pound). No
1079
significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature)
1080
were observed in patients treated with PAXIL CR, or immediate-release paroxetine
1081
hydrochloride, in controlled clinical trials.
1082
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with
1083
immediate-release paroxetine and 415 patients treated with placebo in controlled clinical trials,
1084
no clinically significant changes were seen in the ECGs of either group.
1085
Liver Function Tests: In a pool of 2 placebo-controlled clinical trials, patients treated with
1086
PAXIL CR or placebo exhibited abnormal values on liver function tests at comparable rates. In
1087
particular, the controlled-release paroxetine-versus-placebo comparisons for alkaline
1088
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
1089
with marked abnormalities.
1090
In a study of elderly patients with major depressive disorder, 3 of 104 patients treated with
1091
PAXIL CR and none of 109 placebo patients experienced liver transaminase elevations of
1092
potential clinical concern.
36
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1093
Two of the patients treated with PAXIL CR dropped out of the study due to abnormal liver
1094
function tests; the third patient experienced normalization of transaminase levels with continued
1095
treatment. Also, in the pool of 3 studies of patients with panic disorder, 4 of 444 patients treated
1096
with PAXIL CR and none of 445 placebo patients experienced liver transaminase elevations of
1097
potential clinical concern. Elevations in all 4 patients decreased substantially after
1098
discontinuation of PAXIL CR. The clinical significance of these findings is unknown.
1099
In placebo-controlled clinical trials with the immediate-release formulation of paroxetine,
1100
patients exhibited abnormal values on liver function tests at no greater rate than that seen in
1101
placebo-treated patients.
1102
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
1103
hallucinations were observed in 22 of 9,089 patients receiving drug and in 4 of 3,187 patients
1104
receiving placebo.
1105
Other Events Observed During the Clinical Development of Paroxetine: The
1106
following adverse events were reported during the clinical development of PAXIL CR and/or the
1107
clinical development of the immediate-release formulation of paroxetine.
1108
Adverse events for which frequencies are provided below occurred in clinical trials with the
1109
controlled-release formulation of paroxetine. During its premarketing assessment in major
1110
depressive disorder, panic disorder, social anxiety disorder, and PMDD, multiple doses of
1111
PAXIL CR were administered to 1,627 patients in phase 3 double-blind, controlled, outpatient
1112
studies. Untoward events associated with this exposure were recorded by clinical investigators
1113
using terminology of their own choosing. Consequently, it is not possible to provide a
1114
meaningful estimate of the proportion of individuals experiencing adverse events without first
1115
grouping similar types of untoward events into a smaller number of standardized event
1116
categories.
1117
In the tabulations that follow, reported adverse events were classified using a
1118
COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of
1119
the 1,627 patients exposed to PAXIL CR who experienced an event of the type cited on at least 1
1120
occasion while receiving PAXIL CR. All reported events are included except those already listed
1121
in Tables 2 through 7 and those events where a drug cause was remote. If the COSTART term
1122
for an event was so general as to be uninformative, it was deleted or, when possible, replaced
1123
with a more informative term. It is important to emphasize that although the events reported
1124
occurred during treatment with paroxetine, they were not necessarily caused by it.
1125
Events are further categorized by body system and listed in order of decreasing frequency
1126
according to the following definitions: Frequent adverse events are those occurring on 1 or more
1127
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
1128
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1129
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.
1130
Adverse events for which frequencies are not provided occurred during the premarketing
1131
assessment of immediate-release paroxetine in phase 2 and 3 studies of major depressive
1132
disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized
37
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1133
anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to
1134
immediate-release paroxetine varied greatly and included (in overlapping categories) open and
1135
double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and
1136
fixed-dose and titration studies. Only those events not previously listed for controlled-release
1137
paroxetine are included. The extent to which these events may be associated with PAXIL CR is
1138
unknown.
1139
Events are listed alphabetically within the respective body system. Events of major clinical
1140
importance are also described in the PRECAUTIONS section.
1141
Body as a Whole: Infrequent were chills, face edema, fever, flu syndrome, malaise; rare
1142
were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed
1143
were adrenergic syndrome, neck rigidity, sepsis.
1144
Cardiovascular System: Infrequent were angina pectoris, bradycardia, hematoma,
1145
hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia,
1146
syncope; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation,
1147
cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct,
1148
myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles,
1149
thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.
1150
Digestive System: Infrequent were bruxism, dysphagia, eructation, gastritis,
1151
gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function test abnormal,
1152
melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis,
1153
glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction,
1154
peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody
1155
diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions,
1156
fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth
1157
ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue
1158
edema.
1159
Endocrine System: Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus,
1160
hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis.
1161
Hemic and Lymphatic System: Infrequent were anemia, eosinophilia, hypochromic
1162
anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also
1163
observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis,
1164
lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.
1165
Metabolic and Nutritional Disorders: Infrequent were generalized edema,
1166
hyperglycemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare
1167
were bilirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase
1168
increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased,
1169
gout, hypercalcemia, hypercholesteremia, hyperphosphatemia, hypocalcemia, hypoglycemia,
1170
hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.
1171
Musculoskeletal System: Infrequent were arthritis, bursitis, tendonitis; rare were
1172
myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis,
38
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1173
tenosynovitis, tetany.
1174
Nervous System: Frequent were depression; infrequent were amnesia, convulsion,
1175
depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia,
1176
hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis,
1177
vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis,
1178
withdrawal syndrome; also observed were abnormal gait, akathisia, akinesia, aphasia,
1179
choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal
1180
syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction,
1181
manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic
1182
depression, reflexes decreased, reflexes increased, stupor, trismus.
1183
Respiratory System: Frequent were pharyngitis; infrequent were asthma, dyspnea,
1184
epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema,
1185
hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum
1186
increased.
1187
Skin and Appendages: Frequent were rash; infrequent were acne, alopecia, dry skin,
1188
eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash,
1189
seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema
1190
nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer,
1191
sweating decreased, vesiculobullous rash.
1192
Special Senses: Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis,
1193
photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed
1194
were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness,
1195
exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss.
1196
Urogenital System: Frequent were dysmenorrhea*; infrequent were albuminuria,
1197
amenorrhea*, breast pain*, cystitis, dysuria, prostatitis*, urinary retention; rare were breast
1198
enlargement*, breast neoplasm*, female lactation, hematuria, kidney calculus, metrorrhagia*,
1199
nephritis, nocturia, pregnancy and puerperal disorders*, salpingitis, urinary incontinence, uterine
1200
fibroids enlarged*; also observed were breast atrophy, ejaculatory disturbance, endometrial
1201
disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria,
1202
urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage.
1203
*Based on the number of men and women as appropriate.
1204
Postmarketing Reports: Voluntary reports of adverse events in patients taking
1205
immediate-release paroxetine hydrochloride that have been received since market introduction
1206
and not listed above that may have no causal relationship with the drug include acute
1207
pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis,
1208
and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré
1209
syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of
1210
inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea;
1211
extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity,
1212
dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of
39
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1213
pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension,
1214
allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs
1215
syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes),
1216
thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including
1217
aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic
1218
syndromes (such as Henoch-Schönlein purpura). There has been a case report of an elevated
1219
phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin coadministration.
1220
There has been a case report of severe hypotension when immediate-release paroxetine was
1221
added to chronic metoprolol treatment.
1222
DRUG ABUSE AND DEPENDENCE
1223
Controlled Substance Class: PAXIL CR is not a controlled substance.
1224
Physical and Psychologic Dependence: PAXIL CR has not been systematically studied
1225
in animals or humans for its potential for abuse, tolerance or physical dependence. While the
1226
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
1227
not systematic and it is not possible to predict on the basis of this limited experience the extent to
1228
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
1229
patients should be evaluated carefully for history of drug abuse, and such patients should be
1230
observed closely for signs of misuse or abuse of PAXIL CR (e.g., development of tolerance,
1231
incrementations of dose, drug-seeking behavior).
1232
OVERDOSAGE
1233
Human Experience: Since the introduction of immediate-release paroxetine hydrochloride in
1234
the United States, 342 spontaneous cases of deliberate or accidental overdosage during
1235
paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with
1236
paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of
1237
the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the
1238
amount of paroxetine ingested were generally confounded by the ingestion of other drugs or
1239
alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known
1240
outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of
1241
paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.
1242
Commonly reported adverse events associated with paroxetine overdosage include
1243
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
1244
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
1245
substances) include mydriasis, convulsions (including status epilepticus), ventricular
1246
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
1247
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
1248
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
1249
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
1250
Overdosage Management: No specific antidotes for paroxetine are known. Treatment
1251
should consist of those general measures employed in the management of overdosage with any
40
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1252
drugs effective in the treatment of major depressive disorder.
1253
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
1254
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
1255
is not recommended. Due to the large volume of distribuiton of this drug, forced diuresis,
1256
dialysis, hemoperfusion, or exchange perfusion are unlikely to be of benefit.
1257
A specific caution involves patients taking or recently having taken paroxetine who might
1258
ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
1259
parent tricyclic and an active metabolite may increase the possibility of clinically significant
1260
sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drugs
1261
Metabolized by Cytochrome CYP2D6).
1262
In managing overdosage, consider the possibility of multiple-drug involvement. The physician
1263
should consider contacting a poison control center for additional information on the treatment of
1264
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
1265
Desk Reference (PDR).
1266
DOSAGE AND ADMINISTRATION
1267
Major Depressive Disorder: Usual Initial Dosage: PAXIL CR should be administered as
1268
a single daily dose, usually in the morning, with or without food. The recommended initial dose
1269
is 25 mg/day. Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials
1270
demonstrating the effectiveness of PAXIL CR in the treatment of major depressive disorder. As
1271
with all drugs effective in the treatment of major depressive disorder, the full effect may be
1272
delayed. Some patients not responding to a 25-mg dose may benefit from dose increases, in
1273
12.5-mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at
1274
intervals of at least 1 week.
1275
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1276
swallowed whole.
1277
Maintenance Therapy: There is no body of evidence available to answer the question of
1278
how long the patient treated with PAXIL CR should remain on it. It is generally agreed that acute
1279
episodes of major depressive disorder require several months or longer of sustained
1280
pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission is
1281
identical to the dose needed to maintain and/or sustain euthymia is unknown.
1282
Systematic evaluation of the efficacy of immediate-release paroxetine hydrochloride has
1283
shown that efficacy is maintained for periods of up to 1 year with doses that averaged about
1284
30 mg, which corresponds to a 37.5-mg dose of PAXIL CR, based on relative bioavailability
1285
considerations (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
41
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1286
Panic Disorder: Usual Initial Dosage: PAXIL CR should be administered as a single daily
1287
dose, usually in the morning. Patients should be started on 12.5 mg/day. Dose changes should
1288
occur in 12.5-mg/day increments and at intervals of at least 1 week. Patients were dosed in a
1289
range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of PAXIL CR.
1290
The maximum dosage should not exceed 75 mg/day.
1291
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1292
swallowed whole.
1293
Maintenance Therapy: Long-term maintenance of efficacy with the immediate-release
1294
formulation of paroxetine was demonstrated in a 3-month relapse prevention trial. In this trial,
1295
patients with panic disorder assigned to immediate-release paroxetine demonstrated a lower
1296
relapse rate compared to patients on placebo. Panic disorder is a chronic condition, and it is
1297
reasonable to consider continuation for a responding patient. Dosage adjustments should be
1298
made to maintain the patient on the lowest effective dosage, and patients should be periodically
1299
reassessed to determine the need for continued treatment.
1300
Social Anxiety Disorder: Usual Initial Dosage: PAXIL CR should be administered as a
1301
single daily dose, usually in the morning, with or without food. The recommended initial dose is
1302
12.5 mg/day. Patients were dosed in a range of 12.5 mg to 37.5 mg/day in the clinical trial
1303
demonstrating the effectiveness of PAXIL CR in the treatment of social anxiety disorder. If the
1304
dose is increased, this should occur at intervals of at least 1 week, in increments of 12.5 mg/day,
1305
up to a maximum of 37.5 mg/day.
1306
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1307
swallowed whole.
1308
Maintenance Therapy: There is no body of evidence available to answer the question of
1309
how long the patient treated with PAXIL CR should remain on it. Although the efficacy of
1310
PAXIL CR beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials,
1311
social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider
1312
continuation of treatment for a responding patient. Dosage adjustments should be made to
1313
maintain the patient on the lowest effective dosage, and patients should be periodically
1314
reassessed to determine the need for continued treatment.
1315
Premenstrual Dysphoric Disorder: Usual Initial Dosage: PAXIL CR should be
1316
administered as a single daily dose, usually in the morning, with or without food. PAXIL CR
1317
may be administered either daily throughout the menstrual cycle or limited to the luteal phase of
1318
the menstrual cycle, depending on physician assessment. The recommended initial dose is
1319
12.5 mg/day. In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective.
1320
Dose changes should occur at intervals of at least 1 week.
1321
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1322
swallowed whole.
1323
Maintenance/Continuation Therapy: The effectiveness of PAXIL CR for a period
1324
exceeding 3 menstrual cycles has not been systematically evaluated in controlled trials.
1325
However, women commonly report that symptoms worsen with age until relieved by the onset of
42
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1326
menopause. Therefore, it is reasonable to consider continuation of a responding patient. Patients
1327
should be periodically reassessed to determine the need for continued treatment.
1328
Special Populations: Treatment of Pregnant Women During the Third Trimester:
1329
Neonates exposed to PAXIL CR and other SSRIs or SNRIs, late in the third trimester have
1330
developed complications requiring prolonged hospitalization, respiratory support, and tube
1331
feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine
1332
during the third trimester, the physician should carefully consider the potential risks and benefits
1333
of treatment. The physician may consider tapering paroxetine in the third trimester.
1334
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
1335
Hepatic Impairment: The recommended initial dose of PAXIL CR is 12.5 mg/day for elderly
1336
patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases
1337
may be made if indicated. Dosage should not exceed 50 mg/day.
1338
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
1339
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL CR.
1340
Similarly, at least 14 days should be allowed after stopping PAXIL CR before starting an MAOI.
1341
Discontinuation of Treatment With PAXIL CR: Symptoms associated with discontinuation
1342
of immediate-release paroxetine hydrochloride or PAXIL CR have been reported (see
1343
PRECAUTIONS: Discontinuation of Treatment with PAXIL CR). Patients should be monitored
1344
for these symptoms when discontinuing treatment, regardless of the indication for which PAXIL
1345
CR is being prescribed. A gradual reduction in the dose rather than abrupt cessation is
1346
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
1347
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
1348
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
1349
rate.
1350
HOW SUPPLIED
1351
PAXIL CR is supplied as an enteric film-coated, controlled-release, round tablet, as follows:
1352
12.5-mg yellow tablets
1353
NDC 0029-3206-13 Bottles of 30 (engraved with PAXIL CR and 12.5)
1354
NDC 0029-4606-13 Bottles of 30 (engraved with GSK and 12.5)
1355
25-mg pink tablets
1356
NDC 0029-3207-13 Bottles of 30 (engraved with PAXIL CR and 25)
1357
NDC 0029-4607-13 Bottles of 30 (engraved with GSK and 25)
1358
37.5 mg blue tablets
1359
NDC 0029-3208-13 Bottles of 30 (engraved with PAXIL CR and 37.5)
1360
NDC 0029-4608-13 Bottles of 30 (engraved with GSK and 37.5)
1361
Store at or below 25°C (77°F) [see USP].
1362
1363
PAXIL CR is a registered trademark of GlaxoSmithKline.
1364
GEOMATRIX is a trademark of Jago Pharma, Muttenz, Switzerland.
43
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:29.794078
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020031s062s065s069,020710s026s029s033,020936s040s043lbl.pdf', 'application_number': 20031, 'submission_type': 'SUPPL ', 'submission_number': 62}
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12,147
|
structural formula
1
PRESCRIBING INFORMATION
2
PAXIL®
3
(paroxetine hydrochloride)
4
Tablets and Oral Suspension
5
6
Suicidality and Antidepressant Drugs
7
Antidepressants increased the risk compared to placebo of suicidal thinking and
8
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
9
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
10
use of PAXIL or any other antidepressant in a child, adolescent, or young adult must
11
balance this risk with the clinical need. Short-term studies did not show an increase in the
12
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
13
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
14
older. Depression and certain other psychiatric disorders are themselves associated with
15
increases in the risk of suicide. Patients of all ages who are started on antidepressant
16
therapy should be monitored appropriately and observed closely for clinical worsening,
17
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
18
the need for close observation and communication with the prescriber. PAXIL is not
19
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
20
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
21
DESCRIPTION
22
PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the
23
hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'
24
fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate
25
and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8
26
(329.4 as free base). The structural formula of paroxetine hydrochloride is:
27
28
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
29
120° to 138°C and a solubility of 5.4 mg/mL in water.
30
Tablets: Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as
31
follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive
32
ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate,
33
polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of
1
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
34
the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C
35
Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.
36
Suspension for Oral Administration: Each 5 mL of orange-colored, orange-flavored liquid
37
contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist
38
of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol,
39
methylparaben, propylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium
40
saccharin, flavorings, FD&C Yellow No. 6 aluminum lake, and simethicone emulsion, USP.
41
CLINICAL PHARMACOLOGY
42
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
43
disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD),
44
generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be
45
linked to potentiation of serotonergic activity in the central nervous system resulting from
46
inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically
47
relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into
48
human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly
49
selective inhibitor of neuronal serotonin reuptake and has only very weak effects on
50
norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate
51
that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine
52
(D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic,
53
and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and
54
cardiovascular effects for other psychotropic drugs.
55
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
56
compound, they are essentially inactive.
57
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
58
solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours
59
(CV 32%) after oral dosing of 30 mg tablets of PAXIL daily for 30 days. Paroxetine is
60
extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in
61
pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part
62
by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the
63
feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are
64
deficient in CYP2D6 (poor metabolizers).
65
In a meta analysis of paroxetine from 4 studies done in healthy volunteers following
66
multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower
67
Cmax or AUC than females.
68
Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension
69
and tablet.
70
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
71
hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets
72
daily for 30 days, steady-state paroxetine concentrations were achieved by approximately
73
10 days for most subjects, although it may take substantially longer in an occasional patient. At
2
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74
steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr.
75
(CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax
76
and Cmin values were about 6 and 14 times what would be predicted from single-dose studies.
77
Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been
78
predicted from single-dose data in these subjects. The excess accumulation is a consequence of
79
the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.
80
The effects of food on the bioavailability of paroxetine were studied in subjects administered
81
a single dose with and without food. AUC was only slightly increased (6%) when drug was
82
administered with food but the Cmax was 29% greater, while the time to reach peak plasma
83
concentration decreased from 6.4 hours post-dosing to 4.9 hours.
84
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
85
plasma.
86
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
87
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
88
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
89
warfarin.
90
Metabolism and Excretion: The mean elimination half-life is approximately 21 hours
91
(CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose
92
proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg
93
daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was
94
observed in both populations, again reflecting a saturable metabolic pathway. In comparison to
95
Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than
96
doubled.
97
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
98
polar and conjugated products of oxidation and methylation, which are readily cleared.
99
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
100
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
101
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
102
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
103
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
104
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
105
interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6).
106
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
107
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
108
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
109
1% as the parent compound over the 10-day post-dosing period.
110
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
111
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and
112
hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below
113
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
3
Reference ID: 2920253
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114
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
115
about a 2-fold increase in plasma concentrations (AUC, Cmax).
116
The initial dosage should therefore be reduced in patients with severe renal or hepatic
117
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
118
AND ADMINISTRATION).
119
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20,
120
30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin
121
concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be
122
reduced (see DOSAGE AND ADMINISTRATION).
123
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
124
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
125
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
126
desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions).
127
Clinical Trials
128
Major Depressive Disorder: The efficacy of PAXIL as a treatment for major depressive
129
disorder has been established in 6 placebo-controlled studies of patients with major depressive
130
disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective
131
than placebo in treating major depressive disorder by at least 2 of the following measures:
132
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
133
Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in
134
improvement of the HDRS sub-factor scores, including the depressed mood item, sleep
135
disturbance factor, and anxiety factor.
136
A study of outpatients with major depressive disorder who had responded to PAXIL (HDRS
137
total score <8) during an initial 8-week open-treatment phase and were then randomized to
138
continuation on PAXIL or placebo for 1 year demonstrated a significantly lower relapse rate for
139
patients taking PAXIL (15%) compared to those on placebo (39%). Effectiveness was similar for
140
male and female patients.
141
Obsessive Compulsive Disorder: The effectiveness of PAXIL in the treatment of obsessive
142
compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled
143
studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD
144
(DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale
145
(YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients
146
were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily
147
doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses
148
of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points,
149
respectively, on the YBOCS total score which was significantly greater than the approximate 4
150
point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a
151
flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg
152
daily). In this study, patients receiving paroxetine experienced a mean reduction of
4
Reference ID: 2920253
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153
approximately 7 points on the YBOCS total score, which was significantly greater than the mean
154
reduction of approximately 4 points in placebo-treated patients.
155
The following table provides the outcome classification by treatment group on Global
156
Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
157
Outcome Classification (%) on CGI-Global Improvement Item
for Completers in Study 1
Outcome
Classification
Placebo
(n = 74)
PAXIL 20 mg
(n = 75)
PAXIL 40 mg
(n = 66)
PAXIL 60 mg
(n = 66)
Worse
14%
7%
7%
3%
No Change
44%
35%
22%
19%
Minimally Improved
24%
33%
29%
34%
Much Improved
11%
18%
22%
24%
Very Much Improved
7%
7%
20%
20%
158
159
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
160
function of age or gender.
161
The long-term maintenance effects of PAXIL in OCD were demonstrated in a long-term
162
extension to Study 1. Patients who were responders on paroxetine during the 3-month
163
double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were
164
randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase.
165
Patients randomized to paroxetine were significantly less likely to relapse than comparably
166
treated patients who were randomized to placebo.
167
Panic Disorder: The effectiveness of PAXIL in the treatment of panic disorder was
168
demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients
169
(Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia.
170
In these studies, PAXIL was shown to be significantly more effective than placebo in treating
171
panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical
172
Global Impression Severity of Illness score.
173
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine
174
doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed
175
only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were
176
free of panic attacks, compared to 44% of placebo-treated patients.
177
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and
178
placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of
179
placebo-treated patients.
180
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to
181
placebo in patients concurrently receiving standardized cognitive behavioral therapy. At
182
endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks
183
compared to 14% of placebo patients.
184
In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was
5
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185
approximately 40 mg/day of paroxetine.
186
Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an
187
extension to Study 1. Patients who were responders during the 10-week double-blind phase and
188
during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or
189
40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized
190
to paroxetine were significantly less likely to relapse than comparably treated patients who were
191
randomized to placebo.
192
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
193
function of age or gender.
194
Social Anxiety Disorder: The effectiveness of PAXIL in the treatment of social anxiety
195
disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1,
196
2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the
197
effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of
198
responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very
199
much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social
200
Anxiety Scale (LSAS).
201
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and
202
placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the
203
CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In
204
Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to
205
29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI
206
Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients,
207
respectively.
208
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with
209
placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the
210
LSAS Total Score and the CGI Improvement responder criterion; there were trends for
211
superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in
212
this study of any additional benefit for doses higher than 20 mg/day.
213
Subgroup analyses generally did not indicate differences in treatment outcomes as a function
214
of age, race, or gender.
215
Generalized Anxiety Disorder: The effectiveness of PAXIL in the treatment of Generalized
216
Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled
217
studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).
218
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with
219
placebo. Doses of 20 mg or 40 mg of PAXIL were both demonstrated to be significantly superior
220
to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not
221
sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to
222
the 20 mg/day dose.
223
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo.
224
PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating
6
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225
Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine
226
(20 mg to 50 mg daily), did not demonstrate statistically significant superiority of PAXIL over
227
placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.
228
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or
229
gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
230
In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety
231
Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to
232
50 mg/day of PAXIL, were randomized to continuation of PAXIL at their same dose, or to
233
placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase
234
was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of
235
Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase
236
of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or
237
withdrawal due to lack of efficacy. Patients receiving continued PAXIL experienced a
238
significantly lower relapse rate over the subsequent 24 weeks compared to those receiving
239
placebo.
240
Posttraumatic Stress Disorder: The effectiveness of PAXIL in the treatment of
241
Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo
242
controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The
243
mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year
244
to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD
245
anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out
246
of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered
247
PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement
248
Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the
249
following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal.
250
The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2
251
total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were
252
defined as patients having a score of 1 (very much improved) or 2 (much improved).
253
Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to
254
placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to
255
placebo on change from baseline for the CAPS-2 total score and on proportion of responders on
256
the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the
257
40 mg/day dose compared to the 20 mg/day dose.
258
Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to
259
placebo. PAXIL was demonstrated to be significantly superior to placebo on change from
260
baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.
261
A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,
262
demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS
263
2 total score, but not on proportion of responders on the CGI-I.
264
The majority of patients in these trials were women (68% women: 377 out of 551 subjects in
7
Reference ID: 2920253
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265
Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not
266
indicate differences in treatment outcomes as a function of gender. There were an insufficient
267
number of patients who were 65 years and older or were non-Caucasian to conduct subgroup
268
analyses on the basis of age or race, respectively.
269
INDICATIONS AND USAGE
270
Major Depressive Disorder: PAXIL is indicated for the treatment of major depressive
271
disorder.
272
The efficacy of PAXIL in the treatment of a major depressive episode was established in
273
6-week controlled trials of outpatients whose diagnoses corresponded most closely to the
274
DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical
275
Trials). A major depressive episode implies a prominent and relatively persistent depressed or
276
dysphoric mood that usually interferes with daily functioning (nearly every day for at least
277
2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in
278
sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in
279
sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
280
concentration, and a suicide attempt or suicidal ideation.
281
The effects of PAXIL in hospitalized depressed patients have not been adequately studied.
282
The efficacy of PAXIL in maintaining a response in major depressive disorder for up to 1 year
283
was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical
284
Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should
285
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
286
Obsessive Compulsive Disorder: PAXIL is indicated for the treatment of obsessions and
287
compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV.
288
The obsessions or compulsions cause marked distress, are time-consuming, or significantly
289
interfere with social or occupational functioning.
290
The efficacy of PAXIL was established in two 12-week trials with obsessive compulsive
291
outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive
292
compulsive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
293
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
294
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
295
intentional behaviors (compulsions) that are recognized by the person as excessive or
296
unreasonable.
297
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In
298
this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on
299
placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who
300
elects to use PAXIL for extended periods should periodically re-evaluate the long-term
301
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
302
Panic Disorder: PAXIL is indicated for the treatment of panic disorder, with or without
303
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
8
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304
unexpected panic attacks and associated concern about having additional attacks, worry about
305
the implications or consequences of the attacks, and/or a significant change in behavior related to
306
the attacks.
307
The efficacy of PAXIL was established in three 10- to 12-week trials in panic disorder
308
patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
309
CLINICAL PHARMACOLOGY: Clinical Trials).
310
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
311
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
312
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
313
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
314
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
315
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
316
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
317
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
318
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In
319
this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate
320
compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials).
321
Nevertheless, the physician who prescribes PAXIL for extended periods should periodically
322
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
323
ADMINISTRATION).
324
Social Anxiety Disorder: PAXIL is indicated for the treatment of social anxiety disorder,
325
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
326
characterized by a marked and persistent fear of 1 or more social or performance situations in
327
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
328
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
329
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
330
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
331
the person's normal routine, occupational or academic functioning, or social activities or
332
relationships, or there is marked distress about having the phobias. Lesser degrees of
333
performance anxiety or shyness generally do not require psychopharmacological treatment.
334
The efficacy of PAXIL was established in three 12-week trials in adult patients with social
335
anxiety disorder (DSM-IV). PAXIL has not been studied in children or adolescents with social
336
phobia (see CLINICAL PHARMACOLOGY: Clinical Trials).
337
The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more
338
than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
339
Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically
340
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
341
ADMINISTRATION).
342
Generalized Anxiety Disorder: PAXIL is indicated for the treatment of Generalized Anxiety
343
Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of
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everyday life usually does not require treatment with an anxiolytic.
345
The efficacy of PAXIL in the treatment of GAD was established in two 8-week
346
placebo-controlled trials in adults with GAD. PAXIL has not been studied in children or
347
adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY: Clinical
348
Trials).
349
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry
350
(apprehensive expectation) that is persistent for at least 6 months and which the person finds
351
difficult to control. It must be associated with at least 3 of the following 6 symptoms:
352
Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or
353
mind going blank, irritability, muscle tension, sleep disturbance.
354
The efficacy of PAXIL in maintaining a response in patients with Generalized Anxiety
355
Disorder, who responded during an 8-week acute treatment phase while taking PAXIL and were
356
then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo
357
controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the
358
physician who elects to use PAXIL for extended periods should periodically re-evaluate the
359
long-term usefulness of the drug for the individual patient (see DOSAGE AND
360
ADMINISTRATION).
361
Posttraumatic Stress Disorder: PAXIL is indicated for the treatment of Posttraumatic
362
Stress Disorder (PTSD).
363
The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebo
364
controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY: Clinical
365
Trials).
366
PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or
367
threatened death or serious injury, or threat to the physical integrity of self or others, and a
368
response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of
369
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
370
thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity
371
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
372
inability to recall details of the event, and/or numbing of general responsiveness manifested as
373
diminished interest in significant activities, estrangement from others, restricted range of affect,
374
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
375
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
376
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
377
and that they cause clinically significant distress or impairment in social, occupational, or other
378
important areas of functioning.
379
The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has
380
not been systematically evaluated in placebo-controlled trials. Therefore, the physician who
381
elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term
382
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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CONTRAINDICATIONS
384
PAXIL should not be used in patients taking monoamine oxidase inhibitors (MAOIs),
385
including linezolid (an antibiotic which is a reversible non-selective MAOI) and
386
methylthioninium chloride (methylene blue), or within 2 weeks of stopping treatment with
387
MAOIs (see WARNINGS).
388
Concomitant use with thioridazine is contraindicated (see WARNINGS and
389
PRECAUTIONS).
390
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
391
PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the
392
inactive ingredients in PAXIL.
393
WARNINGS
394
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
395
both adult and pediatric, may experience worsening of their depression and/or the emergence of
396
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
397
are taking antidepressant medications, and this risk may persist until significant remission
398
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
399
disorders themselves are the strongest predictors of suicide. There has been a long-standing
400
concern, however, that antidepressants may have a role in inducing worsening of depression and
401
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
402
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
403
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
404
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
405
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
406
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
407
antidepressants compared to placebo in adults aged 65 and older.
408
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
409
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short
410
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo
411
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short
412
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
413
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
414
increase in the younger patients for almost all drugs studied. There were differences in absolute
415
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
416
differences (drug vs placebo), however, were relatively stable within age strata and across
417
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
418
per 1,000 patients treated) are provided in Table 1.
419
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420
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
421
422
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
423
the number was not sufficient to reach any conclusion about drug effect on suicide.
424
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
425
months. However, there is substantial evidence from placebo-controlled maintenance trials in
426
adults with depression that the use of antidepressants can delay the recurrence of depression.
427
All patients being treated with antidepressants for any indication should be monitored
428
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
429
in behavior, especially during the initial few months of a course of drug therapy, or at times
430
of dose changes, either increases or decreases.
431
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
432
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
433
been reported in adult and pediatric patients being treated with antidepressants for major
434
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
435
Although a causal link between the emergence of such symptoms and either the worsening of
436
depression and/or the emergence of suicidal impulses has not been established, there is concern
437
that such symptoms may represent precursors to emerging suicidality.
438
Consideration should be given to changing the therapeutic regimen, including possibly
439
discontinuing the medication, in patients whose depression is persistently worse, or who are
440
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
441
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
442
patient’s presenting symptoms.
443
If the decision has been made to discontinue treatment, medication should be tapered, as
444
rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
445
certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION:
446
Discontinuation of Treatment With PAXIL, for a description of the risks of discontinuation of
447
PAXIL).
448
Families and caregivers of patients being treated with antidepressants for major
449
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
450
alerted about the need to monitor patients for the emergence of agitation, irritability,
451
unusual changes in behavior, and the other symptoms described above, as well as the
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452
emergence of suicidality, and to report such symptoms immediately to healthcare
453
providers. Such monitoring should include daily observation by families and caregivers.
454
Prescriptions for PAXIL should be written for the smallest quantity of tablets consistent with
455
good patient management, in order to reduce the risk of overdose.
456
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
457
presentation of bipolar disorder. It is generally believed (though not established in controlled
458
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
459
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
460
symptoms described above represent such a conversion is unknown. However, prior to initiating
461
treatment with an antidepressant, patients with depressive symptoms should be adequately
462
screened to determine if they are at risk for bipolar disorder; such screening should include a
463
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
464
depression. It should be noted that PAXIL is not approved for use in treating bipolar depression.
465
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
466
another serotonin reuptake inhibitor drug in combination with a monoamine oxidase
467
inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including
468
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of
469
vital signs, and mental status changes that include extreme agitation progressing to
470
delirium and coma. These reactions have also been reported in patients who have recently
471
discontinued that drug and have been started on an MAOI. Some cases presented with
472
features resembling neuroleptic malignant syndrome. While there are no human data
473
showing such an interaction with PAXIL, limited animal data on the effects of combined
474
use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate
475
blood pressure and evoke behavioral excitation. Therefore, it is recommended that PAXIL
476
not be used in combination with an MAOI (including linezolid, an antibiotic which is a
477
reversible non-selective MAOI), and methylthioninium chloride [methylene blue]), or
478
within 14 days of discontinuing treatment with an MAOI (see CONTRAINDICATIONS).
479
At least 2 weeks should be allowed after stopping PAXIL before starting an MAOI.
480
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions:
481
The development of a potentially life-threatening serotonin syndrome or Neuroleptic
482
Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs
483
alone, including treatment with PAXIL, but particularly with concomitant use of
484
serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin
485
(including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin
486
syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
487
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
488
neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal
489
symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form
490
can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle
491
rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental
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492
status changes. Patients should be monitored for the emergence of serotonin syndrome or
493
NMS-like signs and symptoms.
494
The concomitant use of PAXIL with MAOIs intended to treat depression is
495
contraindicated.
496
If concomitant treatment of PAXIL with a 5-hydroxytryptamine receptor agonist
497
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
498
during treatment initiation and dose increases.
499
The concomitant use of PAXIL with serotonin precursors (such as tryptophan) is not
500
recommended.
501
Treatment with PAXIL and any concomitant serotonergic or antidopaminergic agents,
502
including antipsychotics, should be discontinued immediately if the above events occur and
503
supportive symptomatic treatment should be initiated.
504
Potential Interaction With Thioridazine: Thioridazine administration alone produces
505
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
506
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
507
dose related.
508
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
509
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
510
used in combination with thioridazine (see CONTRAINDICATIONS and
511
PRECAUTIONS).
512
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
513
infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of
514
congenital malformations, particularly cardiovascular malformations. The findings from these
515
studies are summarized below:
516
•
A study based on Swedish national registry data demonstrated that infants exposed to
517
paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular
518
malformations (2% risk in paroxetine-exposed infants) compared to the entire registry
519
population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No
520
increase in the risk of overall congenital malformations was seen in the paroxetine-exposed
521
infants. The cardiac malformations in the paroxetine-exposed infants were primarily
522
ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in
523
severity from those that resolve spontaneously to those which require surgery.
524
•
A separate retrospective cohort study from the United States (United Healthcare data)
525
evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester
526
(n = 815 for paroxetine). This study showed a trend towards an increased risk for
527
cardiovascular malformations for paroxetine (risk of 1.5%) compared to other
528
antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the
529
12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study
530
also suggested an increased risk of overall major congenital malformations including
531
cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants
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532
(OR 1.8; 95% confidence interval 1.2 to 2.8).
533
•
Two large case-control studies using separate databases, each with >9,000 birth defect
534
cases and >4,000 controls, found that maternal use of paroxetine during the first trimester
535
of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow
536
tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1.0 to 6.0,
537
7 exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval,
538
1.3 to 8.8, 6 exposed infants).
539
Other studies have found varying results as to whether there was an increased risk of overall,
540
cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data
541
over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and
542
congenital malformations included the above-noted studies in addition to others (n = 17 studies
543
that included overall malformations and n = 14 studies that included cardiovascular
544
malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested
545
an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95%
546
confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1
547
to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to
548
determine the extent to which the observed prevalence of cardiovascular malformations might
549
have contributed to that of overall malformations, nor was it possible to determine whether any
550
specific types of cardiovascular malformations might have contributed to the observed
551
prevalence of all cardiovascular malformations.
552
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential
553
harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment,
554
consideration should be given to either discontinuing paroxetine therapy or switching to another
555
antidepressant (see PRECAUTIONS: Discontinuation of Treatment With PAXIL). For women
556
who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should
557
only be initiated after consideration of the other available treatment options.
558
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
559
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
560
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
561
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
562
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
563
trimester of gestation and continued throughout lactation. This effect occurred at a dose of
564
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
565
rat pup mortality was not determined. The cause of these deaths is not known.
566
Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs or serotonin and
567
norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
568
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
569
complications can arise immediately upon delivery. Reported clinical findings have included
570
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
571
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
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Reference ID: 2920253
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572
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
573
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
574
clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome or
575
Neuroleptic Malignant Syndrome (NMS)-like Reactions).
576
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
577
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
578
the general population and is associated with substantial neonatal morbidity and mortality. In a
579
retrospective case-control study of 377 women whose infants were born with PPHN and 836
580
women whose infants were born healthy, the risk for developing PPHN was approximately six
581
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
582
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
583
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
584
study that has investigated the potential risk. The study did not include enough cases with
585
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
586
There have also been postmarketing reports of premature births in pregnant women exposed
587
to paroxetine or other SSRIs.
588
When treating a pregnant woman with paroxetine during the third trimester, the physician
589
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
590
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
591
women with a history of major depression who were euthymic at the beginning of pregnancy,
592
women who discontinued antidepressant medication during pregnancy were more likely to
593
experience a relapse of major depression than women who continued antidepressant medication.
594
PRECAUTIONS
595
General: Activation of Mania/Hypomania: During premarketing testing, hypomania or
596
mania occurred in approximately 1.0% of unipolar patients treated with PAXIL compared to
597
1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients
598
classified as bipolar, the rate of manic episodes was 2.2% for PAXIL and 11.6% for the
599
combined active-control groups. As with all drugs effective in the treatment of major depressive
600
disorder, PAXIL should be used cautiously in patients with a history of mania.
601
Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with
602
PAXIL, a rate similar to that associated with other drugs effective in the treatment of major
603
depressive disorder. PAXIL should be used cautiously in patients with a history of seizures. It
604
should be discontinued in any patient who develops seizures.
605
Discontinuation of Treatment With PAXIL: Recent clinical trials supporting the various
606
approved indications for PAXIL employed a taper-phase regimen, rather than an abrupt
607
discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials
608
involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a
609
daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before
610
treatment was stopped.
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611
With this regimen in those studies, the following adverse events were reported at an incidence
612
of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams,
613
paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and
614
were self-limiting and did not require medical intervention.
615
During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports
616
of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt),
617
including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances
618
(e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache,
619
lethargy, emotional lability, insomnia, and hypomania. While these events are generally self
620
limiting, there have been reports of serious discontinuation symptoms.
621
Patients should be monitored for these symptoms when discontinuing treatment with PAXIL.
622
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
623
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
624
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
625
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
626
ADMINISTRATION).
627
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of
628
treatment with PAXIL in pediatric patients.
629
Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk
630
of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a
631
result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other
632
studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of
633
paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study
634
suggests that the risk may increase with longer duration of coadministration. When tamoxifen is
635
used for the treatment or prevention of breast cancer, prescribers should consider using an
636
alternative antidepressant with little or no CYP2D6 inhibition.
637
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
638
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
639
such as an inability to sit or stand still usually associated with subjective distress. This is most
640
likely to occur within the first few weeks of treatment.
641
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
642
including PAXIL. In many cases, this hyponatremia appears to be the result of the syndrome of
643
inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
644
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
645
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
646
volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of
647
PAXIL should be considered in patients with symptomatic hyponatremia and appropriate
648
medical intervention should be instituted.
649
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
650
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
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651
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
652
seizure, coma, respiratory arrest, and death.
653
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
654
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
655
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
656
and cohort design) have demonstrated an association between use of drugs that interfere with
657
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
658
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
659
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
660
with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
661
coagulation.
662
Bone Fracture: Epidemiological studies on bone fracture risk following exposure to some
663
antidepressants, including SSRIs, have reported an association between antidepressant treatment
664
and fractures. There are multiple possible causes for this observation and it is unknown to what
665
extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological
666
fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral
667
density, should be considered in patients treated with paroxetine who present with unexplained
668
bone pain, point tenderness, swelling, or bruising.
669
Use in Patients With Concomitant Illness: Clinical experience with PAXIL in patients
670
with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in
671
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
672
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
673
PAXIL. A few cases of acute angle closure glaucoma associated with paroxetine therapy have
674
been reported in the literature. As mydriasis can cause acute angle closure in patients with
675
narrow angle glaucoma, caution should be used when PAXIL is prescribed for patients with
676
narrow angle glaucoma.
677
PAXIL has not been evaluated or used to any appreciable extent in patients with a recent
678
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
679
excluded from clinical studies during the product’s premarket testing. Evaluation of
680
electrocardiograms of 682 patients who received PAXIL in double-blind, placebo-controlled
681
trials, however, did not indicate that PAXIL is associated with the development of significant
682
ECG abnormalities. Similarly, PAXIL does not cause any clinically important changes in heart
683
rate or blood pressure.
684
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
685
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
686
be used in such patients (see DOSAGE AND ADMINISTRATION).
687
Information for Patients: PAXIL should not be chewed or crushed, and should be swallowed
688
whole.
689
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
690
PAXIL and triptans, tramadol, or other serotonergic agents.
18
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
691
Prescribers or other health professionals should inform patients, their families, and their
692
caregivers about the benefits and risks associated with treatment with PAXIL and should counsel
693
them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines,
694
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available
695
for PAXIL. The prescriber or health professional should instruct patients, their families, and their
696
caregivers to read the Medication Guide and should assist them in understanding its contents.
697
Patients should be given the opportunity to discuss the contents of the Medication Guide and to
698
obtain answers to any questions they may have. The complete text of the Medication Guide is
699
reprinted at the end of this document.
700
Patients should be advised of the following issues and asked to alert their prescriber if these
701
occur while taking PAXIL.
702
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
703
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
704
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
705
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
706
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
707
down. Families and caregivers of patients should be advised to look for the emergence of such
708
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
709
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
710
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
711
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
712
close monitoring and possibly changes in the medication.
713
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
714
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
715
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
716
interfere with serotonin reuptake and these agents has been associated with an increased risk of
717
bleeding.
718
Interference With Cognitive and Motor Performance: Any psychoactive drug may
719
impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been
720
shown to impair psychomotor performance, patients should be cautioned about operating
721
hazardous machinery, including automobiles, until they are reasonably certain that therapy with
722
PAXIL does not affect their ability to engage in such activities.
723
Completing Course of Therapy: While patients may notice improvement with treatment
724
with PAXIL in 1 to 4 weeks, they should be advised to continue therapy as directed.
725
Concomitant Medication: Patients should be advised to inform their physician if they are
726
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
727
interactions.
728
Alcohol: Although PAXIL has not been shown to increase the impairment of mental and
729
motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
730
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
19
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
731
intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic
732
and Nonteratogenic Effects).
733
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
734
infant (see PRECAUTIONS: Nursing Mothers).
735
Laboratory Tests: There are no specific laboratory tests recommended.
736
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
737
between paroxetine and tryptophan may occur when they are coadministered. Adverse
738
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
739
reported when tryptophan was administered to patients taking PAXIL. Consequently,
740
concomitant use of PAXIL with tryptophan is not recommended (see WARNINGS: Serotonin
741
Syndrome or Neuroleptic Malignant Syndrom (NMS)-like Reactions).
742
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
743
Pimozide: In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg
744
daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in
745
pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The
746
increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine.
747
Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT
748
interval, concomitant use of pimozide and PAXIL is contraindicated (see
749
CONTRAINDICATIONS).
750
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
751
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
752
PAXIL is coadministered with other drugs that may affect the serotonergic neurotransmitter
753
systems, such as triptans, lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS:
754
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions).
755
The concomitant use of PAXIL with MAOIs (including linezolid and methylene blue) is
756
contraindicated (see CONTRAINDICATIONS). The concomitant use of PAXIL with other
757
SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions:
758
Tryptophan).
759
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
760
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
761
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
762
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
763
of PAXIL and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That
764
Interfere With Hemostasis).
765
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
766
an SSRI and a triptan. If concomitant use of PAXIL with a triptan is clinically warranted, careful
767
observation of the patient is advised, particularly during treatment initiation and dose increases
768
(see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like
769
Reactions).
770
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
20
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
771
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
772
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
773
where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma
774
concentrations of paroxetine were increased by approximately 50% during coadministration with
775
oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are
776
administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be
777
guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not
778
studied.
779
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
780
single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once
781
daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
782
respectively) compared to paroxetine administered alone. The effect of paroxetine on
783
phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear
784
pharmacokinetics, the results of this study may not address the case where the 2 drugs are both
785
being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when
786
coadministered with phenobarbital; any subsequent adjustment should be guided by clinical
787
effect.
788
Phenytoin: When a single oral 30-mg dose of PAXIL was administered at phenytoin steady
789
state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of
790
50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a
791
single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once
792
daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to
793
phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above
794
studies may not address the case where the 2 drugs are both being chronically dosed. No initial
795
dosage adjustments are considered necessary when these drugs are coadministered; any
796
subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS:
797
Postmarketing Reports).
798
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
799
treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are
800
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
801
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
802
(>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily
803
dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose
804
desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold,
805
respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been
806
evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to
807
8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased
808
9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the
809
active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The
810
effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs
21
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
811
were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,
812
paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This
813
resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in
814
atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.
815
Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be
816
initiated at a reduced dose when it is given with paroxetine.
817
Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not
818
been formally studied but may require lower doses than usually prescribed for either PAXIL or
819
the other drug.
820
Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme,
821
including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,
822
amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type
823
1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme
824
(e.g., quinidine), should be approached with caution.
825
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
826
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
827
coadministered (see CONTRAINDICATIONS and WARNINGS).
828
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6
829
by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and
830
hence reduced efficacy of tamoxifen (see PRECAUTIONS).
831
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
832
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
833
PRECAUTIONS: Tricyclic Antidepressants [TCAs]).
834
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
835
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
836
cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In
837
addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be
838
at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several
839
substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and
840
cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and
841
its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4
842
substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical
843
significance.
844
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of
845
tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism.
846
Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be
847
reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS: Drugs Metabolized by
848
Cytochrome CYP2D6).
849
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
850
protein, administration of PAXIL to a patient taking another drug that is highly protein bound
22
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
851
may cause increased free concentrations of the other drug, potentially resulting in adverse events.
852
Conversely, adverse effects could result from displacement of paroxetine by other highly bound
853
drugs.
854
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
855
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
856
the case-control and cohort design that have demonstrated an association between use of
857
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
858
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
859
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
860
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
861
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
862
Alcohol: Although PAXIL does not increase the impairment of mental and motor skills
863
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
864
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction
865
between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome,
866
caution is advised when PAXIL is coadministered with lithium.
867
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
868
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
869
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
870
paroxetine and digoxin should be undertaken with caution.
871
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
872
kinetics. The effects of paroxetine on diazepam were not evaluated.
873
Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0
874
24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%,
875
respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen,
876
the dose of procyclidine should be reduced.
877
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
878
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
879
coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of
880
propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS:
881
Postmarketing Reports).
882
Theophylline: Reports of elevated theophylline levels associated with treatment with
883
PAXIL have been reported. While this interaction has not been formally studied, it is
884
recommended that theophylline levels be monitored when these drugs are concurrently
885
administered.
886
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
887
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
888
clinical effect (tolerability and efficacy).
889
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
890
ECT and PAXIL.
23
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
891
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
892
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
893
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and
894
3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and
895
PTSD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than
896
that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only
897
2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of
898
male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for
899
control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
900
trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats
901
were not affected. Although there was a dose-related increase in the number of tumors in mice,
902
there was no drug-related increase in the number of mice with tumors. The relevance of these
903
findings to humans is unknown.
904
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
905
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
906
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
907
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
908
Impairment of Fertility: Some clinical studies have shown that SSRIs (including
909
paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some
910
men.
911
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of
912
15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety
913
disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible
914
lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to
915
52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at
916
50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested
917
spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder,
918
social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2
919
basis).
920
Pregnancy: Pregnancy Category D. See WARNINGS: Usage in Pregnancy: Teratogenic and
921
Nonteratogenic Effects.
922
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
923
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
924
should be exercised when PAXIL is administered to a nursing woman.
925
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
926
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Three placebo
927
controlled trials in 752 pediatric patients with MDD have been conducted with PAXIL, and the
928
data were not sufficient to support a claim for use in pediatric patients. Anyone considering the
929
use of PAXIL in a child or adolescent must balance the potential risks with the clinical need.
930
Decreased appetite and weight loss have been observed in association with the use of SSRIs.
24
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
931
Consequently, regular monitoring of weight and growth should be performed in children and
932
adolescents treated with an SSRI such as Paxil.
933
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
934
events were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a
935
rate at least twice that for pediatric patients receiving placebo: emotional lability (including self
936
harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased
937
appetite, tremor, sweating, hyperkinesia, and agitation.
938
Events reported upon discontinuation of treatment with PAXIL in the pediatric clinical trials
939
that included a taper phase regimen, which occurred in at least 2% of patients who received
940
PAXIL and which occurred at a rate at least twice that of placebo, were: emotional lability
941
(including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness,
942
dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION:
943
Discontinuation of Treatment With PAXIL).
944
Geriatric Use: SSRIs and SNRIs, including PAXIL, have been associated with cases of
945
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
946
event (see PRECAUTIONS: Hyponatremia).
947
In worldwide premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL
948
(approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased
949
clearance in the elderly, and a lower starting dose is recommended; there were, however, no
950
overall differences in the adverse event profile between elderly and younger patients, and
951
effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY
952
and DOSAGE AND ADMINISTRATION).
953
ADVERSE REACTIONS
954
Associated With Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients
955
treated with PAXIL in worldwide clinical trials in major depressive disorder and 16.1%
956
(84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients
957
treated with PAXIL in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD,
958
and PTSD, respectively, discontinued treatment due to an adverse event. The most common
959
events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events
960
associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo)
961
included the following:
962
25
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Major
Depressive
Disorder
OCD
Panic Disorder
Social Anxiety
Disorder
Generalized
Anxiety Disorder
PTSD
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
CNS
Somnolence
2.3%
0.7%
—
1.9%
0.3%
3.4%
0.3%
2.0%
0.2%
2.8%
0.6%
Insomnia
—
—
1.7%
0%
1.3%
0.3%
3.1%
0%
—
—
Agitation
1.1%
0.5%
—
—
—
Tremor
1.1%
0.3%
—
1.7%
0%
1.0%
0.2%
Anxiety
—
—
—
1.1%
0%
—
—
Dizziness
—
—
1.5%
0%
1.9%
0%
1.0%
0.2%
—
—
Gastroin
testinal
Constipation
—
1.1%
0%
—
—
Nausea
3.2%
1.1%
1.9%
0%
3.2%
1.2%
4.0%
0.3%
2.0%
0.2%
2.2%
0.6%
Diarrhea
1.0%
0.3%
—
Dry mouth
1.0%
0.3%
—
—
—
Vomiting
1.0%
0.3%
—
1.0%
0%
—
—
Flatulence
1.0%
0.3%
—
—
Other
Asthenia
Abnormal
1.6%
0.4%
1.9%
0.4%
2.5%
0.6%
1.8%
0.2%
1.6%
0.2%
Ejaculationa
1.6%
0%
2.1%
0%
4.9%
0.6%
2.5%
0.5%
—
—
Sweating
1.0%
0.3%
—
1.1%
0%
1.1%
0.2%
—
—
Impotencea
Libido
—
1.5%
0%
—
—
Decreased
1.0%
0%
—
—
963
Where numbers are not provided the incidence of the adverse events in patients treated with
964
PAXIL was not >1% or was not greater than or equal to 2 times the incidence of placebo.
965
a. Incidence corrected for gender.
966
967
Commonly Observed Adverse Events: Major Depressive Disorder: The most
968
commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
969
greater and incidence for PAXIL at least twice that for placebo, derived from Table 2) were:
970
Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor,
971
nervousness, ejaculatory disturbance, and other male genital disorders.
972
Obsessive Compulsive Disorder: The most commonly observed adverse events
973
associated with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at
974
least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite,
975
constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
976
Panic Disorder: The most commonly observed adverse events associated with the use of
977
paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for placebo,
978
derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor,
26
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
979
abnormal ejaculation, female genital disorders, and impotence.
980
Social Anxiety Disorder: The most commonly observed adverse events associated with
981
the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for
982
placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased
983
appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital
984
disorders, and impotence.
985
Generalized Anxiety Disorder: The most commonly observed adverse events associated
986
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
987
that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased
988
appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal
989
ejaculation.
990
Posttraumatic Stress Disorder: The most commonly observed adverse events associated
991
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
992
that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea,
993
decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders,
994
and impotence.
995
Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in
996
the tables following cannot be used to predict the incidence of side effects in the course of usual
997
medical practice where patient characteristics and other factors differ from those that prevailed in
998
the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from
999
other clinical investigations involving different treatments, uses, and investigators. The cited
1000
figures, however, do provide the prescribing physician with some basis for estimating the
1001
relative contribution of drug and nondrug factors to the side effect incidence rate in the
1002
populations studied.
1003
Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an
1004
incidence of 1% or more among paroxetine-treated patients who participated in short-term
1005
(6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to
1006
50 mg/day. Reported adverse events were classified using a standard COSTART-based
1007
Dictionary terminology.
1008
27
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1009
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
1010
Clinical Trials for Major Depressive Disordera
Body System
Preferred Term
PAXIL
(n = 421)
Placebo
(n = 421)
Body as a Whole
Headache
Asthenia
18%
15%
17%
6%
Cardiovascular
Palpitation
Vasodilation
3%
3%
1%
1%
Dermatologic
Sweating
Rash
11%
2%
2%
1%
Gastrointestinal
Nausea
26%
9%
Dry Mouth
18%
12%
Constipation
14%
9%
Diarrhea
12%
8%
Decreased Appetite
6%
2%
Flatulence
4%
2%
Oropharynx Disorderb
2%
0%
Dyspepsia
2%
1%
Musculoskeletal
Myopathy
Myalgia
Myasthenia
2%
2%
1%
1%
1%
0%
Nervous System
Somnolence
23%
9%
Dizziness
13%
6%
Insomnia
13%
6%
Tremor
8%
2%
Nervousness
5%
3%
Anxiety
5%
3%
Paresthesia
4%
2%
Libido Decreased
3%
0%
Drugged Feeling
2%
1%
Confusion
1%
0%
Respiration
Yawn
4%
0%
Special Senses
Blurred Vision
Taste Perversion
4%
2%
1%
0%
Urogenital System
Ejaculatory Disturbancec,d
13%
0%
Other Male Genital Disordersc,e
10%
0%
Urinary Frequency
3%
1%
Urination Disorderf
3%
0%
Female Genital Disordersc,g
2%
0%
1011
a. Events reported by at least 1% of patients treated with PAXIL are included, except the
1012
following events which had an incidence on placebo ≥ PAXIL: Abdominal pain, agitation,
1013
back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis,
1014
postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”),
1015
trauma, and vomiting.
1016
b. Includes mostly “lump in throat” and “tightness in throat.”
28
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1017
c. Percentage corrected for gender.
1018
d. Mostly “ejaculatory delay.”
1019
e. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual
1020
dysfunction,” and “impotence.”
1021
f. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
1022
g. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
1023
1024
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:
1025
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD
1026
patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
1027
patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on
1028
PAXIL who participated in placebo-controlled trials of 10- to 12-weeks duration in which
1029
patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety
1030
disorder on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
1031
patients were dosed in a range of 20 mg to 50 mg/day.
1032
1033
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
1034
Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety
1035
Disordera
Body System
Preferred Term
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
PAXIL
(n = 542)
Placebo
(n = 265)
PAXIL
(n = 469)
Placebo
(n = 324)
PAXIL
(n = 425)
Placebo
(n = 339)
Body as a Whole
Asthenia
Abdominal Pain
Chest Pain
Back Pain
Chills
Trauma
22%
—
3%
—
2%
—
14%
—
2%
—
1%
—
14%
4%
—
3%
2%
—
5%
3%
—
2%
1%
—
22%
—
—
—
—
3%
14%
—
—
—
—
1%
Cardiovascular
Vasodilation
Palpitation
4%
2%
1%
0%
—
—
—
—
—
—
—
—
Dermatologic
Sweating
Rash
9%
3%
3%
2%
14%
—
6%
—
9%
—
2%
—
Gastrointestinal
Nausea
23%
10%
23%
17%
25%
7%
Dry Mouth
18%
9%
18%
11%
9%
3%
Constipation
16%
6%
8%
5%
5%
2%
Diarrhea
Decreased
10%
10%
12%
7%
9%
6%
Appetite
9%
3%
7%
3%
8%
2%
Dyspepsia
—
—
—
—
4%
2%
Flatulence
Increased
—
—
—
—
4%
2%
29
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Obsessive
Compulsive
Disorder
Panic
Disorder
Social Anxiety
Disorder
Appetite
4%
3%
2%
1%
—
—
Vomiting
—
—
—
—
2%
1%
Musculoskeletal
Myalgia
—
—
—
—
4%
3%
Nervous System
Insomnia
Somnolence
24%
24%
13%
7%
18%
19%
10%
11%
21%
22%
16%
5%
Dizziness
12%
6%
14%
10%
11%
7%
Tremor
11%
1%
9%
1%
9%
1%
Nervousness
9%
8%
—
—
8%
7%
Libido Decreased
7%
4%
9%
1%
12%
1%
Agitation
Anxiety
Abnormal
—
—
—
—
5%
5%
4%
4%
3%
5%
1%
4%
Dreams
4%
1%
—
—
—
—
Concentration
Impaired
Depersonalization
Myoclonus
Amnesia
3%
3%
3%
2%
2%
0%
0%
1%
—
—
3%
—
—
—
2%
—
4%
—
2%
—
1%
—
1%
—
Respiratory System
Rhinitis
Pharyngitis
Yawn
—
—
—
—
—
—
3%
—
—
0%
—
—
—
4%
5%
—
2%
1%
Special Senses
Abnormal Vision
Taste Perversion
4%
2%
2%
0%
—
—
—
—
4%
—
1%
—
Urogenital System
Abnormal
Ejaculationb
Dysmenorrhea
Female Genital
23%
—
1%
—
21%
—
1%
—
28%
5%
1%
4%
Disorderb
3%
0%
9%
1%
9%
1%
Impotenceb
Urinary
Frequency
Urination
8%
3%
1%
1%
5%
2%
0%
0%
5%
—
1%
—
Impaired
Urinary Tract
Infection
3%
2%
0%
1%
—
2%
—
1%
—
—
—
—
1036
a. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients
1037
treated with PAXIL are included, except the following events which had an incidence on
1038
placebo ≥PAXIL: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased,
1039
depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder,
1040
rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough
1041
increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache,
30
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1042
infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory
1043
disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social
1044
anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and
1045
sinusitis.
1046
b. Percentage corrected for gender.
1047
1048
Generalized Anxiety Disorder and Posttraumatic Stress Disorder: Table 4
1049
enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on
1050
PAXIL who participated in placebo-controlled trials of 8-weeks duration in which patients were
1051
dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on PAXIL who
1052
participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a
1053
range of 20 mg/day to 50 mg/day.
1054
31
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1055
Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
1056
Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disordera
Body System
Preferred Term
Generalized Anxiety
Disorder
Posttraumatic Stress
Disorder
PAXIL
(n = 735)
Placebo
(n = 529)
PAXIL
(n = 676)
Placebo
(n = 504)
Body as a Whole
Asthenia
Headache
Infection
Abdominal Pain
Trauma
14%
17%
6%
6%
14%
3%
12%
—
5%
4%
6%
4%
—
4%
3%
5%
Cardiovascular
Vasodilation
3%
1%
2%
1%
Dermatologic
Sweating
6%
2%
5%
1%
Gastrointestinal
Nausea
Dry Mouth
Constipation
Diarrhea
Decreased Appetite
Vomiting
Dyspepsia
20%
11%
10%
9%
5%
3%
—
5%
5%
2%
7%
1%
2%
—
19%
10%
5%
11%
6%
3%
5%
8%
5%
3%
5%
3%
2%
3%
Nervous System
Insomnia
Somnolence
Dizziness
Tremor
Nervousness
Libido Decreased
Abnormal Dreams
11%
15%
6%
5%
4%
9%
8%
5%
5%
1%
3%
2%
12%
16%
6%
4%
—
5%
3%
11%
5%
5%
1%
—
2%
2%
Respiratory
System
Respiratory Disorder
Sinusitis
Yawn
7%
4%
4%
5%
3%
—
—
—
2%
—
—
<1%
Special Senses
Abnormal Vision
2%
1%
3%
1%
Urogenital
System
Abnormal
Ejaculation
b
Female Genital
Disorder
b
Impotence
b
25%
4%
4%
2%
1%
3%
13%
5%
9%
2%
1%
1%
1057
a. Events reported by at least 2% of GAD and PTSD in patients treated with PAXIL are
1058
included, except the following events which had an incidence on placebo ≥PAXIL [GAD]:
1059
Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain,
1060
headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis.
1061
b. Percentage corrected for gender.
1062
1063
Dose Dependency of Adverse Events: A comparison of adverse event rates in a
1064
fixed-dose study comparing 10, 20, 30, and 40 mg/day of PAXIL with placebo in the treatment
1065
of major depressive disorder revealed a clear dose dependency for some of the more common
1066
adverse events associated with use of PAXIL, as shown in Table 5:
32
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1067
1068
Table 5 . Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial
1069
in the Treatment of Major Depressive Disordera
Body System/Preferred Term
Placebo
n = 51
PAXIL
10 mg
n = 102
20 mg
n = 104
30 mg
n = 101
40 mg
n = 102
Body as a Whole
Asthenia
0.0%
2.9%
10.6%
13.9%
12.7%
Dermatology
Sweating
2.0%
1.0%
6.7%
8.9%
11.8%
Gastrointestinal
Constipation
5.9%
4.9%
7.7%
9.9%
12.7%
Decreased Appetite
2.0%
2.0%
5.8%
4.0%
4.9%
Diarrhea
7.8%
9.8%
19.2%
7.9%
14.7%
Dry Mouth
2.0%
10.8%
18.3%
15.8%
20.6%
Nausea
13.7%
14.7%
26.9%
34.7%
36.3%
Nervous System
Anxiety
0.0%
2.0%
5.8%
5.9%
5.9%
Dizziness
3.9%
6.9%
6.7%
8.9%
12.7%
Nervousness
0.0%
5.9%
5.8%
4.0%
2.9%
Paresthesia
0.0%
2.9%
1.0%
5.0%
5.9%
Somnolence
7.8%
12.7%
18.3%
20.8%
21.6%
Tremor
0.0%
0.0%
7.7%
7.9%
14.7%
Special Senses
Blurred Vision
2.0%
2.9%
2.9%
2.0%
7.8%
Urogenital System
Abnormal Ejaculation
0.0%
5.8%
6.5%
10.6%
13.0%
Impotence
0.0%
1.9%
4.3%
6.4%
1.9%
Male Genital Disorders
0.0%
3.8%
8.7%
6.4%
3.7%
1070
a. Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups
1071
and ≥ twice the placebo incidence for at least 1 paroxetine group.
1072
1073
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
1074
OCD, there was no clear relationship between adverse events and the dose of PAXIL to which
1075
patients were assigned. No new adverse events were observed in the group treated with 60 mg of
1076
PAXIL compared to any of the other treatment groups.
1077
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of PAXIL in the treatment of
1078
panic disorder, there was no clear relationship between adverse events and the dose of PAXIL to
1079
which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor,
1080
and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in
1081
patients receiving 60 mg of PAXIL compared to any of the other treatment groups.
1082
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
1083
social anxiety disorder, for most of the adverse events, there was no clear relationship between
33
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1084
adverse events and the dose of PAXIL to which patients were assigned.
1085
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1086
generalized anxiety disorder, for most of the adverse events, there was no clear relationship
1087
between adverse events and the dose of PAXIL to which patients were assigned, except for the
1088
following adverse events: Asthenia, constipation, and abnormal ejaculation.
1089
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
1090
posttraumatic stress disorder, for most of the adverse events, there was no clear relationship
1091
between adverse events and the dose of PAXIL to which patients were assigned, except for
1092
impotence and abnormal ejaculation.
1093
Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence
1094
of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less
1095
to other effects (e.g., dry mouth, somnolence, and asthenia).
1096
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
1097
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
1098
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
1099
evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward
1100
sexual experiences.
1101
Reliable estimates of the incidence and severity of untoward experiences involving sexual
1102
desire, performance, and satisfaction are difficult to obtain, however, in part because patients and
1103
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
1104
untoward sexual experience and performance cited in product labeling, are likely to
1105
underestimate their actual incidence.
1106
In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the
1107
reported incidence of sexual side effects in males and females with major depressive disorder,
1108
OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.
1109
1110
Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials
PAXIL
Placebo
n (males)
1446
1042
Decreased Libido
6-15%
0-5%
Ejaculatory Disturbance
13-28%
0-2%
Impotence
2-9%
0-3%
n (females)
1822
1340
Decreased Libido
0-9%
0-2%
Orgasmic Disturbance
2-9%
0-1%
1111
1112
There are no adequate and well-controlled studies examining sexual dysfunction with
1113
paroxetine treatment.
1114
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
1115
known outcome, patients recovered without sequelae.
1116
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
34
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1117
SSRIs, physicians should routinely inquire about such possible side effects.
1118
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
1119
treatment with PAXIL for some patients but, on average, patients in controlled trials had minimal
1120
(about 1 pound) weight loss versus smaller changes on placebo and active control. No significant
1121
changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were
1122
observed in patients treated with PAXIL in controlled clinical trials.
1123
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with PAXIL and
1124
415 patients treated with placebo in controlled clinical trials, no clinically significant changes
1125
were seen in the ECGs of either group.
1126
Liver Function Tests: In placebo-controlled clinical trials, patients treated with PAXIL
1127
exhibited abnormal values on liver function tests at no greater rate than that seen in
1128
placebo-treated patients. In particular, the PAXIL-versus-placebo comparisons for alkaline
1129
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
1130
with marked abnormalities.
1131
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
1132
hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients
1133
receiving placebo.
1134
Other Events Observed During the Premarketing Evaluation of PAXIL: During its
1135
premarketing assessment in major depressive disorder, multiple doses of PAXIL were
1136
administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure
1137
to PAXIL varied greatly and included (in overlapping categories) open and double-blind studies,
1138
uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration
1139
studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder,
1140
generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676
1141
patients, respectively, received multiple doses of PAXIL. Untoward events associated with this
1142
exposure were recorded by clinical investigators using terminology of their own choosing.
1143
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
1144
experiencing adverse events without first grouping similar types of untoward events into a
1145
smaller number of standardized event categories.
1146
In the tabulations that follow, reported adverse events were classified using a standard
1147
COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the
1148
proportion of the 9,089 patients exposed to multiple doses of PAXIL who experienced an event
1149
of the type cited on at least 1 occasion while receiving PAXIL. All reported events are included
1150
except those already listed in Tables 2 to 5, those reported in terms so general as to be
1151
uninformative and those events where a drug cause was remote. It is important to emphasize that
1152
although the events reported occurred during treatment with paroxetine, they were not
1153
necessarily caused by it.
1154
Events are further categorized by body system and listed in order of decreasing frequency
1155
according to the following definitions: Frequent adverse events are those occurring on 1 or more
1156
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
35
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1157
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1158
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events
1159
of major clinical importance are also described in the PRECAUTIONS section.
1160
Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain;
1161
rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis,
1162
ulcer.
1163
Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia,
1164
hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris,
1165
arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular
1166
accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial
1167
ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis,
1168
thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
1169
Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis,
1170
gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal
1171
hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia,
1172
cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal
1173
incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction,
1174
jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis,
1175
stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
1176
Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism,
1177
thyroiditis.
1178
Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy,
1179
purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia,
1180
hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal
1181
lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia,
1182
thrombocythemia, thrombocytopenia.
1183
Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema,
1184
SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased,
1185
bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma
1186
globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia,
1187
hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic
1188
dehydrogenase increased, non-protein nitrogen (NPN) increased.
1189
Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare:
1190
Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
1191
Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking,
1192
alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia,
1193
hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction,
1194
neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia,
1195
choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug
1196
dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion,
36
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1197
hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy,
1198
nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes
1199
increased, stupor, torticollis, trismus, withdrawal syndrome.
1200
Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation,
1201
pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary
1202
edema, sputum increased, stridor, voice alteration.
1203
Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis,
1204
dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema,
1205
erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis;
1206
herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy,
1207
skin ulcer, sweating decreased, vesiculobullous rash.
1208
Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation,
1209
conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia,
1210
anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye
1211
hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia,
1212
ptosis, retinal hemorrhage, taste loss, visual field defect.
1213
Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria,
1214
menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency,
1215
vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis,
1216
female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis,
1217
metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith,
1218
vaginal hemorrhage, vaginal moniliasis.
1219
Postmarketing Reports: Voluntary reports of adverse events in patients taking PAXIL that
1220
have been received since market introduction and not listed above that may have no causal
1221
relationship with the drug include acute pancreatitis, elevated liver function tests (the most
1222
severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated
1223
with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic
1224
epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive
1225
of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia,
1226
bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been
1227
associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal
1228
failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic
1229
neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia
1230
(including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired
1231
hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and
1232
agranulocytosis), and vasculitic syndromes (such as Henoch-Schönlein purpura). There has been
1233
a case report of an elevated phenytoin level after 4 weeks of PAXIL and phenytoin
1234
coadministration. There has been a case report of severe hypotension when PAXIL was added to
1235
chronic metoprolol treatment.
37
Reference ID: 2920253
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1236
DRUG ABUSE AND DEPENDENCE
1237
Controlled Substance Class: PAXIL is not a controlled substance.
1238
Physical and Psychologic Dependence: PAXIL has not been systematically studied in
1239
animals or humans for its potential for abuse, tolerance or physical dependence. While the
1240
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
1241
not systematic and it is not possible to predict on the basis of this limited experience the extent to
1242
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
1243
patients should be evaluated carefully for history of drug abuse, and such patients should be
1244
observed closely for signs of misuse or abuse of PAXIL (e.g., development of tolerance,
1245
incrementations of dose, drug-seeking behavior).
1246
OVERDOSAGE
1247
Human Experience: Since the introduction of PAXIL in the United States, 342 spontaneous
1248
cases of deliberate or accidental overdosage during paroxetine treatment have been reported
1249
worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with
1250
other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve
1251
paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were
1252
generally confounded by the ingestion of other drugs or alcohol or the presence of significant
1253
comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without
1254
sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum
1255
recommended daily dose) in a patient who recovered.
1256
Commonly reported adverse events associated with paroxetine overdosage include
1257
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
1258
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
1259
substances) include mydriasis, convulsions (including status epilepticus), ventricular
1260
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
1261
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
1262
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
1263
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
1264
Overdosage Management: No specific antidotes for paroxetine are known. Treatment
1265
should consist of those general measures employed in the management of overdosage with any
1266
drugs effective in the treatment of major depressive disorder.
1267
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
1268
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
1269
is not recommended. Due to the large volume of distribution of this drug, forced diuresis,
1270
dialysis, hemoperfusion, or exchange transfusion are unlikely to be of benefit.
1271
A specific caution involves patients who are taking or have recently taken paroxetine who
1272
might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
1273
parent tricyclic and/or an active metabolite may increase the possibility of clinically significant
1274
sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drugs
38
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1275
Metabolized by Cytochrome CYP2D6).
1276
In managing overdosage, consider the possibility of multiple drug involvement. The physician
1277
should consider contacting a poison control center for additional information on the treatment of
1278
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
1279
Desk Reference (PDR).
1280
DOSAGE AND ADMINISTRATION
1281
Major Depressive Disorder: Usual Initial Dosage: PAXIL should be administered as a
1282
single daily dose with or without food, usually in the morning. The recommended initial dose is
1283
20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating
1284
the effectiveness of PAXIL in the treatment of major depressive disorder. As with all drugs
1285
effective in the treatment of major depressive disorder, the full effect may be delayed. Some
1286
patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day
1287
increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least
1288
1 week.
1289
Maintenance Therapy: There is no body of evidence available to answer the question of
1290
how long the patient treated with PAXIL should remain on it. It is generally agreed that acute
1291
episodes of major depressive disorder require several months or longer of sustained
1292
pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose
1293
needed to maintain and/or sustain euthymia is unknown.
1294
Systematic evaluation of the efficacy of PAXIL has shown that efficacy is maintained for
1295
periods of up to 1 year with doses that averaged about 30 mg.
1296
Obsessive Compulsive Disorder: Usual Initial Dosage: PAXIL should be administered
1297
as a single daily dose with or without food, usually in the morning. The recommended dose of
1298
PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the
1299
dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at
1300
least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials
1301
demonstrating the effectiveness of PAXIL in the treatment of OCD. The maximum dosage
1302
should not exceed 60 mg/day.
1303
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month
1304
relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a
1305
lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY:
1306
Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a
1307
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1308
effective dosage, and patients should be periodically reassessed to determine the need for
1309
continued treatment.
1310
Panic Disorder: Usual Initial Dosage: PAXIL should be administered as a single daily dose
1311
with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic
1312
disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in
1313
10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to
39
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1314
60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL. The maximum dosage
1315
should not exceed 60 mg/day.
1316
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month
1317
relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine
1318
demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL
1319
PHARMACOLOGY: Clinical Trials). Panic disorder is a chronic condition, and it is reasonable
1320
to consider continuation for a responding patient. Dosage adjustments should be made to
1321
maintain the patient on the lowest effective dosage, and patients should be periodically
1322
reassessed to determine the need for continued treatment.
1323
Social Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a single
1324
daily dose with or without food, usually in the morning. The recommended and initial dosage is
1325
20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a
1326
range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social
1327
anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional
1328
benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials).
1329
Maintenance Therapy: There is no body of evidence available to answer the question of
1330
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1331
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety
1332
disorder is recognized as a chronic condition, and it is reasonable to consider continuation of
1333
treatment for a responding patient. Dosage adjustments should be made to maintain the patient
1334
on the lowest effective dosage, and patients should be periodically reassessed to determine the
1335
need for continued treatment.
1336
Generalized Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a
1337
single daily dose with or without food, usually in the morning. In clinical trials the effectiveness
1338
of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended
1339
starting dosage and the established effective dosage is 20 mg/day. There is not sufficient
1340
evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur
1341
in 10 mg/day increments and at intervals of at least 1 week.
1342
Maintenance Therapy: Systematic evaluation of continuing PAXIL for periods of up to
1343
24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL
1344
during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see
1345
CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically
1346
reassessed to determine the need for maintenance treatment.
1347
Posttraumatic Stress Disorder: Usual Initial Dosage: PAXIL should be administered as
1348
a single daily dose with or without food, usually in the morning. The recommended starting
1349
dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of
1350
PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed
1351
dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day
1352
compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at
1353
intervals of at least 1 week.
40
Reference ID: 2920253
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1354
Maintenance Therapy: There is no body of evidence available to answer the question of
1355
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
1356
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is
1357
recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a
1358
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
1359
effective dosage, and patients should be periodically reassessed to determine the need for
1360
continued treatment.
1361
Special Populations: Treatment of Pregnant Women During the Third Trimester:
1362
Neonates exposed to PAXIL and other SSRIs or SNRIs, late in the third trimester have
1363
developed complications requiring prolonged hospitalization, respiratory support, and tube
1364
feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine
1365
during the third trimester, the physician should carefully consider the potential risks and benefits
1366
of treatment. The physician may consider tapering paroxetine in the third trimester.
1367
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
1368
Hepatic Impairment: The recommended initial dose is 10 mg/day for elderly patients,
1369
debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be
1370
made if indicated. Dosage should not exceed 40 mg/day.
1371
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
1372
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL.
1373
Similarly, at least 14 days should be allowed after stopping PAXIL before starting an MAOI.
1374
Discontinuation of Treatment With PAXIL: Symptoms associated with discontinuation of
1375
PAXIL have been reported (see PRECAUTIONS: Discontinuation of Treatment With PAXIL).
1376
Patients should be monitored for these symptoms when discontinuing treatment, regardless of the
1377
indication for which PAXIL is being prescribed. A gradual reduction in the dose rather than
1378
abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a
1379
decrease in the dose or upon discontinuation of treatment, then resuming the previously
1380
prescribed dose may be considered. Subsequently, the physician may continue decreasing the
1381
dose but at a more gradual rate.
1382
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
1383
HOW SUPPLIED
1384
Tablets: Film-coated, modified-oval as follows:
1385
10-mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
1386
NDC 0029-3210-13 Bottles of 30
1387
20-mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
1388
NDC 0029-3211-13 Bottles of 30
1389
30-mg blue tablets engraved on the front with PAXIL and on the back with 30.
1390
NDC 0029-3212-13 Bottles of 30
1391
40-mg green tablets engraved on the front with PAXIL and on the back with 40.
1392
NDC 0029-3213-13 Bottles of 30
41
Reference ID: 2920253
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1393
Store tablets between 15° and 30°C (59° and 86°F).
1394
Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in 250 mL white bottles.
1395
NDC 0029-3215-48
1396
Store suspension at or below 25°C (77°F).
1397
PAXIL is a registered trademark of GlaxoSmithKline.
1398
1399
1400
1401
42
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1402
1403
Medication Guide
1404
PAXIL® (PAX-il)
1405
(paroxetine hydrochloride)
1406
Tablets and Oral Suspension
1407
1408
Read the Medication Guide that comes with PAXIL before you start taking it and each time you
1409
get a refill. There may be new information. This Medication Guide does not take the place of
1410
talking to your healthcare provider about your medical condition or treatment. Talk with your
1411
healthcare provider if there is something you do not understand or want to learn more about.
1412
What is the most important information I
should know about PAXIL?
PAXIL and other antidepressant medicines
may cause serious side effects, including:
1.
Suicidal thoughts or actions:
• PAXIL and other antidepressant
medicines may increase suicidal
thoughts or actions in some
children, teenagers, or young adults
within the first few months of
treatment or when the dose is
changed.
• Depression or other serious mental
illnesses are the most important
causes of suicidal thoughts or
actions.
• Watch for these changes and call
your healthcare provider right away
if you notice:
• New or sudden changes in mood,
behavior, actions, thoughts, or
feelings, especially if severe.
• Pay particular attention to such
changes when PAXIL is started
or when the dose is changed.
Keep all follow-up visits with your
healthcare provider and call between
visits if you are worried about
symptoms.
Call your healthcare provider right
away if you have any of the following
symptoms, or call 911 if an
emergency, especially if they are new,
worse, or worry you:
• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic
attacks
• feeling agitated, restless, angry,
or irritable
• trouble sleeping
• an increase in activity or talking
more than what is normal for you
• other unusual changes in
behavior or mood
Call your healthcare provider right away
if you have any of the following
symptoms, or call 911 if an emergency.
PAXIL may be associated with these
serious side effects:
2.
Serotonin Syndrome or Neuroleptic
Malignant Syndrome-like reactions.
This condition can be life-
threatening and may include:
• agitation, hallucinations, coma, or
43
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
other changes in mental status
• coordination problems or muscle
twitching (overactive reflexes)
• racing heartbeat, high or low blood
pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity
3.
Severe allergic reactions:
• trouble breathing
• swelling of the face, tongue, eyes,
or mouth
• rash, itchy welts (hives), or blisters,
alone or with fever or joint pain
4.
Abnormal bleeding: PAXIL and
other antidepressant medicines may
increase your risk of bleeding or
bruising, especially if you take the
blood thinner warfarin (Coumadin®,
Jantoven®), a non-steroidal anti
inflammatory drug (NSAIDs, like
ibuprofen or naproxen), or aspirin.
5.
Seizures or convulsions
6.
Manic episodes:
• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual
7.
Changes in appetite or weight.
Children and adolescents should have
height and weight monitored during
treatment.
8.
Low salt (sodium) levels in the
blood. Elderly people may be at
greater risk for this. Symptoms may
include:
• headache
• weakness or feeling unsteady
• confusion, problems concentrating
or thinking, or memory problems
Do not stop PAXIL without first talking
to your healthcare provider. Stopping
PAXIL too quickly may cause serious
symptoms including:
• anxiety, irritability, high or low mood,
feeling restless, or changes in sleep
habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking,
confusion
What is PAXIL?
PAXIL is a prescription medicine used to
treat depression. It is important to talk with
your healthcare provider about the risks of
treating depression and also the risks of not
treating it. You should discuss all treatment
choices with your healthcare provider.
PAXIL is also used to treat:
• Major Depressive Disorder (MDD)
• Obsessive Compulsive Disorder (OCD)
• Panic Disorder
• Social Anxiety Disorder
• Generalized Anxiety Disorder (GAD)
• Post Traumatic Stress Disorder (PTSD)
Talk to your healthcare provider if you do
not think that your condition is getting better
with treatment using PAXIL.
Who should not take PAXIL?
Do not take PAXIL if you:
• are allergic to paroxetine hydrochloride
or any of the ingredients in PAXIL. See
the end of this Medication Guide for a
complete list of ingredients in PAXIL.
2
Reference ID: 2920253
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• take a Monoamine Oxidase Inhibitor
(MAOI), such as PARNATE®
(tranylcypromine), NARDIL®
(phenelzine), or the antibiotic ZYVOX®
(linezolid). Ask your healthcare provider
or pharmacist if you are not sure if you
take an MAOI.
•
Do not take an MAOI within 2
weeks of stopping PAXIL.
•
Do not start PAXIL if you stopped
taking an MAOI in the last 2 weeks.
•
People who take PAXIL close in
time to an MAOI may have serious
or even life-threatening side
effects. Get medical help right
away if you have any of these
symptoms:
• high fever
• uncontrolled muscle spasms
• stiff muscles
• rapid changes in heart rate or
blood pressure
• confusion
• loss of consciousness (pass out)
• take MELLARIL® (thioridazine). Do
not take MELLARIL® together with
PAXIL because this can cause serious
heart rhythm problems or sudden
death.
• take the antipsychotic medicine
pimozide (ORAP®) because this can
cause serious heart problems.
What should I tell my healthcare provider
before taking PAXIL? Ask if you are not
sure.
Before starting PAXIL, tell your healthcare
provider if you:
• are pregnant, may be pregnant, or
plan to become pregnant. There is a
possibility that PAXIL may harm your
unborn baby, including an increased risk
of birth defects, particularly heart
defects. Other risks may include a
serious condition in which there is not
enough oxygen in the baby’s blood.
Your baby may also have certain other
symptoms shortly after birth. Premature
births have also been reported in some
women who used PAXIL during
pregnancy.
• are breastfeeding. PAXIL passes into
your milk. Talk to your healthcare
provider about the best way to feed your
baby while taking PAXIL.
• are taking certain drugs such as:
• triptans used to treat migraine
headache
• other antidepressants (SSRIs, SNRIs,
tricyclics, or lithium) or
antipsychotics
• drugs that affect serotonin, such as
lithium, tramadol, tryptophan, St.
John’s wort
• certain drugs used to treat irregular
heart beats
• certain drugs used to treat
schizophrenia
• certain drugs used to treat HIV
infection
• certain drugs that affect the blood,
such as warfarin, aspirin, and
ibuprofen
• certain drugs used to treat epilepsy
• atomoxetine
• cimetidine
• fentanyl
• metoprolol
• pimozide
• procyclidine
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• tamoxifen
• have liver problems
• have kidney problems
• have heart problems
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have a history of a stroke
• have high blood pressure
• have or had bleeding problems
• have glaucoma (high pressure in the eye)
Tell your healthcare provider about all
the medicines you take, including
prescription and non-prescription medicines,
vitamins, and herbal supplements. PAXIL
and some medicines may interact with each
other, may not work as well, or may cause
serious side effects.
Your healthcare provider or pharmacist can
tell you if it is safe to take PAXIL with your
other medicines. Do not start or stop any
medicine while taking PAXIL without
talking to your healthcare provider first.
If you take PAXIL, you should not take any
other medicines that contain paroxetine
hydrochloride, including PAXIL CR and
PEXEVA® (paroxetine mesylate).
How should I take PAXIL?
• Take PAXIL exactly as prescribed. Your
healthcare provider may need to change
the dose of PAXIL until it is the right
dose for you.
• PAXIL may be taken with or without
food.
• If you are taking PAXIL Oral
Suspension, shake the suspension well
before use.
• If you miss a dose of PAXIL, take the
missed dose as soon as you remember. If
it is almost time for the next dose, skip
the missed dose and take your next dose
at the regular time. Do not take two
doses of PAXIL at the same time.
• If you take too much PAXIL, call your
healthcare provider or poison control
center right away, or get emergency
treatment.
• Do not stop taking PAXIL suddenly
without talking to your doctor (unless
you have symptoms of a severe allergic
reaction). If you need to stop taking
PAXIL, your healthcare provider can tell
you how to safely stop taking it.
What should I avoid while taking
PAXIL?
PAXIL can cause sleepiness or may affect
your ability to make decisions, think clearly,
or react quickly. You should not drive,
operate heavy machinery, or do other
dangerous activities until you know how
PAXIL affects you. Do not drink alcohol
while using PAXIL.
What are possible side effects of PAXIL?
PAXIL may cause serious side effects,
including all of those described in the
section entitled “What is the most important
information I should know about PAXIL?”
Common possible side effects in people who
take PAXIL include:
• nausea
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• sleepiness
• weakness
• dizziness
• feeling anxious or trouble sleeping
• sexual problems
• sweating
• shaking
• not feeling hungry
• dry mouth
• constipation
• infection
• yawning
Tell your healthcare provider if you have
any side effect that bothers you or that does
not go away. These are not all the possible
side effects of PAXIL. For more
information, ask your healthcare provider or
pharmacist.
CALL YOUR DOCTOR FOR
MEDICAL ADVICE ABOUT SIDE
EFFECTS. YOU MAY REPORT SIDE
EFFECTS TO THE FDA AT 1-800-FDA
1088 or 1-800-332-1088.
How should I store PAXIL?
• Store PAXIL Tablets at room
temperature between 59º and 86ºF (15º
and 30ºC).
• Store PAXIL Oral Suspension at or
below 77ºF (25ºC).
• Keep PAXIL away from light.
• Keep bottle of PAXIL closed tightly.
Keep PAXIL and all medicines out of the
reach of children.
General information about PAXIL
Medicines are sometimes prescribed for
purposes other than those listed in a
Medication Guide. Do not use PAXIL for a
condition for which it was not prescribed.
Do not give PAXIL to other people, even if
they have the same condition. It may harm
them.
This Medication Guide summarizes the most
important information about PAXIL. If you
would like more information, talk with your
healthcare provider. You may ask your
healthcare provider or pharmacist for
information about PAXIL that is written for
healthcare professionals.
For more information about PAXIL call 1
888-825-5249 or go to www.us.gsk.com.
What are the ingredients in PAXIL?
Active ingredient: paroxetine
hydrochloride
Inactive ingredients in tablets: dibasic
calcium phosphate dihydrate, hypromellose,
magnesium stearate, polyethylene glycols,
polysorbate 80, sodium starch glycolate,
titanium dioxide, and 1 or more of the
following: D&C Red No. 30 aluminum lake,
D&C Yellow No. 10 aluminum lake, FD&C
Blue No. 2 aluminum lake, FD&C Yellow
No. 6 aluminum lake.
Inactive ingredients in suspension for oral
administration: polacrilin potassium,
microcrystalline cellulose, propylene glycol,
glycerin, sorbitol, methylparaben,
propylparaben, sodium citrate dihydrate,
citric acid anhydrous, sodium saccharin,
flavorings, FD&C Yellow No. 6 aluminum
lake, and simethicone emulsion, USP.
PAXIL is a registered trademark of
GlaxoSmithKline. The other brands listed
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For current labeling information, please visit https://www.fda.gov/drugsatfda
are trademarks of their respective owners
its products.
and are not trademarks of GlaxoSmithKline.
The makers of these brands are not affiliated
This Medication Guide has been approved
with and do not endorse GlaxoSmithKline or
by the U.S. Food and Drug Administration.
Month Year
PXL:XMG company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
©2010, GlaxoSmithKline. All rights reserved.
October 2010
PXL:55PI
6
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1
PRESCRIBING INFORMATION
2
PAXIL CR®
3
(paroxetine hydrochloride)
4
Controlled-Release Tablets
5
6
Suicidality and Antidepressant Drugs
7
Antidepressants increased the risk compared to placebo of suicidal thinking and
8
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
9
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
10
use of PAXIL CR or any other antidepressant in a child, adolescent, or young adult must
11
balance this risk with the clinical need. Short-term studies did not show an increase in the
12
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
13
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
14
older. Depression and certain other psychiatric disorders are themselves associated with
15
increases in the risk of suicide. Patients of all ages who are started on antidepressant
16
therapy should be monitored appropriately and observed closely for clinical worsening,
17
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
18
the need for close observation and communication with the prescriber. PAXIL CR is not
19
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
20
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
21
DESCRIPTION
22
PAXIL CR (paroxetine hydrochloride) is an orally administered psychotropic drug with a
23
chemical structure unrelated to other selective serotonin reuptake inhibitors or to tricyclic,
24
tetracyclic, or other available antidepressant or antipanic agents. It is the hydrochloride salt of a
25
phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)-3S-[(3',4'
26
methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical
27
formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The
28
structural formula of paroxetine hydrochloride is:
29
30
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
31
120° to 138°C and a solubility of 5.4 mg/mL in water.
32
Each enteric, film-coated, controlled-release tablet contains paroxetine hydrochloride
33
equivalent to paroxetine as follows: 12.5 mg–yellow, 25 mg–pink, 37.5 mg–blue. One layer of structural formula
1
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34
the tablet consists of a degradable barrier layer and the other contains the active material in a
35
hydrophilic matrix.
36
Inactive ingredients consist of hypromellose, polyvinylpyrrolidone, lactose monohydrate,
37
magnesium stearate, silicon dioxide, glyceryl behenate, methacrylic acid copolymer type C,
38
sodium lauryl sulfate, polysorbate 80, talc, triethyl citrate, titanium dioxide, polyethylene
39
glycols, and 1 or more of the following colorants: Yellow ferric oxide, red ferric oxide, D&C
40
Red No. 30 aluminum lake, FD&C Yellow No. 6 aluminum lake, D&C Yellow No. 10
41
aluminum lake, FD&C Blue No. 2 aluminum lake.
42
CLINICAL PHARMACOLOGY
43
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
44
disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder (PMDD) is
45
presumed to be linked to potentiation of serotonergic activity in the central nervous system
46
resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT).
47
Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the
48
uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine
49
is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak
50
effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies
51
indicate that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-,
52
dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic,
53
histaminergic, and alpha1-adrenergic receptors has been associated with various anticholinergic,
54
sedative, and cardiovascular effects for other psychotropic drugs.
55
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
56
compound, they are essentially inactive.
57
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
58
solution of the hydrochloride salt. The elimination half-life is approximately 15 to 20 hours after
59
a single dose of PAXIL CR. Paroxetine is extensively metabolized and the metabolites are
60
considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses.
61
Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily
62
excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has
63
not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).
64
Absorption and Distribution: Tablets of PAXIL CR contain a degradable polymeric
65
matrix (GEOMATRIX™) designed to control the dissolution rate of paroxetine over a period of
66
approximately 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric
67
coat delays the start of drug release until tablets of PAXIL CR have left the stomach.
68
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
69
hydrochloride salt. In a study in which normal male and female subjects (n = 23) received single
70
oral doses of PAXIL CR at 4 dosage strengths (12.5 mg, 25 mg, 37.5 mg, and 50 mg), paroxetine
71
Cmax and AUC0-inf increased disproportionately with dose (as seen also with immediate-release
72
formulations). Mean Cmax and AUC0-inf values at these doses were 2.0, 5.5, 9.0, and 12.5 ng/mL,
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73
and 121, 261, 338, and 540 ng•hr./mL, respectively. Tmax was observed typically between 6 and
74
10 hours post-dose, reflecting a reduction in absorption rate compared with immediate-release
75
formulations. The bioavailability of 25 mg PAXIL CR is not affected by food.
76
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
77
plasma.
78
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
79
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
80
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
81
warfarin.
82
Metabolism and Excretion: The mean elimination half-life of paroxetine was 15 to
83
20 hours throughout a range of single doses of PAXIL CR (12.5 mg, 25 mg, 37.5 mg, and
84
50 mg). During repeated administration of PAXIL CR (25 mg once daily), steady state was
85
reached within 2 weeks (i.e., comparable to immediate-release formulations). In a repeat-dose
86
study in which normal male and female subjects (n = 23) received PAXIL CR (25 mg daily),
87
mean steady state Cmax, Cmin, and AUC0-24 values were 30 ng/mL, 20 ng/mL, and 550 ng•hr./mL,
88
respectively.
89
Based on studies using immediate-release formulations, steady-state drug exposure based on
90
AUC0-24 was several-fold greater than would have been predicted from single-dose data. The
91
excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes
92
paroxetine is readily saturable.
93
In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses
94
of the immediate-release formulation of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg
95
daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a
96
saturable metabolic pathway. In comparison to Cmin values after 20 mg daily, values after 40 mg
97
daily were only about 2 to 3 times greater than doubled.
98
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
99
polar and conjugated products of oxidation and methylation, which are readily cleared.
100
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
101
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
102
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
103
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
104
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
105
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
106
interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6).
107
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
108
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
109
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
110
1% as the parent compound over the 10-day post-dosing period.
111
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
112
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic
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113
impairment. The mean plasma concentrations in patients with creatinine clearance below
114
30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
115
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
116
about a 2-fold increase in plasma concentrations (AUC, Cmax).
117
The initial dosage should therefore be reduced in patients with severe renal or hepatic
118
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
119
AND ADMINISTRATION).
120
Elderly Patients: In a multiple-dose study in the elderly at daily doses of 20, 30, and
121
40 mg of the immediate-release formulation, Cmin concentrations were about 70% to 80% greater
122
than the respective Cmin concentrations in nonelderly subjects. Therefore the initial dosage in the
123
elderly should be reduced (see DOSAGE AND ADMINISTRATION).
124
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
125
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
126
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
127
desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions).
128
Clinical Trials
129
Major Depressive Disorder: The efficacy of PAXIL CR controlled-release tablets as a
130
treatment for major depressive disorder has been established in two 12-week, flexible-dose,
131
placebo-controlled studies of patients with DSM-IV Major Depressive Disorder. One study
132
included patients in the age range 18 to 65 years, and a second study included elderly patients,
133
ranging in age from 60 to 88. In both studies, PAXIL CR was shown to be significantly more
134
effective than placebo in treating major depressive disorder as measured by the following:
135
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
136
Global Impression (CGI)–Severity of Illness score.
137
A study of outpatients with major depressive disorder who had responded to
138
immediate-release paroxetine tablets (HDRS total score <8) during an initial 8-week
139
open-treatment phase and were then randomized to continuation on immediate-release paroxetine
140
tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking
141
immediate-release paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness
142
was similar for male and female patients.
143
Panic Disorder: The effectiveness of PAXIL CR in the treatment of panic disorder was
144
evaluated in three 10-week, multicenter, flexible-dose studies (Studies 1, 2, and 3) comparing
145
paroxetine controlled-release (12.5 to 75 mg daily) to placebo in adult outpatients who had panic
146
disorder (DSM-IV), with or without agoraphobia. These trials were assessed on the basis of their
147
outcomes on 3 variables: (1) the proportions of patients free of full panic attacks at endpoint; (2)
148
change from baseline to endpoint in the median number of full panic attacks; and (3) change
149
from baseline to endpoint in the median Clinical Global Impression Severity score. For Studies 1
150
and 2, PAXIL CR was consistently superior to placebo on 2 of these 3 variables. Study 3 failed
151
to consistently demonstrate a significant difference between PAXIL CR and placebo on any of
152
these variables.
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153
For all 3 studies, the mean dose of PAXIL CR for completers at endpoint was approximately
154
50 mg/day. Subgroup analyses did not indicate that there were any differences in treatment
155
outcomes as a function of age or gender.
156
Long-term maintenance effects of the immediate-release formulation of paroxetine in panic
157
disorder were demonstrated in an extension study. Patients who were responders during a
158
10-week double-blind phase with immediate-release paroxetine and during a 3-month
159
double-blind extension phase were randomized to either immediate-release paroxetine or placebo
160
in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were
161
significantly less likely to relapse than comparably treated patients who were randomized to
162
placebo.
163
Social Anxiety Disorder: The efficacy of PAXIL CR as a treatment for social anxiety
164
disorder has been established, in part, on the basis of extrapolation from the established
165
effectiveness of the immediate-release formulation of paroxetine. In addition, the effectiveness
166
of PAXIL CR in the treatment of social anxiety disorder was demonstrated in a 12-week,
167
multicenter, double-blind, flexible-dose, placebo-controlled study of adult outpatients with a
168
primary diagnosis of social anxiety disorder (DSM-IV). In the study, the effectiveness of
169
PAXIL CR (12.5 to 37.5 mg daily) compared to placebo was evaluated on the basis of (1)
170
change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score and (2) the
171
proportion of responders who scored 1 or 2 (very much improved or much improved) on the
172
Clinical Global Impression (CGI) Global Improvement score.
173
PAXIL CR demonstrated statistically significant superiority over placebo on both the LSAS
174
total score and the CGI Improvement responder criterion. For patients who completed the trial,
175
64% of patients treated with PAXIL CR compared to 34.7% of patients treated with placebo
176
were CGI Improvement responders.
177
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
178
function of gender. Subgroup analyses of studies utilizing the immediate-release formulation of
179
paroxetine generally did not indicate differences in treatment outcomes as a function of age, race,
180
or gender.
181
Premenstrual Dysphoric Disorder: The effectiveness of PAXIL CR for the treatment of
182
PMDD utilizing a continuous dosing regimen has been established in 2 placebo-controlled trials.
183
Patients in these trials met DSM-IV criteria for PMDD. In a pool of 1,030 patients, treated with
184
daily doses of PAXIL CR 12.5 or 25 mg/day, or placebo the mean duration of the PMDD
185
symptoms was approximately 11 ± 7 years. Patients on systemic hormonal contraceptives were
186
excluded from these trials. Therefore, the efficacy of PAXIL CR in combination with systemic
187
(including oral) hormonal contraceptives for the continuous daily treatment of PMDD is
188
unknown. In both positive studies, patients (N = 672) were treated with 12.5 mg/day or
189
25 mg/day of PAXIL CR or placebo continuously throughout the menstrual cycle for a period of
190
3 menstrual cycles. The VAS-Total score is a patient-rated instrument that mirrors the diagnostic
191
criteria of PMDD as identified in the DSM-IV, and includes assessments for mood, physical
192
symptoms, and other symptoms. 12.5 mg/day and 25 mg/day of PAXIL CR were significantly
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193
more effective than placebo as measured by change from baseline to the endpoint on the luteal
194
phase VAS-Total score.
195
In a third study employing intermittent dosing, patients (N = 366) were treated for the 2 weeks
196
prior to the onset of menses (luteal phase dosing, also known as intermittent dosing) with
197
12.5 mg/day or 25 mg/day of PAXIL CR or placebo for a period of 3 months. 12.5 mg/day and
198
25 mg/day of PAXIL CR, as luteal phase dosing, was significantly more effective than placebo
199
as measured by change from baseline luteal phase VAS total score.
200
There is insufficient information to determine the effect of race or age on outcome in
201
these studies.
202
INDICATIONS AND USAGE
203
Major Depressive Disorder: PAXIL CR is indicated for the treatment of major depressive
204
disorder.
205
The efficacy of PAXIL CR in the treatment of a major depressive episode was established in
206
two 12-week controlled trials of outpatients whose diagnoses corresponded to the DSM-IV
207
category of major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
208
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly
209
every day for at least 2 weeks) depressed mood or loss of interest or pleasure in nearly all
210
activities, representing a change from previous functioning, and includes the presence of at least
211
5 of the following 9 symptoms during the same 2-week period: Depressed mood, markedly
212
diminished interest or pleasure in usual activities, significant change in weight and/or appetite,
213
insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of
214
guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal
215
ideation.
216
The antidepressant action of paroxetine in hospitalized depressed patients has not been
217
adequately studied.
218
PAXIL CR has not been systematically evaluated beyond 12 weeks in controlled clinical
219
trials; however, the effectiveness of immediate-release paroxetine hydrochloride in maintaining a
220
response in major depressive disorder for up to 1 year has been demonstrated in a
221
placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials). The physician
222
who elects to use PAXIL CR for extended periods should periodically re-evaluate the long-term
223
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
224
Panic Disorder: PAXIL CR is indicated for the treatment of panic disorder, with or without
225
agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
226
unexpected panic attacks and associated concern about having additional attacks, worry about
227
the implications or consequences of the attacks, and/or a significant change in behavior related to
228
the attacks.
229
The efficacy of PAXIL CR controlled-release tablets was established in two 10-week trials in
230
panic disorder patients whose diagnoses corresponded to the DSM-IV category of panic disorder
231
(see CLINICAL PHARMACOLOGY: Clinical Trials).
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232
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
233
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
234
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
235
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
236
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
237
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
238
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11)
239
fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
240
Long-term maintenance of efficacy with the immediate-release formulation of paroxetine was
241
demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder
242
assigned to immediate-release paroxetine demonstrated a lower relapse rate compared to patients
243
on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician
244
who prescribes PAXIL CR for extended periods should periodically re-evaluate the long-term
245
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
246
Social Anxiety Disorder: PAXIL CR is indicated for the treatment of social anxiety disorder,
247
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
248
characterized by a marked and persistent fear of 1 or more social or performance situations in
249
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
250
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
251
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
252
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
253
the person's normal routine, occupational or academic functioning, or social activities or
254
relationships, or there is marked distress about having the phobias. Lesser degrees of
255
performance anxiety or shyness generally do not require psychopharmacological treatment.
256
The efficacy of PAXIL CR as a treatment for social anxiety disorder has been established, in
257
part, on the basis of extrapolation from the established effectiveness of the immediate-release
258
formulation of paroxetine. In addition, the efficacy of PAXIL CR was established in a 12-week
259
trial, in adult outpatients with social anxiety disorder (DSM-IV). PAXIL CR has not been studied
260
in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY: Clinical
261
Trials).
262
The effectiveness of PAXIL CR in long-term treatment of social anxiety disorder, i.e., for
263
more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
264
Therefore, the physician who elects to prescribe PAXIL CR for extended periods should
265
periodically re-evaluate the long-term usefulness of the drug for the individual patient (see
266
DOSAGE AND ADMINISTRATION).
267
Premenstrual Dysphoric Disorder: PAXIL CR is indicated for the treatment of PMDD.
268
The efficacy of PAXIL CR in the treatment of PMDD has been established in 3
269
placebo-controlled trials (see CLINICAL PHARMACOLOGY: Clinical Trials).
270
The essential features of PMDD, according to DSM-IV, include markedly depressed mood,
271
anxiety or tension, affective lability, and persistent anger or irritability. Other features include
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decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite
273
or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast
274
tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur
275
regularly during the luteal phase and remit within a few days following the onset of menses; the
276
disturbance markedly interferes with work or school or with usual social activities and
277
relationships with others. In making the diagnosis, care should be taken to rule out other cyclical
278
mood disorders that may be exacerbated by treatment with an antidepressant.
279
The effectiveness of PAXIL CR in long-term use, that is, for more than 3 menstrual cycles,
280
has not been systematically evaluated in controlled trials. Therefore, the physician who elects to
281
use PAXIL CR for extended periods should periodically re-evaluate the long-term usefulness of
282
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
283
CONTRAINDICATIONS
284
PAXIL CR should not be used in patients taking monoamine oxidase inhibitors (MAOIs),
285
including linezolid (an antibiotic which is a reversible non-selective MAOI) and
286
methylthioninium chloride (methylene blue), or within 2 weeks of stopping treatment with
287
MAOIs (see WARNINGS).
288
Concomitant use with thioridazine is contraindicated (see WARNINGS and
289
PRECAUTIONS).
290
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
291
PAXIL CR is contraindicated in patients with a hypersensitivity to paroxetine or to any of the
292
inactive ingredients in PAXIL CR.
293
WARNINGS
294
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
295
both adult and pediatric, may experience worsening of their depression and/or the emergence of
296
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
297
are taking antidepressant medications, and this risk may persist until significant remission
298
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
299
disorders themselves are the strongest predictors of suicide. There has been a long-standing
300
concern, however, that antidepressants may have a role in inducing worsening of depression and
301
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
302
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
303
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
304
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
305
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
306
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
307
antidepressants compared to placebo in adults aged 65 and older.
308
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
309
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short
310
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo
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controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short
312
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
313
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
314
increase in the younger patients for almost all drugs studied. There were differences in absolute
315
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
316
differences (drug vs placebo), however, were relatively stable within age strata and across
317
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
318
per 1,000 patients treated) are provided in Table 1.
319
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
320
321
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
322
the number was not sufficient to reach any conclusion about drug effect on suicide.
323
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
324
months. However, there is substantial evidence from placebo-controlled maintenance trials in
325
adults with depression that the use of antidepressants can delay the recurrence of depression.
326
All patients being treated with antidepressants for any indication should be monitored
327
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
328
in behavior, especially during the initial few months of a course of drug therapy, or at times
329
of dose changes, either increases or decreases.
330
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
331
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
332
been reported in adult and pediatric patients being treated with antidepressants for major
333
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
334
Although a causal link between the emergence of such symptoms and either the worsening of
335
depression and/or the emergence of suicidal impulses has not been established, there is concern
336
that such symptoms may represent precursors to emerging suicidality.
337
Consideration should be given to changing the therapeutic regimen, including possibly
338
discontinuing the medication, in patients whose depression is persistently worse, or who are
339
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
340
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
341
patient’s presenting symptoms.
342
If the decision has been made to discontinue treatment, medication should be tapered, as
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rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
344
certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION:
345
Discontinuation of Treatment With PAXIL CR, for a description of the risks of discontinuation of
346
PAXIL CR).
347
Families and caregivers of patients being treated with antidepressants for major
348
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
349
alerted about the need to monitor patients for the emergence of agitation, irritability,
350
unusual changes in behavior, and the other symptoms described above, as well as the
351
emergence of suicidality, and to report such symptoms immediately to healthcare
352
providers. Such monitoring should include daily observation by families and caregivers.
353
Prescriptions for PAXIL CR should be written for the smallest quantity of tablets consistent with
354
good patient management, in order to reduce the risk of overdose.
355
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
356
presentation of bipolar disorder. It is generally believed (though not established in controlled
357
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
358
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
359
symptoms described above represent such a conversion is unknown. However, prior to initiating
360
treatment with an antidepressant, patients with depressive symptoms should be adequately
361
screened to determine if they are at risk for bipolar disorder; such screening should include a
362
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
363
depression. It should be noted that PAXIL CR is not approved for use in treating bipolar
364
depression.
365
Potential for Interaction With Monoamine Oxidase Inhibitors: In patients receiving
366
another serotonin reuptake inhibitor drug in combination with an MAOI, there have been
367
reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus,
368
autonomic instability with possible rapid fluctuations of vital signs, and mental status
369
changes that include extreme agitation progressing to delirium and coma. These reactions
370
have also been reported in patients who have recently discontinued that drug and have
371
been started on an MAOI. Some cases presented with features resembling neuroleptic
372
malignant syndrome. While there are no human data showing such an interaction with
373
paroxetine hydrochloride, limited animal data on the effects of combined use of paroxetine
374
and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and
375
evoke behavioral excitation. Therefore, it is recommended that PAXIL CR not be used in
376
combination with an MAOI (including linezolid, an antibiotic which is a reversible non
377
selective MAOI, and methylthioninium chloride [methylene blue]), or within 14 days of
378
discontinuing treatment with an MAOI (see CONTRAINDICATIONS). At least 2 weeks
379
should be allowed after stopping PAXIL CR before starting an MAOI.
380
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions:
381
The development of a potentially life-threatening serotonin syndrome or Neuroleptic
382
Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs
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alone, including treatment with PAXIL CR, but particularly with concomitant use of
384
serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin
385
(including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin
386
syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
387
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
388
neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal
389
symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form
390
can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle
391
rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental
392
status changes. Patients should be monitored for the emergence of serotonin syndrome or
393
NMS-like signs and symptoms.
394
The concomitant use of PAXIL CR with MAOIs intended to treat depression is
395
contraindicated.
396
If concomitant treatment of PAXIL CR with a 5-hydroxytryptamine receptor agonist
397
(triptan) is clinically warranted, careful observation of the patient is advised, particularly
398
during treatment initiation and dose increases.
399
The concomitant use of PAXIL CR with serotonin precursors (such as tryptophan) is
400
not recommended.
401
Treatment with PAXIL CR and any concomitant serotonergic or antidopaminergic
402
agents, including antipsychotics, should be discontinued immediately if the above events
403
occur and supportive symptomatic treatment should be initiated.
404
Potential Interaction With Thioridazine: Thioridazine administration alone produces
405
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
406
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
407
dose related.
408
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
409
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
410
used in combination with thioridazine (see CONTRAINDICATIONS and
411
PRECAUTIONS).
412
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
413
infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of
414
congenital malformations, particularly cardiovascular malformations. The findings from these
415
studies are summarized below:
416
•
A study based on Swedish national registry data demonstrated that infants exposed to
417
paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular
418
malformations (2% risk in paroxetine-exposed infants) compared to the entire registry
419
population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No
420
increase in the risk of overall congenital malformations was seen in the paroxetine-exposed
421
infants. The cardiac malformations in the paroxetine-exposed infants were primarily
422
ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in
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423
severity from those that resolve spontaneously to those which require surgery.
424
•
A separate retrospective cohort study from the United States (United Healthcare data)
425
evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester
426
(n = 815 for paroxetine). This study showed a trend towards an increased risk for
427
cardiovascular malformations for paroxetine (risk of 1.5%) compared to other
428
antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the
429
12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study
430
also suggested an increased risk of overall major congenital malformations including
431
cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants
432
(OR 1.8; 95% confidence interval 1.2 to 2.8).
433
•
Two large case-control studies using separate databases, each with >9,000 birth defect
434
cases and >4,000 controls, found that maternal use of paroxetine during the first trimester
435
of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow
436
tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, 7
437
exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to
438
8.8, 6 exposed infants).
439
Other studies have found varying results as to whether there was an increased risk of overall,
440
cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data
441
over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and
442
congenital malformations included the above-noted studies in addition to others (n = 17 studies
443
that included overall malformations and n = 14 studies that included cardiovascular
444
malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested
445
an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95%
446
confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1
447
to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to
448
determine the extent to which the observed prevalence of cardiovascular malformations might
449
have contributed to that of overall malformations, nor was it possible to determine whether any
450
specific types of cardiovascular malformations might have contributed to the observed
451
prevalence of all cardiovascular malformations.
452
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential
453
harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment,
454
consideration should be given to either discontinuing paroxetine therapy or switching to another
455
antidepressant (see PRECAUTIONS: Discontinuation of Treatment With PAXIL CR). For
456
women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine
457
should only be initiated after consideration of the other available treatment options.
458
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
459
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
460
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
461
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
462
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
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trimester of gestation and continued throughout lactation. This effect occurred at a dose of
464
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
465
rat pup mortality was not determined. The cause of these deaths is not known.
466
Nonteratogenic Effects: Neonates exposed to PAXIL CR and other SSRIs or serotonin
467
and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
468
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
469
complications can arise immediately upon delivery. Reported clinical findings have included
470
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
471
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and
472
constant crying. These features are consistent with either a direct toxic effect of SSRIs and
473
SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the
474
clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome or
475
Neuroleptic Malignant Syndrome (NMS)-like Reactions).
476
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent
477
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in
478
the general population and is associated with substantial neonatal morbidity and mortality. In a
479
retrospective case-control study of 377 women whose infants were born with PPHN and 836
480
women whose infants were born healthy, the risk for developing PPHN was approximately six
481
fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who
482
had not been exposed to antidepressants during pregnancy. There is currently no corroborative
483
evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first
484
study that has investigated the potential risk. The study did not include enough cases with
485
exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
486
There have also been postmarketing reports of premature births in pregnant women exposed
487
to paroxetine or other SSRIs.
488
When treating a pregnant woman with paroxetine during the third trimester, the physician
489
should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND
490
ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201
491
women with a history of major depression who were euthymic at the beginning of pregnancy,
492
women who discontinued antidepressant medication during pregnancy were more likely to
493
experience a relapse of major depression than women who continued antidepressant medication.
494
PRECAUTIONS
495
General: Activation of Mania/Hypomania: During premarketing testing of
496
immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately
497
1.0% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of
498
placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic
499
episodes was 2.2% for immediate-release paroxetine and 11.6% for the combined active-control
500
groups. Among 1,627 patients with major depressive disorder, panic disorder, social anxiety
501
disorder, or PMDD treated with PAXIL CR in controlled clinical studies, there were no reports
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502
of mania or hypomania. As with all drugs effective in the treatment of major depressive disorder,
503
PAXIL CR should be used cautiously in patients with a history of mania.
504
Seizures: During premarketing testing of immediate-release paroxetine hydrochloride,
505
seizures occurred in 0.1% of paroxetine-treated patients, a rate similar to that associated with
506
other drugs effective in the treatment of major depressive disorder. Among 1,627 patients who
507
received PAXIL CR in controlled clinical trials in major depressive disorder, panic disorder,
508
social anxiety disorder, or PMDD, 1 patient (0.1%) experienced a seizure. PAXIL CR should be
509
used cautiously in patients with a history of seizures. It should be discontinued in any patient
510
who develops seizures.
511
Discontinuation of Treatment With PAXIL CR: Adverse events while discontinuing
512
therapy with PAXIL CR were not systematically evaluated in most clinical trials; however, in
513
recent placebo-controlled clinical trials utilizing daily doses of PAXIL CR up to 37.5 mg/day,
514
spontaneously reported adverse events while discontinuing therapy with PAXIL CR were
515
evaluated. Patients receiving 37.5 mg/day underwent an incremental decrease in the daily dose
516
by 12.5 mg/day to a dose of 25 mg/day for 1 week before treatment was stopped. For patients
517
receiving 25 mg/day or 12.5 mg/day, treatment was stopped without an incremental decrease in
518
dose. With this regimen in those studies, the following adverse events were reported for
519
PAXIL CR, at an incidence of 2% or greater for PAXIL CR and were at least twice that reported
520
for placebo: Dizziness, nausea, nervousness, and additional symptoms described by the
521
investigator as associated with tapering or discontinuing PAXIL CR (e.g., emotional lability,
522
headache, agitation, electric shock sensations, fatigue, and sleep disturbances). These events
523
were reported as serious in 0.3% of patients who discontinued therapy with PAXIL CR.
524
During marketing of PAXIL CR and other SSRIs and SNRIs, there have been spontaneous
525
reports of adverse events occurring upon discontinuation of these drugs, (particularly when
526
abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory
527
disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety,
528
confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events
529
are generally self-limiting, there have been reports of serious discontinuation symptoms.
530
Patients should be monitored for these symptoms when discontinuing treatment with
531
PAXIL CR. A gradual reduction in the dose rather than abrupt cessation is recommended
532
whenever possible. If intolerable symptoms occur following a decrease in the dose or upon
533
discontinuation of treatment, then resuming the previously prescribed dose may be considered.
534
Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see
535
DOSAGE AND ADMINISTRATION).
536
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of
537
treatment with paroxetine in pediatric patients.
538
Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk
539
of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a
540
result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other
541
studies have failed to demonstrate such a risk. It is uncertain whether the co-administration of
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542
paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study
543
suggests that the risk may increase with longer duration of coadministration. When tamoxifen is
544
used for the treatment or prevention of breast cancer, prescribers should consider using an
545
alternative antidepressant with little or no CYP2D6 inhibition.
546
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
547
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
548
such as an inability to sit or stand still usually associated with subjective distress. This is most
549
likely to occur within the first few weeks of treatment.
550
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
551
including PAXIL CR. In many cases, this hyponatremia appears to be the result of the syndrome
552
of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
553
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
554
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
555
volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of
556
PAXIL CR should be considered in patients with symptomatic hyponatremia and appropriate
557
medical intervention should be instituted.
558
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
559
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
560
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
561
seizure, coma, respiratory arrest, and death.
562
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
563
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
564
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
565
and cohort design) have demonstrated an association between use of drugs that interfere with
566
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
567
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
568
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
569
with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
570
coagulation.
571
Bone Fracture: Epidemiological studies on bone fracture risk following exposure to some
572
antidepressants, including SSRIs, have reported an association between antidepressant treatment
573
and fractures. There are multiple possible causes for this observation and it is unknown to what
574
extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological
575
fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral
576
density, should be considered in patients treated with paroxetine who present with unexplained
577
bone pain, point tenderness, swelling, or bruising.
578
Use in Patients With Concomitant Illness: Clinical experience with immediate-release
579
paroxetine hydrochloride in patients with certain concomitant systemic illness is limited. Caution
580
is advisable in using PAXIL CR in patients with diseases or conditions that could affect
581
metabolism or hemodynamic responses.
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582
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
583
paroxetine hydrochloride. A few cases of acute angle closure glaucoma associated with therapy
584
with immediate-release paroxetine have been reported in the literature. As mydriasis can cause
585
acute angle closure in patients with narrow angle glaucoma, caution should be used when
586
PAXIL CR is prescribed for patients with narrow angle glaucoma.
587
PAXIL CR or the immediate-release formulation has not been evaluated or used to any
588
appreciable extent in patients with a recent history of myocardial infarction or unstable heart
589
disease. Patients with these diagnoses were excluded from clinical studies during premarket
590
testing. Evaluation of electrocardiograms of 682 patients who received immediate-release
591
paroxetine hydrochloride in double-blind, placebo-controlled trials, however, did not indicate
592
that paroxetine is associated with the development of significant ECG abnormalities. Similarly,
593
paroxetine hydrochloride does not cause any clinically important changes in heart rate or blood
594
pressure.
595
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
596
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
597
be used in such patients (see DOSAGE AND ADMINISTRATION).
598
Information for Patients: PAXIL CR should not be chewed or crushed, and should be
599
swallowed whole.
600
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
601
PAXIL CR and triptans, tramadol, or other serotonergic agents.
602
Prescribers or other health professionals should inform patients, their families, and their
603
caregivers about the benefits and risks associated with treatment with PAXIL CR and should
604
counsel them in its appropriate use. A patient Medication Guide about “Antidepressant
605
Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is
606
available for PAXIL CR. The prescriber or health professional should instruct patients, their
607
families, and their caregivers to read the Medication Guide and should assist them in
608
understanding its contents. Patients should be given the opportunity to discuss the contents of the
609
Medication Guide and to obtain answers to any questions they may have. The complete text of
610
the Medication Guide is reprinted at the end of this document.
611
Patients should be advised of the following issues and asked to alert their prescriber if these
612
occur while taking PAXIL CR.
613
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
614
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
615
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
616
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
617
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
618
down. Families and caregivers of patients should be advised to look for the emergence of such
619
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
620
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
621
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
16
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
622
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
623
close monitoring and possibly changes in the medication.
624
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
625
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
626
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
627
interfere with serotonin reuptake and these agents has been associated with an increased risk of
628
bleeding.
629
Interference With Cognitive and Motor Performance: Any psychoactive drug may
630
impair judgment, thinking, or motor skills. Although in controlled studies immediate-release
631
paroxetine hydrochloride has not been shown to impair psychomotor performance, patients
632
should be cautioned about operating hazardous machinery, including automobiles, until they are
633
reasonably certain that therapy with PAXIL CR does not affect their ability to engage in such
634
activities.
635
Completing Course of Therapy: While patients may notice improvement with use of
636
PAXIL CR in 1 to 4 weeks, they should be advised to continue therapy as directed.
637
Concomitant Medications: Patients should be advised to inform their physician if they are
638
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
639
interactions.
640
Alcohol: Although immediate-release paroxetine hydrochloride has not been shown to
641
increase the impairment of mental and motor skills caused by alcohol, patients should be advised
642
to avoid alcohol while taking PAXIL CR.
643
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
644
intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic
645
and Nonteratogenic Effects).
646
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
647
infant (see PRECAUTIONS: Nursing Mothers).
648
Laboratory Tests: There are no specific laboratory tests recommended.
649
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
650
between paroxetine and tryptophan may occur when they are coadministered. Adverse
651
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
652
reported when tryptophan was administered to patients taking immediate-release paroxetine.
653
Consequently, concomitant use of PAXIL CR with tryptophan is not recommended (see
654
WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions).
655
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
656
Pimozide: In a controlled study of healthy volunteers, after immediate-release paroxetine
657
hydrochloride was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide
658
was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to
659
pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6
660
inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its
661
known ability to prolong the QT interval, concomitant use of pimozide and PAXIL CR is
17
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
662
contraindicated (see CONTRAINDICATIONS).
663
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
664
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
665
PAXIL CR is coadministered with other drugs that may affect the serotonergic neurotransmitter
666
systems, such as triptans, lithium, fentanyl, tramadol, or St. John's Wort (see WARNINGS:
667
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions). The
668
concomitant use of PAXIL CR with MAOIs (including linezolid and methylene blue) is
669
contraindicated (see CONTRAINDICATIONS). The concomitant use of PAXIL CR with other
670
SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions,
671
Tryptophan).
672
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
673
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
674
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
675
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
676
of PAXIL CR and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs
677
That Interfere With Hemostasis).
678
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
679
an SSRI and a triptan. If concomitant use of PAXIL CR with a triptan is clinically warranted,
680
careful observation of the patient is advised, particularly during treatment initiation and dose
681
increases (see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)
682
like Reactions).
683
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
684
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
685
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
686
where immediate-release paroxetine (30 mg once daily) was dosed orally for 4 weeks,
687
steady-state plasma concentrations of paroxetine were increased by approximately 50% during
688
coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore,
689
when these drugs are administered concurrently, dosage adjustment of PAXIL CR after the
690
starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s
691
pharmacokinetics was not studied.
692
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
693
single oral 30-mg dose of immediate-release paroxetine was administered at phenobarbital
694
steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an
695
average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of
696
paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits
697
nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs
698
are both being chronically dosed. No initial dosage adjustment with PAXIL CR is considered
699
necessary when coadministered with phenobarbital; any subsequent adjustment should be guided
700
by clinical effect.
701
Phenytoin: When a single oral 30-mg dose of immediate-release paroxetine was
18
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
702
administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T½
703
were reduced (by an average of 50% and 35%, respectively) compared to immediate-release
704
paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin
705
was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was
706
slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs
707
exhibit nonlinear pharmacokinetics, the above studies may not address the case where the
708
2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary
709
when PAXIL CR is coadministered with phenytoin; any subsequent adjustments should be
710
guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports).
711
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
712
treatment of major depressive disorder (paroxetine, other SSRIs, and many tricyclics), are
713
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
714
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
715
(>90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In 1 study, daily
716
dosing of immediate-release paroxetine (20 mg once daily) under steady-state conditions
717
increased single-dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately
718
2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6
719
substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients
720
stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone
721
approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and
722
increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone)
723
approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has
724
been evaluated when both drugs were at steady state. In healthy volunteers who were extensive
725
metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg
726
atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values
727
that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than
728
when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it
729
is recommended that atomoxetine be initiated at a reduced dose when given with paroxetine.
730
Concomitant use of PAXIL CR with other drugs metabolized by cytochrome CYP2D6 has not
731
been formally studied but may require lower doses than usually prescribed for either PAXIL CR
732
or the other drug.
733
Therefore, coadministration of PAXIL CR with other drugs that are metabolized by this
734
isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g.,
735
nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines,
736
risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that
737
inhibit this enzyme (e.g., quinidine), should be approached with caution.
738
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
739
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
740
coadministered (see CONTRAINDICATIONS and WARNINGS).
741
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6
19
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
742
by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and
743
hence reduced efficacy of tamoxifen (see PRECAUTIONS).
744
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
745
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
746
PRECAUTIONS: Tricyclic Antidepressants [TCAs]).
747
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
748
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
749
CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro
750
studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times
751
more potent than paroxetine as an inhibitor of the metabolism of several substrates for this
752
enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the
753
assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on
754
terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s
755
extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.
756
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of TCAs
757
with PAXIL CR, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations
758
may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is
759
coadministered with PAXIL CR (see PRECAUTIONS: Drugs Metabolized by Cytochrome
760
CYP2D6).
761
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
762
protein, administration of PAXIL CR to a patient taking another drug that is highly protein
763
bound may cause increased free concentrations of the other drug, potentially resulting in adverse
764
events. Conversely, adverse effects could result from displacement of paroxetine by other highly
765
bound drugs.
766
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
767
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
768
the case-control and cohort design that have demonstrated an association between use of
769
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
770
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
771
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
772
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
773
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
774
Alcohol: Although paroxetine does not increase the impairment of mental and motor skills
775
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL CR.
776
Lithium: A multiple-dose study with immediate-release paroxetine hydrochloride has shown
777
that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However,
778
due to the potential for serotonin syndrome, caution is advised when immediate-release
779
paroxetine hydrochloride is coadministered with lithium.
780
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
781
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
20
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
782
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
783
PAXIL CR and digoxin should be undertaken with caution.
784
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
785
kinetics. The effects of paroxetine on diazepam were not evaluated.
786
Procyclidine: Daily oral dosing of immediate-release paroxetine (30 mg once daily)
787
increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by
788
35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If
789
anticholinergic effects are seen, the dose of procyclidine should be reduced.
790
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
791
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
792
coadministration with immediate-release paroxetine (30 mg once daily) for the final 10 days. The
793
effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS:
794
Postmarketing Reports).
795
Theophylline: Reports of elevated theophylline levels associated with immediate-release
796
paroxetine treatment have been reported. While this interaction has not been formally studied, it
797
is recommended that theophylline levels be monitored when these drugs are concurrently
798
administered.
799
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
800
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
801
clinical effect (tolerability and efficacy).
802
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
803
ECT and PAXIL CR.
804
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
805
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
806
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to approximately 2
807
(mouse) and 3 (rat) times the MRHD on a mg/m2 basis. There was a significantly greater number
808
of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for
809
control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
810
trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats
811
were not affected. Although there was a dose-related increase in the number of tumors in mice,
812
there was no drug-related increase in the number of mice with tumors. The relevance of these
813
findings to humans is unknown.
814
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
815
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
816
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
817
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
818
Impairment of Fertility: Some clinical studies have shown that SSRIs (including
819
paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some
820
men.
821
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of
21
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
822
15 mg/kg/day, which is approximately twice the MRHD on a mg/m2 basis. Irreversible lesions
823
occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks.
824
These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and
825
atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at
826
25 mg/kg/day (approximately 8 and 4 times the MRHD on a mg/m2 basis).
827
Pregnancy: Pregnancy Category D. See WARNINGS: Usage in Pregnancy: Teratogenic and
828
Nonteratogenic Effects.
829
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
830
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
831
should be exercised when PAXIL CR is administered to a nursing woman.
832
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
833
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Three placebo
834
controlled trials in 752 pediatric patients with MDD have been conducted with immediate
835
release PAXIL, and the data were not sufficient to support a claim for use in pediatric patients.
836
Anyone considering the use of PAXIL CR in a child or adolescent must balance the potential
837
risks with the clinical need. Decreased appetite and weight loss have been observed in association
838
with the use of SSRIs. Consequently, regular monitoring of weight and growth should be
839
performed in children and adolescents treated with an SSRI such as PAXIL CR.
840
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
841
events were reported in at least 2% of pediatric patients treated with immediate-release
842
paroxetine hydrochloride and occurred at a rate at least twice that for pediatric patients receiving
843
placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and
844
mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.
845
Events reported upon discontinuation of treatment with immediate-release paroxetine
846
hydrochloride in the pediatric clinical trials that included a taper phase regimen, which occurred
847
in at least 2% of patients who received immediate-release paroxetine hydrochloride and which
848
occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal
849
ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and
850
abdominal pain (see DOSAGE AND ADMINISTRATIONS: Discontinuation of Treatment With
851
PAXIL CR).
852
Geriatric Use: SSRIs and SNRIs, including PAXIL CR, have been associated with cases of
853
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
854
event (see PRECAUTIONS: Hyponatremia).
855
In worldwide premarketing clinical trials with immediate-release paroxetine hydrochloride,
856
17% of paroxetine-treated patients (approximately 700) were 65 years or older. Pharmacokinetic
857
studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended;
858
there were, however, no overall differences in the adverse event profile between elderly and
859
younger patients, and effectiveness was similar in younger and older patients (see CLINICAL
860
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
861
In a controlled study focusing specifically on elderly patients with major depressive disorder,
22
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
862
PAXIL CR was demonstrated to be safe and effective in the treatment of elderly patients (>60
863
years) with major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials and
864
ADVERSE REACTIONS: Table 3.)
865
ADVERSE REACTIONS
866
The information included under the “Adverse Findings Observed in Short-Term,
867
Placebo-Controlled Trials With PAXIL CR” subsection of ADVERSE REACTIONS is based on
868
data from 11 placebo-controlled clinical trials. Three of these studies were conducted in patients
869
with major depressive disorder, 3 studies were done in patients with panic disorder, 1 study was
870
conducted in patients with social anxiety disorder, and 4 studies were done in female patients
871
with PMDD. Two of the studies in major depressive disorder, which enrolled patients in the age
872
range 18 to 65 years, are pooled. Information from a third study of major depressive disorder,
873
which focused on elderly patients (60 to 88 years), is presented separately as is the information
874
from the panic disorder studies and the information from the PMDD studies. Information on
875
additional adverse events associated with PAXIL CR and the immediate-release formulation of
876
paroxetine hydrochloride is included in a separate subsection (see Other Events Observed During
877
the Clinical Development of Paroxetine).
878
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials With PAXIL
879
CR:
880
Adverse Events Associated With Discontinuation of Treatment: Major Depressive
881
Disorder: Ten percent (21/212) of patients treated with PAXIL CR discontinued treatment due
882
to an adverse event in a pool of 2 studies of patients with major depressive disorder. The most
883
common events (≥1%) associated with discontinuation and considered to be drug related (i.e.,
884
those events associated with dropout at a rate approximately twice or greater for PAXIL CR
885
compared to placebo) included the following:
PAXIL CR
(n = 212)
Placebo
(n = 211)
Nausea
3.7%
0.5%
Asthenia
1.9%
0.5%
Dizziness
1.4%
0.0%
Somnolence
1.4%
0.0%
886
887
In a placebo-controlled study of elderly patients with major depressive disorder, 13% (13/104)
888
of patients treated with PAXIL CR discontinued due to an adverse event. Events meeting the
889
above criteria included the following:
23
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nausea
Headache
Depression
LFT’s abnormal
890
PAXIL CR
Placebo
(n = 104)
(n = 109)
2.9%
0.0%
1.9%
0.9%
1.9%
0.0%
1.9%
0.0%
891
Panic Disorder: Eleven percent (50/444) of patients treated with PAXIL CR in panic
892
disorder studies discontinued treatment due to an adverse event. Events meeting the above
893
criteria included the following:
PAXIL CR
Placebo
(n = 444)
(n = 445)
Nausea
2.9%
0.4%
Insomnia
1.8%
0.0%
Headache
1.4%
0.2%
Asthenia
1.1%
0.0%
894
895
Social Anxiety Disorder: Three percent (5/186) of patients treated with PAXIL CR in the
896
social anxiety disorder study discontinued treatment due to an adverse event. Events meeting the
897
above criteria included the following:
PAXIL CR
Placebo
(n = 186)
(n = 184)
Nausea
2.2%
0.5%
Headache
1.6%
0.5%
Diarrhea
1.1%
0.5%
898
899
Premenstrual Dysphoric Disorder: Spontaneously reported adverse events were
900
monitored in studies of both continuous and intermittent dosing of PAXIL CR in the treatment of
901
PMDD. Generally, there were few differences in the adverse event profiles of the 2 dosing
902
regimens. Thirteen percent (88/681) of patients treated with PAXIL CR in PMDD studies of
903
continuous dosing discontinued treatment due to an adverse event.
904
The most common events (≥1%) associated with discontinuation in either group treated with
905
PAXIL CR with an incidence rate that is at least twice that of placebo in PMDD trials that
906
employed a continuous dosing regimen are shown in the following table. This table also shows
907
those events that were dose dependent (indicated with an asterisk) as defined as events having an
908
incidence rate with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR
909
(as well as the placebo group).
24
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PAXIL CR
25 mg
(n = 348)
PAXIL CR
12.5 mg
(n = 333)
Placebo
(n = 349)
TOTAL
15%
9.9%
6.3%
Nauseaa
6.0%
2.4%
0.9%
Asthenia
4.9%
3.0%
1.4%
Somnolencea
4.3%
1.8%
0.3%
Insomnia
2.3%
1.5%
0.0%
Concentration Impaireda
2.0%
0.6%
0.3%
Dry moutha
2.0%
0.6%
0.3%
Dizzinessa
1.7%
0.6%
0.6%
Decreased Appetitea
1.4%
0.6%
0.0%
Sweatinga
1.4%
0.0%
0.3%
Tremora
1.4%
0.3%
0.0%
Yawna
1.1%
0.0%
0.0%
Diarrhea
0.9%
1.2%
0.0%
910
a. Events considered to be dose dependent are defined as events having an incidence rate with
911
25 mg of PAXIL CR that was at least twice that with 12.5 mg of PAXIL CR (as well as the
912
placebo group).
913
914
Commonly Observed Adverse Events: Major Depressive Disorder: The most
915
commonly observed adverse events associated with the use of PAXIL CR in a pool of 2 trials
916
(incidence of 5.0% or greater and incidence for PAXIL CR at least twice that for placebo,
917
derived from Table 2) were: Abnormal ejaculation, abnormal vision, constipation, decreased
918
libido, diarrhea, dizziness, female genital disorders, nausea, somnolence, sweating, trauma,
919
tremor, and yawning.
920
Using the same criteria, the adverse events associated with the use of PAXIL CR in a study of
921
elderly patients with major depressive disorder were: Abnormal ejaculation, constipation,
922
decreased appetite, dry mouth, impotence, infection, libido decreased, sweating, and tremor.
923
Panic Disorder: In the pool of panic disorder studies, the adverse events meeting these
924
criteria were: Abnormal ejaculation, somnolence, impotence, libido decreased, tremor, sweating,
925
and female genital disorders (generally anorgasmia or difficulty achieving orgasm).
926
Social Anxiety Disorder: In the social anxiety disorder study, the adverse events meeting
927
these criteria were: Nausea, asthenia, abnormal ejaculation, sweating, somnolence, impotence,
928
insomnia, and libido decreased.
929
Premenstrual Dysphoric Disorder: The most commonly observed adverse events
930
associated with the use of PAXIL CR either during continuous dosing or luteal phase dosing
931
(incidence of 5% or greater and incidence for PAXIL CR at least twice that for placebo, derived
932
from Table 6) were: Nausea, asthenia, libido decreased, somnolence, insomnia, female genital
933
disorders, sweating, dizziness, diarrhea, and constipation.
934
In the luteal phase dosing PMDD trial, which employed dosing of 12.5 mg/day or 25 mg/day
25
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
935
of PAXIL CR limited to the 2 weeks prior to the onset of menses over 3 consecutive menstrual
936
cycles, adverse events were evaluated during the first 14 days of each off-drug phase. When the
937
3 off-drug phases were combined, the following adverse events were reported at an incidence of
938
2% or greater for PAXIL CR and were at least twice the rate of that reported for placebo:
939
Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia (2.4% versus 0.8%),
940
sinusitis (2.4% versus 0%), and asthenia (2.0% versus 0.8%).
941
Incidence in Controlled Clinical Trials: Table 2 enumerates adverse events that occurred at
942
an incidence of 1% or more among patients treated with PAXIL CR, aged 18 to 65, who
943
participated in 2 short-term (12-week) placebo-controlled trials in major depressive disorder in
944
which patients were dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse
945
events reported at an incidence of 5% or greater among elderly patients (ages 60 to 88) treated
946
with PAXIL CR who participated in a short-term (12-week) placebo-controlled trial in major
947
depressive disorder in which patients were dosed in a range of 12.5 mg to 50 mg/day. Table 4
948
enumerates adverse events reported at an incidence of 1% or greater among patients (19 to 72
949
years) treated with PAXIL CR who participated in short-term (10-week) placebo-controlled trials
950
in panic disorder in which patients were dosed in a range of 12.5 mg to 75 mg/day. Table 5
951
enumerates adverse events reported at an incidence of 1% or greater among adult patients treated
952
with PAXIL CR who participated in a short-term (12-week), double-blind, placebo-controlled
953
trial in social anxiety disorder in which patients were dosed in a range of 12.5 to 37.5 mg/day.
954
Table 6 enumerates adverse events that occurred at an incidence of 1% or more among patients
955
treated with PAXIL CR who participated in three, 12-week, placebo-controlled trials in PMDD
956
in which patients were dosed at 12.5 mg/day or 25 mg/day and in one 12-week
957
placebo-controlled trial in which patients were dosed for 2 weeks prior to the onset of menses
958
(luteal phase dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified
959
using a standard COSTART-based Dictionary terminology.
960
The prescriber should be aware that these figures cannot be used to predict the incidence of
961
side effects in the course of usual medical practice where patient characteristics and other factors
962
differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be
963
compared with figures obtained from other clinical investigations involving different treatments,
964
uses, and investigators. The cited figures, however, do provide the prescribing physician with
965
some basis for estimating the relative contribution of drug and nondrug factors to the side effect
966
incidence rate in the population studied.
26
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
967
968
Table 2. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
969
PAXIL CR in a Pool of 2 Studies in Major Depressive Disordera,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 212)
Placebo
(n = 211)
Body as a Whole
Headache
27%
20%
Asthenia
14%
9%
Infectionc
8%
5%
Abdominal Pain
7%
4%
Back Pain
5%
3%
Traumad
5%
1%
Paine
3%
1%
Allergic Reactionf
2%
1%
Cardiovascular System
Tachycardia
Vasodilatationg
1%
2%
0%
0%
Digestive System
Nausea
22%
10%
Diarrhea
18%
7%
Dry Mouth
15%
8%
Constipation
10%
4%
Flatulence
6%
4%
Decreased Appetite
4%
2%
Vomiting
2%
1%
Nervous System
Somnolence
22%
8%
Insomnia
17%
9%
Dizziness
14%
4%
Libido Decreased
7%
3%
Tremor
7%
1%
Hypertonia
3%
1%
Paresthesia
3%
1%
Agitation
2%
1%
Confusion
1%
0%
Respiratory System
Yawn
5%
0%
Rhinitis
4%
1%
Cough Increased
2%
1%
Bronchitis
1%
0%
27
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
970
Skin and Appendages
Sweating
Photosensitivity
6%
2%
2%
0%
Special Senses
Abnormal Visionh
Taste Perversion
5%
2%
1%
0%
Urogenital System
Abnormal Ejaculationi,j
Female Genital Disorderi,k
Impotencei
Urinary Tract Infection
Menstrual Disorderi
Vaginitisi
26%
10%
5%
3%
2%
2%
1%
<1%
3%
1%
<1%
0%
971
a. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the
972
placebo incidence are not included. These events are: Abnormal dreams, anxiety, arthralgia,
973
depersonalization, dysmenorrhea, dyspepsia, hyperkinesia, increased appetite, myalgia,
974
nervousness, pharyngitis, purpura, rash, respiratory disorder, sinusitis, urinary frequency, and
975
weight gain.
976
b. <1% means greater than zero and less than 1%.
977
c. Mostly flu.
978
d. A wide variety of injuries with no obvious pattern.
979
e. Pain in a variety of locations with no obvious pattern.
980
f. Most frequently seasonal allergic symptoms.
981
g. Usually flushing.
982
h. Mostly blurred vision.
983
i. Based on the number of males or females.
984
j. Mostly anorgasmia or delayed ejaculation.
985
k. Mostly anorgasmia or delayed orgasm.
28
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
986
987
Table 3. Treatment-Emergent Adverse Events Occurring in ≥5% of
988
Patients Treated With PAXIL CR in a Study of Elderly Patients With Major Depressive
989
Disordera,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 104)
Placebo
(n = 109)
Body as a Whole
Headache
17%
13%
Asthenia
15%
14%
Trauma
8%
5%
Infection
6%
2%
Digestive System
Dry Mouth
18%
7%
Diarrhea
15%
9%
Constipation
13%
5%
Dyspepsia
13%
10%
Decreased Appetite
12%
5%
Flatulence
8%
7%
Nervous System
Somnolence
21%
12%
Insomnia
10%
8%
Dizziness
9%
5%
Libido Decreased
8%
<1%
Tremor
7%
0%
Skin and Appendages
Sweating
10%
<1%
Urogenital System
Abnormal Ejaculationc,d
Impotencec
17%
9%
3%
3%
990
a. Adverse events for which the PAXIL CR reporting incidence was less than or equal to the
991
placebo incidence are not included. These events are nausea and respiratory disorder.
992
b. <1% means greater than zero and less than 1%.
993
c. Based on the number of males.
994
d. Mostly anorgasmia or delayed ejaculation.
995
29
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
996
Table 4. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
997
PAXIL CR in a Pool of 3 Panic Disorder Studiesa,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 444)
Placebo
(n = 445)
Body as a Whole
Asthenia
15%
10%
Abdominal Pain
6%
4%
Traumac
5%
4%
Cardiovascular System
Vasodilationd
3%
2%
Digestive System
Nausea
23%
17%
Dry Mouth
13%
9%
Diarrhea
12%
9%
Constipation
9%
6%
Decreased Appetite
8%
6%
Metabolic/Nutritional
Disorders
Weight Loss
1%
0%
Musculoskeletal System
Myalgia
5%
3%
Nervous System
Insomnia
20%
11%
Somnolence
20%
9%
Libido Decreased
9%
4%
Nervousness
8%
7%
Tremor
8%
2%
Anxiety
5%
4%
Agitation
3%
2%
Hypertoniae
2%
<1%
Myoclonus
2%
<1%
Respiratory System
Sinusitis
Yawn
8%
3%
5%
0%
Skin and Appendages
Sweating
7%
2%
Special Senses
Abnormal Visionf
3%
<1%
Urogenital System
Abnormal Ejaculationg,h
27%
3%
Impotenceg
10%
1%
Female Genital Disordersi,j
7%
1%
Urinary Frequency
2%
<1%
Urination Impaired
2%
<1%
Vaginitisi
1%
<1%
30
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
998
a. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the
999
placebo rate are not included. These events are: Abnormal dreams, allergic reaction, back
1000
pain, bronchitis, chest pain, concentration impaired, confusion, cough increased, depression,
1001
dizziness, dysmenorrhea, dyspepsia, fever, flatulence, headache, increased appetite, infection,
1002
menstrual disorder, migraine, pain, paresthesia, pharyngitis, respiratory disorder, rhinitis,
1003
tachycardia, taste perversion, thinking abnormal, urinary tract infection, and vomiting.
1004
b. <1% means greater than zero and less than 1%.
1005
c. Various physical injuries.
1006
d. Mostly flushing.
1007
e. Mostly muscle tightness or stiffness.
1008
f. Mostly blurred vision.
1009
g. Based on the number of male patients.
1010
h. Mostly anorgasmia or delayed ejaculation.
1011
i. Based on the number of female patients.
1012
j. Mostly anorgasmia or difficulty achieving orgasm.
1013
1014
Table 5. Treatment-Emergent Adverse Effects Occurring in ≥1% of Patients Treated
1015
With PAXIL CR in a Social Anxiety Disorder Studya,b
Body System/Adverse Event
% Reporting Event
PAXIL CR
(n = 186)
Placebo
(n = 184)
Body as a Whole
Headache
23%
17%
Asthenia
18%
7%
Abdominal Pain
5%
4%
Back Pain
4%
1%
Traumac
3%
<1%
Allergic Reactiond
2%
<1%
Chest Pain
1%
<1%
Cardiovascular System
Hypertension
2%
0%
Migraine
2%
1%
Tachycardia
2%
1%
Digestive System
Nausea
22%
6%
Diarrhea
9%
8%
Constipation
5%
2%
Dry Mouth
3%
2%
Dyspepsia
2%
<1%
Decreased Appetite
1%
<1%
31
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tooth Disorder
1%
0%
Metabolic/Nutritional
Disorders
Weight Gain
3%
1%
Weight Loss
1%
0%
Nervous System
Insomnia
9%
4%
Somnolence
9%
4%
Libido Decreased
8%
1%
Dizziness
7%
4%
Tremor
4%
2%
Anxiety
2%
1%
Concentration Impaired
2%
0%
Depression
2%
1%
Myoclonus
1%
<1%
Paresthesia
1%
<1%
Respiratory System
Yawn
2%
0%
Skin and Appendages
Sweating
Eczema
14%
1%
3%
0%
Special Senses
Abnormal Visione
2%
0%
Abnormality of
Accommodation
2%
0%
Urogenital System
Abnormal Ejaculationf,g
15%
1%
Impotencef
9%
0%
Female Genital Disordersh,i
3%
0%
1016
a. Adverse events for which the reporting rate for PAXIL CR was less than or equal to the
1017
placebo rate are not included. These events are: Dysmenorrhea, flatulence, gastroenteritis,
1018
hypertonia, infection, pain, pharyngitis, rash, respiratory disorder, rhinitis, and vomiting.
1019
b. <1% means greater than zero and less than 1%.
1020
c. Various physical injuries.
1021
d. Most frequently seasonal allergic symptoms.
1022
e. Mostly blurred vision.
1023
f. Based on the number of male patients.
1024
g. Mostly anorgasmia or delayed ejaculation.
1025
h. Based on the number of female patients.
1026
i. Mostly anorgasmia or difficulty achieving orgasm.
32
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1027
1028
Table 6. Treatment-Emergent Adverse Events Occurring in ≥1% of Patients Treated With
1029
PAXIL CR in a Pool of 3 Premenstrual Dysphoric Disorder Studies With Continuous
1030
Dosing or in 1 Premenstrual Dysphoric Disorder Study With Luteal Phase Dosinga,b,c
Body System/Adverse
Event
% Reporting Event
Continuous Dosing
Luteal Phase Dosing
PAXIL CR
(n = 681)
Placebo
(n = 349)
PAXIL CR
(n = 246)
Placebo
(n = 120)
Body as a Whole
Asthenia
Headache
Infection
Abdominal pain
17%
6%
15%
12%
6%
4%
-
-
15%
4%
-
-
-
-
3%
0%
Cardiovascular System
Migraine
1%
<1%
-
-
Digestive System
Nausea
Diarrhea
Constipation
Dry Mouth
Increased Appetite
Decreased Appetite
Dyspepsia
Gingivitis
17%
7%
6%
2%
5%
1%
4%
2%
3%
<1%
2%
<1%
2%
1%
-
-
18%
2%
6%
0%
2%
<1%
2%
<1%
-
-
2%
0%
2%
2%
1%
0%
Metabolic and
Nutritional Disorders
Generalized Edema
-
-
1%
<1%
Weight Gain
-
-
1%
<1%
Musculoskeletal
System
Arthralgia
2%
1%
-
-
Nervous System
Libido Decreased
12%
5%
9%
6%
Somnolence
9%
2%
3%
<1%
Insomnia
8%
2%
7%
3%
Dizziness
7%
3%
6%
3%
Tremor
4%
<1%
5%
0%
Concentration Impaired
3%
<1%
1%
0%
Nervousness
2%
<1%
3%
2%
Anxiety
2%
1%
-
-
33
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lack of Emotion
Depression
Vertigo
Abnormal Dreams
Amnesia
2%
-
-
1%
-
<1%
-
-
<1%
-
-
2%
2%
-
1%
-
<1%
<1%
-
0%
Respiratory System
Sinusitis
Yawn
Bronchitis
Cough Increased
-
2%
-
1%
-
<1%
-
<1%
4%
-
2%
-
2%
-
0%
-
Skin and Appendages
Sweating
7%
<1%
6%
<1%
Special Senses
Abnormal Vision
-
-
1%
0%
Urogenital System
Female Genital
Disordersd
Menorrhagia
Vaginal Moniliasis
Menstrual Disorder
8%
1%
1%
-
1%
<1%
<1%
-
2%
-
-
1%
0%
-
-
0%
1031
a. Adverse events for which the reporting rate of PAXIL CR was less than or equal to the
1032
placebo rate are not included. These events for continuous dosing are: Abdominal pain, back
1033
pain, pain, trauma, weight gain, myalgia, pharyngitis, respiratory disorder, rhinitis, sinusitis,
1034
pruritis, dysmenorrhea, menstrual disorder, urinary tract infection, and vomiting. The events
1035
for luteal phase dosing are: Allergic reaction, back pain, headache, infection, pain, trauma,
1036
myalgia, anxiety, pharyngitis, respiratory disorder, cystitis, and dysmenorrhea.
1037
b. <1% means greater than zero and less than 1%.
1038
c. The luteal phase and continuous dosing PMDD trials were not designed for making direct
1039
comparisons between the 2 dosing regimens. Therefore, a comparison between the 2 dosing
1040
regimens of the PMDD trials of incidence rates shown in Table 6 should be avoided.
1041
d. Mostly anorgasmia or difficulty achieving orgasm.
1042
1043
Dose Dependency of Adverse Events: Table 7 shows results in PMDD trials of
1044
common adverse events, defined as events with an incidence of ≥1% with 25 mg of PAXIL CR
1045
that was at least twice that with 12.5 mg of PAXIL CR and with placebo.
1046
1047
Table 7. Incidence of Common Adverse Events in Placebo, 12.5 mg, and 25 mg of
1048
PAXIL CR in a Pool of 3 Fixed-Dose PMDD Trials
34
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PAXIL CR
25 mg
(n = 348)
PAXIL CR
12.5 mg
(n = 333)
Placebo
(n = 349)
Common Adverse Event
Sweating
Tremor
Concentration Impaired
Yawn
Paresthesia
Hyperkinesia
Vaginitis
8.9%
6.0%
4.3%
3.2%
1.4%
1.1%
1.1%
4.2%
1.5%
1.5%
0.9%
0.3%
0.3%
0.3%
0.9%
0.3%
0.6%
0.3%
0.3%
0.0%
0.3%
1049
1050
A comparison of adverse event rates in a fixed-dose study comparing immediate-release
1051
paroxetine with placebo in the treatment of major depressive disorder revealed a clear dose
1052
dependency for some of the more common adverse events associated with the use of
1053
immediate-release paroxetine.
1054
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
1055
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
1056
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
1057
evidence suggests that SSRIs can cause such untoward sexual experiences.
1058
Reliable estimates of the incidence and severity of untoward experiences involving sexual
1059
desire, performance, and satisfaction are difficult to obtain; however, in part because patients and
1060
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
1061
untoward sexual experience and performance cited in product labeling, are likely to
1062
underestimate their actual incidence.
1063
The percentage of patients reporting symptoms of sexual dysfunction in the pool of 2
1064
placebo-controlled trials in nonelderly patients with major depressive disorder, in the pool of 3
1065
placebo-controlled trials in patients with panic disorder, in the placebo-controlled trial in patients
1066
with social anxiety disorder, and in the intermittent dosing and the pool of 3 placebo-controlled
1067
continuous dosing trials in female patients with PMDD are as follows:
1068
35
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Major Depressive
Disorder
Panic Disorder
Social Anxiety
Disorder
PMDD
Continuous Dosing
PMDD
Luteal Phase
Dosing
PAXIL
CR
Placebo
PAXIL
CR
Placebo
PAXIL
CR
Placebo
PAXIL
CR
Placebo
PAXIL
CR
Placebo
n (males)
78
78
162
194
88
97
n/a
n/a
n/a
n/a
Decreased
Libido
10%
5%
9%
6%
13%
1%
n/a
n/a
n/a
n/a
Ejaculatory
Disturbance
26%
1%
27%
3%
15%
1%
n/a
n/a
n/a
n/a
Impotence
5%
3%
10%
1%
9%
0%
n/a
n/a
n/a
n/a
n (females)
134
133
282
251
98
87
681
349
246
120
Decreased
Libido
4%
2%
8%
2%
4%
1%
12%
5%
9%
6%
Orgasmic
Disturbance
10%
<1%
7%
1%
3%
0%
8%
1%
2%
0%
1069
1070
There are no adequate, controlled studies examining sexual dysfunction with paroxetine
1071
treatment.
1072
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
1073
known outcome, patients recovered without sequelae.
1074
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
1075
SSRIs, physicians should routinely inquire about such possible side effects.
1076
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
1077
treatment with paroxetine for some patients but, on average, patients in controlled trials with
1078
PAXIL CR or the immediate-release formulation, had minimal weight loss (about 1 pound). No
1079
significant changes in vital signs (systolic and diastolic blood pressure, pulse, and temperature)
1080
were observed in patients treated with PAXIL CR, or immediate-release paroxetine
1081
hydrochloride, in controlled clinical trials.
1082
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with
1083
immediate-release paroxetine and 415 patients treated with placebo in controlled clinical trials,
1084
no clinically significant changes were seen in the ECGs of either group.
1085
Liver Function Tests: In a pool of 2 placebo-controlled clinical trials, patients treated with
1086
PAXIL CR or placebo exhibited abnormal values on liver function tests at comparable rates. In
1087
particular, the controlled-release paroxetine-versus-placebo comparisons for alkaline
1088
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
1089
with marked abnormalities.
1090
In a study of elderly patients with major depressive disorder, 3 of 104 patients treated with
1091
PAXIL CR and none of 109 placebo patients experienced liver transaminase elevations of
1092
potential clinical concern.
36
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
1093
Two of the patients treated with PAXIL CR dropped out of the study due to abnormal liver
1094
function tests; the third patient experienced normalization of transaminase levels with continued
1095
treatment. Also, in the pool of 3 studies of patients with panic disorder, 4 of 444 patients treated
1096
with PAXIL CR and none of 445 placebo patients experienced liver transaminase elevations of
1097
potential clinical concern. Elevations in all 4 patients decreased substantially after
1098
discontinuation of PAXIL CR. The clinical significance of these findings is unknown.
1099
In placebo-controlled clinical trials with the immediate-release formulation of paroxetine,
1100
patients exhibited abnormal values on liver function tests at no greater rate than that seen in
1101
placebo-treated patients.
1102
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
1103
hallucinations were observed in 22 of 9,089 patients receiving drug and in 4 of 3,187 patients
1104
receiving placebo.
1105
Other Events Observed During the Clinical Development of Paroxetine: The
1106
following adverse events were reported during the clinical development of PAXIL CR and/or the
1107
clinical development of the immediate-release formulation of paroxetine.
1108
Adverse events for which frequencies are provided below occurred in clinical trials with the
1109
controlled-release formulation of paroxetine. During its premarketing assessment in major
1110
depressive disorder, panic disorder, social anxiety disorder, and PMDD, multiple doses of
1111
PAXIL CR were administered to 1,627 patients in phase 3 double-blind, controlled, outpatient
1112
studies. Untoward events associated with this exposure were recorded by clinical investigators
1113
using terminology of their own choosing. Consequently, it is not possible to provide a
1114
meaningful estimate of the proportion of individuals experiencing adverse events without first
1115
grouping similar types of untoward events into a smaller number of standardized event
1116
categories.
1117
In the tabulations that follow, reported adverse events were classified using a
1118
COSTART-based dictionary. The frequencies presented, therefore, represent the proportion of
1119
the 1,627 patients exposed to PAXIL CR who experienced an event of the type cited on at least 1
1120
occasion while receiving PAXIL CR. All reported events are included except those already listed
1121
in Tables 2 through 7 and those events where a drug cause was remote. If the COSTART term
1122
for an event was so general as to be uninformative, it was deleted or, when possible, replaced
1123
with a more informative term. It is important to emphasize that although the events reported
1124
occurred during treatment with paroxetine, they were not necessarily caused by it.
1125
Events are further categorized by body system and listed in order of decreasing frequency
1126
according to the following definitions: Frequent adverse events are those occurring on 1 or more
1127
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
1128
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1129
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.
1130
Adverse events for which frequencies are not provided occurred during the premarketing
1131
assessment of immediate-release paroxetine in phase 2 and 3 studies of major depressive
1132
disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized
37
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1133
anxiety disorder, and posttraumatic stress disorder. The conditions and duration of exposure to
1134
immediate-release paroxetine varied greatly and included (in overlapping categories) open and
1135
double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and
1136
fixed-dose and titration studies. Only those events not previously listed for controlled-release
1137
paroxetine are included. The extent to which these events may be associated with PAXIL CR is
1138
unknown.
1139
Events are listed alphabetically within the respective body system. Events of major clinical
1140
importance are also described in the PRECAUTIONS section.
1141
Body as a Whole: Infrequent were chills, face edema, fever, flu syndrome, malaise; rare
1142
were abscess, anaphylactoid reaction, anticholinergic syndrome, hypothermia; also observed
1143
were adrenergic syndrome, neck rigidity, sepsis.
1144
Cardiovascular System: Infrequent were angina pectoris, bradycardia, hematoma,
1145
hypertension, hypotension, palpitation, postural hypotension, supraventricular tachycardia,
1146
syncope; rare were bundle branch block; also observed were arrhythmia nodal, atrial fibrillation,
1147
cerebrovascular accident, congestive heart failure, low cardiac output, myocardial infarct,
1148
myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles,
1149
thrombophlebitis, thrombosis, vascular headache, ventricular extrasystoles.
1150
Digestive System: Infrequent were bruxism, dysphagia, eructation, gastritis,
1151
gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, liver function test abnormal,
1152
melena, pancreatitis, rectal hemorrhage, toothache, ulcerative stomatitis; rare were colitis,
1153
glossitis, gum hyperplasia, hepatosplenomegaly, increased salivation, intestinal obstruction,
1154
peptic ulcer, stomach ulcer, throat tightness; also observed were aphthous stomatitis, bloody
1155
diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions,
1156
fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, jaundice, mouth
1157
ulceration, salivary gland enlargement, sialadenitis, stomatitis, tongue discoloration, tongue
1158
edema.
1159
Endocrine System: Infrequent were ovarian cyst, testes pain; rare were diabetes mellitus,
1160
hyperthyroidism; also observed were goiter, hypothyroidism, thyroiditis.
1161
Hemic and Lymphatic System: Infrequent were anemia, eosinophilia, hypochromic
1162
anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rare were thrombocytopenia; also
1163
observed were anisocytosis, basophilia, bleeding time increased, lymphedema, lymphocytosis,
1164
lymphopenia, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia.
1165
Metabolic and Nutritional Disorders: Infrequent were generalized edema,
1166
hyperglycemia, hypokalemia, peripheral edema, SGOT increased, SGPT increased, thirst; rare
1167
were bilirubinemia, dehydration, hyperkalemia, obesity; also observed were alkaline phosphatase
1168
increased, BUN increased, creatinine phosphokinase increased, gamma globulins increased,
1169
gout, hypercalcemia, hypercholesteremia, hyperphosphatemia, hypocalcemia, hypoglycemia,
1170
hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.
1171
Musculoskeletal System: Infrequent were arthritis, bursitis, tendonitis; rare were
1172
myasthenia, myopathy, myositis; also observed were generalized spasm, osteoporosis,
38
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1173
tenosynovitis, tetany.
1174
Nervous System: Frequent were depression; infrequent were amnesia, convulsion,
1175
depersonalization, dystonia, emotional lability, hallucinations, hyperkinesia, hypesthesia,
1176
hypokinesia, incoordination, libido increased, neuralgia, neuropathy, nystagmus, paralysis,
1177
vertigo; rare were ataxia, coma, diplopia, dyskinesia, hostility, paranoid reaction, torticollis,
1178
withdrawal syndrome; also observed were abnormal gait, akathisia, akinesia, aphasia,
1179
choreoathetosis, circumoral paresthesia, delirium, delusions, dysarthria, euphoria, extrapyramidal
1180
syndrome, fasciculations, grand mal convulsion, hyperalgesia, irritability, manic reaction,
1181
manic-depressive reaction, meningitis, myelitis, peripheral neuritis, psychosis, psychotic
1182
depression, reflexes decreased, reflexes increased, stupor, trismus.
1183
Respiratory System: Frequent were pharyngitis; infrequent were asthma, dyspnea,
1184
epistaxis, laryngitis, pneumonia; rare were stridor; also observed were dysphonia, emphysema,
1185
hemoptysis, hiccups, hyperventilation, lung fibrosis, pulmonary edema, respiratory flu, sputum
1186
increased.
1187
Skin and Appendages: Frequent were rash; infrequent were acne, alopecia, dry skin,
1188
eczema, pruritus, urticaria; rare were exfoliative dermatitis, furunculosis, pustular rash,
1189
seborrhea; also observed were angioedema, ecchymosis, erythema multiforme, erythema
1190
nodosum, hirsutism, maculopapular rash, skin discoloration, skin hypertrophy, skin ulcer,
1191
sweating decreased, vesiculobullous rash.
1192
Special Senses: Infrequent were conjunctivitis, earache, keratoconjunctivitis, mydriasis,
1193
photophobia, retinal hemorrhage, tinnitus; rare were blepharitis, visual field defect; also observed
1194
were amblyopia, anisocoria, blurred vision, cataract, conjunctival edema, corneal ulcer, deafness,
1195
exophthalmos, glaucoma, hyperacusis, night blindness, parosmia, ptosis, taste loss.
1196
Urogenital System: Frequent were dysmenorrhea*; infrequent were albuminuria,
1197
amenorrhea*, breast pain*, cystitis, dysuria, prostatitis*, urinary retention; rare were breast
1198
enlargement*, breast neoplasm*, female lactation, hematuria, kidney calculus, metrorrhagia*,
1199
nephritis, nocturia, pregnancy and puerperal disorders*, salpingitis, urinary incontinence, uterine
1200
fibroids enlarged*; also observed were breast atrophy, ejaculatory disturbance, endometrial
1201
disorder, epididymitis, fibrocystic breast, leukorrhea, mastitis, oliguria, polyuria, pyuria,
1202
urethritis, urinary casts, urinary urgency, urolith, uterine spasm, vaginal hemorrhage.
1203
*Based on the number of men and women as appropriate.
1204
Postmarketing Reports: Voluntary reports of adverse events in patients taking
1205
immediate-release paroxetine hydrochloride that have been received since market introduction
1206
and not listed above that may have no causal relationship with the drug include acute
1207
pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis,
1208
and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré
1209
syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of
1210
inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea;
1211
extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity,
1212
dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of
39
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1213
pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension,
1214
allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs
1215
syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes),
1216
thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including
1217
aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic
1218
syndromes (such as Henoch-Schönlein purpura). There has been a case report of an elevated
1219
phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin coadministration.
1220
There has been a case report of severe hypotension when immediate-release paroxetine was
1221
added to chronic metoprolol treatment.
1222
DRUG ABUSE AND DEPENDENCE
1223
Controlled Substance Class: PAXIL CR is not a controlled substance.
1224
Physical and Psychologic Dependence: PAXIL CR has not been systematically studied
1225
in animals or humans for its potential for abuse, tolerance or physical dependence. While the
1226
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
1227
not systematic and it is not possible to predict on the basis of this limited experience the extent to
1228
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
1229
patients should be evaluated carefully for history of drug abuse, and such patients should be
1230
observed closely for signs of misuse or abuse of PAXIL CR (e.g., development of tolerance,
1231
incrementations of dose, drug-seeking behavior).
1232
OVERDOSAGE
1233
Human Experience: Since the introduction of immediate-release paroxetine hydrochloride in
1234
the United States, 342 spontaneous cases of deliberate or accidental overdosage during
1235
paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with
1236
paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of
1237
the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the
1238
amount of paroxetine ingested were generally confounded by the ingestion of other drugs or
1239
alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known
1240
outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of
1241
paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.
1242
Commonly reported adverse events associated with paroxetine overdosage include
1243
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
1244
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
1245
substances) include mydriasis, convulsions (including status epilepticus), ventricular
1246
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
1247
hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
1248
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
1249
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
1250
Overdosage Management: No specific antidotes for paroxetine are known. Treatment
1251
should consist of those general measures employed in the management of overdosage with any
40
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1252
drugs effective in the treatment of major depressive disorder.
1253
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
1254
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
1255
is not recommended. Due to the large volume of distribuiton of this drug, forced diuresis,
1256
dialysis, hemoperfusion, or exchange perfusion are unlikely to be of benefit.
1257
A specific caution involves patients taking or recently having taken paroxetine who might
1258
ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
1259
parent tricyclic and an active metabolite may increase the possibility of clinically significant
1260
sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drugs
1261
Metabolized by Cytochrome CYP2D6).
1262
In managing overdosage, consider the possibility of multiple-drug involvement. The physician
1263
should consider contacting a poison control center for additional information on the treatment of
1264
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
1265
Desk Reference (PDR).
1266
DOSAGE AND ADMINISTRATION
1267
Major Depressive Disorder: Usual Initial Dosage: PAXIL CR should be administered as
1268
a single daily dose, usually in the morning, with or without food. The recommended initial dose
1269
is 25 mg/day. Patients were dosed in a range of 25 mg to 62.5 mg/day in the clinical trials
1270
demonstrating the effectiveness of PAXIL CR in the treatment of major depressive disorder. As
1271
with all drugs effective in the treatment of major depressive disorder, the full effect may be
1272
delayed. Some patients not responding to a 25-mg dose may benefit from dose increases, in
1273
12.5-mg/day increments, up to a maximum of 62.5 mg/day. Dose changes should occur at
1274
intervals of at least 1 week.
1275
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1276
swallowed whole.
1277
Maintenance Therapy: There is no body of evidence available to answer the question of
1278
how long the patient treated with PAXIL CR should remain on it. It is generally agreed that acute
1279
episodes of major depressive disorder require several months or longer of sustained
1280
pharmacologic therapy. Whether the dose of an antidepressant needed to induce remission is
1281
identical to the dose needed to maintain and/or sustain euthymia is unknown.
1282
Systematic evaluation of the efficacy of immediate-release paroxetine hydrochloride has
1283
shown that efficacy is maintained for periods of up to 1 year with doses that averaged about
1284
30 mg, which corresponds to a 37.5-mg dose of PAXIL CR, based on relative bioavailability
1285
considerations (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
41
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1286
Panic Disorder: Usual Initial Dosage: PAXIL CR should be administered as a single daily
1287
dose, usually in the morning. Patients should be started on 12.5 mg/day. Dose changes should
1288
occur in 12.5-mg/day increments and at intervals of at least 1 week. Patients were dosed in a
1289
range of 12.5 to 75 mg/day in the clinical trials demonstrating the effectiveness of PAXIL CR.
1290
The maximum dosage should not exceed 75 mg/day.
1291
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1292
swallowed whole.
1293
Maintenance Therapy: Long-term maintenance of efficacy with the immediate-release
1294
formulation of paroxetine was demonstrated in a 3-month relapse prevention trial. In this trial,
1295
patients with panic disorder assigned to immediate-release paroxetine demonstrated a lower
1296
relapse rate compared to patients on placebo. Panic disorder is a chronic condition, and it is
1297
reasonable to consider continuation for a responding patient. Dosage adjustments should be
1298
made to maintain the patient on the lowest effective dosage, and patients should be periodically
1299
reassessed to determine the need for continued treatment.
1300
Social Anxiety Disorder: Usual Initial Dosage: PAXIL CR should be administered as a
1301
single daily dose, usually in the morning, with or without food. The recommended initial dose is
1302
12.5 mg/day. Patients were dosed in a range of 12.5 mg to 37.5 mg/day in the clinical trial
1303
demonstrating the effectiveness of PAXIL CR in the treatment of social anxiety disorder. If the
1304
dose is increased, this should occur at intervals of at least 1 week, in increments of 12.5 mg/day,
1305
up to a maximum of 37.5 mg/day.
1306
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1307
swallowed whole.
1308
Maintenance Therapy: There is no body of evidence available to answer the question of
1309
how long the patient treated with PAXIL CR should remain on it. Although the efficacy of
1310
PAXIL CR beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials,
1311
social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider
1312
continuation of treatment for a responding patient. Dosage adjustments should be made to
1313
maintain the patient on the lowest effective dosage, and patients should be periodically
1314
reassessed to determine the need for continued treatment.
1315
Premenstrual Dysphoric Disorder: Usual Initial Dosage: PAXIL CR should be
1316
administered as a single daily dose, usually in the morning, with or without food. PAXIL CR
1317
may be administered either daily throughout the menstrual cycle or limited to the luteal phase of
1318
the menstrual cycle, depending on physician assessment. The recommended initial dose is
1319
12.5 mg/day. In clinical trials, both 12.5 mg/day and 25 mg/day were shown to be effective.
1320
Dose changes should occur at intervals of at least 1 week.
1321
Patients should be cautioned that PAXIL CR should not be chewed or crushed, and should be
1322
swallowed whole.
1323
Maintenance/Continuation Therapy: The effectiveness of PAXIL CR for a period
1324
exceeding 3 menstrual cycles has not been systematically evaluated in controlled trials.
1325
However, women commonly report that symptoms worsen with age until relieved by the onset of
42
Reference ID: 2920253
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1326
menopause. Therefore, it is reasonable to consider continuation of a responding patient. Patients
1327
should be periodically reassessed to determine the need for continued treatment.
1328
Special Populations: Treatment of Pregnant Women During the Third Trimester:
1329
Neonates exposed to PAXIL CR and other SSRIs or SNRIs, late in the third trimester have
1330
developed complications requiring prolonged hospitalization, respiratory support, and tube
1331
feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine
1332
during the third trimester, the physician should carefully consider the potential risks and benefits
1333
of treatment. The physician may consider tapering paroxetine in the third trimester.
1334
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
1335
Hepatic Impairment: The recommended initial dose of PAXIL CR is 12.5 mg/day for elderly
1336
patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases
1337
may be made if indicated. Dosage should not exceed 50 mg/day.
1338
Switching Patients to or From a Monoamine Oxidase Inhibitor: At least 14 days
1339
should elapse between discontinuation of an MAOI and initiation of therapy with PAXIL CR.
1340
Similarly, at least 14 days should be allowed after stopping PAXIL CR before starting an MAOI.
1341
Discontinuation of Treatment With PAXIL CR: Symptoms associated with discontinuation
1342
of immediate-release paroxetine hydrochloride or PAXIL CR have been reported (see
1343
PRECAUTIONS: Discontinuation of Treatment with PAXIL CR). Patients should be monitored
1344
for these symptoms when discontinuing treatment, regardless of the indication for which PAXIL
1345
CR is being prescribed. A gradual reduction in the dose rather than abrupt cessation is
1346
recommended whenever possible. If intolerable symptoms occur following a decrease in the dose
1347
or upon discontinuation of treatment, then resuming the previously prescribed dose may be
1348
considered. Subsequently, the physician may continue decreasing the dose but at a more gradual
1349
rate.
1350
HOW SUPPLIED
1351
PAXIL CR is supplied as an enteric film-coated, controlled-release, round tablet, as follows:
1352
12.5-mg yellow tablets
1353
NDC 0029-3206-13 Bottles of 30 (engraved with PAXIL CR and 12.5)
1354
NDC 0029-4606-13 Bottles of 30 (engraved with GSK and 12.5)
1355
25-mg pink tablets
1356
NDC 0029-3207-13 Bottles of 30 (engraved with PAXIL CR and 25)
1357
NDC 0029-4607-13 Bottles of 30 (engraved with GSK and 25)
1358
37.5 mg blue tablets
1359
NDC 0029-3208-13 Bottles of 30 (engraved with PAXIL CR and 37.5)
1360
NDC 0029-4608-13 Bottles of 30 (engraved with GSK and 37.5)
1361
Store at or below 25°C (77°F) [see USP].
1362
1363
PAXIL CR is a registered trademark of GlaxoSmithKline.
1364
GEOMATRIX is a trademark of Jago Pharma, Muttenz, Switzerland.
43
Reference ID: 2920253
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:30.135687
|
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12,148
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PRESCRIBING INFORMATION
PAXIL®
(paroxetine hydrochloride)
Tablets and Oral Suspension
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term studies of
major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the
use of PAXIL or any other antidepressant in a child, adolescent, or young adult must
balance this risk with the clinical need. Short-term studies did not show an increase in the
risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there
was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
older. Depression and certain other psychiatric disorders are themselves associated with
increases in the risk of suicide. Patients of all ages who are started on antidepressant
therapy should be monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
the need for close observation and communication with the prescriber. PAXIL is not
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide
Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
DESCRIPTION
PAXIL (paroxetine hydrochloride) is an orally administered psychotropic drug. It is the
hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'
fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate
and has the empirical formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8
(329.4 as free base). The structural formula of paroxetine hydrochloride is: structural formula
Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of
120° to 138°C and a solubility of 5.4 mg/mL in water.
Tablets: Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as
follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–green. Inactive
ingredients consist of dibasic calcium phosphate dihydrate, hypromellose, magnesium stearate,
polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1 or more of
1
Reference ID: 3595524
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake, FD&C
Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.
Suspension for Oral Administration: Each 5 mL of orange-colored, orange-flavored liquid
contains paroxetine hydrochloride equivalent to paroxetine, 10 mg. Inactive ingredients consist
of polacrilin potassium, microcrystalline cellulose, propylene glycol, glycerin, sorbitol,
methylparaben, propylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium
saccharin, flavorings, FD&C Yellow No. 6 aluminum lake, and simethicone emulsion, USP.
CLINICAL PHARMACOLOGY
Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive
disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD),
generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be
linked to potentiation of serotonergic activity in the central nervous system resulting from
inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically
relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into
human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly
selective inhibitor of neuronal serotonin reuptake and has only very weak effects on
norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate
that paroxetine has little affinity for muscarinic, alpha1-, alpha2-, beta-adrenergic-, dopamine
(D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors; antagonism of muscarinic, histaminergic,
and alpha1-adrenergic receptors has been associated with various anticholinergic, sedative, and
cardiovascular effects for other psychotropic drugs.
Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent
compound, they are essentially inactive.
Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a
solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours
(CV 32%) after oral dosing of 30 mg tablets of PAXIL daily for 30 days. Paroxetine is
extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in
pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part
by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the
feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are
deficient in CYP2D6 (poor metabolizers).
In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple
dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower Cmax or AUC than
females.
Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension
and tablet.
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the
hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets
daily for 30 days, steady-state paroxetine concentrations were achieved by approximately
2
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10 days for most subjects, although it may take substantially longer in an occasional patient. At
steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr.
(CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cmax
and Cmin values were about 6 and 14 times what would be predicted from single-dose studies.
Steady-state drug exposure based on AUC0-24 was about 8 times greater than would have been
predicted from single-dose data in these subjects. The excess accumulation is a consequence of
the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.
The effects of food on the bioavailability of paroxetine were studied in subjects administered
a single dose with and without food. AUC was only slightly increased (6%) when drug was
administered with food but the Cmax was 29% greater, while the time to reach peak plasma
concentration decreased from 6.4 hours post-dosing to 4.9 hours.
Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the
plasma.
Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and
400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be
less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or
warfarin.
Metabolism and Excretion: The mean elimination half-life is approximately 21 hours
(CV 32%) after oral dosing of 30 mg tablets daily for 30 days of PAXIL. In steady-state dose
proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg
daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was
observed in both populations, again reflecting a saturable metabolic pathway. In comparison to
Cmin values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than
doubled.
Paroxetine is extensively metabolized after oral administration. The principal metabolites are
polar and conjugated products of oxidation and methylation, which are readily cleared.
Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been
isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of
the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is
accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account
for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of
treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug
interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6).
Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine
with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.
About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than
1% as the parent compound over the 10-day post-dosing period.
Other Clinical Pharmacology Information: Specific Populations: Renal and Liver
Disease: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic
impairment. The mean plasma concentrations in patients with creatinine clearance below
3
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30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with
creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had
about a 2-fold increase in plasma concentrations (AUC, Cmax).
The initial dosage should therefore be reduced in patients with severe renal or hepatic
impairment, and upward titration, if necessary, should be at increased intervals (see DOSAGE
AND ADMINISTRATION).
Elderly Patients: In a multiple-dose study in the elderly at daily paroxetine doses of 20,
30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin
concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be
reduced (see DOSAGE AND ADMINISTRATION).
Drug-Drug Interactions: In vitro drug interaction studies reveal that paroxetine inhibits
CYP2D6. Clinical drug interaction studies have been performed with substrates of CYP2D6 and
show that paroxetine can inhibit the metabolism of drugs metabolized by CYP2D6 including
desipramine, risperidone, and atomoxetine (see PRECAUTIONS: Drug Interactions).
Clinical Trials
Major Depressive Disorder: The efficacy of PAXIL as a treatment for major depressive
disorder has been established in 6 placebo-controlled studies of patients with major depressive
disorder (aged 18 to 73). In these studies, PAXIL was shown to be significantly more effective
than placebo in treating major depressive disorder by at least 2 of the following measures:
Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical
Global Impression (CGI)-Severity of Illness. PAXIL was significantly better than placebo in
improvement of the HDRS sub-factor scores, including the depressed mood item, sleep
disturbance factor, and anxiety factor.
A study of outpatients with major depressive disorder who had responded to PAXIL (HDRS
total score <8) during an initial 8-week open-treatment phase and were then randomized to
continuation on PAXIL or placebo for 1 year demonstrated a significantly lower relapse rate for
patients taking PAXIL (15%) compared to those on placebo (39%). Effectiveness was similar for
male and female patients.
Obsessive Compulsive Disorder: The effectiveness of PAXIL in the treatment of obsessive
compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled
studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD
(DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale
(YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients
were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily
doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses
of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points,
respectively, on the YBOCS total score which was significantly greater than the approximate 4
point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a
flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg
4
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daily). In this study, patients receiving paroxetine experienced a mean reduction of
approximately 7 points on the YBOCS total score, which was significantly greater than the mean
reduction of approximately 4 points in placebo-treated patients.
The following table provides the outcome classification by treatment group on Global
Improvement items of the Clinical Global Impression (CGI) scale for Study 1.
Outcome Classification (%) on CGI-Global Improvement Item
for Completers in Study 1
Outcome
Classification
Placebo
(n = 74)
PAXIL 20 mg
(n = 75)
PAXIL 40 mg
(n = 66)
PAXIL 60 mg
(n = 66)
Worse
14%
7%
7%
3%
No Change
44%
35%
22%
19%
Minimally Improved
24%
33%
29%
34%
Much Improved
11%
18%
22%
24%
Very Much Improved
7%
7%
20%
20%
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age or gender.
The long-term maintenance effects of PAXIL in OCD were demonstrated in a long-term
extension to Study 1. Patients who were responders on paroxetine during the 3-month
double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were
randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase.
Patients randomized to paroxetine were significantly less likely to relapse than comparably
treated patients who were randomized to placebo.
Panic Disorder: The effectiveness of PAXIL in the treatment of panic disorder was
demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia.
In these studies, PAXIL was shown to be significantly more effective than placebo in treating
panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical
Global Impression Severity of Illness score.
Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine
doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed
only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were
free of panic attacks, compared to 44% of placebo-treated patients.
Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and
placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of
placebo-treated patients.
Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to
placebo in patients concurrently receiving standardized cognitive behavioral therapy. At
endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks
compared to 14% of placebo patients.
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In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was
approximately 40 mg/day of paroxetine.
Long-term maintenance effects of PAXIL in panic disorder were demonstrated in an
extension to Study 1. Patients who were responders during the 10-week double-blind phase and
during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or
40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized
to paroxetine were significantly less likely to relapse than comparably treated patients who were
randomized to placebo.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a
function of age or gender.
Social Anxiety Disorder: The effectiveness of PAXIL in the treatment of social anxiety
disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1,
2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the
effectiveness of PAXIL compared to placebo was evaluated on the basis of (1) the proportion of
responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very
much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social
Anxiety Scale (LSAS).
Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and
placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the
CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In
Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to
29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI
Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients,
respectively.
Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with
placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the
LSAS Total Score and the CGI Improvement responder criterion; there were trends for
superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in
this study of any additional benefit for doses higher than 20 mg/day.
Subgroup analyses generally did not indicate differences in treatment outcomes as a function
of age, race, or gender.
Generalized Anxiety Disorder: The effectiveness of PAXIL in the treatment of Generalized
Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled
studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV).
Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with
placebo. Doses of 20 mg or 40 mg of PAXIL were both demonstrated to be significantly superior
to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not
sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to
the 20 mg/day dose.
Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo.
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Reference ID: 3595524
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PAXIL demonstrated statistically significant superiority over placebo on the Hamilton Rating
Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine
(20 mg to 50 mg daily), did not demonstrate statistically significant superiority of PAXIL over
placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.
Subgroup analyses did not indicate differences in treatment outcomes as a function of race or
gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age.
In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety
Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to
50 mg/day of PAXIL, were randomized to continuation of PAXIL at their same dose, or to
placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase
was defined by having a decrease of ≥2 points compared to baseline on the CGI-Severity of
Illness scale, to a score of ≤3. Relapse during the double-blind phase was defined as an increase
of ≥2 points compared to baseline on the CGI-Severity of Illness scale to a score of ≥4, or
withdrawal due to lack of efficacy. Patients receiving continued PAXIL experienced a
significantly lower relapse rate over the subsequent 24 weeks compared to those receiving
placebo.
Posttraumatic Stress Disorder: The effectiveness of PAXIL in the treatment of
Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-
controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The
mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year
to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD
anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out
of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered
PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement
Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of PTSD with the
following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal.
The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2
total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were
defined as patients having a score of 1 (very much improved) or 2 (much improved).
Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to
placebo. Doses of 20 mg and 40 mg of PAXIL were demonstrated to be significantly superior to
placebo on change from baseline for the CAPS-2 total score and on proportion of responders on
the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the
40 mg/day dose compared to the 20 mg/day dose.
Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to
placebo. PAXIL was demonstrated to be significantly superior to placebo on change from
baseline for the CAPS-2 total score and on proportion of responders on the CGI-I.
A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,
demonstrated PAXIL to be significantly superior to placebo on change from baseline for CAPS
2 total score, but not on proportion of responders on the CGI-I.
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The majority of patients in these trials were women (68% women: 377 out of 551 subjects in
Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not
indicate differences in treatment outcomes as a function of gender. There were an insufficient
number of patients who were 65 years and older or were non-Caucasian to conduct subgroup
analyses on the basis of age or race, respectively.
INDICATIONS AND USAGE
Major Depressive Disorder: PAXIL is indicated for the treatment of major depressive
disorder.
The efficacy of PAXIL in the treatment of a major depressive episode was established in
6-week controlled trials of outpatients whose diagnoses corresponded most closely to the
DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical
Trials). A major depressive episode implies a prominent and relatively persistent depressed or
dysphoric mood that usually interferes with daily functioning (nearly every day for at least
2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in
sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in
sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired
concentration, and a suicide attempt or suicidal ideation.
The effects of PAXIL in hospitalized depressed patients have not been adequately studied.
The efficacy of PAXIL in maintaining a response in major depressive disorder for up to 1 year
was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical
Trials). Nevertheless, the physician who elects to use PAXIL for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Obsessive Compulsive Disorder: PAXIL is indicated for the treatment of obsessions and
compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV.
The obsessions or compulsions cause marked distress, are time-consuming, or significantly
interfere with social or occupational functioning.
The efficacy of PAXIL was established in two 12-week trials with obsessive compulsive
outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive
compulsive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts,
impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized by the person as excessive or
unreasonable.
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In
this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on
placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who
elects to use PAXIL for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder: PAXIL is indicated for the treatment of panic disorder, with or without
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agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of
unexpected panic attacks and associated concern about having additional attacks, worry about
the implications or consequences of the attacks, and/or a significant change in behavior related to
the attacks.
The efficacy of PAXIL was established in three 10- to 12-week trials in panic disorder
patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
CLINICAL PHARMACOLOGY: Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings
of unreality) or depersonalization (being detached from oneself); (10) fear of losing control;
(11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In
this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate
compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials).
Nevertheless, the physician who prescribes PAXIL for extended periods should periodically
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Social Anxiety Disorder: PAXIL is indicated for the treatment of social anxiety disorder,
also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is
characterized by a marked and persistent fear of 1 or more social or performance situations in
which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to
the feared situation almost invariably provokes anxiety, which may approach the intensity of a
panic attack. The feared situations are avoided or endured with intense anxiety or distress. The
avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with
the person's normal routine, occupational or academic functioning, or social activities or
relationships, or there is marked distress about having the phobias. Lesser degrees of
performance anxiety or shyness generally do not require psychopharmacological treatment.
The efficacy of PAXIL was established in three 12-week trials in adult patients with social
anxiety disorder (DSM-IV). PAXIL has not been studied in children or adolescents with social
phobia (see CLINICAL PHARMACOLOGY: Clinical Trials).
The effectiveness of PAXIL in long-term treatment of social anxiety disorder, i.e., for more
than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.
Therefore, the physician who elects to prescribe PAXIL for extended periods should periodically
re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Generalized Anxiety Disorder: PAXIL is indicated for the treatment of Generalized Anxiety
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Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of
everyday life usually does not require treatment with an anxiolytic.
The efficacy of PAXIL in the treatment of GAD was established in two 8-week
placebo-controlled trials in adults with GAD. PAXIL has not been studied in children or
adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY: Clinical
Trials).
Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry
(apprehensive expectation) that is persistent for at least 6 months and which the person finds
difficult to control. It must be associated with at least 3 of the following 6 symptoms:
Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or
mind going blank, irritability, muscle tension, sleep disturbance.
The efficacy of PAXIL in maintaining a response in patients with Generalized Anxiety
Disorder, who responded during an 8-week acute treatment phase while taking PAXIL and were
then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-
controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the
physician who elects to use PAXIL for extended periods should periodically re-evaluate the
long-term usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Posttraumatic Stress Disorder: PAXIL is indicated for the treatment of Posttraumatic
Stress Disorder (PTSD).
The efficacy of PAXIL in the treatment of PTSD was established in two 12-week placebo-
controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY: Clinical
Trials).
PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or
threatened death or serious injury, or threat to the physical integrity of self or others, and a
response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of
exposure to the traumatic event include reexperiencing of the event in the form of intrusive
thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity
on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event,
inability to recall details of the event, and/or numbing of general responsiveness manifested as
diminished interest in significant activities, estrangement from others, restricted range of affect,
or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in social, occupational, or other
important areas of functioning.
The efficacy of PAXIL in longer-term treatment of PTSD, i.e., for more than 12 weeks, has
not been systematically evaluated in placebo-controlled trials. Therefore, the physician who
elects to prescribe PAXIL for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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CONTRAINDICATIONS
The use of MAOIs intended to treat psychiatric disorders with PAXIL or within 14 days of
stopping treatment with PAXIL is contraindicated because of an increased risk of serotonin
syndrome. The use of PAXIL within 14 days of stopping an MAOI intended to treat psychiatric
disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION).
Starting PAXIL in a patient who is being treated with MAOIs such as linezolid or intravenous
methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see
WARNINGS and DOSAGE AND ADMINISTRATION).
Concomitant use with thioridazine is contraindicated (see WARNINGS and
PRECAUTIONS).
Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the
inactive ingredients in PAXIL.
WARNINGS
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
both adult and pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
are taking antidepressant medications, and this risk may persist until significant remission
occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-standing
concern, however, that antidepressants may have a role in inducing worsening of depression and
the emergence of suicidality in certain patients during the early phases of treatment. Pooled
analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others)
showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-
term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
increase in the younger patients for almost all drugs studied. There were differences in absolute
risk of suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1,000 patients treated) are provided in Table 1.
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Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as
rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION:
Discontinuation of Treatment With PAXIL, for a description of the risks of discontinuation of
PAXIL).
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
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unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to healthcare
providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for PAXIL should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that PAXIL is not approved for use in treating bipolar depression.
Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome
has been reported with SNRIs and SSRIs, including PAXIL, alone but particularly with
concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that
impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor,
rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin
syndrome.
The concomitant use of PAXIL with MAOIs intended to treat psychiatric disorders is
contraindicated. PAXIL should also not be started in a patient who is being treated with MAOIs
such as linezolid or intravenous methylene blue. All reports with methylene blue that provided
information on the route of administration involved intravenous administration in the dose range
of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes
(such as oral tablets or local tissue injection) or at lower doses. There may be circumstances
when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous
methylene blue in a patient taking PAXIL. PAXIL should be discontinued before initiating
treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND
ADMINISTRATION).
If concomitant use of PAXIL with certain other serotonergic drugs, i.e., triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is
clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly
during treatment initiation and dose increases.
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Treatment with PAXIL and any concomitant serotonergic agents should be discontinued
immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma:The pupillary dilation that occurs following use of many
antidepressant drugs including Paxil may trigger an angle closure attack in a patient with
anatomically narrow angles who does not have a patent iridectomy.
Potential Interaction With Thioridazine: Thioridazine administration alone produces
prolongation of the QTc interval, which is associated with serious ventricular arrhythmias,
such as torsade de pointes–type arrhythmias, and sudden death. This effect appears to be
dose related.
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will
elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be
used in combination with thioridazine (see CONTRAINDICATIONS and
PRECAUTIONS).
Usage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that
infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of
congenital malformations, particularly cardiovascular malformations. The findings from these
studies are summarized below:
•
A study based on Swedish national registry data demonstrated that infants exposed to
paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular
malformations (2% risk in paroxetine-exposed infants) compared to the entire registry
population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No
increase in the risk of overall congenital malformations was seen in the paroxetine-exposed
infants. The cardiac malformations in the paroxetine-exposed infants were primarily
ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in
severity from those that resolve spontaneously to those which require surgery.
•
A separate retrospective cohort study from the United States (United Healthcare data)
evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester
(n = 815 for paroxetine). This study showed a trend towards an increased risk for
cardiovascular malformations for paroxetine (risk of 1.5%) compared to other
antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the
12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study
also suggested an increased risk of overall major congenital malformations including
cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants
(OR 1.8; 95% confidence interval 1.2 to 2.8).
•
Two large case-control studies using separate databases, each with >9,000 birth defect
cases and >4,000 controls, found that maternal use of paroxetine during the first trimester
of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow
tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1.0 to 6.0,
7 exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval,
1.3 to 8.8, 6 exposed infants).
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Other studies have found varying results as to whether there was an increased risk of overall,
cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data
over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and
congenital malformations included the above-noted studies in addition to others (n = 17 studies
that included overall malformations and n = 14 studies that included cardiovascular
malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested
an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95%
confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1
to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to
determine the extent to which the observed prevalence of cardiovascular malformations might
have contributed to that of overall malformations, nor was it possible to determine whether any
specific types of cardiovascular malformations might have contributed to the observed
prevalence of all cardiovascular malformations.
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential
harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment,
consideration should be given to either discontinuing paroxetine therapy or switching to another
antidepressant (see PRECAUTIONS: Discontinuation of Treatment With PAXIL). For women
who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should
only be initiated after consideration of the other available treatment options.
Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats
and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately
8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2
basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was
an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last
trimester of gestation and continued throughout lactation. This effect occurred at a dose of
1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for
rat pup mortality was not determined. The cause of these deaths is not known.
Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs or serotonin and
norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed
complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such
complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,
vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness,
irritability, and constant crying. These features are consistent with either a direct toxic
effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be
noted that, in some cases, the clinical picture is consistent with serotonin syndrome
(see WARNINGS: Serotonin Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent
pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live
births in the general population and is associated with substantial neonatal morbidity
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and mortality. Several recent epidemiologic studies suggest a positive statistical
association between SSRI use (including PAXIL) in pregnancy and PPHN. Other
studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201
pregnant women with a history of major depression, who were either on antidepressants
or had received antidepressants less than 12 weeks prior to their last menstrual period,
and were in remission. Women who discontinued antidepressant medication during
pregnancy showed a significant increase in relapse of their major depression compared
to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with PAXIL, the physician should carefully consider both
the potential risks of taking an SSRI, along with the established benefits of treating depression
with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE
AND ADMINISTRATION and ADVERSE REACTIONS: Postmarketing Reports).
PRECAUTIONS
General: Activation of Mania/Hypomania: During premarketing testing, hypomania or
mania occurred in approximately 1.0% of unipolar patients treated with PAXIL compared to
1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients
classified as bipolar, the rate of manic episodes was 2.2% for PAXIL and 11.6% for the
combined active-control groups. As with all drugs effective in the treatment of major depressive
disorder, PAXIL should be used cautiously in patients with a history of mania.
Seizures: During premarketing testing, seizures occurred in 0.1% of patients treated with
PAXIL, a rate similar to that associated with other drugs effective in the treatment of major
depressive disorder. PAXIL should be used cautiously in patients with a history of seizures. It
should be discontinued in any patient who develops seizures.
Discontinuation of Treatment With PAXIL: Recent clinical trials supporting the various
approved indications for PAXIL employed a taper-phase regimen, rather than an abrupt
discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials
involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a
daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before
treatment was stopped.
With this regimen in those studies, the following adverse events were reported at an incidence
of 2% or greater for PAXIL and were at least twice that reported for placebo: Abnormal dreams,
paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and
were self-limiting and did not require medical intervention.
During marketing of PAXIL and other SSRIs and SNRIs, there have been spontaneous reports
of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt),
including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances
(e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache,
lethargy, emotional lability, insomnia, and hypomania. While these events are generally self
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limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with PAXIL.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of
treatment, then resuming the previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of
treatment with PAXIL in pediatric patients.
Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk
of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a
result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions). However, other
studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of
paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study
suggests that the risk may increase with longer duration of coadministration. When tamoxifen is
used for the treatment or prevention of breast cancer, prescribers should consider using an
alternative antidepressant with little or no CYP2D6 inhibition.
Akathisia: The use of paroxetine or other SSRIs has been associated with the development
of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation
such as an inability to sit or stand still usually associated with subjective distress. This is most
likely to occur within the first few weeks of treatment.
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
including PAXIL. In many cases, this hyponatremia appears to be the result of the syndrome of
inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than
110 mmol/L have been reported. Elderly patients may be at greater risk of developing
hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of
PAXIL should be considered in patients with symptomatic hyponatremia and appropriate
medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope,
seizure, coma, respiratory arrest, and death.
Abnormal Bleeding: SSRIs and SNRIs, including paroxetine, may increase the risk of
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and
other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control
and cohort design) have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to
SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated
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with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect
coagulation.
Bone Fracture: Epidemiological studies on bone fracture risk following exposure to some
antidepressants, including SSRIs, have reported an association between antidepressant treatment
and fractures. There are multiple possible causes for this observation and it is unknown to what
extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological
fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral
density, should be considered in patients treated with paroxetine who present with unexplained
bone pain, point tenderness, swelling, or bruising.
Use in Patients With Concomitant Illness: Clinical experience with PAXIL in patients
with certain concomitant systemic illness is limited. Caution is advisable in using PAXIL in
patients with diseases or conditions that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with
PAXIL. A few cases of acute angle closure glaucoma associated with paroxetine therapy have
been reported in the literature. As mydriasis can cause acute angle closure in patients with
narrow angle glaucoma, caution should be used when PAXIL is prescribed for patients with
narrow angle glaucoma.
PAXIL has not been evaluated or used to any appreciable extent in patients with a recent
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
excluded from clinical studies during the product’s premarket testing. Evaluation of
electrocardiograms of 682 patients who received PAXIL in double-blind, placebo-controlled
trials, however, did not indicate that PAXIL is associated with the development of significant
ECG abnormalities. Similarly, PAXIL does not cause any clinically important changes in heart
rate or blood pressure.
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment
(creatinine clearance <30 mL/min.) or severe hepatic impairment. A lower starting dose should
be used in such patients (see DOSAGE AND ADMINISTRATION).
Information for Patients: PAXIL should not be chewed or crushed, and should be swallowed
whole.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
PAXIL and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking Paxil can cause mild pupillary dilation, which in
susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma
is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be
treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure
glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle
closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with PAXIL and should counsel
them in its appropriate use. A patient Medication Guide is available for PAXIL. The prescriber
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or health professional should instruct patients, their families, and their caregivers to read the
Medication Guide and should assist them in understanding its contents. Patients should be given
the opportunity to discuss the contents of the Medication Guide and to obtain answers to any
questions they may have. The complete text of the Medication Guide is reprinted at the end of
this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking PAXIL.
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
down. Families and caregivers of patients should be advised to look for the emergence of such
symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
close monitoring and possibly changes in the medication.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin,
warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that
interfere with serotonin reuptake and these agents has been associated with an increased risk of
bleeding.
Interference With Cognitive and Motor Performance: Any psychoactive drug may
impair judgment, thinking, or motor skills. Although in controlled studies PAXIL has not been
shown to impair psychomotor performance, patients should be cautioned about operating
hazardous machinery, including automobiles, until they are reasonably certain that therapy with
PAXIL does not affect their ability to engage in such activities.
Completing Course of Therapy: While patients may notice improvement with treatment
with PAXIL in 1 to 4 weeks, they should be advised to continue therapy as directed.
Concomitant Medication: Patients should be advised to inform their physician if they are
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
interactions.
Alcohol: Although PAXIL has not been shown to increase the impairment of mental and
motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
Pregnancy: Patients should be advised to notify their physician if they become pregnant or
intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic
Effects and Nonteratogenic Effects).
Nursing: Patients should be advised to notify their physician if they are breastfeeding an
infant (see PRECAUTIONS: Nursing Mothers).
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Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Tryptophan: As with other serotonin reuptake inhibitors, an interaction
between paroxetine and tryptophan may occur when they are coadministered. Adverse
experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been
reported when tryptophan was administered to patients taking PAXIL. Consequently,
concomitant use of PAXIL with tryptophan is not recommended (see WARNINGS: Serotonin
Syndrome).
Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
Pimozide: In a controlled study of healthy volunteers, after PAXIL was titrated to 60 mg
daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in
pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The
increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine.
Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT
interval, concomitant use of pimozide and PAXIL is contraindicated (see
CONTRAINDICATIONS).
Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including
paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when
PAXIL is coadministered with other drugs that may affect the serotonergic neurotransmitter
systems, such as triptans, lithium, fentanyl, tramadol, or St. John’s Wort (see WARNINGS:
Serotonin Syndrome).
The concomitant use of PAXIL with MAOIs (including linezolid and intravenous methylene
blue) is contraindicated (see CONTRAINDICATIONS). The concomitant use of PAXIL with
other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions:
Tryptophan).
Thioridazine: See CONTRAINDICATIONS and WARNINGS.
Warfarin: Preliminary data suggest that there may be a pharmacodynamic interaction (that
causes an increased bleeding diathesis in the face of unaltered prothrombin time) between
paroxetine and warfarin. Since there is little clinical experience, the concomitant administration
of PAXIL and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That
Interfere With Hemostasis).
Triptans: There have been rare postmarketing reports of serotonin syndrome with the use of
an SSRI and a triptan. If concomitant use of PAXIL with a triptan is clinically warranted, careful
observation of the patient is advised, particularly during treatment initiation and dose increases
(see WARNINGS: Serotonin Syndrome).
Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of
paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Cimetidine: Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study
where PAXIL (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma
concentrations of paroxetine were increased by approximately 50% during coadministration with
oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are
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administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be
guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not
studied.
Phenobarbital: Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a
single oral 30-mg dose of PAXIL was administered at phenobarbital steady state (100 mg once
daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
respectively) compared to paroxetine administered alone. The effect of paroxetine on
phenobarbital pharmacokinetics was not studied. Since PAXIL exhibits nonlinear
pharmacokinetics, the results of this study may not address the case where the 2 drugs are both
being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when
coadministered with phenobarbital; any subsequent adjustment should be guided by clinical
effect.
Phenytoin: When a single oral 30-mg dose of PAXIL was administered at phenytoin steady
state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of
50% and 35%, respectively) compared to PAXIL administered alone. In a separate study, when a
single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once
daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to
phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above
studies may not address the case where the 2 drugs are both being chronically dosed. No initial
dosage adjustments are considered necessary when these drugs are coadministered; any
subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS:
Postmarketing Reports).
Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the
treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are
metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by
CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients
(>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily
dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose
desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold,
respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been
evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to
8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased
9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the
active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The
effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs
were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,
paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This
resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in
atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone.
Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be
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initiated at a reduced dose when it is given with paroxetine.
Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not
been formally studied but may require lower doses than usually prescribed for either PAXIL or
the other drug.
Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme,
including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,
amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type
1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme
(e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrhythmias and sudden death potentially
associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be
coadministered (see CONTRAINDICATIONS and WARNINGS).
Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6
by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and
hence reduced efficacy of tamoxifen (see PRECAUTIONS).
At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is
governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see
PRECAUTIONS: Tricyclic Antidepressants [TCAs]).
Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving
the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for
cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In
addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be
at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several
substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and
cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and
its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4
substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical
significance.
Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of
tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism.
Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be
reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS: Drugs Metabolized by
Cytochrome CYP2D6).
Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma
protein, administration of PAXIL to a patient taking another drug that is highly protein bound
may cause increased free concentrations of the other drug, potentially resulting in adverse events.
Conversely, adverse effects could result from displacement of paroxetine by other highly bound
drugs.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin):
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of
22
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the case-control and cohort design that have demonstrated an association between use of
psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have
been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving
warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
Alcohol: Although PAXIL does not increase the impairment of mental and motor skills
caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction
between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome,
caution is advised when PAXIL is coadministered with lithium.
Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered
with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the
presence of paroxetine. Since there is little clinical experience, the concurrent administration of
paroxetine and digoxin should be undertaken with caution.
Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine
kinetics. The effects of paroxetine on diazepam were not evaluated.
Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0
24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%,
respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen,
the dose of procyclidine should be reduced.
Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for
18 days, the established steady-state plasma concentrations of propranolol were unaltered during
coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of
propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS:
Postmarketing Reports).
Theophylline: Reports of elevated theophylline levels associated with treatment with
PAXIL have been reported. While this interaction has not been formally studied, it is
recommended that theophylline levels be monitored when these drugs are concurrently
administered.
Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine
significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by
clinical effect (tolerability and efficacy).
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of
ECT and PAXIL.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Two-year
carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and
25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and
3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and
PTSD on a mg/m2 basis. Because the MRHD for major depressive disorder is slightly less than
23
Reference ID: 3595524
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that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only
2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of
male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for
control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear
trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats
were not affected. Although there was a dose-related increase in the number of tumors in mice,
there was no drug-related increase in the number of mice with tumors. The relevance of these
findings to humans is unknown.
Mutagenesis: Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in
vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation
assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse
bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
Impairment of Fertility: Some clinical studies have shown that SSRIs (including
paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some
men.
A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of
15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety
disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m2 basis. Irreversible
lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to
52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at
50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested
spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder,
social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m2
basis).
Pregnancy: Pregnancy Category D. See WARNINGS: Usage in Pregnancy: Teratogenic
Effects and Nonteratogenic Effects.
Labor and Delivery: The effect of paroxetine on labor and delivery in humans is unknown.
Nursing Mothers: Like many other drugs, paroxetine is secreted in human milk, and caution
should be exercised when PAXIL is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Three placebo-
controlled trials in 752 pediatric patients with MDD have been conducted with PAXIL, and the
data were not sufficient to support a claim for use in pediatric patients. Anyone considering the
use of PAXIL in a child or adolescent must balance the potential risks with the clinical need.
Decreased appetite and weight loss have been observed in association with the use of SSRIs.
Consequently, regular monitoring of weight and growth should be performed in children and
adolescents treated with an SSRI such as PAXIL.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse
events were reported in at least 2% of pediatric patients treated with PAXIL and occurred at a
rate at least twice that for pediatric patients receiving placebo: emotional lability (including self
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Reference ID: 3595524
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harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased
appetite, tremor, sweating, hyperkinesia, and agitation.
Events reported upon discontinuation of treatment with PAXIL in the pediatric clinical trials
that included a taper phase regimen, which occurred in at least 2% of patients who received
PAXIL and which occurred at a rate at least twice that of placebo, were: emotional lability
(including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness,
dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION:
Discontinuation of Treatment With PAXIL).
Geriatric Use: SSRIs and SNRIs, including PAXIL, have been associated with cases of
clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse
event (see PRECAUTIONS: Hyponatremia).
In worldwide premarketing clinical trials with PAXIL, 17% of patients treated with PAXIL
(approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased
clearance in the elderly, and a lower starting dose is recommended; there were, however, no
overall differences in the adverse event profile between elderly and younger patients, and
effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Associated With Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients
treated with PAXIL in worldwide clinical trials in major depressive disorder and 16.1%
(84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients
treated with PAXIL in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD,
and PTSD, respectively, discontinued treatment due to an adverse event. The most common
events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events
associated with dropout at a rate approximately twice or greater for PAXIL compared to placebo)
included the following:
25
Reference ID: 3595524
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Major
Depressive
Disorder
OCD
Panic Disorder
Social Anxiety
Disorder
Generalized
Anxiety
Disorder
PTSD
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
PAXIL
Placebo
CNS
Somnolence
2.3%
0.7%
—
1.9%
0.3%
3.4%
0.3%
2.0%
0.2%
2.8%
0.6%
Insomnia
—
—
1.7%
0%
1.3%
0.3%
3.1%
0%
—
—
Agitation
1.1%
0.5%
—
—
—
Tremor
1.1%
0.3%
—
1.7%
0%
1.0%
0.2%
Anxiety
—
—
—
1.1%
0%
—
—
Dizziness
—
—
1.5%
0%
1.9%
0%
1.0%
0.2%
—
—
Gastroin
testinal
Constipation
—
1.1%
0%
—
—
Nausea
3.2%
1.1%
1.9%
0%
3.2%
1.2%
4.0%
0.3%
2.0%
0.2%
2.2%
0.6%
Diarrhea
1.0%
0.3%
—
Dry mouth
1.0%
0.3%
—
—
—
Vomiting
1.0%
0.3%
—
1.0%
0%
—
—
Flatulence
1.0%
0.3%
—
—
Other
Asthenia
Abnormal
1.6%
0.4%
1.9%
0.4%
2.5%
0.6%
1.8%
0.2%
1.6%
0.2%
Ejaculationa
1.6%
0%
2.1%
0%
4.9%
0.6%
2.5%
0.5%
—
—
Sweating
1.0%
0.3%
—
1.1%
0%
1.1%
0.2%
—
—
Impotencea
Libido
—
1.5%
0%
—
—
Decreased
1.0%
0%
—
—
Where numbers are not provided the incidence of the adverse events in patients treated with
PAXIL was not >1% or was not greater than or equal to 2 times the incidence of placebo.
a. Incidence corrected for gender.
Commonly Observed Adverse Events: Major Depressive Disorder: The most
commonly observed adverse events associated with the use of paroxetine (incidence of 5% or
greater and incidence for PAXIL at least twice that for placebo, derived from Table 2) were:
Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor,
nervousness, ejaculatory disturbance, and other male genital disorders.
Obsessive Compulsive Disorder: The most commonly observed adverse events
associated with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at
least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite,
constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
26
Reference ID: 3595524
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Panic Disorder: The most commonly observed adverse events associated with the use of
paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for placebo,
derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor,
abnormal ejaculation, female genital disorders, and impotence.
Social Anxiety Disorder: The most commonly observed adverse events associated with
the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice that for
placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased
appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital
disorders, and impotence.
Generalized Anxiety Disorder: The most commonly observed adverse events associated
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased
appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal
ejaculation.
Posttraumatic Stress Disorder: The most commonly observed adverse events associated
with the use of paroxetine (incidence of 5% or greater and incidence for PAXIL at least twice
that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea,
decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders,
and impotence.
Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in
the tables following cannot be used to predict the incidence of side effects in the course of usual
medical practice where patient characteristics and other factors differ from those that prevailed in
the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from
other clinical investigations involving different treatments, uses, and investigators. The cited
figures, however, do provide the prescribing physician with some basis for estimating the
relative contribution of drug and nondrug factors to the side effect incidence rate in the
populations studied.
Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an
incidence of 1% or more among paroxetine-treated patients who participated in short-term
(6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to
50 mg/day. Reported adverse events were classified using a standard COSTART-based
Dictionary terminology.
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Reference ID: 3595524
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Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Major Depressive Disordera
Body System
Preferred Term
PAXIL
(n = 421)
Placebo
(n = 421)
Body as a Whole
Headache
Asthenia
18%
15%
17%
6%
Cardiovascular
Palpitation
Vasodilation
3%
3%
1%
1%
Dermatologic
Sweating
Rash
11%
2%
2%
1%
Gastrointestinal
Nausea
26%
9%
Dry Mouth
18%
12%
Constipation
14%
9%
Diarrhea
12%
8%
Decreased Appetite
6%
2%
Flatulence
4%
2%
Oropharynx Disorderb
2%
0%
Dyspepsia
2%
1%
Musculoskeletal
Myopathy
Myalgia
Myasthenia
2%
2%
1%
1%
1%
0%
Nervous System
Somnolence
23%
9%
Dizziness
13%
6%
Insomnia
13%
6%
Tremor
8%
2%
Nervousness
5%
3%
Anxiety
5%
3%
Paresthesia
4%
2%
Libido Decreased
3%
0%
Drugged Feeling
2%
1%
Confusion
1%
0%
Respiration
Yawn
4%
0%
Special Senses
Blurred Vision
Taste Perversion
4%
2%
1%
0%
Urogenital System
Ejaculatory Disturbancec,d
13%
0%
Other Male Genital Disordersc,e
10%
0%
Urinary Frequency
3%
1%
Urination Disorderf
3%
0%
Female Genital Disordersc,g
2%
0%
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a. Events reported by at least 1% of patients treated with PAXIL are included, except the
following events which had an incidence on placebo ≥ PAXIL: Abdominal pain, agitation,
back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis,
postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”),
trauma, and vomiting.
b. Includes mostly “lump in throat” and “tightness in throat.”
c. Percentage corrected for gender.
d. Mostly “ejaculatory delay.”
e. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual
dysfunction,” and “impotence.”
f. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
g. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD
patients on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on
PAXIL who participated in placebo-controlled trials of 10- to 12-weeks duration in which
patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety
disorder on PAXIL who participated in placebo-controlled trials of 12-weeks duration in which
patients were dosed in a range of 20 mg to 50 mg/day.
Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials
for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disordera
Body System
Preferred Term
Obsessive Compulsive
Disorder
Panic Disorder
Social Anxiety
Disorder
PAXIL
(n = 542)
Placebo
(n = 265)
PAXIL
(n = 469)
Placebo
(n = 324)
PAXIL
(n = 425)
Placebo
(n = 339)
Body as a Whole
Asthenia
Abdominal Pain
Chest Pain
Back Pain
Chills
Trauma
22%
—
3%
—
2%
—
14%
—
2%
—
1%
—
14%
4%
—
3%
2%
—
5%
3%
—
2%
1%
—
22%
—
—
—
—
3%
14%
—
—
—
—
1%
Cardiovascular
Vasodilation
Palpitation
4%
2%
1%
0%
—
—
—
—
—
—
—
—
Dermatologic
Sweating
Rash
9%
3%
3%
2%
14%
—
6%
—
9%
—
2%
—
Gastrointestinal
Nausea
Dry Mouth
23%
18%
10%
9%
23%
18%
17%
11%
25%
9%
7%
3%
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Reference ID: 3595524
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Constipation
16%
6%
8%
5%
5%
2%
Diarrhea
10%
10%
12%
7%
9%
6%
Decreased Appetite
9%
3%
7%
3%
8%
2%
Dyspepsia
—
—
—
—
4%
2%
Flatulence
—
—
—
—
4%
2%
Increased Appetite
4%
3%
2%
1%
—
—
Vomiting
—
—
—
—
2%
1%
Musculoskeletal
Myalgia
—
—
—
—
4%
3%
Nervous System
Insomnia
Somnolence
Dizziness
Tremor
Nervousness
Libido Decreased
Agitation
Anxiety
Abnormal Dreams
Concentration
Impaired
Depersonalization
Myoclonus
Amnesia
24%
24%
12%
11%
9%
7%
—
—
4%
3%
3%
3%
2%
13%
7%
6%
1%
8%
4%
—
—
1%
2%
0%
0%
1%
18%
19%
14%
9%
—
9%
5%
5%
—
—
—
3%
—
10%
11%
10%
1%
—
1%
4%
4%
—
—
—
2%
—
21%
22%
11%
9%
8%
12%
3%
5%
—
4%
—
2%
—
16%
5%
7%
1%
7%
1%
1%
4%
—
1%
—
1%
—
Respiratory
Rhinitis
—
—
3%
0%
—
—
System
Pharyngitis
Yawn
—
—
—
—
—
—
—
—
4%
5%
2%
1%
Special Senses
Abnormal Vision
Taste Perversion
4%
2%
2%
0%
—
—
—
—
4%
—
1%
—
Urogenital System
Abnormal
Ejaculationb
Dysmenorrhea
Female Genital
Disorderb
Impotenceb
Urinary Frequency
Urination Impaired
Urinary Tract
Infection
23%
—
3%
8%
3%
3%
2%
1%
—
0%
1%
1%
0%
1%
21%
—
9%
5%
2%
—
2%
1%
—
1%
0%
0%
—
1%
28%
5%
9%
5%
—
—
—
1%
4%
1%
1%
—
—
—
a. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients
treated with PAXIL are included, except the following events which had an incidence on
30
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placebo ≥PAXIL: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased,
depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder,
rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough
increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache,
infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory
disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social
anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and
sinusitis.
b. Percentage corrected for gender.
Generalized Anxiety Disorder and Posttraumatic Stress Disorder: Table 4
enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on
PAXIL who participated in placebo-controlled trials of 8-weeks duration in which patients were
dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on PAXIL who
participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a
range of 20 mg/day to 50 mg/day.
31
Reference ID: 3595524
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Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disordera
Body System
Preferred Term
Generalized Anxiety
Disorder
Posttraumatic Stress
Disorder
PAXIL
(n = 735)
Placebo
(n = 529)
PAXIL
(n = 676)
Placebo
(n = 504)
Body as a
Asthenia
14%
6%
12%
4%
Whole
Headache
17%
14%
—
—
Infection
6%
3%
5%
4%
Abdominal Pain
4%
3%
Trauma
6%
5%
Cardiovascular
Vasodilation
3%
1%
2%
1%
Dermatologic
Sweating
6%
2%
5%
1%
Gastrointestinal
Nausea
20%
5%
19%
8%
Dry Mouth
11%
5%
10%
5%
Constipation
10%
2%
5%
3%
Diarrhea
9%
7%
11%
5%
Decreased Appetite
5%
1%
6%
3%
Vomiting
3%
2%
3%
2%
Dyspepsia
—
—
5%
3%
Nervous
Insomnia
11%
8%
12%
11%
System
Somnolence
15%
5%
16%
5%
Dizziness
6%
5%
6%
5%
Tremor
5%
1%
4%
1%
Nervousness
4%
3%
—
—
Libido Decreased
9%
2%
5%
2%
Abnormal Dreams
3%
2%
Respiratory
System
Respiratory Disorder
Sinusitis
Yawn
7%
4%
4%
5%
3%
—
—
—
2%
—
—
<1%
Special Senses
Abnormal Vision
2%
1%
3%
1%
Urogenital
Abnormal
25%
2%
13%
2%
System
Ejaculation
b
Female Genital
Disorder
b
4%
1%
5%
1%
Impotence
b
4%
3%
9%
1%
a. Events reported by at least 2% of GAD and PTSD in patients treated with PAXIL are
included, except the following events which had an incidence on placebo ≥PAXIL [GAD]:
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Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain,
headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis.
b. Percentage corrected for gender.
Dose Dependency of Adverse Events: A comparison of adverse event rates in a
fixed-dose study comparing 10, 20, 30, and 40 mg/day of PAXIL with placebo in the treatment
of major depressive disorder revealed a clear dose dependency for some of the more common
adverse events associated with use of PAXIL, as shown in Table 5:
Table 5. Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial
in the Treatment of Major Depressive Disordera
Body System/Preferred Term
Placebo
n = 51
PAXIL
10 mg
n = 102
20 mg
n = 104
30 mg
n = 101
40 mg
n = 102
Body as a Whole
Asthenia
0.0%
2.9%
10.6%
13.9%
12.7%
Dermatology
Sweating
2.0%
1.0%
6.7%
8.9%
11.8%
Gastrointestinal
Constipation
5.9%
4.9%
7.7%
9.9%
12.7%
Decreased Appetite
2.0%
2.0%
5.8%
4.0%
4.9%
Diarrhea
7.8%
9.8%
19.2%
7.9%
14.7%
Dry Mouth
2.0%
10.8%
18.3%
15.8%
20.6%
Nausea
13.7%
14.7%
26.9%
34.7%
36.3%
Nervous System
Anxiety
0.0%
2.0%
5.8%
5.9%
5.9%
Dizziness
3.9%
6.9%
6.7%
8.9%
12.7%
Nervousness
0.0%
5.9%
5.8%
4.0%
2.9%
Paresthesia
0.0%
2.9%
1.0%
5.0%
5.9%
Somnolence
7.8%
12.7%
18.3%
20.8%
21.6%
Tremor
0.0%
0.0%
7.7%
7.9%
14.7%
Special Senses
Blurred Vision
2.0%
2.9%
2.9%
2.0%
7.8%
Urogenital System
Abnormal Ejaculation
0.0%
5.8%
6.5%
10.6%
13.0%
Impotence
0.0%
1.9%
4.3%
6.4%
1.9%
Male Genital Disorders
0.0%
3.8%
8.7%
6.4%
3.7%
a. Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups
and ≥ twice the placebo incidence for at least 1 paroxetine group.
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In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
OCD, there was no clear relationship between adverse events and the dose of PAXIL to which
patients were assigned. No new adverse events were observed in the group treated with 60 mg of
PAXIL compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and 10, 20, and 40 mg of PAXIL in the treatment of
panic disorder, there was no clear relationship between adverse events and the dose of PAXIL to
which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor,
and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in
patients receiving 60 mg of PAXIL compared to any of the other treatment groups.
In a fixed-dose study comparing placebo and 20, 40, and 60 mg of PAXIL in the treatment of
social anxiety disorder, for most of the adverse events, there was no clear relationship between
adverse events and the dose of PAXIL to which patients were assigned.
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
generalized anxiety disorder, for most of the adverse events, there was no clear relationship
between adverse events and the dose of PAXIL to which patients were assigned, except for the
following adverse events: Asthenia, constipation, and abnormal ejaculation.
In a fixed-dose study comparing placebo and 20 and 40 mg of PAXIL in the treatment of
posttraumatic stress disorder, for most of the adverse events, there was no clear relationship
between adverse events and the dose of PAXIL to which patients were assigned, except for
impotence and abnormal ejaculation.
Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence
of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less
to other effects (e.g., dry mouth, somnolence, and asthenia).
Male and Female Sexual Dysfunction With SSRIs: Although changes in sexual desire,
sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric
disorder, they may also be a consequence of pharmacologic treatment. In particular, some
evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward
sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences involving sexual
desire, performance, and satisfaction are difficult to obtain, however, in part because patients and
physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of
untoward sexual experience and performance cited in product labeling, are likely to
underestimate their actual incidence.
In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the
reported incidence of sexual side effects in males and females with major depressive disorder,
OCD, panic disorder, social anxiety disorder, GAD, and PTSD are displayed in Table 6.
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Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials
PAXIL
Placebo
n (males)
1446
1042
Decreased Libido
6-15%
0-5%
Ejaculatory Disturbance
13-28%
0-2%
Impotence
2-9%
0-3%
n (females)
1822
1340
Decreased Libido
0-9%
0-2%
Orgasmic Disturbance
2-9%
0-1%
There are no adequate and well-controlled studies examining sexual dysfunction with
paroxetine treatment.
Paroxetine treatment has been associated with several cases of priapism. In those cases with a
known outcome, patients recovered without sequelae.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of
treatment with PAXIL for some patients but, on average, patients in controlled trials had minimal
(about 1 pound) weight loss versus smaller changes on placebo and active control. No significant
changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were
observed in patients treated with PAXIL in controlled clinical trials.
ECG Changes: In an analysis of ECGs obtained in 682 patients treated with PAXIL and
415 patients treated with placebo in controlled clinical trials, no clinically significant changes
were seen in the ECGs of either group.
Liver Function Tests: In placebo-controlled clinical trials, patients treated with PAXIL
exhibited abnormal values on liver function tests at no greater rate than that seen in
placebo-treated patients. In particular, the PAXIL-versus-placebo comparisons for alkaline
phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients
with marked abnormalities.
Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride,
hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients
receiving placebo.
Other Events Observed During the Premarketing Evaluation of PAXIL: During its
premarketing assessment in major depressive disorder, multiple doses of PAXIL were
administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure
to PAXIL varied greatly and included (in overlapping categories) open and double-blind studies,
uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration
studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder,
generalized anxiety disorder, and posttraumatic stress disorder, 542, 469, 522, 735, and 676
patients, respectively, received multiple doses of PAXIL. Untoward events associated with this
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exposure were recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
experiencing adverse events without first grouping similar types of untoward events into a
smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a standard
COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the
proportion of the 9,089 patients exposed to multiple doses of PAXIL who experienced an event
of the type cited on at least 1 occasion while receiving PAXIL. All reported events are included
except those already listed in Tables 2 to 5, those reported in terms so general as to be
uninformative and those events where a drug cause was remote. It is important to emphasize that
although the events reported occurred during treatment with paroxetine, they were not
necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: Frequent adverse events are those occurring on 1 or more
occasions in at least 1/100 patients (only those not already listed in the tabulated results from
placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in
1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events
of major clinical importance are also described in the PRECAUTIONS section.
Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain;
rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis,
ulcer.
Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia,
hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris,
arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular
accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial
ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis,
thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis,
gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal
hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia,
cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal
incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction,
jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis,
stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism,
thyroiditis.
Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy,
purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia,
hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal
lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia,
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thrombocythemia, thrombocytopenia.
Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema,
SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased,
bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma
globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia,
hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic
dehydrogenase increased, non-protein nitrogen (NPN) increased.
Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare:
Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking,
alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia,
hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction,
neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia,
choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug
dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion,
hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy,
nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes
increased, stupor, torticollis, trismus, withdrawal syndrome.
Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation,
pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary
edema, sputum increased, stridor, voice alteration.
Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis,
dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema,
erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis;
herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy,
skin ulcer, sweating decreased, vesiculobullous rash.
Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation,
conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia,
anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye
hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia,
ptosis, retinal hemorrhage, taste loss, visual field defect.
Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria,
menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency,
vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis,
female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis,
metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith,
vaginal hemorrhage, vaginal moniliasis.
Postmarketing Reports: Voluntary reports of adverse events in patients taking PAXIL that
have been received since market introduction and not listed above that may have no causal
relationship with the drug include acute pancreatitis, elevated liver function tests (the most
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severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated
with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic
epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive
of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia,
bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been
associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal
failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic
neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia
(including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired
hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and
agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature
births in pregnant women. There has been a case report of an elevated phenytoin level after 4
weeks of PAXIL and phenytoin coadministration. There has been a case report of severe
hypotension when PAXIL was added to chronic metoprolol treatment.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: PAXIL is not a controlled substance.
Physical and Psychologic Dependence: PAXIL has not been systematically studied in
animals or humans for its potential for abuse, tolerance or physical dependence. While the
clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were
not systematic and it is not possible to predict on the basis of this limited experience the extent to
which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently,
patients should be evaluated carefully for history of drug abuse, and such patients should be
observed closely for signs of misuse or abuse of PAXIL (e.g., development of tolerance,
incrementations of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience: Since the introduction of PAXIL in the United States, 342 spontaneous
cases of deliberate or accidental overdosage during paroxetine treatment have been reported
worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with
other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve
paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were
generally confounded by the ingestion of other drugs or alcohol or the presence of significant
comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without
sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum
recommended daily dose) in a patient who recovered.
Commonly reported adverse events associated with paroxetine overdosage include
somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other
notable signs and symptoms observed with overdoses involving paroxetine (alone or with other
substances) include mydriasis, convulsions (including status epilepticus), ventricular
dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope,
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hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction
(including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin
syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
Overdosage Management: No specific antidotes for paroxetine are known. Treatment
should consist of those general measures employed in the management of overdosage with any
drugs effective in the treatment of major depressive disorder.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
signs. General supportive and symptomatic measures are also recommended. Induction of emesis
is not recommended. Due to the large volume of distribution of this drug, forced diuresis,
dialysis, hemoperfusion, or exchange transfusion are unlikely to be of benefit.
A specific caution involves patients who are taking or have recently taken paroxetine who
might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the
parent tricyclic and/or an active metabolite may increase the possibility of clinically significant
sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drugs
Metabolized by Cytochrome CYP2D6).
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center for additional information on the treatment of
any overdose. Telephone numbers for certified poison control centers are listed in the Physicians'
Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
Major Depressive Disorder: Usual Initial Dosage: PAXIL should be administered as a
single daily dose with or without food, usually in the morning. The recommended initial dose is
20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating
the effectiveness of PAXIL in the treatment of major depressive disorder. As with all drugs
effective in the treatment of major depressive disorder, the full effect may be delayed. Some
patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day
increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least
1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL should remain on it. It is generally agreed that acute
episodes of major depressive disorder require several months or longer of sustained
pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose
needed to maintain and/or sustain euthymia is unknown.
Systematic evaluation of the efficacy of PAXIL has shown that efficacy is maintained for
periods of up to 1 year with doses that averaged about 30 mg.
Obsessive Compulsive Disorder: Usual Initial Dosage: PAXIL should be administered
as a single daily dose with or without food, usually in the morning. The recommended dose of
PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the
dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at
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least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials
demonstrating the effectiveness of PAXIL in the treatment of OCD. The maximum dosage
should not exceed 60 mg/day.
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month
relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a
lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY:
Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
effective dosage, and patients should be periodically reassessed to determine the need for
continued treatment.
Panic Disorder: Usual Initial Dosage: PAXIL should be administered as a single daily dose
with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic
disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in
10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to
60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL. The maximum dosage
should not exceed 60 mg/day.
Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month
relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine
demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL
PHARMACOLOGY: Clinical Trials). Panic disorder is a chronic condition, and it is reasonable
to consider continuation for a responding patient. Dosage adjustments should be made to
maintain the patient on the lowest effective dosage, and patients should be periodically
reassessed to determine the need for continued treatment.
Social Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a single
daily dose with or without food, usually in the morning. The recommended and initial dosage is
20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a
range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social
anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional
benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials).
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety
disorder is recognized as a chronic condition, and it is reasonable to consider continuation of
treatment for a responding patient. Dosage adjustments should be made to maintain the patient
on the lowest effective dosage, and patients should be periodically reassessed to determine the
need for continued treatment.
Generalized Anxiety Disorder: Usual Initial Dosage: PAXIL should be administered as a
single daily dose with or without food, usually in the morning. In clinical trials the effectiveness
of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended
starting dosage and the established effective dosage is 20 mg/day. There is not sufficient
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evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur
in 10 mg/day increments and at intervals of at least 1 week.
Maintenance Therapy: Systematic evaluation of continuing PAXIL for periods of up to
24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL
during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see
CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically
reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder: Usual Initial Dosage: PAXIL should be administered as
a single daily dose with or without food, usually in the morning. The recommended starting
dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of
PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed
dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day
compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at
intervals of at least 1 week.
Maintenance Therapy: There is no body of evidence available to answer the question of
how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL
beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is
recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a
responding patient. Dosage adjustments should be made to maintain the patient on the lowest
effective dosage, and patients should be periodically reassessed to determine the need for
continued treatment.
Special Populations: Treatment of Pregnant Women During the Third Trimester:
Neonates exposed to PAXIL and other SSRIs or SNRIs, late in the third trimester have
developed complications requiring prolonged hospitalization, respiratory support, and tube
feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine
during the third trimester, the physician should carefully consider the potential risks and benefits
of treatment.
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or
Hepatic Impairment: The recommended initial dose is 10 mg/day for elderly patients,
debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be
made if indicated. Dosage should not exceed 40 mg/day.
Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to
Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an
MAOI intended to treat psychiatric disorders and initiation of therapy with PAXIL. Conversely,
at least 14 days should be allowed after stopping PAXIL before starting an MAOI intended to
treat psychiatric disorders (see CONTRAINDICATIONS).
Use of PAXIL With Other MAOIs, Such as Linezolid or Methylene Blue: Do not start
PAXIL in a patient who is being treated with linezolid or intravenous methylene blue because
there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of
a psychiatric condition, other interventions, including hospitalization, should be considered (see
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CONTRAINDICATIONS).
In some cases, a patient already receiving therapy with PAXIL may require urgent treatment
with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or
intravenous methylene blue treatment are not available and the potential benefits of linezolid or
intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in
a particular patient, PAXIL should be stopped promptly, and linezolid or intravenous methylene
blue can be administered. The patient should be monitored for symptoms of serotonin syndrome
for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue,
whichever comes first. Therapy with PAXIL may be resumed 24 hours after the last dose of
linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by
local injection) or in intravenous doses much lower than 1 mg/kg with PAXIL is unclear. The
clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin
syndrome with such use (see WARNINGS).
Discontinuation of Treatment With PAXIL: Symptoms associated with discontinuation of
PAXIL have been reported (see PRECAUTIONS: Discontinuation of Treatment With PAXIL).
Patients should be monitored for these symptoms when discontinuing treatment, regardless of the
indication for which PAXIL is being prescribed. A gradual reduction in the dose rather than
abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a
decrease in the dose or upon discontinuation of treatment, then resuming the previously
prescribed dose may be considered. Subsequently, the physician may continue decreasing the
dose but at a more gradual rate.
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
HOW SUPPLIED
Tablets: Film-coated, modified-oval as follows:
10-mg yellow, scored tablets engraved on the front with PAXIL and on the back with 10.
NDC 60505-3663-3 Bottles of 30
20-mg pink, scored tablets engraved on the front with PAXIL and on the back with 20.
NDC 60505-3664-3 Bottles of 30
30-mg blue tablets engraved on the front with PAXIL and on the back with 30.
NDC 60505-3665-3 Bottles of 30
40-mg green tablets engraved on the front with PAXIL and on the back with 40.
NDC 60505-3666-3 Bottles of 30
Store tablets between 15° and 30°C (59° and 86°F).
Oral Suspension: Orange-colored, orange-flavored, 10 mg/5 mL, in white bottles containing
250 mL.
NDC 60505-0402-5
Store suspension at or below 25°C (77°F).
PAXIL is a registered trademark of GlaxoSmithKline.
42
Reference ID: 3595524
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Distributed by:
Apotex Corp.
Weston, FL 33326
2012, GlaxoSmithKline. All rights reserved.
June 2014
PXL-AP: 6PI
Medication Guide
PAXIL® (PAX-il)
(paroxetine hydrochloride)
Tablets and Oral Suspension
Read the Medication Guide that comes with PAXIL before you start taking it and each time you
get a refill. There may be new information. This Medication Guide does not take the place of
talking to your healthcare provider about your medical condition or treatment. Talk with your
healthcare provider if there is something you do not understand or want to learn more about.
What is the most important information I should know about PAXIL?
PAXIL and other antidepressant medicines may cause serious side effects, including:
1.
Suicidal thoughts or actions:
• PAXIL and other antidepressant medicines may increase suicidal thoughts or
actions in some children, teenagers, or young adults within the first few months of
treatment or when the dose is changed.
• Depression or other serious mental illnesses are the most important causes of suicidal
thoughts or actions.
• Watch for these changes and call your healthcare provider right away if you notice:
• New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if
severe.
• Pay particular attention to such changes when PAXIL is started or when the dose is
changed.
43
Reference ID: 3595524
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Keep all follow-up visits with your healthcare provider and call between visits if you are
worried about symptoms.
Call your healthcare provider right away if you have any of the following symptoms,
or call 911 if an emergency, especially if they are new, worse, or worry you:
• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic attacks
• feeling agitated, restless, angry, or irritable
• trouble sleeping
• an increase in activity or talking more than what is normal for you
• other unusual changes in behavior or mood
Call your healthcare provider right away if you have any of the following symptoms, or call
911 if an emergency. PAXIL may be associated with these serious side effects:
2.
Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This
condition can be life-threatening and may include:
• agitation, hallucinations, coma, or other changes in mental status
• coordination problems or muscle twitching (overactive reflexes)
• racing heartbeat, high or low blood pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity
3.
Visual problems
• eye pain
• changes in vision
• swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye examination
to see if you are at risk and receive preventative treatment if you are.
4.
Severe allergic reactions:
• trouble breathing
• swelling of the face, tongue, eyes, or mouth
• rash, itchy welts (hives), or blisters, alone or with fever or joint pain
5.
Abnormal bleeding: PAXIL and other antidepressant medicines may increase your risk of
bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin® ,
Jantoven®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen),
or aspirin.
6.
Seizures or convulsions
7.
Manic episodes:
44
Reference ID: 3595524
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• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual
8.
Changes in appetite or weight. Children and adolescents should have height and weight
monitored during treatment.
9.
Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this.
Symptoms may include:
• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking, or memory problems
Do not stop PAXIL without first talking to your healthcare provider. Stopping PAXIL too
quickly may cause serious symptoms including:
• anxiety, irritability, high or low mood, feeling restless, or changes in sleep habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking, confusion
What is PAXIL?
PAXIL is a prescription medicine used to treat depression. It is important to talk with your
healthcare provider about the risks of treating depression and also the risks of not treating it. You
should discuss all treatment choices with your healthcare provider. PAXIL is also used to treat:
• Major Depressive Disorder (MDD)
• Obsessive Compulsive Disorder (OCD)
• Panic Disorder
• Social Anxiety Disorder
• Generalized Anxiety Disorder (GAD)
• Posttraumatic Stress Disorder (PTSD)
Talk to your healthcare provider if you do not think that your condition is getting better with
treatment using PAXIL.
Who should not take PAXIL?
Do not take PAXIL if you:
• are allergic to paroxetine or any of the ingredients in PAXIL. See the end of this Medication
Guide for a complete list of ingredients in PAXIL.
45
Reference ID: 3595524
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• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if
you are not sure if you take an MAOI, including the antibiotic linezolid.
• Do not take an MAOI within 2 weeks of stopping PAXIL unless directed to do so by
your physician.
• Do not start PAXIL if you stopped taking an MAOI in the last 2 weeks unless directed to
do so by your physician.
• People who take PAXIL close in time to an MAOI may have serious or even life-
threatening side effects. Get medical help right away if you have any of these
symptoms:
• high fever
• uncontrolled muscle spasms
• stiff muscles
• rapid changes in heart rate or blood pressure
• confusion
• loss of consciousness (pass out)
• take MELLARIL® (thioridazine). Do not take MELLARIL® together with PAXIL
because this can cause serious heart rhythm problems or sudden death.
• take the antipsychotic medicine pimozide (ORAP®) because this can cause serious heart
problems.
What should I tell my healthcare provider before taking PAXIL? Ask if you are not sure.
Before starting PAXIL, tell your healthcare provider if you:
• are pregnant, may be pregnant, or plan to become pregnant. There is a possibility that
PAXIL may harm your unborn baby, including an increased risk of birth defects, particularly
heart defects. Other risks may include a serious condition in which there is not enough
oxygen in the baby’s blood. Your baby may also have certain other symptoms shortly after
birth. Premature births have also been reported in some women who used PAXIL during
pregnancy.
• are breastfeeding. PAXIL passes into your milk. Talk to your healthcare provider about the
best way to feed your baby while taking PAXIL.
• are taking certain drugs such as:
• triptans used to treat migraine headache
• other antidepressants (SSRIs, SNRIs, tricyclics, or lithium) or antipsychotics
• drugs that affect serotonin, such as lithium, tramadol, tryptophan, St. John’s wort
• certain drugs used to treat irregular heart beats
• certain drugs used to treat schizophrenia
• certain drugs used to treat HIV infection
• certain drugs that affect the blood, such as warfarin, aspirin, and ibuprofen
• certain drugs used to treat epilepsy
• atomoxetine
46
Reference ID: 3595524
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• cimetidine
• fentanyl
• metoprolol
• pimozide
• procyclidine
• tamoxifen
• have liver problems
• have kidney problems
• have heart problems
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have a history of a stroke
• have high blood pressure
• have or had bleeding problems
• have glaucoma (high pressure in the eye)
Tell your healthcare provider about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. PAXIL and some medicines may
interact with each other, may not work as well, or may cause serious side effects.
Your healthcare provider or pharmacist can tell you if it is safe to take PAXIL with your other
medicines. Do not start or stop any medicine while taking PAXIL without talking to your
healthcare provider first.
If you take PAXIL, you should not take any other medicines that contain paroxetine, including
PAXIL CR and PEXEVA® (paroxetine mesylate).
How should I take PAXIL?
• Take PAXIL exactly as prescribed. Your healthcare provider may need to change the dose of
PAXIL until it is the right dose for you.
• PAXIL may be taken with or without food.
• If you are taking PAXIL Oral Suspension, shake the suspension well before use.
• If you miss a dose of PAXIL, take the missed dose as soon as you remember. If it is almost
time for the next dose, skip the missed dose and take your next dose at the regular time. Do
not take two doses of PAXIL at the same time.
• If you take too much PAXIL, call your healthcare provider or poison control center right
away, or get emergency treatment.
• Do not stop taking PAXIL suddenly without talking to your doctor (unless you have
symptoms of a severe allergic reaction). If you need to stop taking PAXIL, your healthcare
provider can tell you how to safely stop taking it.
47
Reference ID: 3595524
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What should I avoid while taking PAXIL?
PAXIL can cause sleepiness or may affect your ability to make decisions, think clearly, or react
quickly. You should not drive, operate heavy machinery, or do other dangerous activities until
you know how PAXIL affects you. Do not drink alcohol while using PAXIL.
What are possible side effects of PAXIL?
PAXIL may cause serious side effects, including all of those described in the section entitled
“What is the most important information I should know about PAXIL?”
Common possible side effects in people who take PAXIL include:
• nausea
• sleepiness
• weakness
• dizziness
• feeling anxious or trouble sleeping
• sexual problems
• sweating
• shaking
• not feeling hungry
• dry mouth
• constipation
• infection
• yawning
Tell your healthcare provider if you have any side effect that bothers you or that does not go
away. These are not all the possible side effects of PAXIL. For more information, ask your
healthcare provider or pharmacist.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY
REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088 or 1-800-332-1088.
How should I store PAXIL?
• Store PAXIL Tablets at room temperature between 59º and 86ºF (15º and 30ºC).
• Store PAXIL Oral Suspension at or below 77ºF (25ºC).
• Keep PAXIL away from light.
• Keep bottle of PAXIL closed tightly.
Keep PAXIL and all medicines out of the reach of children.
General information about PAXIL
48
Reference ID: 3595524
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use PAXIL for a condition for which it was not prescribed. Do not give PAXIL to other
people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about PAXIL. If you would
like more information, talk with your healthcare provider. You may ask your healthcare provider
or pharmacist for information about PAXIL that is written for healthcare professionals.
For more information about PAXIL call 1-800-706-5575.
What are the ingredients in PAXIL?
Active ingredient: paroxetine hydrochloride
Inactive ingredients in tablets: dibasic calcium phosphate dihydrate, hypromellose, magnesium
stearate, polyethylene glycols, polysorbate 80, sodium starch glycolate, titanium dioxide, and 1
or more of the following: D&C Red No. 30 aluminum lake, D&C Yellow No. 10 aluminum lake,
FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake.
Inactive ingredients in suspension for oral administration: polacrilin potassium,
microcrystalline cellulose, propylene glycol, glycerin, sorbitol, methylparaben, propylparaben,
sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, flavorings, FD&C Yellow
No. 6 aluminum lake, and simethicone emulsion, USP.
PAXIL and PAXIL CR are registered trademarks of GlaxoSmithKline.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Distributed by:
Apotex Corp.
Weston, FL 33326
2013, GlaxoSmithKline. All rights reserved.
June 2014
PXL-AP:5MG
49
Reference ID: 3595524
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:46:30.166337
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020031s071,020710s035lbl.pdf', 'application_number': 20031, 'submission_type': 'SUPPL ', 'submission_number': 71}
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company logo
Lotensin HCT®
benazepril hydrochloride and hydrochlorothiazide USP
Combination Tablets
5 mg/6.25 mg
10 mg/12.5 mg
20 mg/12.5 mg
20 mg/25 mg
Rx only
Prescribing Information
USE IN PREGNANCY
When used in pregnancy, ACE inhibitors can cause injury and even death to the
developing fetus. When pregnancy is detected, Lotensin HCT should be discontinued as soon as
possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in
water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is
3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benza
zepine-1-acetic acid monohydrochloride; its structural formula is structural formula
Its empirical formula is C24H28N2O5·HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting
enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.
Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline
powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in
n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether,
in chloroform, and in dilute mineral acids. Hydrochlorothiazide’s chemical name is
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural
formula is
Reference ID: 2960155
This label may not be the latest approved by FDA.
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structural formula
Its empirical formula is C7 H8 ClN3 O4 S2, and its molecular weight is 297.73. Hydrochloro
thiazide is a thiazide diuretic.
Lotensin HCT is a combination of benazepril hydrochloride and hydrochlorothiazide USP. The
tablets are formulated for oral administration with a combination of 5, 10, or 20 mg of benazepril
hydrochloride and 6.25, 12.5, or 25 mg of hydrochlorothiazide USP. The inactive ingredients of
the tablets are cellulose compounds, crospovidone, hydrogenated castor oil, iron oxides
(10/12.5-mg, 20/12.5-mg, and 20/25-mg tablets), lactose, polyethylene glycol, talc, and titanium
dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects
and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to
the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone
secretion by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. Hypertensive patients treated with benazepril alone for up to
52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with
benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum
potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to
angiotensin II and did not interfere with the hemodynamic effects of the autonomic
neurotransmitters acetylcholine, epinephrine, and norepinephrine.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotensin
HCT remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be
primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an
antihypertensive effect even in patients with low-renin hypertension.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of
electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately
equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma
volume, with consequent increases in plasma renin activity, increases in aldosterone secretion,
increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone
Reference ID: 2960155
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link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the
potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is unknown.
Pharmacokinetics and Metabolism
Following oral administration of Lotensin HCT, peak plasma concentrations of benazepril are
reached within 0.5-1.0 hours. As determined by urinary recovery, the extent of absorption is at
least 37%. The absorption of hydrochlorothiazide is somewhat slower (1-2.5 hours) and
somewhat more complete (50%-80%). In fasting subjects, the rate and extent of absorption of
benazepril and hydrochlorothiazide from Lotensin HCT are not different, respectively, from the
rate and extent of absorption of benazepril and hydrochlorothiazide from immediate-release
monotherapy formulations.
The absorption of benazepril from Lotensin® tablets is not influenced by the presence of food in
the gastrointestinal tract, but possible effects of food upon absorption of either component from
Lotensin HCT tablets have not been studied. The reported studies of food effects on
hydrochlorothiazide absorption have been inconclusive. The absorption of hydrochlorothiazide
is increased by agents that reduce gastrointestinal motility, but it is reported to be reduced by
50% in patients with congestive heart failure.
Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite,
benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake
in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein
binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by
equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be
unaffected by age, hepatic dysfunction, or – over the concentration range of 0.24-23.6 µmol/L –
concentration.
Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6-7.8 L/kg, and
its measured plasma protein binding is 67.9%. The drug also accumulates in red blood cells, so
that whole blood levels are 1.6-1.8 times those measured in plasma.
In studies of rats given 14C-benazepril, benazepril and its metabolites crossed the blood-brain
barrier only to an extremely low extent. Multiple doses of benazepril did not result in
accumulation in any tissue except the lung, where, as with other ACE inhibitors in similar
studies, there was a slight increase in concentration due to slow elimination in that organ.
Some placental passage occurred when benazepril was administered to pregnant rats. In humans,
hydrochlorothiazide crosses the placenta freely, and levels in umbilical-cord blood are similar to
those in the maternal circulation.
Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE
inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and
benazeprilat. Only trace amounts of an administered dose of benazepril can be recovered
unchanged in the urine; about 20% of the dose is excreted as benazeprilat, 4% as benazepril
glucuronide, and 8% as benazeprilat glucuronide.
In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially
unaltered. Similarly, the pharmacokinetics of benazepril and benazeprilat do not appear to be
influenced by age.
Reference ID: 2960155
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The kinetics of benazepril are dose-proportional within the dosage range of 5-20 mg. Small
deviations from dose proportionality were observed when the broader range of 2-80 mg was
studied, possibly due to the saturable binding of the compound to ACE.
The effective half-life of accumulation of benazeprilat following multiple dosing of benazepril
hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should be
reached after 2 or 3 doses of benazepril hydrochloride given once daily.
During chronic administration (28 days) of once-daily doses of benazepril between 5 mg and 20
mg, the kinetics did not change, and there was no significant accumulation. Accumulation ratios
based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of
benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not
detected in the dialysate.
Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects
with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately
11%-12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary
clearance may compensate to an extent for deficient renal clearance.
The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal
insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal
function. In patients with creatinine clearance ≤30 mL/min, peak benazeprilat levels and the
initial (alpha phase) half-life increase, and time to steady state may be delayed (see DOSAGE
AND ADMINISTRATION).
Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours. In a
study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the
half-life of hydrochlorothiazide elimination was lengthened to 21 hours.
Pharmacodynamics
Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE
activity by at least 80%-90% for at least 24 hours after dosing. For up to 4 hours after a 10-mg
dose, pressor responses to exogenous angiotensin I were inhibited by 60%-90%.
Administration of benazepril to patients with mild-to-moderate hypertension results in a
reduction of both supine and standing blood pressure to about the same extent, with no
compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can
occur in patients who are salt and/or volume depleted (see WARNINGS, Hypotension).
In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions
achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for
24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure
(systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The reductions at trough are
about 50% of those seen at peak.
Four dose-response studies of benazepril monotherapy using once-daily dosing were conducted
in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective
once-daily dose of benazepril was 10 mg; further falls in blood pressure, especially at morning
trough, were seen with higher doses in the studied dosing range (10-80 mg). In studies
comparing the same daily dose of benazepril given as a single morning dose or as a twice-daily
Reference ID: 2960155
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dose, blood pressure reductions at the time of morning trough blood levels were greater with the
divided regimen.
During chronic therapy with benazepril, the maximum reduction in blood pressure with any
given dose is generally achieved after 1-2 weeks. The antihypertensive effects of benazepril have
continued during therapy for at least 2 years. Abrupt withdrawal of benazepril has not been
associated with a rapid increase in blood pressure.
In patients with mild-to-moderate hypertension, total daily doses of Lotensin 20-40 mg were
similar in effectiveness to total daily doses of captopril 50-100 mg, hydrochlorothiazide
25-50 mg, nifedipine SR 40-80 mg, and propranolol 80-160 mg.
The antihypertensive effects of benazepril were not appreciably different in patients receiving
high- or low-sodium diets.
In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in
peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or
no change in heart rate. In normal human volunteers, single doses of benazepril caused an
increase in renal blood flow but had no effect on glomerular filtration rate.
In clinical trials of benazepril/hydrochlorothiazide using benazepril doses of 5-20 mg and
hydrochlorothiazide doses of 6.25-25 mg, the antihypertensive effects were sustained for at least
24 hours, and they increased with increasing dose of either component. Although benazepril
monotherapy is somewhat less effective in blacks than in nonblacks, the efficacy of combination
therapy appears to be independent of race.
By blocking the renin-angiotensin-aldosterone axis, administration of benazepril tends to reduce
the potassium loss associated with the diuretic. In clinical trials of Lotensin HCT, the average
change in serum potassium was near zero in subjects who received 5/6.25 mg or 20/12.5 mg, but
the average subject who received 10/12.5 mg or 20/25 mg experienced a mild reduction in serum
potassium, similar to that experienced by the average subject receiving the same dose of
hydrochlorothiazide monotherapy.
INDICATIONS AND USAGE
Lotensin HCT is indicated for the treatment of hypertension.
This fixed combination drug is not indicated for the initial therapy of hypertension (see
DOSAGE AND ADMINISTRATION).
In using Lotensin HCT, consideration should be given to the fact that another
angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in
patients with renal impairment or collagen-vascular disease. Available data are insufficient to
show that benazepril does not have a similar risk (see WARNINGS, Neutropenia/
Agranulocytosis).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to nonblacks.
CONTRAINDICATIONS
Lotensin HCT is contraindicated in patients who are anuric.
Reference ID: 2960155
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Lotensin HCT is also contraindicated in patients who are hypersensitive to benazepril, to any
other ACE inhibitor, to hydrochlorothiazide, or to other sulfonamide-derived drugs.
Hypersensitivity reactions are more likely to occur in patients with a history of allergy or
bronchial asthma.
Lotensin HCT is also contraindicated in patients with a history of angioedema with or without
previous ACE inhibitor treatment.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including Lotensin HCT) may be subject to a variety of adverse reactions, some of
them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In
U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who
received placebo and in about 0.5% of the subjects who received benazepril. Angioedema
associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
tongue, or glottis occurs, treatment with Lotensin HCT should be discontinued and appropriate
therapy instituted immediately. When involvement of the tongue, glottis, or larynx appears likely
to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection
1:1000 (0.3-0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE
REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hypotension
Lotensin HCT can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has
been only rarely associated with hypotension in uncomplicated hypertensive patients.
Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt
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depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or
vomiting. Volume and/or salt depletion should be corrected before initiating therapy with
Lotensin HCT.
Lotensin HCT should be used cautiously in patients receiving concomitant therapy with other
antihypertensives. The thiazide component of Lotensin HCT may potentiate the action of other
antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The
antihypertensive effects of the thiazide component may also be enhanced in the
postsympathectomy patient.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria,
azotemia, and (rarely) with acute renal failure and death. In such patients, Lotensin HCT therapy
should be started under close medical supervision; they should be followed closely for the first 2
weeks of treatment and whenever the dose of benazepril or diuretic is increased.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated
with intravenous infusion of physiological saline. Lotensin HCT treatment usually can be
continued following restoration of blood pressure and volume.
Impaired Renal Function
Lotensin HCT should be used with caution in patients with severe renal disease. Thiazides may
precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative.
When the renin-angiotensin-aldosterone system is inhibited by benazepril, changes in renal
function may be anticipated in susceptible individuals. In patients with severe congestive heart
failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone
system, treatment with angiotensin-converting enzyme inhibitors (including benazepril) may be
associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or
death.
In a small study of hypertensive patients with unilateral or bilateral renal artery stenosis,
treatment with benazepril was associated with increases in blood urea nitrogen and serum
creatinine; these increases were reversible upon discontinuation of benazepril therapy,
concomitant diuretic therapy, or both. When such patients are treated with Lotensin HCT, renal
function should be monitored during the first few weeks of therapy.
Some benazepril-treated hypertensive patients with no apparent preexisting renal vascular
disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and
transient, especially when benazepril has been given concomitantly with a diuretic. Dosage
reduction of Lotensin HCT may be required. Evaluation of the hypertensive patient should
always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
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Neutropenia/Agranulocytosis
Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients (incidence
probably less than once per 10,000 exposures) but more frequently (incidence possibly as great
as once per 1000 exposures) in patients with renal impairment, especially those who also have
collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Available data
from clinical trials of benazepril are insufficient to show that benazepril does not cause
agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in
patients with collagen-vascular disease, especially if the disease is associated with impaired
renal function.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant
women. Several dozen cases have been reported in the world literature. When pregnancy is
detected, Lotensin HCT should be discontinued as soon as possible and monitoring of the fetal
development should be performed on a regular basis.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to
the ACE-inhibitor exposure.
In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated
with a potentially increased risk of birth defects. In women planning to become pregnant, ACE
inhibitors (including Lotensin HCT) should not be used. Women of child-bearing age should be
made aware of the potential risk and ACE inhibitors (including Lotensin HCT) should only be
given after careful counseling and consideration of individual risks and benefits.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, benazepril should be discontinued unless it is considered
life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or
biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.
Patients and physicians should be aware, however, that oligohydramnios may not appear until
after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may
be required as means of reversing hypotension and/or substituting for disordered renal function.
Benazepril, which crosses the placenta, can theoretically be removed from the neonatal
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circulation by these means; there are occasional reports of benefit from these maneuvers, but
experience is limited.
Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice,
thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
No teratogenic effects were seen when benazepril and hydrochlorothiazide were administered to
pregnant rats at a dose ratio of 4:5. On a mg/kg basis, the doses used were up to 167 times the
maximum recommended human dose. Similarly, no teratogenic effects were seen when
benazepril and hydrochlorothiazide were administered to pregnant mice at total doses up to 160
mg/kg/day, with benazepril:hydrochlorothiazide ratios of 15:1. When hydrochlorothiazide was
orally administered without benazepril to pregnant mice and rats during their respective periods
of major organogenesis, at doses up to 3000 and 1000 mg/kg/day respectively, there was no
evidence of harm to the fetus. Similarly, no teratogenic effects of benazepril were seen in studies
of pregnant rats, mice, and rabbits; on a mg/kg basis, the doses used in these studies were 300
times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum
recommended human dose.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
Impaired Hepatic Function
Lotensin HCT should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma (see Hepatic Failure, above). In patients with hepatic dysfunction due to cirrhosis,
levels of benazeprilat are essentially unaltered. No formal pharmacokinetic studies have been
carried out in hypertensive patients with impaired liver function.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus
erythematosus.
Acute Myopia and Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute
transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased
visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary
treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.
Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide
or penicillin allergy.
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PRECAUTIONS
General
Derangements of Serum Electrolytes: In clinical trials of benazepril monotherapy,
hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal)
occurred in approximately 1% of hypertensive patients receiving benazepril. In most cases, these
were isolated values which resolved despite continued therapy. Risk factors for the development
of hyperkalemia included renal insufficiency, diabetes mellitus, and the concomitant use of
potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt
substitutes.
Conversely, treatment with thiazide diuretics has been associated with hypokalemia,
hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest
as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting.
Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of
digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients
experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes,
and in patients receiving concomitant therapy with corticosteroids or ACTH.
The opposite effects of benazepril and hydrochlorothiazide on serum potassium will
approximately balance each other in many patients, so that no net effect upon serum potassium
will be seen. In other patients, one or the other effect may be dominant. Initial and periodic
determinations of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
Chloride deficits are generally mild and require specific treatment only under extraordinary
circumstances (e.g., in liver disease or renal disease). Dilutional hyponatremia may occur in
edematous patients; appropriate therapy is water restriction rather than administration of salt,
except in rare instances when the hyponatremia is life-threatening. In actual salt depletion,
appropriate replacement is the therapy of choice.
Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy,
pathological changes in the parathyroid gland have been observed, with hypercalcemia and
hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone
resorption, and peptic ulceration) have not been seen.
Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result.
Other Metabolic Disturbances: Thiazide diuretics tend to reduce glucose tolerance and to raise
serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but
frank gout or overt diabetes may be precipitated in susceptible patients.
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential
diagnosis of cough.
Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that
produce hypotension, benazepril will block the angiotensin II formation that could otherwise
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occur secondary to compensatory renin release. Hypotension that occurs as a result of this
mechanism can be corrected by volume expansion.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment
with ACE inhibitors. A patient receiving Lotensin HCT should be told to report immediately any
signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty
in breathing) and to take no more drug until after consulting with the prescribing physician.
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ACE inhibitors. Discuss other treatment options with women planning to become
pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Symptomatic Hypotension: A patient receiving Lotensin HCT should be cautioned that
lightheadedness can occur, especially during the first days of therapy, and that it should be
reported to the prescribing physician. The patient should be told that if syncope occurs, Lotensin
HCT should be discontinued until the physician has been consulted.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or
vomiting can lead to an excessive fall in blood pressure, with the same consequences of
lightheadedness and possible syncope.
Hyperkalemia: A patient receiving Lotensin HCT should be told not to use potassium
supplements or salt substitutes containing potassium without consulting the prescribing
physician.
Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore
throat, fever), which could be a sign of neutropenia.
Laboratory Tests
The hydrochlorothiazide component of Lotensin HCT may decrease serum PBI levels without
signs of thyroid disturbance.
Therapy with Lotensin HCT should be interrupted for a few days before carrying out tests of
parathyroid function.
Drug Interactions
Potassium Supplements and Potassium-Sparing Diuretics: As noted above (Derangements of
Serum Electrolytes), the net effect of Lotensin HCT may be to elevate a patient’s serum
potassium, to reduce it, or to leave it unchanged. Potassium-sparing diuretics (spironolactone,
amiloride, triamterene, and others) or potassium supplements can increase the risk of
hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution,
and the patient’s serum potassium should be monitored frequently.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of
lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as
in therapy with Lotensin HCT, a thiazide diuretic is coadministered with the ACE inhibitor.
Lotensin HCT and lithium should be coadministered with caution, and frequent monitoring of
serum lithium levels is recommended.
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Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible
acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients
receiving benazepril and NSAID therapy.
The antihypertensive effect of ACE inhibitors and thiazide diuretics may be attenuated by NSAIDs. The
diuretic and natriuretic effects of thiazide diuretics may also be reduced when NSAIDs are
coadministered.
Other: Benazepril has been used concomitantly with beta-adrenergic-blocking agents,
calcium-blocking agents, cimetidine, diuretics, digoxin, and hydralazine without evidence of
clinically important adverse interactions. Other ACE inhibitors have had less than additive
effects with beta-adrenergic blockers, presumably because drugs of both classes lower blood
pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically
important effects of benazepril on the serum concentrations or clinical effects of these
anticoagulants.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude
effectiveness of the pressor agent for therapeutic use.
Thiazides may increase the responsiveness to tubocurarine.
The diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by
concurrent administration of nonsteroidal anti-inflammatory agents.
Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the
presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins
bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to
85% and 43%, respectively.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found when benazepril was given to rats and mice for 104
weeks at doses up to 150 mg/kg/day. On a body-weight basis, this dose is over 100 times the
maximum recommended human dose; on a body-surface-area basis, this dose is 18 times (rats)
and 9 times (mice) the maximum recommended human dose. No mutagenic activity was
detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for
forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50-500
mg/kg/day (38-375 times the maximum recommended human dose on a body-weight basis; 6-61
times the maximum recommended dose on a body-surface-area basis), benazepril had no adverse
effect on the reproductive performance of male and female rats.
Under the auspices of the National Toxicology Program, rats and mice received
hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to
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100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in rats or female mice, but there was equivocal evidence of
hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays
using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the
Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo
assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes,
and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in
the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma
Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43-1300 µg/mL.
Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using
an unspecified concentration of hydrochlorothiazide.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diets, to doses up to 100 and 4 mg/kg/day,
respectively, prior to mating and throughout gestation.
Pregnancy
Pregnancy Category D : See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of
lactating women treated with benazepril, so that a newborn child ingesting nothing but breast
milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat.
Thiazides, on the other hand, are definitely excreted into breast milk. Because of the potential for
serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of
benazepril in infants, a decision should be made whether to discontinue nursing or to discontinue
Lotensin HCT, taking into account the importance of the drug to the mother.
Geriatric Use
Of the total number of patients who received Lotensin HCT in U.S. clinical studies of Lotensin
HCT, 19% were 65 or older while about 1.5% were 75 or older. Overall differences in
effectiveness or safety were not observed between these patients and younger patients, and other
reported clinical experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection, and it
may be useful to monitor renal function.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Lotensin HCT has been evaluated for safety in over 2500 patients with hypertension; over 500 of
these patients were treated for at least 6 months, and over 200 were treated for more than 1 year.
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The reported side effects were generally mild and transient, and there was no relationship
between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to
side effects was required in approximately 7% of U.S. patients treated with Lotensin HCT and in
4% of patients treated with placebo.
The most common reasons for discontinuation of therapy with Lotensin HCT in U.S. studies
were cough (1.0%; see PRECAUTIONS), “dizziness” (1.0%), headache (0.6%), and fatigue
(0.6%).
The side effects considered possibly or probably related to study drug that occurred in U.S.
placebo-controlled trials in more than 1% of patients treated with Lotensin HCT are shown in
the table below.
Reactions Possibly or Probably Drug Related
Patients in U.S. Placebo-Controlled Studies
LOTENSIN HCT
Placebo
N = 665
N = 235
N
%
N
%
“Dizziness”
41
6.3
8
3.4
Fatigue
34
5.2
6
2.6
Postural Dizziness
23
3.5
1
0.4
Headache
20
3.1
10
4.3
Cough
14
2.1
3
1.3
Hypertonia
10
1.5
3
1.3
Vertigo
10
1.5
2
0.9
Nausea
9
1.4
2
0.9
Impotence
8
1.2
0
0.0
Somnolence
8
1.2
1
0.4
Other side effects considered possibly or probably related to study drug that occurred in U.S.
placebo-controlled trials in 0.3% to 1.0% of patients treated with Lotensin HCT were the
following:
Angioedema: Edema of the lips or face without other manifestations of angioedema (0.3%). See
WARNINGS, Angioedema.
Cardiovascular: Hypotension (seen in 0.6% of patients), postural hypotension (0.3%),
palpitations, and flushing.
Gastrointestinal: Vomiting, diarrhea, dyspepsia, anorexia, and constipation.
Neurologic and Psychiatric: Insomnia, nervousness, paresthesia, libido decrease, dry mouth,
taste perversion, and tinnitus.
Dermatologic: Rash and sweating.
Other: Gout, urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest pain and
abdominal pain).
Other adverse experiences reported in 0.3% or more of Lotensin HCT patients in U.S. controlled
clinical trials, and rarer events seen in post-marketing experience, were the following; asterisked
entries occurred in more than 1% of patients (in some, a causal relationship to Lotensin HCT is
uncertain):
Angioedema: Edema of the lips or face without other manifestations of angioedema. See
WARNINGS, Angioedema.
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Cardiovascular: Syncope, peripheral vascular disorder, and tachycardia.
Body as a Whole: Infection, back pain*, flu syndrome*, fever, chills, and neck pain.
Dermatologic: Photosensitivity and pruritus.
Gastrointestinal: Gastroenteritis, flatulence, and tooth disorder.
Neurologic and Psychiatric: Hypesthesia, abnormal vision, abnormal dreams, and retinal
disorder.
Respiratory: Upper respiratory infection*, epistaxis, bronchitis, rhinitis*, sinusitis*, and voice
alteration.
Other: Conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency*.
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
Monotherapy with benazepril has been evaluated for safety in over 6000 patients. In clinical
trials, the observed adverse reactions to benazepril were similar to those seen in trials of
Lotensin HCT. In post-marketing experience with benazepril, there have been rare reports of
Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombo-cytopenia.
Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed
to other ACE inhibitors.
Hydrochlorothiazide has been extensively prescribed for many years, but there has not been
enough systematic collection of data to support an estimate of the frequency of the observed
adverse reactions. Within organ-system groups, the reported reactions are listed here in
decreasing order of severity, without regard to frequency.
Unknown frequency: small bowel angioedema, anaphylactoid reactions, hyperkalemia,
agranulocytosis, neutropenia.
Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or
narcotics).
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic) (see WARNINGS), sialadenitis,
vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.
Neurologic: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia,
xanthopsia, weakness, and restlessness.
Musculoskeletal: Muscle spasm.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia.
Metabolic: Hyperglycemia, glycosuria, and hyperuricemia.
Hypersensitivity: Necrotizing angiitis, respiratory distress (including pneumonitis and
pulmonary edema), purpura, urticaria, rash, and photosensitivity.
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis
including toxic epidermal necrolysis.
Clinical Laboratory Test Findings
Serum Electrolytes: See PRECAUTIONS.
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Creatinine: Minor reversible increases in serum creatinine were observed in patients with
essential hypertension treated with Lotensin HCT. Such increases occurred most frequently in
patients with renal artery stenosis (see PRECAUTIONS).
PBI and Tests of Parathyroid Function: See PRECAUTIONS.
Other (Causal Relationships Unknown): Other clinically important changes in standard
laboratory tests were rarely associated with Lotensin HCT administration. Elevations in blood
urea nitrogen, uric acid, glucose, SGOT, and SGPT have been reported (see WARNINGS). In
the somewhat larger patient population exposed to benazepril monotherapy in U.S. trials, the
same abnormalities were reported, together with scattered accounts of hyponatremia, melena,
electrocardiographic changes, leukopenia, eosinophilia, and proteinuria.
OVERDOSAGE
No specific information is available on the treatment of overdosage with Lotensin HCT;
treatment should be symptomatic and supportive. Therapy with Lotensin HCT should be
discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and
hypotension should be treated by established procedures.
Single oral doses of 1 g/kg of benazepril caused reduced activity in mice, and doses of 3 g/kg
were associated with significant lethality. Reduction of activity in rats was not seen until they
had received doses of 5 g/kg, and doses of 6 g/kg were not lethal. In single-dose studies of
hydrochlorothiazide, most rats survived doses up to 2.75 g/kg.
Data from human overdoses of benazepril are scanty, but the most common manifestation of
human benazepril overdosage is likely to be hypotension. In human hydrochlorothiazide
overdose, the most common signs and symptoms observed have been those of dehydration and
electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been
administered, hypokalemia may accentuate cardiac arrhythmias.
Laboratory determinations of serum levels of benazepril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
benazepril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of
the urine) that might accelerate elimination of benazepril and its metabolites. Benazeprilat is
only slightly dialyzable, but dialysis might be considered in overdosed patients with severely
impaired renal function (see WARNINGS).
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Benazepril is an effective treatment of hypertension in once-daily doses of 10-80 mg, while
hydrochlorothiazide is effective in doses of 12.5-50 mg per day. In clinical trials of
benazepril/hydrochlorothiazide combination therapy using benazepril doses of 5-20 mg and
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hydrochlorothiazide doses of 6.25-25 mg, the antihypertensive effects increased with increasing
dose of either component.
The side effects (see WARNINGS) of benazepril are generally rare and apparently independent
of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily
hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more
common than the latter. Therapy with any combination of benazepril and hydrochlorothiazide
will be associated with both sets of dose-independent side effects, but regimens in which
benazepril is combined with low doses of hydrochlorothiazide produce minimal effects on serum
potassium. In clinical trials of Lotensin HCT, the average change in serum potassium was near
zero in subjects who received 5/6.25 mg or 20/12.5 mg, but the average subject who received
10/12.5 mg or 20/25 mg experienced a mild reduction in serum potassium, similar to that
experienced by the average subject receiving the same dose of hydrochlorothiazide
monotherapy.
To minimize dose-independent side effects, it is usually appropriate to begin combination
therapy only after a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately
controlled with benazepril monotherapy may be switched to Lotensin HCT 10/12.5 or Lotensin
HCT 20/12.5. Further increases of either or both components could depend on clinical response.
The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed.
Patients whose blood pressures are adequately controlled with 25 mg of daily
hydrochlorothiazide, but who experience significant potassium loss with this regimen, may
achieve similar blood-pressure control without electrolyte disturbance if they are switched to
Lotensin HCT 5/6.25.
Replacement Therapy: The combination may be substituted for the titrated individual
components.
Use in Renal Impairment: Regimens of therapy with Lotensin HCT need not take account of
renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73m2 (serum
creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment,
loop diuretics are preferred to thiazides, so Lotensin HCT is not recommended (see
WARNINGS).
HOW SUPPLIED
Lotensin HCT is available in tablets of four different strengths:
Benazepril
Hydrochlorothiazide
Tablet Color
5 mg
6.25 mg
white
10 mg
12.5 mg
light pink
20 mg
12.5 mg
grayish-violet
20 mg
25 mg
red
Tablets of each strength are supplied in bottles that contain a desiccant and 100 tablets.
The National Drug Codes for the various packages are
Dose
Bottle of 100
Tablet Imprint
5/6.25
NDC 0078-0451-05
57
10/12.5
NDC 0078-0452-05
72
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20/12.5
NDC 0078-0453-05
74
20/25
NDC 0078-0454-05
75
Tablets are oblong and scored, with “Lotensin HCT” on one side and appropriate number
imprinted on the other side.
Storage: Do not store above 30°C (86°F). Protect from moisture and light. Dispense in tight,
light-resistant container (USP).
T2011-57
May 2011 company logo
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
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|
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2025-02-12T13:46:30.319667
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020033s041lbl.pdf', 'application_number': 20033, 'submission_type': 'SUPPL ', 'submission_number': 41}
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company logo
Lotensin HCT®
benazepril hydrochloride and hydrochlorothiazide USP
Combination Tablets
5 mg/6.25 mg
10 mg/12.5 mg
20 mg/12.5 mg
20 mg/25 mg
Rx only
Prescribing Information
USE IN PREGNANCY
When used in pregnancy, ACE inhibitors can cause injury and even death to the
developing fetus. When pregnancy is detected, Lotensin HCT should be discontinued as soon as
possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in
water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is
3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benza
zepine-1-acetic acid monohydrochloride; its structural formula is structural formula
Its empirical formula is C24H28N2O5·HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting
enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.
Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline
powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in
n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether,
in chloroform, and in dilute mineral acids. Hydrochlorothiazide’s chemical name is
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural
formula is
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structural formula
Its empirical formula is C7 H8 ClN3 O4 S2, and its molecular weight is 297.73. Hydrochloro
thiazide is a thiazide diuretic.
Lotensin HCT is a combination of benazepril hydrochloride and hydrochlorothiazide USP. The
tablets are formulated for oral administration with a combination of 5, 10, or 20 mg of benazepril
hydrochloride and 6.25, 12.5, or 25 mg of hydrochlorothiazide USP. The inactive ingredients of
the tablets are cellulose compounds, crospovidone, hydrogenated castor oil, iron oxides
(10/12.5-mg, 20/12.5-mg, and 20/25-mg tablets), lactose, polyethylene glycol, talc, and titanium
dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects
and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to
the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone
secretion by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. Hypertensive patients treated with benazepril alone for up to
52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with
benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum
potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to
angiotensin II and did not interfere with the hemodynamic effects of the autonomic
neurotransmitters acetylcholine, epinephrine, and norepinephrine.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotensin
HCT remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be
primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an
antihypertensive effect even in patients with low-renin hypertension.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of
electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately
equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma
volume, with consequent increases in plasma renin activity, increases in aldosterone secretion,
increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone
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link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the
potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is unknown.
Pharmacokinetics and Metabolism
Following oral administration of Lotensin HCT, peak plasma concentrations of benazepril are
reached within 0.5-1.0 hours. As determined by urinary recovery, the extent of absorption is at
least 37%. The absorption of hydrochlorothiazide is somewhat slower (1-2.5 hours) and
somewhat more complete (50%-80%). In fasting subjects, the rate and extent of absorption of
benazepril and hydrochlorothiazide from Lotensin HCT are not different, respectively, from the
rate and extent of absorption of benazepril and hydrochlorothiazide from immediate-release
monotherapy formulations.
The absorption of benazepril from Lotensin® tablets is not influenced by the presence of food in
the gastrointestinal tract, but possible effects of food upon absorption of either component from
Lotensin HCT tablets have not been studied. The reported studies of food effects on
hydrochlorothiazide absorption have been inconclusive. The absorption of hydrochlorothiazide
is increased by agents that reduce gastrointestinal motility, but it is reported to be reduced by
50% in patients with congestive heart failure.
Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite,
benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake
in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein
binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by
equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be
unaffected by age, hepatic dysfunction, or – over the concentration range of 0.24-23.6 µmol/L –
concentration.
Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6-7.8 L/kg, and
its measured plasma protein binding is 67.9%. The drug also accumulates in red blood cells, so
that whole blood levels are 1.6-1.8 times those measured in plasma.
In studies of rats given 14C-benazepril, benazepril and its metabolites crossed the blood-brain
barrier only to an extremely low extent. Multiple doses of benazepril did not result in
accumulation in any tissue except the lung, where, as with other ACE inhibitors in similar
studies, there was a slight increase in concentration due to slow elimination in that organ.
Some placental passage occurred when benazepril was administered to pregnant rats. In humans,
hydrochlorothiazide crosses the placenta freely, and levels in umbilical-cord blood are similar to
those in the maternal circulation.
Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE
inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and
benazeprilat. Only trace amounts of an administered dose of benazepril can be recovered
unchanged in the urine; about 20% of the dose is excreted as benazeprilat, 4% as benazepril
glucuronide, and 8% as benazeprilat glucuronide.
In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially
unaltered. Similarly, the pharmacokinetics of benazepril and benazeprilat do not appear to be
influenced by age.
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The kinetics of benazepril are dose-proportional within the dosage range of 5-20 mg. Small
deviations from dose proportionality were observed when the broader range of 2-80 mg was
studied, possibly due to the saturable binding of the compound to ACE.
The effective half-life of accumulation of benazeprilat following multiple dosing of benazepril
hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should be
reached after 2 or 3 doses of benazepril hydrochloride given once daily.
During chronic administration (28 days) of once-daily doses of benazepril between 5 mg and 20
mg, the kinetics did not change, and there was no significant accumulation. Accumulation ratios
based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of
benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not
detected in the dialysate.
Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects
with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately
11%-12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary
clearance may compensate to an extent for deficient renal clearance.
The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal
insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal
function. In patients with creatinine clearance ≤30 mL/min, peak benazeprilat levels and the
initial (alpha phase) half-life increase, and time to steady state may be delayed (see DOSAGE
AND ADMINISTRATION).
Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours. In a
study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the
half-life of hydrochlorothiazide elimination was lengthened to 21 hours.
Pharmacodynamics
Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE
activity by at least 80%-90% for at least 24 hours after dosing. For up to 4 hours after a 10-mg
dose, pressor responses to exogenous angiotensin I were inhibited by 60%-90%.
Administration of benazepril to patients with mild-to-moderate hypertension results in a
reduction of both supine and standing blood pressure to about the same extent, with no
compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can
occur in patients who are salt and/or volume depleted (see WARNINGS, Hypotension).
In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions
achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for
24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure
(systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The reductions at trough are
about 50% of those seen at peak.
Four dose-response studies of benazepril monotherapy using once-daily dosing were conducted
in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective
once-daily dose of benazepril was 10 mg; further falls in blood pressure, especially at morning
trough, were seen with higher doses in the studied dosing range (10-80 mg). In studies
comparing the same daily dose of benazepril given as a single morning dose or as a twice-daily
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dose, blood pressure reductions at the time of morning trough blood levels were greater with the
divided regimen.
During chronic therapy with benazepril, the maximum reduction in blood pressure with any
given dose is generally achieved after 1-2 weeks. The antihypertensive effects of benazepril have
continued during therapy for at least 2 years. Abrupt withdrawal of benazepril has not been
associated with a rapid increase in blood pressure.
In patients with mild-to-moderate hypertension, total daily doses of Lotensin 20-40 mg were
similar in effectiveness to total daily doses of captopril 50-100 mg, hydrochlorothiazide
25-50 mg, nifedipine SR 40-80 mg, and propranolol 80-160 mg.
The antihypertensive effects of benazepril were not appreciably different in patients receiving
high- or low-sodium diets.
In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in
peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or
no change in heart rate. In normal human volunteers, single doses of benazepril caused an
increase in renal blood flow but had no effect on glomerular filtration rate.
In clinical trials of benazepril/hydrochlorothiazide using benazepril doses of 5-20 mg and
hydrochlorothiazide doses of 6.25-25 mg, the antihypertensive effects were sustained for at least
24 hours, and they increased with increasing dose of either component. Although benazepril
monotherapy is somewhat less effective in blacks than in nonblacks, the efficacy of combination
therapy appears to be independent of race.
By blocking the renin-angiotensin-aldosterone axis, administration of benazepril tends to reduce
the potassium loss associated with the diuretic. In clinical trials of Lotensin HCT, the average
change in serum potassium was near zero in subjects who received 5/6.25 mg or 20/12.5 mg, but
the average subject who received 10/12.5 mg or 20/25 mg experienced a mild reduction in serum
potassium, similar to that experienced by the average subject receiving the same dose of
hydrochlorothiazide monotherapy.
INDICATIONS AND USAGE
Lotensin HCT is indicated for the treatment of hypertension.
This fixed combination drug is not indicated for the initial therapy of hypertension (see
DOSAGE AND ADMINISTRATION).
In using Lotensin HCT, consideration should be given to the fact that another
angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in
patients with renal impairment or collagen-vascular disease. Available data are insufficient to
show that benazepril does not have a similar risk (see WARNINGS, Neutropenia/
Agranulocytosis).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to nonblacks.
CONTRAINDICATIONS
Lotensin HCT is contraindicated in patients who are anuric.
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Lotensin HCT is also contraindicated in patients who are hypersensitive to benazepril, to any
other ACE inhibitor, to hydrochlorothiazide, or to other sulfonamide-derived drugs.
Hypersensitivity reactions are more likely to occur in patients with a history of allergy or
bronchial asthma.
Lotensin HCT is also contraindicated in patients with a history of angioedema with or without
previous ACE inhibitor treatment.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including Lotensin HCT) may be subject to a variety of adverse reactions, some of
them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In
U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who
received placebo and in about 0.5% of the subjects who received benazepril. Angioedema
associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
tongue, or glottis occurs, treatment with Lotensin HCT should be discontinued and appropriate
therapy instituted immediately. When involvement of the tongue, glottis, or larynx appears likely
to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection
1:1000 (0.3-0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE
REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hypotension
Lotensin HCT can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has
been only rarely associated with hypotension in uncomplicated hypertensive patients.
Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt
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depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or
vomiting. Volume and/or salt depletion should be corrected before initiating therapy with
Lotensin HCT.
Lotensin HCT should be used cautiously in patients receiving concomitant therapy with other
antihypertensives. The thiazide component of Lotensin HCT may potentiate the action of other
antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The
antihypertensive effects of the thiazide component may also be enhanced in the
postsympathectomy patient.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria,
azotemia, and (rarely) with acute renal failure and death. In such patients, Lotensin HCT therapy
should be started under close medical supervision; they should be followed closely for the first 2
weeks of treatment and whenever the dose of benazepril or diuretic is increased.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated
with intravenous infusion of physiological saline. Lotensin HCT treatment usually can be
continued following restoration of blood pressure and volume.
Impaired Renal Function
Lotensin HCT should be used with caution in patients with severe renal disease. Thiazides may
precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative.
When the renin-angiotensin-aldosterone system is inhibited by benazepril, changes in renal
function may be anticipated in susceptible individuals. In patients with severe congestive heart
failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone
system, treatment with angiotensin-converting enzyme inhibitors (including benazepril) may be
associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or
death.
In a small study of hypertensive patients with unilateral or bilateral renal artery stenosis,
treatment with benazepril was associated with increases in blood urea nitrogen and serum
creatinine; these increases were reversible upon discontinuation of benazepril therapy,
concomitant diuretic therapy, or both. When such patients are treated with Lotensin HCT, renal
function should be monitored during the first few weeks of therapy.
Some benazepril-treated hypertensive patients with no apparent preexisting renal vascular
disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and
transient, especially when benazepril has been given concomitantly with a diuretic. Dosage
reduction of Lotensin HCT may be required. Evaluation of the hypertensive patient should
always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
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Neutropenia/Agranulocytosis
Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients (incidence
probably less than once per 10,000 exposures) but more frequently (incidence possibly as great
as once per 1000 exposures) in patients with renal impairment, especially those who also have
collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Available data
from clinical trials of benazepril are insufficient to show that benazepril does not cause
agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in
patients with collagen-vascular disease, especially if the disease is associated with impaired
renal function.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant
women. Several dozen cases have been reported in the world literature. When pregnancy is
detected, Lotensin HCT should be discontinued as soon as possible and monitoring of the fetal
development should be performed on a regular basis.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this
setting has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these occurrences were due to
the ACE-inhibitor exposure.
In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated
with a potentially increased risk of birth defects. In women planning to become pregnant, ACE
inhibitors (including Lotensin HCT) should not be used. Women of child-bearing age should be
made aware of the potential risk and ACE inhibitors (including Lotensin HCT) should only be
given after careful counseling and consideration of individual risks and benefits.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, benazepril should be discontinued unless it is considered
life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or
biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.
Patients and physicians should be aware, however, that oligohydramnios may not appear until
after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may
be required as means of reversing hypotension and/or substituting for disordered renal function.
Benazepril, which crosses the placenta, can theoretically be removed from the neonatal
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circulation by these means; there are occasional reports of benefit from these maneuvers, but
experience is limited.
Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice,
thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
No teratogenic effects were seen when benazepril and hydrochlorothiazide were administered to
pregnant rats at a dose ratio of 4:5. On a mg/kg basis, the doses used were up to 167 times the
maximum recommended human dose. Similarly, no teratogenic effects were seen when
benazepril and hydrochlorothiazide were administered to pregnant mice at total doses up to 160
mg/kg/day, with benazepril:hydrochlorothiazide ratios of 15:1. When hydrochlorothiazide was
orally administered without benazepril to pregnant mice and rats during their respective periods
of major organogenesis, at doses up to 3000 and 1000 mg/kg/day respectively, there was no
evidence of harm to the fetus. Similarly, no teratogenic effects of benazepril were seen in studies
of pregnant rats, mice, and rabbits; on a mg/kg basis, the doses used in these studies were 300
times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum
recommended human dose.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
Impaired Hepatic Function
Lotensin HCT should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma (see Hepatic Failure, above). In patients with hepatic dysfunction due to cirrhosis,
levels of benazeprilat are essentially unaltered. No formal pharmacokinetic studies have been
carried out in hypertensive patients with impaired liver function.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus
erythematosus.
Acute Myopia and Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute
transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased
visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary
treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.
Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide
or penicillin allergy.
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PRECAUTIONS
General
Derangements of Serum Electrolytes: In clinical trials of benazepril monotherapy,
hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal)
occurred in approximately 1% of hypertensive patients receiving benazepril. In most cases, these
were isolated values which resolved despite continued therapy. Risk factors for the development
of hyperkalemia included renal insufficiency, diabetes mellitus, and the concomitant use of
potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt
substitutes.
Conversely, treatment with thiazide diuretics has been associated with hypokalemia,
hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest
as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting.
Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of
digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients
experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes,
and in patients receiving concomitant therapy with corticosteroids or ACTH.
The opposite effects of benazepril and hydrochlorothiazide on serum potassium will
approximately balance each other in many patients, so that no net effect upon serum potassium
will be seen. In other patients, one or the other effect may be dominant. Initial and periodic
determinations of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
Chloride deficits are generally mild and require specific treatment only under extraordinary
circumstances (e.g., in liver disease or renal disease). Dilutional hyponatremia may occur in
edematous patients; appropriate therapy is water restriction rather than administration of salt,
except in rare instances when the hyponatremia is life-threatening. In actual salt depletion,
appropriate replacement is the therapy of choice.
Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy,
pathological changes in the parathyroid gland have been observed, with hypercalcemia and
hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone
resorption, and peptic ulceration) have not been seen.
Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result.
Other Metabolic Disturbances: Thiazide diuretics tend to reduce glucose tolerance and to raise
serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but
frank gout or overt diabetes may be precipitated in susceptible patients.
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential
diagnosis of cough.
Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that
produce hypotension, benazepril will block the angiotensin II formation that could otherwise
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occur secondary to compensatory renin release. Hypotension that occurs as a result of this
mechanism can be corrected by volume expansion.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment
with ACE inhibitors. A patient receiving Lotensin HCT should be told to report immediately any
signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty
in breathing) and to take no more drug until after consulting with the prescribing physician.
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to ACE inhibitors. Discuss other treatment options with women planning to become
pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Symptomatic Hypotension: A patient receiving Lotensin HCT should be cautioned that
lightheadedness can occur, especially during the first days of therapy, and that it should be
reported to the prescribing physician. The patient should be told that if syncope occurs, Lotensin
HCT should be discontinued until the physician has been consulted.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or
vomiting can lead to an excessive fall in blood pressure, with the same consequences of
lightheadedness and possible syncope.
Hyperkalemia: A patient receiving Lotensin HCT should be told not to use potassium
supplements or salt substitutes containing potassium without consulting the prescribing
physician.
Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore
throat, fever), which could be a sign of neutropenia.
Laboratory Tests
The hydrochlorothiazide component of Lotensin HCT may decrease serum PBI levels without
signs of thyroid disturbance.
Therapy with Lotensin HCT should be interrupted for a few days before carrying out tests of
parathyroid function.
Drug Interactions
Potassium Supplements and Potassium-Sparing Diuretics: As noted above (Derangements of
Serum Electrolytes), the net effect of Lotensin HCT may be to elevate a patient’s serum
potassium, to reduce it, or to leave it unchanged. Potassium-sparing diuretics (spironolactone,
amiloride, triamterene, and others) or potassium supplements can increase the risk of
hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution,
and the patient’s serum potassium should be monitored frequently.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of
lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as
in therapy with Lotensin HCT, a thiazide diuretic is coadministered with the ACE inhibitor.
Lotensin HCT and lithium should be coadministered with caution, and frequent monitoring of
serum lithium levels is recommended.
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Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Other: Benazepril has been used concomitantly with beta-adrenergic-blocking agents,
calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without
evidence of clinically important adverse interactions. Other ACE inhibitors have had less than
additive effects with beta-adrenergic blockers, presumably because drugs of both classes lower
blood pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically
important effects of benazepril on the serum concentrations or clinical effects of these
anticoagulants.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude
effectiveness of the pressor agent for therapeutic use.
Thiazides may increase the responsiveness to tubocurarine.
The diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by
concurrent administration of nonsteroidal anti-inflammatory agents.
Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the
presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins
bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to
85% and 43%, respectively.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found when benazepril was given to rats and mice for 104
weeks at doses up to 150 mg/kg/day. On a body-weight basis, this dose is over 100 times the
maximum recommended human dose; on a body-surface-area basis, this dose is 18 times (rats)
and 9 times (mice) the maximum recommended human dose. No mutagenic activity was
detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for
forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50-500
mg/kg/day (38-375 times the maximum recommended human dose on a body-weight basis; 6-61
times the maximum recommended dose on a body-surface-area basis), benazepril had no adverse
effect on the reproductive performance of male and female rats.
Under the auspices of the National Toxicology Program, rats and mice received
hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to
100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in rats or female mice, but there was equivocal evidence of
hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays
using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the
Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo
assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes,
and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in
the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma
Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43-1300 µg/mL.
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Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using
an unspecified concentration of hydrochlorothiazide.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diets, to doses up to 100 and 4 mg/kg/day,
respectively, prior to mating and throughout gestation.
Pregnancy
Pregnancy Category D : See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of
lactating women treated with benazepril, so that a newborn child ingesting nothing but breast
milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat.
Thiazides, on the other hand, are definitely excreted into breast milk. Because of the potential for
serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of
benazepril in infants, a decision should be made whether to discontinue nursing or to discontinue
Lotensin HCT, taking into account the importance of the drug to the mother.
Geriatric Use
Of the total number of patients who received Lotensin HCT in U.S. clinical studies of Lotensin
HCT, 19% were 65 or older while about 1.5% were 75 or older. Overall differences in
effectiveness or safety were not observed between these patients and younger patients, and other
reported clinical experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection, and it
may be useful to monitor renal function.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Lotensin HCT has been evaluated for safety in over 2500 patients with hypertension; over 500 of
these patients were treated for at least 6 months, and over 200 were treated for more than 1 year.
The reported side effects were generally mild and transient, and there was no relationship
between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to
side effects was required in approximately 7% of U.S. patients treated with Lotensin HCT and in
4% of patients treated with placebo.
The most common reasons for discontinuation of therapy with Lotensin HCT in U.S. studies
were cough (1.0%; see PRECAUTIONS), “dizziness” (1.0%), headache (0.6%), and fatigue
(0.6%).
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The side effects considered possibly or probably related to study drug that occurred in U.S.
placebo-controlled trials in more than 1% of patients treated with Lotensin HCT are shown in
the table below.
Reactions Possibly or Probably Drug Related
Patients in U.S. Placebo-Controlled Studies
LOTENSIN HCT
Placebo
N = 665
N = 235
N
%
N
%
“Dizziness”
41
6.3
8
3.4
Fatigue
34
5.2
6
2.6
Postural Dizziness
23
3.5
1
0.4
Headache
20
3.1
10
4.3
Cough
14
2.1
3
1.3
Hypertonia
10
1.5
3
1.3
Vertigo
10
1.5
2
0.9
Nausea
9
1.4
2
0.9
Impotence
8
1.2
0
0.0
Somnolence
8
1.2
1
0.4
Other side effects considered possibly or probably related to study drug that occurred in U.S.
placebo-controlled trials in 0.3% to 1.0% of patients treated with Lotensin HCT were the
following:
Angioedema: Edema of the lips or face without other manifestations of angioedema (0.3%). See
WARNINGS, Angioedema.
Cardiovascular: Hypotension (seen in 0.6% of patients), postural hypotension (0.3%),
palpitations, and flushing.
Gastrointestinal: Vomiting, diarrhea, dyspepsia, anorexia, and constipation.
Neurologic and Psychiatric: Insomnia, nervousness, paresthesia, libido decrease, dry mouth,
taste perversion, and tinnitus.
Dermatologic: Rash and sweating.
Other: Gout, urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest pain and
abdominal pain).
Other adverse experiences reported in 0.3% or more of Lotensin HCT patients in U.S. controlled
clinical trials, and rarer events seen in post-marketing experience, were the following; asterisked
entries occurred in more than 1% of patients (in some, a causal relationship to Lotensin HCT is
uncertain):
Angioedema: Edema of the lips or face without other manifestations of angioedema. See
WARNINGS, Angioedema.
Cardiovascular: Syncope, peripheral vascular disorder, and tachycardia.
Body as a Whole: Infection, back pain*, flu syndrome*, fever, chills, and neck pain.
Dermatologic: Photosensitivity and pruritus.
Gastrointestinal: Gastroenteritis, flatulence, and tooth disorder.
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Neurologic and Psychiatric: Hypesthesia, abnormal vision, abnormal dreams, and retinal
disorder.
Respiratory: Upper respiratory infection*, epistaxis, bronchitis, rhinitis*, sinusitis*, and voice
alteration.
Other: Conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency*.
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
Monotherapy with benazepril has been evaluated for safety in over 6000 patients. In clinical
trials, the observed adverse reactions to benazepril were similar to those seen in trials of
Lotensin HCT. In post-marketing experience with benazepril, there have been rare reports of
Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombo-cytopenia.
Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed
to other ACE inhibitors.
Hydrochlorothiazide has been extensively prescribed for many years, but there has not been
enough systematic collection of data to support an estimate of the frequency of the observed
adverse reactions. Within organ-system groups, the reported reactions are listed here in
decreasing order of severity, without regard to frequency.
Unknown frequency: small bowel angioedema, anaphylactoid reactions, hyperkalemia,
agranulocytosis, neutropenia.
Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or
narcotics).
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic) (see WARNINGS), sialadenitis,
vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.
Neurologic: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia,
xanthopsia, weakness, and restlessness.
Musculoskeletal: Muscle spasm.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia.
Metabolic: Hyperglycemia, glycosuria, and hyperuricemia.
Hypersensitivity: Necrotizing angiitis, respiratory distress (including pneumonitis and
pulmonary edema), purpura, urticaria, rash, and photosensitivity.
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis
including toxic epidermal necrolysis.
Clinical Laboratory Test Findings
Serum Electrolytes: See PRECAUTIONS.
Creatinine: Minor reversible increases in serum creatinine were observed in patients with
essential hypertension treated with Lotensin HCT. Such increases occurred most frequently in
patients with renal artery stenosis (see PRECAUTIONS).
PBI and Tests of Parathyroid Function: See PRECAUTIONS.
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Other (Causal Relationships Unknown): Other clinically important changes in standard
laboratory tests were rarely associated with Lotensin HCT administration. Elevations in blood
urea nitrogen, uric acid, glucose, SGOT, and SGPT have been reported (see WARNINGS). In
the somewhat larger patient population exposed to benazepril monotherapy in U.S. trials, the
same abnormalities were reported, together with scattered accounts of hyponatremia, melena,
electrocardiographic changes, leukopenia, eosinophilia, and proteinuria.
OVERDOSAGE
No specific information is available on the treatment of overdosage with Lotensin HCT;
treatment should be symptomatic and supportive. Therapy with Lotensin HCT should be
discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and
hypotension should be treated by established procedures.
Single oral doses of 1 g/kg of benazepril caused reduced activity in mice, and doses of 3 g/kg
were associated with significant lethality. Reduction of activity in rats was not seen until they
had received doses of 5 g/kg, and doses of 6 g/kg were not lethal. In single-dose studies of
hydrochlorothiazide, most rats survived doses up to 2.75 g/kg.
Data from human overdoses of benazepril are scanty, but the most common manifestation of
human benazepril overdosage is likely to be hypotension. In human hydrochlorothiazide
overdose, the most common signs and symptoms observed have been those of dehydration and
electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been
administered, hypokalemia may accentuate cardiac arrhythmias.
Laboratory determinations of serum levels of benazepril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
benazepril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of
the urine) that might accelerate elimination of benazepril and its metabolites. Benazeprilat is
only slightly dialyzable, but dialysis might be considered in overdosed patients with severely
impaired renal function (see WARNINGS).
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Benazepril is an effective treatment of hypertension in once-daily doses of 10-80 mg, while
hydrochlorothiazide is effective in doses of 12.5-50 mg per day. In clinical trials of
benazepril/hydrochlorothiazide combination therapy using benazepril doses of 5-20 mg and
hydrochlorothiazide doses of 6.25-25 mg, the antihypertensive effects increased with increasing
dose of either component.
The side effects (see WARNINGS) of benazepril are generally rare and apparently independent
of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily
hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more
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common than the latter. Therapy with any combination of benazepril and hydrochlorothiazide
will be associated with both sets of dose-independent side effects, but regimens in which
benazepril is combined with low doses of hydrochlorothiazide produce minimal effects on serum
potassium. In clinical trials of Lotensin HCT, the average change in serum potassium was near
zero in subjects who received 5/6.25 mg or 20/12.5 mg, but the average subject who received
10/12.5 mg or 20/25 mg experienced a mild reduction in serum potassium, similar to that
experienced by the average subject receiving the same dose of hydrochlorothiazide
monotherapy.
To minimize dose-independent side effects, it is usually appropriate to begin combination
therapy only after a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately
controlled with benazepril monotherapy may be switched to Lotensin HCT 10/12.5 or Lotensin
HCT 20/12.5. Further increases of either or both components could depend on clinical response.
The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed.
Patients whose blood pressures are adequately controlled with 25 mg of daily
hydrochlorothiazide, but who experience significant potassium loss with this regimen, may
achieve similar blood-pressure control without electrolyte disturbance if they are switched to
Lotensin HCT 5/6.25.
Replacement Therapy: The combination may be substituted for the titrated individual
components.
Use in Renal Impairment: Regimens of therapy with Lotensin HCT need not take account of
renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73m2 (serum
creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment,
loop diuretics are preferred to thiazides, so Lotensin HCT is not recommended (see
WARNINGS).
HOW SUPPLIED
Lotensin HCT is available in tablets of four different strengths:
Benazepril
Hydrochlorothiazide
Tablet Color
5 mg
6.25 mg
white
10 mg
12.5 mg
light pink
20 mg
12.5 mg
grayish-violet
20 mg
25 mg
red
Tablets of each strength are supplied in bottles that contain a desiccant and 100 tablets.
The National Drug Codes for the various packages are
Dose
Bottle of 100
Tablet Imprint
5/6.25
NDC 0078-0451-05
57
10/12.5
NDC 0078-0452-05
72
20/12.5
NDC 0078-0453-05
74
20/25
NDC 0078-0454-05
75
Tablets are oblong and scored, with “Lotensin HCT” on one side and appropriate number
imprinted on the other side.
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Storage: Do not store above 30°C (86°F). Protect from moisture and light. Dispense in tight,
light-resistant container (USP).
REV: March 2011
T2011-09 company logo
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
PRINCIPAL DISPLAY PANEL
Package Label
Rx Only
NDC 0078-0451-05
Lotensin HCT® 5/6.25
benazepril HCl 5 mg
hydrochlorothiazide USP 6.25 mg
100 tablets company logo
PRINCIPAL DISPLAY PANEL
Package Label
Rx Only
NDC 0078-0452-05
Lotensin HCT® 10/12.5
benazepril HCl 10 mg
hydrochlorothiazide USP 12.5 mg
100 tablets
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company logo
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PRINCIPAL DISPLAY PANEL
Package Label
Rx Only
NDC 0078-0453-05
Lotensin HCT® 20/12.5
benazepril HCl 20 mg
hydrochlorothiazide USP 12.5 mg
100 tablets company logo
PRINCIPAL DISPLAY PANEL
Package Label
Rx Only
NDC 0078-0454-05
Lotensin HCT® 20/25
benazepril HCl 20 mg
hydrochlorothiazide USP 25 mg
100 tablets company logo
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|
custom-source
|
2025-02-12T13:46:30.389876
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020033s040lbl.pdf', 'application_number': 20033, 'submission_type': 'SUPPL ', 'submission_number': 40}
|
12,151
|
company logo
Lotensin HCT®
benazepril hydrochloride and hydrochlorothiazide USP
Combination Tablets
5 mg/6.25 mg
10 mg/12.5 mg
20 mg/12.5 mg
20 mg/25 mg
Rx only
Prescribing Information
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue Lotensin HCT as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and death to the
developing fetus. See Warnings: Fetal Toxicity
DESCRIPTION
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in
water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is
3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benza
zepine-1-acetic acid monohydrochloride; its structural formula is structural formula
Its empirical formula is C24H28N2O5·HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting
enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.
Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline
powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in
n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether,
in chloroform, and in dilute mineral acids. Hydrochlorothiazide’s chemical name is
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural
formula is
Reference ID: 3073710
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structural formula
Its empirical formula is C 7 H 8 ClN 3 O 4 S 2, and its molecular weight is 297.73. Hydrochloro
thiazide is a thiazide diuretic.
Lotensin HCT is a combination of benazepril hydrochloride and hydrochlorothiazide USP. The
tablets are formulated for oral administration with a combination of 5, 10, or 20 mg of benazepril
hydrochloride and 6.25, 12.5, or 25 mg of hydrochlorothiazide USP. The inactive ingredients of
the tablets are cellulose compounds, crospovidone, hydrogenated castor oil, iron oxides
(10/12.5-mg, 20/12.5-mg, and 20/25-mg tablets), lactose, polyethylene glycol, talc, and titanium
dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects
and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to
the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone
secretion by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased
vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a
small increase of serum potassium. Hypertensive patients treated with benazepril alone for up to
52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with
benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum
potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to
angiotensin II and did not interfere with the hemodynamic effects of the autonomic
neurotransmitters acetylcholine, epinephrine, and norepinephrine.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotensin
HCT remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be
primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an
antihypertensive effect even in patients with low-renin hypertension.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of
electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately
equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma
volume, with consequent increases in plasma renin activity, increases in aldosterone secretion,
increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone
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link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the
potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is unknown.
Pharmacokinetics and Metabolism
Following oral administration of Lotensin HCT, peak plasma concentrations of benazepril are
reached within 0.5-1.0 hours. As determined by urinary recovery, the extent of absorption is at
least 37%. The absorption of hydrochlorothiazide is somewhat slower (1-2.5 hours) and
somewhat more complete (50%-80%). In fasting subjects, the rate and extent of absorption of
benazepril and hydrochlorothiazide from Lotensin HCT are not different, respectively, from the
rate and extent of absorption of benazepril and hydrochlorothiazide from immediate-release
monotherapy formulations.
The absorption of benazepril from Lotensin® tablets is not influenced by the presence of food in
the gastrointestinal tract, but possible effects of food upon absorption of either component from
Lotensin HCT tablets have not been studied. The reported studies of food effects on
hydrochlorothiazide absorption have been inconclusive. The absorption of hydrochlorothiazide
is increased by agents that reduce gastrointestinal motility, but it is reported to be reduced by
50% in patients with congestive heart failure.
Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite,
benazeprilat. Peak plasma concentrations of benazeprilat are reached 1-2 hours after drug intake
in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein
binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by
equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be
unaffected by age, hepatic dysfunction, or – over the concentration range of 0.24-23.6 µmol/L –
concentration.
Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6-7.8 L/kg, and
its measured plasma protein binding is 67.9%. The drug also accumulates in red blood cells, so
that whole blood levels are 1.6-1.8 times those measured in plasma.
In studies of rats given 14C-benazepril, benazepril and its metabolites crossed the blood-brain
barrier only to an extremely low extent. Multiple doses of benazepril did not result in
accumulation in any tissue except the lung, where, as with other ACE inhibitors in similar
studies, there was a slight increase in concentration due to slow elimination in that organ.
Some placental passage occurred when benazepril was administered to pregnant rats. In humans,
hydrochlorothiazide crosses the placenta freely, and levels in umbilical-cord blood are similar to
those in the maternal circulation.
Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE
inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and
benazeprilat. Only trace amounts of an administered dose of benazepril can be recovered
unchanged in the urine; about 20% of the dose is excreted as benazeprilat, 4% as benazepril
glucuronide, and 8% as benazeprilat glucuronide.
In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially
unaltered. Similarly, the pharmacokinetics of benazepril and benazeprilat do not appear to be
influenced by age.
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The kinetics of benazepril are dose-proportional within the dosage range of 5-20 mg. Small
deviations from dose proportionality were observed when the broader range of 2-80 mg was
studied, possibly due to the saturable binding of the compound to ACE.
The effective half-life of accumulation of benazeprilat following multiple dosing of benazepril
hydrochloride is 10-11 hours. Thus, steady-state concentrations of benazeprilat should be
reached after 2 or 3 doses of benazepril hydrochloride given once daily.
During chronic administration (28 days) of once-daily doses of benazepril between 5 mg and 20
mg, the kinetics did not change, and there was no significant accumulation. Accumulation ratios
based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of
benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not
detected in the dialysate.
Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects
with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately
11%-12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary
clearance may compensate to an extent for deficient renal clearance.
The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal
insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal
function. In patients with creatinine clearance 30 mL/min, peak benazeprilat levels and the
initial (alpha phase) half-life increase, and time to steady state may be delayed (see DOSAGE
AND ADMINISTRATION).
Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours. In a
study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the
half-life of hydrochlorothiazide elimination was lengthened to 21 hours.
Pharmacodynamics
Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE
activity by at least 80%-90% for at least 24 hours after dosing. For up to 4 hours after a 10-mg
dose, pressor responses to exogenous angiotensin I were inhibited by 60%-90%.
Administration of benazepril to patients with mild-to-moderate hypertension results in a
reduction of both supine and standing blood pressure to about the same extent, with no
compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can
occur in patients who are salt and/or volume depleted (see WARNINGS, Hypotension).
In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions
achieved 2-4 hours after dosing. The antihypertensive effect of a single dose persisted for
24 hours. In multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure
(systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The reductions at trough are
about 50% of those seen at peak.
Four dose-response studies of benazepril monotherapy using once-daily dosing were conducted
in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective
once-daily dose of benazepril was 10 mg; further falls in blood pressure, especially at morning
trough, were seen with higher doses in the studied dosing range (10-80 mg). In studies
comparing the same daily dose of benazepril given as a single morning dose or as a twice-daily
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dose, blood pressure reductions at the time of morning trough blood levels were greater with the
divided regimen.
During chronic therapy with benazepril, the maximum reduction in blood pressure with any
given dose is generally achieved after 1-2 weeks. The antihypertensive effects of benazepril have
continued during therapy for at least 2 years. Abrupt withdrawal of benazepril has not been
associated with a rapid increase in blood pressure.
In patients with mild-to-moderate hypertension, total daily doses of Lotensin 20-40 mg were
similar in effectiveness to total daily doses of captopril 50-100 mg, hydrochlorothiazide
25-50 mg, nifedipine SR 40-80 mg, and propranolol 80-160 mg.
The antihypertensive effects of benazepril were not appreciably different in patients receiving
high- or low-sodium diets.
In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in
peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or
no change in heart rate. In normal human volunteers, single doses of benazepril caused an
increase in renal blood flow but had no effect on glomerular filtration rate.
In clinical trials of benazepril/hydrochlorothiazide using benazepril doses of 5-20 mg and
hydrochlorothiazide doses of 6.25-25 mg, the antihypertensive effects were sustained for at least
24 hours, and they increased with increasing dose of either component. Although benazepril
monotherapy is somewhat less effective in blacks than in nonblacks, the efficacy of combination
therapy appears to be independent of race.
By blocking the renin-angiotensin-aldosterone axis, administration of benazepril tends to reduce
the potassium loss associated with the diuretic. In clinical trials of Lotensin HCT, the average
change in serum potassium was near zero in subjects who received 5/6.25 mg or 20/12.5 mg, but
the average subject who received 10/12.5 mg or 20/25 mg experienced a mild reduction in serum
potassium, similar to that experienced by the average subject receiving the same dose of
hydrochlorothiazide monotherapy.
INDICATIONS AND USAGE
Lotensin HCT is indicated for the treatment of hypertension.
This fixed combination drug is not indicated for the initial therapy of hypertension (see
DOSAGE AND ADMINISTRATION).
In using Lotensin HCT, consideration should be given to the fact that another
angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in
patients with renal impairment or collagen-vascular disease. Available data are insufficient to
show that benazepril does not have a similar risk (see WARNINGS, Neutropenia/
Agranulocytosis).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to nonblacks.
CONTRAINDICATIONS
Lotensin HCT is contraindicated in patients who are anuric.
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Lotensin HCT is also contraindicated in patients who are hypersensitive to benazepril, to any
other ACE inhibitor, to hydrochlorothiazide, or to other sulfonamide-derived drugs.
Hypersensitivity reactions are more likely to occur in patients with a history of allergy or
bronchial asthma.
Lotensin HCT is also contraindicated in patients with a history of angioedema with or without
previous ACE inhibitor treatment.
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including Lotensin HCT) may be subject to a variety of adverse reactions, some of
them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In
U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who
received placebo and in about 0.5% of the subjects who received benazepril. Angioedema
associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face,
tongue, or glottis occurs, treatment with Lotensin HCT should be discontinued and appropriate
therapy instituted immediately. When involvement of the tongue, glottis, or larynx appears likely
to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection
1:1000 (0.3-0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE
REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting);
in some cases there was no prior history of facial angioedema and C-1 esterase levels were
normal. The angioedema was diagnosed by procedures including abdominal CT scan or
ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE inhibitors
presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Hypotension
Lotensin HCT can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has
been only rarely associated with hypotension in uncomplicated hypertensive patients.
Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt
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depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or
vomiting. Volume and/or salt depletion should be corrected before initiating therapy with
Lotensin HCT.
Lotensin HCT should be used cautiously in patients receiving concomitant therapy with other
antihypertensives. The thiazide component of Lotensin HCT may potentiate the action of other
antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. The
antihypertensive effects of the thiazide component may also be enhanced in the
postsympathectomy patient.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE
inhibitor therapy may cause excessive hypotension, which may be associated with oliguria,
azotemia, and (rarely) with acute renal failure and death. In such patients, Lotensin HCT therapy
should be started under close medical supervision; they should be followed closely for the first 2
weeks of treatment and whenever the dose of benazepril or diuretic is increased.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated
with intravenous infusion of physiological saline. Lotensin HCT treatment usually can be
continued following restoration of blood pressure and volume.
Impaired Renal Function
Lotensin HCT should be used with caution in patients with severe renal disease. Thiazides may
precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative.
When the renin-angiotensin-aldosterone system is inhibited by benazepril, changes in renal
function may be anticipated in susceptible individuals. In patients with severe congestive heart
failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone
system, treatment with angiotensin-converting enzyme inhibitors (including benazepril) may be
associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or
death.
In a small study of hypertensive patients with unilateral or bilateral renal artery stenosis,
treatment with benazepril was associated with increases in blood urea nitrogen and serum
creatinine; these increases were reversible upon discontinuation of benazepril therapy,
concomitant diuretic therapy, or both. When such patients are treated with Lotensin HCT, renal
function should be monitored during the first few weeks of therapy.
Some benazepril-treated hypertensive patients with no apparent preexisting renal vascular
disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and
transient, especially when benazepril has been given concomitantly with a diuretic. Dosage
reduction of Lotensin HCT may be required. Evaluation of the hypertensive patient should
always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
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Neutropenia/Agranulocytosis
Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients (incidence
probably less than once per 10,000 exposures) but more frequently (incidence possibly as great
as once per 1000 exposures) in patients with renal impairment, especially those who also have
collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Available data
from clinical trials of benazepril are insufficient to show that benazepril does not cause
agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in
patients with collagen-vascular disease, especially if the disease is associated with impaired
renal function.
Fetal toxicity
Pregnancy category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue Lotensin HCT as soon as
possible. These adverse outcomes are usually associated with use of these drugs in the second
and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities
after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting
the renin-angiotensin system from other antihypertensive agents. Appropriate management of
maternal hypertension during pregnancy is important to optimize outcomes for both mother and
fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue Lotensin HCT, unless it is considered lifesaving for
the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
Lotensin HCT for hypotension, oliguria, and hyperkalemia [see Precautions, Pediatric Use].
No teratogenic effects of benazapril were seen in studies of pregnant rats, mice, and rabbits. On
a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and
more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg
woman). On a mg/kg basis these these multiples are 300 times (in rats), 90 times (in mice), and
more than 3 times (in rabbits) the maximum recommended human dose. When
hydrochlorothiazide was orally administered without benazepril to pregnant mice and rats during
their respective periods of major organogenesis, at doses up to 3000 and 1000 mg/kg/day
respectively, there was no evidence of harm to the fetus. Similarly, no teratogenic effects of
benazepril were seen in studies of pregnant rats, mice, and rabbits; on a mg/kg basis, the doses
used in these studies were 300 times (in rats), 90 times (in mice), and more than 3 times (in
rabbits) the maximum recommended human dose.
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Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
Impaired Hepatic Function
Lotensin HCT should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate
hepatic coma (see Hepatic Failure, above). In patients with hepatic dysfunction due to cirrhosis,
levels of benazeprilat are essentially unaltered. No formal pharmacokinetic studies have been
carried out in hypertensive patients with impaired liver function.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus
erythematosus.
Acute Myopia and Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute
transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased
visual acuity or ocular pain and typically occur within hours to weeks of drug initiation.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary
treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or
surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.
Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide
or penicillin allergy.
PRECAUTIONS
General
Derangements of Serum Electrolytes: In clinical trials of benazepril monotherapy,
hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal)
occurred in approximately 1% of hypertensive patients receiving benazepril. In most cases, these
were isolated values which resolved despite continued therapy. Risk factors for the development
of hyperkalemia included renal insufficiency, diabetes mellitus, and the concomitant use of
potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt
substitutes.
Conversely, treatment with thiazide diuretics has been associated with hypokalemia,
hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest
as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting.
Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of
digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients
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experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes,
and in patients receiving concomitant therapy with corticosteroids or ACTH.
The opposite effects of benazepril and hydrochlorothiazide on serum potassium will
approximately balance each other in many patients, so that no net effect upon serum potassium
will be seen. In other patients, one or the other effect may be dominant. Initial and periodic
determinations of serum electrolytes to detect possible electrolyte imbalance should be
performed at appropriate intervals.
Chloride deficits are generally mild and require specific treatment only under extraordinary
circumstances (e.g., in liver disease or renal disease). Dilutional hyponatremia may occur in
edematous patients; appropriate therapy is water restriction rather than administration of salt,
except in rare instances when the hyponatremia is life-threatening. In actual salt depletion,
appropriate replacement is the therapy of choice.
Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy,
pathological changes in the parathyroid gland have been observed, with hypercalcemia and
hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone
resorption, and peptic ulceration) have not been seen.
Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result.
Other Metabolic Disturbances: Thiazide diuretics tend to reduce glucose tolerance and to raise
serum levels of cholesterol, triglycerides, and uric acid. These effects are usually minor, but
frank gout or overt diabetes may be precipitated in susceptible patients.
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin,
persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential
diagnosis of cough.
Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that
produce hypotension, benazepril will block the angiotensin II formation that could otherwise
occur secondary to compensatory renin release. Hypotension that occurs as a result of this
mechanism can be corrected by volume expansion.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment
with ACE inhibitors. A patient receiving Lotensin HCT should be told to report immediately any
signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty
in breathing) and to take no more drug until after consulting with the prescribing physician.
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to Lotensin HCT during pregnancy. Discuss treatment options with women planning
to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as
possible.
Symptomatic Hypotension: A patient receiving Lotensin HCT should be cautioned that
lightheadedness can occur, especially during the first days of therapy, and that it should be
reported to the prescribing physician. The patient should be told that if syncope occurs, Lotensin
HCT should be discontinued until the physician has been consulted.
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All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or
vomiting can lead to an excessive fall in blood pressure, with the same consequences of
lightheadedness and possible syncope.
Hyperkalemia: A patient receiving Lotensin HCT should be told not to use potassium
supplements or salt substitutes containing potassium without consulting the prescribing
physician.
Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore
throat, fever), which could be a sign of neutropenia.
Laboratory Tests
The hydrochlorothiazide component of Lotensin HCT may decrease serum PBI levels without
signs of thyroid disturbance.
Therapy with Lotensin HCT should be interrupted for a few days before carrying out tests of
parathyroid function.
Drug Interactions
Potassium Supplements and Potassium-Sparing Diuretics: As noted above (Derangements of
Serum Electrolytes), the net effect of Lotensin HCT may be to elevate a patient’s serum
potassium, to reduce it, or to leave it unchanged. Potassium-sparing diuretics (spironolactone,
amiloride, triamterene, and others) or potassium supplements can increase the risk of
hyperkalemia. If concomitant use of such agents is indicated, they should be given with caution,
and the patient’s serum potassium should be monitored frequently.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving ACE inhibitors during therapy with lithium. Because renal clearance of
lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as
in therapy with Lotensin HCT, a thiazide diuretic is coadministered with the ACE inhibitor.
Lotensin HCT and lithium should be coadministered with caution, and frequent monitoring of
serum lithium levels is recommended.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2
Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with
ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible
acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients
receiving benazepril and NSAID therapy.
The antihypertensive effect of ACE inhibitors and thiazide diuretics may be attenuated by NSAIDs. The
diuretic and natriuretic effects of thiazide diuretics may also be reduced when NSAIDs are
coadministered.
Other: Benazepril has been used concomitantly with beta-adrenergic-blocking agents,
calcium-blocking agents, cimetidine, diuretics, digoxin, and hydralazine without evidence of
clinically important adverse interactions. Other ACE inhibitors have had less than additive
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effects with beta-adrenergic blockers, presumably because drugs of both classes lower blood
pressure by inhibiting parts of the renin-angiotensin system.
Interaction studies with warfarin and acenocoumarol have failed to identify any clinically
important effects of benazepril on the serum concentrations or clinical effects of these
anticoagulants.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude
effectiveness of the pressor agent for therapeutic use.
Thiazides may increase the responsiveness to tubocurarine.
The diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by
concurrent administration of nonsteroidal anti-inflammatory agents.
Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the
presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins
bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to
85% and 43%, respectively.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was found when benazepril was given to rats and mice for 104
weeks at doses up to 150 mg/kg/day. On a body-weight basis, this dose is over 100 times the
maximum recommended human dose; on a body-surface-area basis, this dose is 18 times (rats)
and 9 times (mice) the maximum recommended human dose. No mutagenic activity was
detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for
forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50-500
mg/kg/day (38-375 times the maximum recommended human dose on a body-weight basis; 6-61
times the maximum recommended dose on a body-surface-area basis), benazepril had no adverse
effect on the reproductive performance of male and female rats.
Under the auspices of the National Toxicology Program, rats and mice received
hydrochlorothiazide in their feed for 2 years, at doses up to 600 mg/kg/day in mice and up to
100 mg/kg/day in rats. These studies uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in rats or female mice, but there was equivocal evidence of
hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in in vitro assays
using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (the
Ames test); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo
assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes,
and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in
the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma
Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43-1300 µg/mL.
Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using
an unspecified concentration of hydrochlorothiazide.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diets, to doses up to 100 and 4 mg/kg/day,
respectively, prior to mating and throughout gestation.
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Pregnancy
Nursing Mothers
Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of
lactating women treated with benazepril, so that a newborn child ingesting nothing but breast
milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat.
Thiazides, on the other hand, are definitely excreted into breast milk. Because of the potential for
serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of
benazepril in infants, a decision should be made whether to discontinue nursing or to discontinue
Lotensin HCT, taking into account the importance of the drug to the mother.
Geriatric Use
Of the total number of patients who received Lotensin HCT in U.S. clinical studies of Lotensin
HCT, 19% were 65 or older while about 1.5% were 75 or older. Overall differences in
effectiveness or safety were not observed between these patients and younger patients, and other
reported clinical experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection, and it
may be useful to monitor renal function.
Pediatric Use
Neonates with a history of in utero exposure to Lotensin HCT:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion. Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. Benazepril, which crosses the
placenta, can theoretically be removed from the neonatal circulation by these means; there are
occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience
is limited.
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Lotensin HCT has been evaluated for safety in over 2500 patients with hypertension; over 500 of
these patients were treated for at least 6 months, and over 200 were treated for more than 1 year.
The reported side effects were generally mild and transient, and there was no relationship
between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to
side effects was required in approximately 7% of U.S. patients treated with Lotensin HCT and in
4% of patients treated with placebo.
The most common reasons for discontinuation of therapy with Lotensin HCT in U.S. studies
were cough (1.0%; see PRECAUTIONS), “dizziness” (1.0%), headache (0.6%), and fatigue
(0.6%).
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The side effects considered possibly or probably related to study drug that occurred in U.S.
placebo-controlled trials in more than 1% of patients treated with Lotensin HCT are shown in
the table below.
Reactions Possibly or Probably Drug Related
Patients in U.S. Placebo-Controlled Studies
LOTENSIN HCT
Placebo
N = 665
N = 235
N
%
N
%
“Dizziness”
41
6.3
8
3.4
Fatigue
34
5.2
6
2.6
Postural Dizziness
23
3.5
1
0.4
Headache
20
3.1
10
4.3
Cough
14
2.1
3
1.3
Hypertonia
10
1.5
3
1.3
Vertigo
10
1.5
2
0.9
Nausea
9
1.4
2
0.9
Impotence
8
1.2
0
0.0
Somnolence
8
1.2
1
0.4
Other side effects considered possibly or probably related to study drug that occurred in U.S.
placebo-controlled trials in 0.3% to 1.0% of patients treated with Lotensin HCT were the
following:
Angioedema: Edema of the lips or face without other manifestations of angioedema (0.3%). See
WARNINGS, Angioedema.
Cardiovascular: Hypotension (seen in 0.6% of patients), postural hypotension (0.3%),
palpitations, and flushing.
Gastrointestinal: Vomiting, diarrhea, dyspepsia, anorexia, and constipation.
Neurologic and Psychiatric: Insomnia, nervousness, paresthesia, libido decrease, dry mouth,
taste perversion, and tinnitus.
Dermatologic: Rash and sweating.
Other: Gout, urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest pain and
abdominal pain).
Other adverse experiences reported in 0.3% or more of Lotensin HCT patients in U.S. controlled
clinical trials, and rarer events seen in post-marketing experience, were the following; asterisked
entries occurred in more than 1% of patients (in some, a causal relationship to Lotensin HCT is
uncertain):
Angioedema: Edema of the lips or face without other manifestations of angioedema. See
WARNINGS, Angioedema.
Cardiovascular: Syncope, peripheral vascular disorder, and tachycardia.
Body as a Whole: Infection, back pain*, flu syndrome*, fever, chills, and neck pain.
Dermatologic: Photosensitivity and pruritus.
Gastrointestinal: Gastroenteritis, flatulence, and tooth disorder.
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Neurologic and Psychiatric: Hypesthesia, abnormal vision, abnormal dreams, and retinal
disorder.
Respiratory: Upper respiratory infection*, epistaxis, bronchitis, rhinitis*, sinusitis*, and voice
alteration.
Other: Conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency*.
Monotherapy with benazepril has been evaluated for safety in over 6000 patients. In clinical
trials, the observed adverse reactions to benazepril were similar to those seen in trials of
Lotensin HCT. In post-marketing experience with benazepril, there have been rare reports of
Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombo-cytopenia.
Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed
to other ACE inhibitors.
Hydrochlorothiazide has been extensively prescribed for many years, but there has not been
enough systematic collection of data to support an estimate of the frequency of the observed
adverse reactions. Within organ-system groups, the reported reactions are listed here in
decreasing order of severity, without regard to frequency.
Unknown frequency: small bowel angioedema, anaphylactoid reactions, hyperkalemia,
agranulocytosis, neutropenia.
Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or
narcotics).
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic) (see WARNINGS), sialadenitis,
vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.
Neurologic: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia,
xanthopsia, weakness, and restlessness.
Musculoskeletal: Muscle spasm.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia.
Metabolic: Hyperglycemia, glycosuria, and hyperuricemia.
Hypersensitivity: Necrotizing angiitis, respiratory distress (including pneumonitis and
pulmonary edema), purpura, urticaria, rash, and photosensitivity.
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis
including toxic epidermal necrolysis.
Clinical Laboratory Test Findings
Serum Electrolytes: See PRECAUTIONS.
Creatinine: Minor reversible increases in serum creatinine were observed in patients with
essential hypertension treated with Lotensin HCT. Such increases occurred most frequently in
patients with renal artery stenosis (see PRECAUTIONS).
PBI and Tests of Parathyroid Function: See PRECAUTIONS.
Other (Causal Relationships Unknown): Other clinically important changes in standard
laboratory tests were rarely associated with Lotensin HCT administration. Elevations in blood
urea nitrogen, uric acid, glucose, SGOT, and SGPT have been reported (see WARNINGS). In
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the somewhat larger patient population exposed to benazepril monotherapy in U.S. trials, the
same abnormalities were reported, together with scattered accounts of hyponatremia, melena,
electrocardiographic changes, leukopenia, eosinophilia, and proteinuria.
OVERDOSAGE
No specific information is available on the treatment of overdosage with Lotensin HCT;
treatment should be symptomatic and supportive. Therapy with Lotensin HCT should be
discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and
hypotension should be treated by established procedures.
Single oral doses of 1 g/kg of benazepril caused reduced activity in mice, and doses of 3 g/kg
were associated with significant lethality. Reduction of activity in rats was not seen until they
had received doses of 5 g/kg, and doses of 6 g/kg were not lethal. In single-dose studies of
hydrochlorothiazide, most rats survived doses up to 2.75 g/kg.
Data from human overdoses of benazepril are scanty, but the most common manifestation of
human benazepril overdosage is likely to be hypotension. In human hydrochlorothiazide
overdose, the most common signs and symptoms observed have been those of dehydration and
electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been
administered, hypokalemia may accentuate cardiac arrhythmias.
Laboratory determinations of serum levels of benazepril and its metabolites are not widely
available, and such determinations have, in any event, no established role in the management of
benazepril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of
the urine) that might accelerate elimination of benazepril and its metabolites. Benazeprilat is
only slightly dialyzable, but dialysis might be considered in overdosed patients with severely
impaired renal function (see WARNINGS).
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of
benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research
facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and
effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline
solution.
DOSAGE AND ADMINISTRATION
Benazepril is an effective treatment of hypertension in once-daily doses of 10-80 mg, while
hydrochlorothiazide is effective in doses of 12.5-50 mg per day. In clinical trials of
benazepril/hydrochlorothiazide combination therapy using benazepril doses of 5-20 mg and
hydrochlorothiazide doses of 6.25-25 mg, the antihypertensive effects increased with increasing
dose of either component.
The side effects (see WARNINGS) of benazepril are generally rare and apparently independent
of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily
hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more
common than the latter. Therapy with any combination of benazepril and hydrochlorothiazide
will be associated with both sets of dose-independent side effects, but regimens in which
benazepril is combined with low doses of hydrochlorothiazide produce minimal effects on serum
Reference ID: 3073710
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potassium. In clinical trials of Lotensin HCT, the average change in serum potassium was near
zero in subjects who received 5/6.25 mg or 20/12.5 mg, but the average subject who received
10/12.5 mg or 20/25 mg experienced a mild reduction in serum potassium, similar to that
experienced by the average subject receiving the same dose of hydrochlorothiazide
monotherapy.
To minimize dose-independent side effects, it is usually appropriate to begin combination
therapy only after a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately
controlled with benazepril monotherapy may be switched to Lotensin HCT 10/12.5 or Lotensin
HCT 20/12.5. Further increases of either or both components could depend on clinical response.
The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed.
Patients whose blood pressures are adequately controlled with 25 mg of daily
hydrochlorothiazide, but who experience significant potassium loss with this regimen, may
achieve similar blood-pressure control without electrolyte disturbance if they are switched to
Lotensin HCT 5/6.25.
Replacement Therapy: The combination may be substituted for the titrated individual
components.
Use in Renal Impairment: Regimens of therapy with Lotensin HCT need not take account of
renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73m2 (serum
creatinine roughly 3 mg/dL or 265 µmol/L). In patients with more severe renal impairment,
loop diuretics are preferred to thiazides, so Lotensin HCT is not recommended (see
WARNINGS).
HOW SUPPLIED
Lotensin HCT is available in tablets of four different strengths:
Benazepril
Hydrochlorothiazide
Tablet Color
5 mg
6.25 mg
white
10 mg
12.5 mg
light pink
20 mg
12.5 mg
grayish-violet
20 mg
25 mg
red
Tablets of each strength are supplied in bottles that contain a desiccant and 100 tablets.
The National Drug Codes for the various packages are
Dose
Bottle of 100
Tablet Imprint
5/6.25
NDC 0078-0451-05
57
10/12.5
NDC 0078-0452-05
72
20/12.5
NDC 0078-0453-05
74
20/25
NDC 0078-0454-05
75
Tablets are oblong and scored, with “Lotensin HCT” on one side and appropriate number
imprinted on the other side.
Storage: Do not store above 30C (86F). Protect from moisture and light. Dispense in tight,
light-resistant container (USP).
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company logo
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2011-XX
01/2012
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|
custom-source
|
2025-02-12T13:46:31.162089
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020033s045lbl.pdf', 'application_number': 20033, 'submission_type': 'SUPPL ', 'submission_number': 45}
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12,154
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Aredia®
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor available in 30-mg or 90-mg vials for
intravenous administration. Each 30-mg, and 90-mg vial contains, respectively, 30 mg and 90 mg of sterile,
lyophilized pamidronate disodium and 470 mg and 375 mg of mannitol, USP. The pH of a 1% solution of
pamidronate disodium in distilled water is approximately 8.3. Aredia, a member of the group of chemical
compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated
chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD),
and its structural formula is
Pamidronate disodium is a white-to-practically-white powder. It is soluble in water and in 2N sodium
hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in
organic solvents. Its molecular formula is C3H9NO7P2Na2•5H2O and its molecular weight is 369.1.
Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5 prior to lyophilization).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the mechanism of
antiresorptive action is not completely understood, several factors are thought to contribute to this action.
Aredia adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution
of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity con-
tributes to inhibition of bone resorption. In animal studies, at doses recommended for the treatment of
hypercalcemia, Aredia inhibits bone resorption apparently without inhibiting bone formation and mineraliza-
tion. Of relevance to the treatment of hypercalcemia of malignancy is the finding that Aredia inhibits the accel-
erated bone resorption that results from osteoclast hyperactivity induced by various tumors in animal studies.
Pharmacokinetics
Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous infusion of 30,
60, or 90 mg of Aredia over 4 hours and 90 mg of Aredia over 24 hours (Table 1).
Distribution
The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose over 120 hours.
Metabolism
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Excretion
After administration of 30, 60, and 90 mg of Aredia over 4 hours, and 90 mg of Aredia over 24 hours, an
overall mean ± SD of 46 ± 16% of the drug was excreted unchanged in the urine within 120 hours.
Cumulative urinary excretion was linearly related to dose. The mean ± SD elimination half-life is 28 ± 7
hours. Mean ± SD total and renal clearances of pamidronate were 107 ± 50 mL/min and 49 ± 28 mL/min,
respectively. The rate of elimination from bone has not been determined.
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.
Pediatric
Pamidronate is not labeled for use in the pediatric population.
Renal Insufficiency
The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying
degrees of renal impairment. Each patient received a single 90-mg dose of Aredia infused over 4 hours.
The renal clearance of pamidronate in patients was found to closely correlate with creatinine clearance
(see Figure 1). A trend toward a lower percentage of drug excreted unchanged in urine was observed in
renally impaired patients. Adverse experiences noted were not found to be related to changes in renal
clearance of pamidronate. Given the recommended dose, 90 mg infused over 4 hours, excessive accumu-
lation of pamidronate in renally impaired patients is not anticipated if Aredia is administered on a monthly
basis.
Figure 1:
Pamidronate renal clearance as a function of creatinine
clearance in patients with normal and impaired renal function.
The lines are the mean prediction line and 95% confidence intervals.
Hepatic Insufficiency
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases
with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=7). Each patient received a
single 90-mg dose of Aredia infused over 4 hours. Although there was a statistically significant difference
in the pharmacokinetics between patients with normal and impaired hepatic function, the difference was
not considered clinically relevant. Patients with hepatic impairment exhibited higher mean AUC (53%) and
Cmax (29%), and decreased plasma clearance (33%) values. Nevertheless, pamidronate was still rapidly
cleared from the plasma. Drug levels were not detectable in patients by 12 to 36 hours after drug infusion.
Because Aredia is administered on a monthly basis, drug accumulation is not expected. No changes in
Aredia dosing regimen are recommended for patients with mild to moderate abnormal hepatic function.
Aredia has not been studied in patients with severe hepatic impairment.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
Table 1
Mean (SD, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients
(n=6 for each group)
Maximum
Percent
Total
Renal
Dose
Concentration
of dose
Clearance
Clearance
(infusion rate)
(µg/mL)
excreted in urine
(mL/min)
(mL/min)
30 mg
0.73
43.9
136
58
(4 hrs)
(0.14, 19.1%)
(14.0, 31.9%)
(44, 32.4%)
(27, 46.5%)
60 mg
1.44
47.4
88
42
(4 hrs)
(0.57, 39.6%)
(47.4, 54.4%)
(56, 63.6%)
(28, 66.7%)
90 mg
2.61
45.3
103
44
(4 hrs)
(0.74, 28.3%)
(25.8, 56.9%)
(37, 35.9%)
(16, 36.4%)
90 mg
1.38
47.5
101
52
(24 hrs)
(1.97, 142.7%)
(10.2, 21.5%)
(58, 57.4%)
(42, 80.8%)
After intravenous administration of radiolabeled pamidronate in rats, approximately 50%-60% of the
compound was rapidly adsorbed by bone and slowly eliminated from the body by the kidneys. In rats given
10 mg/kg bolus injections of radiolabeled Aredia, approximately 30% of the compound was found in the
liver shortly after administration and was then redistributed to bone or eliminated by the kidneys over 24-48
hours. Studies in rats injected with radiolabeled Aredia showed that the compound was rapidly cleared
from the circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage. Radioactivity
was eliminated from most soft tissues within 1-4 days; was detectable in liver and spleen for 1 and 3
months, respectively; and remained high in bones, trachea, and teeth for 6 months after dosing. Bone
uptake occurred preferentially in areas of high bone turnover. The terminal phase of elimination half-life in
bone was estimated to be approximately 300 days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia, presumably because
of decreased release of phosphate from bone and increased renal excretion as parathyroid hormone lev-
els, which are usually suppressed in hypercalcemia associated with malignancy, return toward normal.
Phosphate therapy was administered in 30% of the patients in response to a decrease in serum phos-
phate levels. Phosphate levels usually returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to
within or below normal after treatment with Aredia. These changes occur within the first week after treat-
ment, as do decreases in serum calcium levels, and are consistent with an antiresorptive pharmacologic
action.
Hypercalcemia of Malignancy
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic
derangement in metastatic bone disease and hypercalcemia of malignancy. Excessive release of calcium
into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive
dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of
calcium, setting up a cycle of worsening systemic hypercalcemia. Correction of excessive bone resorption
and adequate fluid administration to correct volume deficits are therefore essential to the management of
hypercalcemia.
Most cases of hypercalcemia associated with malignancy occur in patients who have breast cancer;
squamous-cell tumors of the lung or head and neck; renal-cell carcinoma; and certain hematologic malig-
nancies, such as multiple myeloma and some types of lymphomas. A few less-common malignancies,
including vasoactive intestinal-peptide-producing tumors and cholangiocarcinoma, have a high incidence of
hypercalcemia as a metabolic complication. Patients who have hypercalcemia of malignancy can generally
be divided into two groups, according to the pathophysiologic mechanism involved.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such
as parathyroid-hormone-related protein, which are elaborated by the tumor and circulate systemically.
Humoral hypercalcemia usually occurs in squamous-cell malignancies of the lung or head and neck or in
genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal metastases may be absent
or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products
that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hyper-
calcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the sever-
ity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium
levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly
or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for
differences in albumin levels is often used in place of measurement of ionized calcium; several nomograms
are in use for this type of calculation (see DOSAGE AND ADMINISTRATION).
Clinical Trials
In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were enrolled to
receive 30 mg, 60 mg, or 90 mg of Aredia as a single 24-hour intravenous infusion if their corrected serum
calcium levels were ≥12.0 mg/dL after 48 hours of saline hydration.
The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups were 13.8 mg/dL,
13.8 mg/dL, and 13.3 mg/dL, respectively.
The majority of patients (64%) had decreases in albumin-corrected serum calcium levels by 24 hours
after initiation of treatment. Mean-corrected serum calcium levels at days 2-7 after initiation of treatment
with Aredia were significantly reduced from baseline in all three dosage groups. As a result, by 7 days after
initiation of treatment with Aredia, 40%, 61%, and 100% of the patients receiving 30 mg, 60 mg, and
90 mg of Aredia, respectively, had normal-corrected serum calcium levels. Many patients (33%-53%) in the
60-mg and 90-mg dosage groups continued to have normal-corrected serum calcium levels, or a partial
response (≥15% decrease of corrected serum calcium from baseline), at Day 14.
In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium levels
of ≥12.0 mg/dL after at least 24 hours of saline hydration were randomized to receive either 60 mg of Aredia as a
single 24-hour intravenous infusion or 7.5 mg/kg of etidronate disodium as a 2-hour intravenous infusion daily for
3 days. Thirty patients were randomized to receive Aredia and 35 to receive etidronate disodium.
The mean baseline-corrected serum calcium for the Aredia 60-mg and etidronate disodium groups
were 14.6 mg/dL and 13.8 mg/dL, respectively.
By Day 7, 70% of the patients in the Aredia group and 41% of the patients in the etidronate disodium
group had normal-corrected serum calcium levels (P<0.05). When partial responders (≥15% decrease of
serum calcium from baseline) were also included, the response rates were 97% for the Aredia group and
65% for the etidronate disodium group (P<0.01). Mean-corrected serum calcium for the Aredia and
etidronate disodium groups decreased from baseline values to 10.4 and 11.2 mg/dL, respectively, on Day 7.
At Day 14, 43% of patients in the Aredia group and 18% of patients in the etidronate disodium group still
had normal-corrected serum calcium levels, or maintenance of a partial response. For responders in the
Aredia and etidronate disodium groups, the median duration of response was similar (7 and 5 days,
respectively). The time course of effect on corrected serum calcium is summarized in the following table.
Change in Corrected Serum Calcium by Time
from Initiation of Treatment
Time
Mean Change from Baseline in Corrected Serum Calcium (mg/dL)
(hr)
Aredia®
Etidronate Disodium
P-Value1
Baseline
14.6
13.8
24
-0.3
-0.5
48
-1.5
-1.1
72
-2.6
-2.0
96
-3.5
-2.0
<0.01
168
-4.1
-2.5
<0.01
1Comparison between treatment groups
In a third multicenter, randomized, parallel double-blind trial, a group of 69 cancer patients with hyper-
calcemia was enrolled to receive 60 mg of Aredia as a 4- or 24-hour infusion, which was compared to a
saline treatment group. Patients who had a corrected serum calcium level of ≥12.0 mg/dL after 24 hours of
saline hydration were eligible for this trial.
The mean baseline-corrected serum calcium levels for Aredia 60-mg 4-hour infusion, Aredia 60-mg
24-hour infusion, and saline infusion were 14.2 mg/dL, 13.7 mg/dL, and 13.7 mg/dL, respectively.
By Day 7 after initiation of treatment, 78%, 61%, and 22% of the patients had normal-corrected serum
calcium levels for the 60-mg 4-hour infusion, 60-mg 24-hour infusion, and saline infusion, respectively. At
Day 14, 39% of the patients in the Aredia 60-mg 4-hour infusion group and 26% of the patients in the
Aredia 60-mg 24-hour infusion group had normal-corrected serum calcium levels or maintenance of a par-
tial response.
For responders, the median duration of complete responses was 4 days and 6.5 days for Aredia 60-mg
4-hour infusion and Aredia 60-mg 24-hour infusion, respectively.
In all three trials, patients treated with Aredia had similar response rates in the presence or absence of
bone metastases. Concomitant administration of furosemide did not affect response rates.
Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were given a second
course of 60 mg of Aredia over a 4- or 24-hour period. Of these, 41% showed a complete response and
16% showed a partial response to the retreatment, and these responders had about a 3-mg/dL fall in
mean-corrected serum calcium levels 7 days after retreatment.
In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia
(corrected serum calcium ≥12.0 mg/dL) received 90 mg of Aredia as a 2-hour infusion. The mean baseline
corrected serum calcium was 14.0 mg/dL. Patients were not required to receive IV hydration prior to drug
administration, but all subjects did receive at least 500 mL of IV saline hydration concomitantly with the
pamidronate infusion. By Day 10 after drug infusion, 70% of patients had normal corrected serum calcium
levels (<10.8 mg/dL).
Paget’s Disease
Paget’s disease of bone (osteitis deformans) is an idiopathic disease characterized by chronic, focal areas
of bone destruction complicated by concurrent excessive bone repair, affecting one or more bones. These
changes result in thickened but weakened bones that may fracture or bend under stress. Signs and symp-
toms may be bone pain, deformity, fractures, neurological disorders resulting from cranial and spinal nerve
entrapment and from spinal cord and brain stem compression, increased cardiac output to the involved
bone, increased serum alkaline phosphatase levels (reflecting increased bone formation) and/or urine
hydroxyproline excretion (reflecting increased bone resorption).
Clinical Trials
In one double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone were
enrolled to receive 5 mg, 15 mg, or 30 mg of Aredia as a single 4-hour infusion on 3 consecutive days, for
total doses of 15 mg, 45 mg, and 90 mg of Aredia.
The mean baseline serum alkaline phosphatase levels were 1,409 U/L, 983 U/L, and 1,085 U/L, and
the mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and 0.19 for the 15-mg, 45-mg,
and 90-mg groups, respectively.
The effects of Aredia on serum alkaline phosphatase (SAP) and urine hydroxyproline/creatinine ratios
(UOHP/C) are summarized in the following table:
Percent of Patients With
Significant % Decreases in SAP and UOHP/C
SAP
UOHP/C
% Decrease
15 mg
45 mg
90 mg
15 mg
45 mg
90 mg
≥50
26
33
60
15
47
72
≥30
40
65
83
35
57
85
The median maximum percent decreases from baseline in serum alkaline phosphatase and urine
hydroxyproline/creatinine ratios were 25%, 41%, and 57%, and 25%, 47%, and 61% for the 15-mg, 45-mg,
and 90-mg groups, respectively. The median time to response (≥50% decrease) for serum alkaline phos-
phatase was approximately 1 month for the 90-mg group, and the response duration ranged from 1 to 372
days.
No statistically significant differences between treatment groups, or statistically significant changes from
baseline were observed for the bone pain response, mobility, and global evaluation in the 45-mg and 90-mg
groups. Improvement in radiologic lesions occurred in some patients in the 90-mg group.
Twenty-five patients who had Paget’s disease were retreated with 90 mg of Aredia. Of these, 44% had
a ≥50% decrease in serum alkaline phosphatase from baseline after treatment, and 39% had a ≥50%
decrease in urine hydroxyproline/creatinine ratio from baseline after treatment.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast cancer. These
cancers demonstrate a phenomenon known as osteotropism, meaning they possess an extraordinary
affinity for bone. The distribution of osteolytic bone metastases in these cancers is predominantly in the
axial skeleton, particularly the spine, pelvis, and ribs, rather than the appendicular skeleton, although
lesions in the proximal femur and humerus are not uncommon. This distribution is similar to the red bone
marrow in which slow blood flow possibly assists attachment of metastatic cells. The surface-to-volume
ratio of trabecular bone is much higher than cortical bone, and therefore disease processes tend to occur
more floridly in trabecular bone than at sites of cortical tissue.
These bone changes can result in patients having evidence of osteolytic skeletal destruction leading to
severe bone pain that requires either radiation therapy or narcotic analgesics (or both) for symptomatic
relief. These changes also cause pathologic fractures of bone in both the axial and appendicular skeleton.
Axial skeletal fractures of the vertebral bodies may lead to spinal cord compression or vertebral body col-
lapse with significant neurologic complications. Also, patients may experience episode(s) of hypercalcemia.
Clinical Trials
In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple myeloma were
enrolled to receive Aredia or placebo in addition to their underlying antimyeloma therapy to determine the
effect of Aredia on the occurrence of skeletal-related events (SREs). SREs were defined as episodes of
pathologic fractures, radiation therapy to bone, surgery to bone, and spinal cord compression. Patients
received either 90 mg of Aredia or placebo as a monthly 4-hour intravenous infusion for 9 months. Of the
392 patients, 377 were evaluable for efficacy (196 Aredia, 181 placebo). The proportion of patients devel-
oping any SRE was significantly smaller in the Aredia group (24% vs 41%, P<0.001), and the mean skele-
tal morbidity rate (#SRE/year) was significantly smaller for Aredia patients than for placebo patients (mean:
1.1 vs 2.1, P<.02). The times to the first SRE occurrence, pathologic fracture, and radiation to bone were
significantly longer in the Aredia group (P=.001, .006, and .046, respectively). Moreover, fewer Aredia
patients suffered any pathologic fracture (17% vs 30%, P=.004) or needed radiation to bone (14% vs 22%,
P=.049).
In addition, decreases in pain scores from baseline occurred at the last measurement for those Aredia
patients with pain at baseline (P=.026) but not in the placebo group. At the last measurement, a worsening
from baseline was observed in the placebo group for the Spitzer quality of life variable (P<.001) and
ECOG performance status (P<.011) while there was no significant deterioration from baseline in these
parameters observed in Aredia-treated patients.*
After 21 months, the proportion of patients experiencing any skeletal event remained significantly small-
er in the Aredia group than the placebo group (P=.015). In addition, the mean skeletal morbidity rate
(#SRE/year) was 1.3 vs 2.2 for Aredia patients versus placebo patients (P=.008), and time to first SRE
was significantly longer in the Aredia group compared to placebo (P=.016). Fewer Aredia patients suffered
vertebral pathologic fractures (16% vs 27%, P=.005). Survival of all patients was not different between
treatment groups.
Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of 90 mg of
Aredia infused over 2 hours every 3 to 4 weeks for 24 months to that of placebo in preventing SREs in
breast cancer patients with osteolytic bone metastases who had one or more predominantly lytic metas-
tases of at least 1 cm in diameter: one in patients being treated with antineoplastic chemotherapy and the
second in patients being treated with hormonal antineoplastic therapy at trial entry.
382 patients receiving chemotherapy were randomized, 185 to Aredia and 197 to placebo. 372
patients receiving hormonal therapy were randomized, 182 to Aredia and 190 to placebo. All but three
patients were evaluable for efficacy. Patients were followed for 24 months of therapy or until they went off
study. Median duration of follow-up was 13 months in patients receiving chemotherapy and 17 months in
patients receiving hormone therapy. Twenty-five percent of the patients in the chemotherapy study and
37% of the patients in the hormone therapy study received Aredia for 24 months. The efficacy results are
shown in the table below:
Breast Cancer Patients
Breast Cancer Patients
Receiving Chemotherapy
Receiving Hormonal Therapy
Any SRE
Radiation
Fractures
Any SRE
Radiation
Fractures
A
P
A
P
A
P
A
P
A
P
A
P
N
185 195
185
195 185
195
182
189
182
189
182 189
Skeletal
Morbidity Rate
(#SRE/year)
Mean
2.5
3.7
0.8
1.3
1.6
2.2
2.4
3.6
0.6
1.2
1.6
2.2
P-Value
<.001
<.001†
.018†
.021
.013†
.040†
Proportion of
patients having
an SRE
46% 65%
28% 45%
36% 49%
55% 63%
31% 40%
45%
55%
P-Value
<.001
<.001†
.014†
.094
.058†
.054†
Median Time to
SRE (months)
13.9
7.0
NR** 14.2
25.8 13.3
10.9
7.4
NR** 23.4
20.6 12.8
P-Value
<.001
<.001†
.009†
.118
.016†
.113†
†Fractures and radiation to bone were two of several secondary endpoints. The statistical significance of
these analyses may be overestimated since numerous analyses were performed.
**NR = Not Reached.
Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12 months. The com-
plete + partial response rate was 33% in Aredia patients and 18% in placebo patients treated with
chemotherapy (P=.001). No difference was seen between Aredia and placebo in hormonally-treated
patients.
Pain and analgesic scores, ECOG performance status and Spitzer quality of life index were measured
at baseline and periodically during the trials. The changes from baseline to the last measurement carried
forward are shown in the following table:
Mean Change (∆) from Baseline at Last Measurement
Breast Cancer Patients
Breast Cancer Patients
Receiving Chemotherapy
Receiving Hormonal Therapy
Aredia®
Placebo
A vs P
Aredia®
Placebo
A vs P
N
Mean ∆
N
Mean ∆
P-Value*
N
Mean ∆
N
Mean ∆
P-Value*
Pain Score
175
+0.93
183
+1.69
.050
173
+0.50
179
+1.60
.007
Analgesic
Score
175
+0.74
183
+1.55
.009
173
+0.90
179
+2.28
<.001
ECOG PS
178
+0.81
186
+1.19
.002
175
+0.95
182
+0.90
.773
Spitzer
QOL
177
-1.76
185
-2.21
.103
173
-1.86
181
-2.05
.409
Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an improvement
from baseline.
*The statistical significance of analyses of these secondary endpoints of pain, quality of life, and perform-
ance status in all three trials may be overestimated since numerous analyses were performed.
INDICATIONS AND USAGE
Hypercalcemia of Malignancy
Aredia, in conjunction with adequate hydration, is indicated for the treatment of moderate or severe hyper-
calcemia associated with malignancy, with or without bone metastases. Patients who have either epider-
moid or non-epidermoid tumors respond to treatment with Aredia. Vigorous saline hydration, an integral
part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the
urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated
with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be
hydrated adequately throughout the treatment, but overhydration, especially in those patients who have
cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypov-
olemia. The safety and efficacy of Aredia in the treatment of hypercalcemia associated with hyperparathy-
roidism or with other non-tumor-related conditions has not been established.
Paget’s Disease
Aredia is indicated for the treatment of patients with moderate to severe Paget’s disease of bone. The
effectiveness of Aredia was demonstrated primarily in patients with serum alkaline phosphatase ≥3 times
the upper limit of normal. Aredia therapy in patients with Paget’s disease has been effective in reducing
serum alkaline phosphatase and urinary hydroxyproline levels by ≥50% in at least 50% of patients, and by
≥30% in at least 80% of patients. Aredia therapy has also been effective in reducing these biochemical
markers in patients with Paget’s disease who failed to respond, or no longer responded to other treat-
ments.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
Aredia is indicated, in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone
metastases of breast cancer and osteolytic lesions of multiple myeloma. The Aredia treatment effect
appeared to be smaller in the study of breast cancer patients receiving hormonal therapy than in the study
of those receiving chemotherapy, however, overall evidence of clinical benefit has been demonstrated (see
CLINICAL PHARMACOLOGY, Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma, Clinical Trials section).
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other bisphos-
phonates.
WARNINGS
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH
MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA SHOULD NOT EXCEED 90 MG
(see DOSAGE AND ADMINISTRATION for appropriate infusion durations).
Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration
of renal function and potential renal failure.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Patients
treated with Aredia for bone metastases should have the dose withheld if renal function has deteriorated.
(See DOSAGE AND ADMINISTRATION.)
In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) adminis-
tration of Aredia.
Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia was given for 1, 4, or
24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at
3 mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when admin-
istered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular
necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second study,
slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional find-
ings included elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation
at ≥1 mg/kg after each infusion time.
Aredia was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg
as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery period. In rats, nephrotoxici-
ty was observed at ≥6 mg/kg and included increased BUN and creatinine levels and tubular degeneration
and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs,
moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and cre-
atinine levels at ≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially
reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects was consid-
ered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).
PREGNANCY: AREDIA SHOULD NOT BE USED DURING PREGNANCY
Aredia may cause fetal harm when administered to a pregnant woman. (See PRECAUTIONS, Pregnancy
Category D.)
There are no studies in pregnant women using Aredia. If the patient becomes pregnant while taking
this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing poten-
tial should be advised to avoid becoming pregnant.
Studies conducted in young rats have reported the disruption of dental dentine formation following
single- and multi-dose administration of bisphosphonates. The clinical significance of these findings is
unknown.
PRECAUTIONS
General
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, mag-
nesium, and potassium, should be carefully monitored following initiation of therapy with Aredia. Cases of
asymptomatic hypophosphatemia (12%), hypokalemia (7%), hypomagnesemia (11%), and hypocalcemia
(5%-12%), were reported in Aredia-treated patients. Rare cases of symptomatic hypocalcemia (including
tetany) have been reported in association with Aredia therapy. If hypocalcemia occurs, short-term calcium
therapy may be necessary. In Paget’s disease of bone, 17% of patients treated with 90 mg of Aredia
showed serum calcium levels below 8 mg/dL.
Renal Insufficiency
Aredia is excreted intact primarily via the kidney, and the risk of renal adverse reactions may be greater in
patients with impaired renal function. Patients who receive Aredia should have serum creatinine assessed
prior to each treatment. In patients receiving Aredia for bone metastases, who show evidence of deteriora-
tion in renal function, Aredia treatment should be withheld until renal function returns to baseline (see
WARNINGS and DOSAGE AND ADMINISTRATION).
Aredia has not been tested in patients who have class Dc renal impairment (creatinine >5.0 mg/dL),
and has been tested in few multiple myeloma patients with serum creatinine ≥3.0 mg/dL. (See also
CLINICAL PHARMACOLOGY, Pharmacokinetics.) For the treatment of bone metastases, the use of
Aredia in patients with severe renal impairment is not recommended. In other indications, clinical judgment
should determine whether the potential benefit outweighs the potential risk in such patients.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment regimens
including bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids.
The majority of reported cases have been associated with dental procedures such as tooth extraction.
Many had signs of local infection including osteomyelitis.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with
bisphosphonates in patients with concomitant risk factors (e.g., cancer, chemotherapy, corticosteroids,
poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients
who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For
patients requiring dental procedures, there are no data available to suggest whether discontinuation of bis-
phosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide
the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle
pain has been reported in patients taking bisphosphonates. However, such reports have been
infrequent. This category of drugs includes Aredia (pamidronate disodium for injection). The time
to onset of symptoms varied from one day to several months after starting the drug. Most patients
had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged
with the same drug or another bisphosphonate.
Laboratory Tests
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Serum calci-
um, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin must be close-
ly monitored in patients treated with Aredia. Patients who have preexisting anemia, leukopenia, or throm-
bocytopenia should be monitored carefully in the first 2 weeks following treatment.
Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of Aredia.
Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study (daily oral administration) in rats, there was a positive dose response
relationship for benign adrenal pheochromocytoma in males (P<0.00001). Although this condition was also
observed in females, the incidence was not statistically significant. When the dose calculations were adjust-
ed to account for the limited oral bioavailability of Aredia in rats, the lowest daily dose associated with adre-
nal pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma was also
observed in low numbers in the control animals and is considered a relatively common spontaneous neo-
plasm in the rat. Aredia (daily oral administration) was not carcinogenic in an 80-week study in mice.
Aredia was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and Escherichia/ liver-
microsome test, nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test, and micronu-
cleus test in the rat.
In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg
of Aredia orally; however, this occurred only when animals were mated with members of the same dose
group. Aredia has not been administered intravenously in such a study.
-20
0
50
0
100
150
20
40
60
80
100
120
140
160
Pamidronate Renal CL vs CLcr
Renal CL (mL/min)
CLcr (mL/min)
Observed
Predicted
Lower 95% CI
Upper 95% CI
• 5H2O
PO3HNa
NH2 - CH2 - CH2 - C - OH
PO3HNa
©Novartis
T2005-27
Aredia®
pamidronate disodium for injection
Aredia®
pamidronate disodium for injection
Description: Aredia
Rev. Date: April 2005
Number of Colors: 1
Black
Material Group No.:
• USLFLTH
• USLFLTI
•
Dimensions: 17 x 15
Do Not Print Dotted Lines FPO - For Position Only
LD&C: ___________________________ Date: ______________
LD&C: ___________________________ Date: ______________
Engineer: ___________________
________ Date: ______________
Component No.:
•
5000347
•
5000348
•
T2005-27
Supersedes Component No.:
•
5000083
•
5000084
•
T2004-70
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy Category D (See WARNINGS)
There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia produces maternal tox-
icity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest
recommended human dose for a single intravenous infusion. As it has been shown that Aredia can cross
the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats
and rabbits, it should not be given to women during pregnancy.
Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over
periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the
amount available for release back into the systemic circulation, is directly related to the total dose and
duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do
cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is
greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other
abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The
impact of variables such as time between cessation of bisphosphonate therapy to conception, the particu-
lar bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not
been established.
Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when Aredia is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Aredia in pediatric patients have not been established.
ADVERSE REACTIONS
Clinical Studies
Hypercalcemia of Malignancy
Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of
Aredia in 34% of patients in clinical trials. In the saline trial, 18% of patients had a temperature elevation
of at least 1°C 24 to 48 hours after treatment.
Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the
site of catheter insertion were most common in patients treated with 90 mg of Aredia. Symptomatic treat-
ment resulted in rapid resolution in all patients.
Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleri-
tis, and one case of uveitis upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the four U.S. controlled hypercalcemia clinical
studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the
seizures were considered to be drug-related by the investigators. However, a possible relationship
between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline
arm 1 patient (4%) had a seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90-mg Aredia over 24 hours
to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate
clinical trials suggests that the overall safety profile in patients who received 90-mg Aredia over 24 hours
is similar to those who received 90-mg Aredia over 2 hours. The only notable differences observed were an
increase in the proportion of patients in the Aredia 24-hour group who experienced fluid overload and elec-
trolyte/mineral abnormalities.
At least 15% of patients treated with Aredia for hypercalcemia of malignancy also experienced the fol-
lowing adverse events during a clinical trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting
Genitourinary: Urinary tract infection
Musculoskeletal: Bone pain
Laboratory Abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia
Many of these adverse experiences may have been related to the underlying disease state. The follow-
ing table lists the adverse experiences considered to be treatment-related during comparative, controlled
U.S. trials.
Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials
Percent of Patients
Etidronate
Aredia®
Disodium
Saline
60 mg
60 mg
90 mg
7.5 mg/kg
over 4 hr
over 24 hr
over 24 hr
x 3 days
n=23
n=73
n=17
n=35
n=23
General
Edema
0
1
0
0
0
Fatigue
0
0
12
0
0
Fever
26
19
18
9
0
Fluid overload
0
0
0
6
0
Infusion-site reaction
0
4
18
0
0
Moniliasis
0
0
6
0
0
Rigors
0
0
0
0
4
Gastrointestinal
Abdominal pain
0
1
0
0
0
Anorexia
4
1
12
0
0
Constipation
4
0
6
3
0
Diarrhea
0
1
0
0
0
Dyspepsia
4
0
0
0
0
Gastrointestinal
hemorrhage
0
0
6
0
0
Nausea
4
0
18
6
0
Stomatitis
0
1
0
3
0
Vomiting
4
0
0
0
0
Respiratory
Dyspnea
0
0
0
3
0
Rales
0
0
6
0
0
Rhinitis
0
0
6
0
0
Upper respiratory
infection
0
3
0
0
0
CNS
Anxiety
0
0
0
0
4
Convulsions
0
0
0
3
0
Insomnia
0
1
0
0
0
Nervousness
0
0
0
0
4
Psychosis
4
0
0
0
0
Somnolence
0
1
6
0
0
Taste perversion
0
0
0
3
0
Cardiovascular
Atrial fibrillation
0
0
6
0
4
Atrial flutter
0
1
0
0
0
Cardiac failure
0
1
0
0
0
Hypertension
0
0
6
0
4
Syncope
0
0
6
0
0
Tachycardia
0
0
6
0
4
Endocrine
Hypothyroidism
0
0
6
0
0
Hemic and Lymphatic
Anemia
0
0
6
0
0
Leukopenia
4
0
0
0
0
Neutropenia
0
1
0
0
0
Thrombocytopenia
0
1
0
0
0
Musculoskeletal
Myalgia
0
1
0
0
0
Urogenital
Uremia
4
0
0
0
0
Laboratory Abnormalities
Hypocalcemia
0
1
12
0
0
Hypokalemia
4
4
18
0
0
Hypomagnesemia
4
10
12
3
4
Hypophosphatemia
0
9
18
3
0
Abnormal liver
function
0
0
0
3
0
Paget’s Disease
Transient mild elevation of temperature >1°C above pretreatment baseline was noted within 48 hours after
completion of treatment in 21% of the patients treated with 90 mg of Aredia in clinical trials.
Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia,
increased sweating) were more common in patients with Paget’s disease treated with 90 mg of Aredia
than in patients with hypercalcemia of malignancy treated with the same dose.
Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients
with Paget’s disease treated with 90 mg of Aredia in two U.S. clinical trials, were fever, nausea, back pain,
and bone pain.
At least 10% of all Aredia-treated patients with Paget’s disease also experienced the following adverse
experiences during clinical trials:
Cardiovascular: Hypertension
Musculoskeletal: Arthrosis, bone pain
Nervous system: Headache
Most of these adverse experiences may have been related to the underlying disease state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
The most commonly reported (>15%) adverse experiences occurred with similar frequencies in the
Aredia- and placebo-treatment groups, and most of these adverse experiences may have been related to
the underlying disease state or cancer therapy.
Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
Aredia®
Aredia®
All
90 mg
90 mg
Aredia®
over 4 hours
Placebo
over 2 hours
Placebo
90 mg
Placebo
N=205
N=187
N=367
N=386
N=572
N=573
%
%
%
%
%
%
General
Asthenia
16.1
17.1
25.6
19.2
22.2
18.5
Fatigue
31.7
28.3
40.3
28.8
37.2
29.0
Fever
38.5
38.0
38.1
32.1
38.5
34.0
Metastases
1.0
3.0
31.3
24.4
20.5
17.5
Pain
13.2
11.8
15.0
18.1
14.3
16.1
Digestive System
Anorexia
17.1
17.1
31.1
24.9
26.0
22.3
Constipation
28.3
31.7
36.0
38.6
33.2
35.1
Diarrhea
26.8
26.8
29.4
30.6
28.5
29.7
Dyspepsia
17.6
13.4
18.3
15.0
22.6
17.5
Nausea
35.6
37.4
63.5
59.1
53.5
51.8
Pain Abdominal
19.5
16.0
24.3
18.1
22.6
17.5
Vomiting
16.6
19.8
46.3
39.1
35.7
32.8
Hemic and Lymphatic
Anemia
47.8
41.7
39.5
36.8
42.5
38.4
Granulocytopenia
20.5
15.5
19.3
20.5
19.8
18.8
Thrombocytopenia
16.6
17.1
12.5
14.0
14.0
15.0
Musculoskeletal System
Arthralgias
10.7
7.0
15.3
12.7
13.6
10.8
Myalgia
25.4
15.0
26.4
22.5
26.0
20.1
Skeletal Pain
61.0
71.7
70.0
75.4
66.8
74.0
CNS
Anxiety
7.8
9.1
18.0
16.8
14.3
14.3
Headache
24.4
19.8
27.2
23.6
26.2
22.3
Insomnia
17.1
17.2
25.1
19.4
22.2
19.0
Respiratory System
Coughing
26.3
22.5
25.3
19.7
25.7
20.6
Dyspnea
22.0
21.4
35.1
24.4
30.4
23.4
Pleural Effusion
2.9
4.3
15.0
9.1
10.7
7.5
Sinusitis
14.6
16.6
16.1
10.4
15.6
12.0
Upper Respiratory Tract
Infection
32.2
28.3
19.6
20.2
24.1
22.9
Urogenital System
Urinary Tract Infection
15.6
9.1
20.2
17.6
18.5
15.6
Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and
anemia were slightly more common in the Aredia patients whereas stomatitis and alopecia occurred at a
frequency similar to that in placebo patients. In the breast cancer trials, mild elevations of serum creati-
nine occurred in 18.5% of Aredia patients and 12.3% of placebo patients. Mineral and electrolyte distur-
bances, including hypocalcemia, were reported rarely and in similar percentages of Aredia-treated patients
compared with those in the placebo group. The reported frequencies of hypocalcemia, hypokalemia,
hypophosphatemia, and hypomagnesemia for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%,
respectively, and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively. In previous
hypercalcemia of malignancy trials, patients treated with Aredia (60 or 90 mg over 24 hours) developed
electrolyte abnormalities more frequently (see ADVERSE REACTIONS, Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the Aredia group than in the placebo
group (13.6% and 26% vs 10.8% and 20.1%, respectively).
In multiple myeloma patients, there were five Aredia-related serious and unexpected adverse experi-
ences. Four of these were reported during the 12-month extension of the multiple myeloma trial. Three of
the reports were of worsening renal function developing in patients with progressive multiple myeloma or
multiple myeloma-associated amyloidosis. The fourth report was the adult respiratory distress syndrome
developing in a patient recovering from pneumonia and acute gangrenous cholecystitis. One Aredia-treated
patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy
throat within 24 hours after the sixth infusion.
In the breast cancer trials, there were four Aredia-related adverse experiences, all moderate in severity,
that caused a patient to discontinue participation in the trial. One was due to interstitial pneumonitis,
another to malaise and dyspnea. One Aredia patient discontinued the trial due to a symptomatic hypocal-
cemia. Another Aredia patient discontinued therapy due to severe bone pain after each infusion, which the
investigator felt was trial-drug-related.
Renal Toxicity
In a study of the safety and efficacy of Aredia 90 mg (2-hour infusion) versus Zometa 4 mg (15-minute
infusion) in bone metastases patients with multiple myeloma or breast cancer, renal deterioration was
defined as an increase in serum creatinine of 0.5 mg/dL for patients with normal baseline creatinine
(<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL).
The following are data on the incidence of renal deterioration in patients in this trial. See Table below.
Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer Patients with
Normal and Abnormal Serum Creatinine at Baseline*
Patient Population/Baseline Creatinine
Aredia® 90 mg/2 hours
Zometa® 4 mg/15 minutes
n/N
(%)
n/N
(%)
Normal
20/246
(8.1%)
23/246
(9.3%)
Abnormal
2/22
(9.1%)
1/26
(3.8%)
Total
22/268
(8.2%)
24/272
(8.8%)
*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.
Post-Marketing Experience
Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema,
and, very rarely, anaphylactic shock. Aredia is contraindicated in patients with clinically significant hypersensi-
tivity to Aredia or other bisphosphonates (see CONTRAINDICATIONS).
Cases of osteonecrosis (primarily of the jaws) have been reported since market introduction.
Osteonecrosis of the jaws has other well documented multiple risk factors. It is not possible to determine if
these events are related to Aredia or other bisphosphonates, to concomitant drugs or other therapies
(e.g., chemotherapy, radiotherapy, corticosteroid), to patient’s underlying disease, or to other comorbid risk
factors (e.g., anemia, infection, preexisting oral disease). (See PRECAUTIONS.)
OVERDOSAGE
There have been several cases of drug maladministration of intravenous Aredia in hypercalcemia patients
with total doses of 225 mg to 300 mg given over 2 1/2 to 4 days. All of these patients survived, but they
experienced hypocalcemia that required intravenous and/or oral administration of calcium. Single doses
of Aredia should not exceed 90 mg and the duration of the intravenous infusion should be no less
than 2 hours. (See WARNINGS.)
In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for 3 days experi-
enced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perver-
sion, noted about 6 hours after the first infusion. The fever and hypotension were rapidly corrected with
steroids.
If overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated
with short-term intravenous calcium.
DOSAGE AND ADMINISTRATION
Hypercalcemia of Malignancy
Consideration should be given to the severity of as well as the symptoms of hypercalcemia. Vigorous
saline hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia. Overhydration
should be avoided in patients who have potential for cardiac failure. In hypercalcemia associated with
hematologic malignancies, the use of glucocorticoid therapy may be helpful.
Moderate Hypercalcemia
The recommended dose of Aredia in moderate hypercalcemia (corrected serum calcium* of
approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over 2
to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in
patients with preexisting renal insufficiency.
Severe Hypercalcemia
The recommended dose of Aredia in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL)
is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e.,
>2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insuf-
ficiency.
*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).
Retreatment
A limited number of patients have received more than one treatment with Aredia for hypercalcemia.
Retreatment with Aredia, in patients who show complete or partial response initially, may be carried out if
serum calcium does not return to normal or remain normal after initial treatment. It is recommended that
a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. The
dose and manner of retreatment is identical to that of the initial therapy.
Paget’s Disease
The recommended dose of Aredia in patients with moderate to severe Paget’s disease of bone is
30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.
Retreatment
A limited number of patients with Paget’s disease have received more than one treatment of Aredia in
clinical trials. When clinically indicated, patients should be retreated at the dose of initial therapy.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of Aredia in patients with osteolytic bone lesions of multiple myeloma is
90 mg administered as a 4-hour infusion given on a monthly basis.
Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration
prior to Aredia infusion.
Limited information is available on the use of Aredia in multiple myeloma patients with a serum creati-
nine ≥3.0 mg/dL.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment
should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned to within 10% of
the baseline value.
The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final
analysis after 21 months demonstrated overall benefits (see CLINICAL TRIALS section).
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg adminis-
tered over a 2-hour infusion given every 3-4 weeks.
Aredia has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate,
mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen.
It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment
should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned to within 10% of
the baseline value.
The optimal duration of therapy is not known, however, in two breast cancer studies, final analyses
performed after 24 months of therapy demonstrated overall benefits (see CLINICAL TRIALS section).
Preparation of Solution
Reconstitution
Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial, resulting in a
solution of 30 mg/10 mL or 90 mg/10 mL. The pH of the reconstituted solution is 6.0-7.4. The drug should
be completely dissolved before the solution is withdrawn.
Method of Administration
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH
MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA SHOULD NOT EXCEED 90 MG.
(SEE WARNINGS.)
There must be strict adherence to the intravenous administration recommendations for Aredia in order
to decrease the risk of deterioration in renal function.
Hypercalcemia of Malignancy
The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60-mg
and 90-mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium
Chloride, USP, or 5% Dextrose Injection, USP. This infusion solution is stable for up to 24 hours at room
temperature.
Paget’s Disease
The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium
Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period for 3 consecutive
days.
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% Sodium Chloride,
USP, or 5% Dextrose Injection, USP, and administered over a 2-hour period every 3-4 weeks.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride,
USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period on a monthly basis.
Aredia must not be mixed with calcium-containing infusion solutions, such as Ringer’s solu-
tion, and should be given in a single intravenous solution and line separate from all other drugs.
Note: Parenteral drug products should be inspected visually for particulate matter and discol-
oration prior to administration, whenever solution and container permit.
Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration at
2°C-8°C (36°F-46°F) for up to 24 hours.
HOW SUPPLIED
Vials - 30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and 470 mg of
mannitol, USP.
Carton of 4 vials.....................................................................................NDC 0083-2601-04
Vials - 90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and 375 mg of
mannitol, USP.
Carton of 1 vial.......................................................................................NDC 0083-2609-01
Do not store above 30°C (86°F).
T2005-27
REV: APRIL 2005 Printed in U.S.A.
5000347
5000348
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Aredia® pamidronate disodium for injection
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:31.217655
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020036s031lbl.pdf', 'application_number': 20036, 'submission_type': 'SUPPL ', 'submission_number': 31}
|
12,152
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T2001-xx
xxxxxxxx
Aredia
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor available in 30-mg or 90-mg vials for
intravenous administration. Each 30-mg, and 90-mg vial contains, respectively, 30 mg and 90 mg of sterile,
lyophilized pamidronate disodium and 470 mg and 375 mg of mannitol, USP. The pH of a 1% solution of
pamidronate disodium in distilled water is approximately 8.3. Aredia, a member of the group of chemical
compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated
chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD),
and its structural formula is
Pamidronate disodium is a white-to-practically-white powder. It is soluble in water and in 2N sodium
hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in
organic solvents. Its molecular formula is C3H9NO7P2Na2•5H2O and its molecular weight is 369.1.
Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5 prior to
lyophilization).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the mechanism of
antiresorptive action is not completely understood, several factors are thought to contribute to this action.
Aredia adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution of
this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity
contributes to inhibition of bone resorption. In animal studies, at doses recommended for the treatment of
hypercalcemia, Aredia inhibits bone resorption apparently without inhibiting bone formation and
mineralization. Of relevance to the treatment of hypercalcemia of malignancy is the finding that Aredia
inhibits the accelerated bone resorption that results from osteoclast hyperactivity induced by various tumors
in animal studies.
Pharmacokinetics
Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous infusion of 30,
60, or 90 mg of Aredia over 4 hours and 90 mg of Aredia over 24 hours (Table 1).
Distribution
The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose over 120 hours.
Metabolism
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Excretion
After administration of 30, 60, and 90 mg of Aredia over 4 hours, and 90 mg of Aredia over 24 hours, an
overall mean ± SD of 46 ± 16% of the drug was excreted unchanged in the urine within 120 hours.
Cumulative urinary excretion was linearly related to dose. The mean ± SD elimination half-life is 28 ± 7
hours. Mean ± SD total and renal clearances of pamidronate were 107 ± 50 mL/min and 49 ± 28 mL/min,
respectively. The rate of elimination from bone has not been determined.
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.
Pediatric
Pamidronate is not labeled for use in the pediatric population.
Renal Insufficiency
The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying
degrees of renal impairment. Each patient received a single 90-mg dose of Aredia infused over 4 hours.
The renal clearance of pamidronate in patients was found to closely correlate with creatinine clearance (see
Figure 1). A trend toward a lower percentage of drug excreted unchanged in urine was observed in renally
impaired patients. Adverse experiences noted were not found to be related to changes in renal clearance of
pamidronate. Given the recommended dose, 90 mg infused over 4 hours, excessive accumulation of
pamidronate in renally impaired patients is not anticipated if Aredia is administered on a monthly basis.
Figure 1: Pamidronate renal clearance as a function of creatinine clearance in patients
with normal and impaired renal function.
The lines are the mean prediction line and 95% confidence intervals.
Hepatic Insufficiency
There are no human pharmacokinetic data for Aredia in patients who have hepatic insufficiency.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Table 1
Mean (SD, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients
(n=6 for each group)
Maximum
Percent
Total
Renal
Dose
Concentration
of dose
Clearance
Clearance
(infusion rate)
(µg/mL)
excreted in urine
(mL/min)
(mL/min)
30 mg
0.73
43.9
136
58
(4 hrs)
(0.14, 19.1%)
(14.0, 31.9%)
(44, 32.4%)
(27, 46.5%)
60 mg
1.44
47.4
88
42
(4 hrs)
(0.57, 39.6%)
(47.4, 54.4%)
(56, 63.6%)
(28, 66.7%)
90 mg
2.61
45.3
103
44
(4 hrs)
(0.74, 28.3%)
(25.8, 56.9%)
(37, 35.9%)
(16, 36.4%)
90 mg
1.38
47.5
101
52
(24 hrs)
(1.97, 142.7%)
(10.2, 21.5%)
(58, 57.4%)
(42, 80.8%)
After intravenous administration of radiolabeled pamidronate in rats, approximately 50%-60% of the
compound was rapidly adsorbed by bone and slowly eliminated from the body by the kidneys. In rats given
10 mg/kg bolus injections of radiolabeled Aredia, approximately 30% of the compound was found in the
liver shortly after administration and was then redistributed to bone or eliminated by the kidneys over 24-48
hours. Studies in rats injected with radiolabeled Aredia showed that the compound was rapidly cleared
from the circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage. Radioactivity
was eliminated from most soft tissues within 1-4 days; was detectable in liver and spleen for 1 and 3
months, respectively; and remained high in bones, trachea, and teeth for 6 months after dosing. Bone
uptake occurred preferentially in areas of high bone turnover. The terminal phase of elimination half-life in
bone was estimated to be approximately 300 days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia, presumably because of
decreased release of phosphate from bone and increased renal excretion as parathyroid hormone levels,
which are usually suppressed in hypercalcemia associated with malignancy, return toward normal.
Phosphate therapy was administered in 30% of the patients in response to a decrease in serum phosphate
levels. Phosphate levels usually returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to
within or below normal after treatment with Aredia. These changes occur within the first week after
treatment, as do decreases in serum calcium levels, and are consistent with an antiresorptive pharmacologic
action.
Hypercalcemia of Malignancy
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic
derangement in metastatic bone disease and hypercalcemia of malignancy. Excessive release of calcium
into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive
dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of
calcium, setting up a cycle of worsening systemic hypercalcemia. Correction of excessive bone resorption
and adequate fluid administration to correct volume deficits are therefore essential to the management of
hypercalcemia.
Most cases of hypercalcemia associated with malignancy occur in patients who have breast cancer;
squamous-cell tumors of the lung or head and neck; renal-cell carcinoma; and certain hematologic
malignancies, such as multiple myeloma and some types of lymphomas. A few less-common malignancies,
including vasoactive intestinal-peptide-producing tumors and cholangiocarcinoma, have a high incidence of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
hypercalcemia as a metabolic complication. Patients who have hypercalcemia of malignancy can generally
be divided into two groups, according to the pathophysiologic mechanism involved.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as
parathyroid-hormone-related protein, which are elaborated by the tumor and circulate systemically.
Humoral hypercalcemia usually occurs in squamous-cell malignancies of the lung or head and neck or in
genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal metastases may be absent or
minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that
stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated
hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity
of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium
levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly
or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for
differences in albumin levels is often used in place of measurement of ionized calcium; several nomograms
are in use for this type of calculation (see DOSAGE AND ADMINISTRATION).
Clinical Trials
In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were enrolled to
receive 30 mg, 60 mg, or 90 mg of Aredia as a single 24-hour intravenous infusion if their corrected serum
calcium levels were ≥12.0 mg/dL after 48 hours of saline hydration.
The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups were 13.8 mg/dL,
13.8 mg/dL, and 13.3 mg/dL, respectively.
The majority of patients (64%) had decreases in albumin-corrected serum calcium levels by 24 hours after
initiation of treatment. Mean-corrected serum calcium levels at days 2-7 after initiation of treatment with
Aredia were significantly reduced from baseline in all three dosage groups. As a result, by 7 days after
initiation of treatment with Aredia, 40%, 61%, and 100% of the patients receiving 30 mg, 60 mg, and 90 mg
of Aredia, respectively, had normal-corrected serum calcium levels. Many patients (33%-53%) in the 60-
mg and 90-mg dosage groups continued to have normal-corrected serum calcium levels, or a partial
response (≥15% decrease of corrected serum calcium from baseline), at day 14.
In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium
levels of ≥12.0 mg/dL after at least 24 hours of saline hydration were randomized to receive either 60 mg of
Aredia as a single 24-hour intravenous infusion or 7.5 mg/kg of Didronel (etidronate disodium) as a 2-hour
intravenous infusion daily for 3 days. Thirty patients were randomized to receive Aredia and 35 to receive
Didronel.
The mean baseline-corrected serum calcium for the Aredia 60-mg and Didronel groups were 14.6 mg/dL
and 13.8 mg/dL, respectively.
By day 7, 70% of the patients in the Aredia group and 41% of the patients in the Didronel group had
normal-corrected serum calcium levels (P<0.05). When partial responders (≥15% decrease of serum
calcium from baseline) were also included, the response rates were 97% for the Aredia group and 65% for
the Didronel group (P<0.01). Mean-corrected serum calcium for the Aredia and Didronel groups decreased
from baseline values to 10.4 and 11.2 mg/dL, respectively, on day 7. At day 14, 43% of patients in the
Aredia group and 18% of patients in the Didronel group still had normal-corrected serum calcium levels, or
maintenance of a partial response. For responders in the Aredia and Didronel groups, the median duration
of response was similar (7 and 5 days, respectively). The time course of effect on corrected serum calcium
is summarized in the following table.
Change in Corrected Serum Calcium by Time
from Initiation of Treatment
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Time
Mean Change from Baseline in Corrected Serum
(hr)
Calcium (mg/dL)
Aredia Didronel
P-Value1
Baseline 14.6
13.8
24
-0.3
-0.5
48
-1.5
-1.1
72
-2.6
-2.0
96
-3.5
-2.0
<0.01
168
-4.1
-2.5
<0.01
1 Comparison between treatment groups
In a third multicenter, randomized, parallel double-blind trial, a group of 69 cancer patients with
hypercalcemia was enrolled to receive 60 mg of Aredia as a 4- or 24-hour infusion, which was compared to
a saline treatment group. Patients who had a corrected serum calcium level of ≥12.0 mg/dL after 24 hours
of saline hydration were eligible for this trial.
The mean baseline-corrected serum calcium levels for Aredia 60-mg 4-hour infusion, Aredia 60-mg 24-hour
infusion, and saline infusion were 14.2 mg/dL, 13.7 mg/dL, and 13.7 mg/dL, respectively.
By day 7 after initiation of treatment, 78%, 61%, and 22% of the patients had normal-corrected serum
calcium levels for the 60-mg 4-hour infusion, 60-mg 24-hour infusion, and saline infusion, respectively. At
day 14, 39% of the patients in the Aredia 60-mg 4-hour infusion group and 26% of the patients in the
Aredia 60-mg 24-hour infusion group had normal-corrected serum calcium levels or maintenance of a
partial response.
For responders, the median duration of complete responses was 4 days and 6.5 days for Aredia 60-mg 4-
hour infusion and Aredia 60-mg 24-hour infusion, respectively.
In all three trials, patients treated with Aredia had similar response rates in the presence or absence of bone
metastases. Concomitant administration of furosemide did not affect response rates.
Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were given a second
course of 60 mg of Aredia over a 4- or 24-hour period. Of these, 41% showed a complete response and
16% showed a partial response to the retreatment, and these responders had about a 3-mg/dL fall in mean-
corrected serum calcium levels 7 days after retreatment.
In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia
(corrected serum calcium > 12.0 mg/dl) received 90 mg of Aredia as a 2-hour infusion. The mean baseline
corrected serum calcium was 14.0 mg/dl. Patients were not required to receive IV hydration prior to drug
administration, but all subjects did receive at least 500 ml of IV saline hydration concomitantly with the
pamidronate infusion. By day 10 after drug infusion, 70% of patients had normal corrected serum calcium
levels (< 10.8 mg/dl).
Paget's Disease
Paget's disease of bone (osteitis deformans) is an idiopathic disease characterized by chronic, focal areas of
bone destruction complicated by concurrent excessive bone repair, affecting one or more bones. These
changes result in thickened but weakened bones that may fracture or bend under stress. Signs and
symptoms may be bone pain, deformity, fractures, neurological disorders resulting from cranial and spinal
nerve entrapment and from spinal cord and brain stem compression, increased cardiac output to the
involved bone, increased serum alkaline phosphatase levels (reflecting increased bone formation) and/or
urine hydroxyproline excretion (reflecting increased bone resorption).
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Clinical Trials
In one double-blind clinical trial, 64 patients with moderate to severe Paget's disease of bone were enrolled
to receive 5 mg, 15 mg, or 30 mg of Aredia as a single 4-hour infusion on 3 consecutive days, for total
doses of 15 mg, 45 mg, and 90 mg of Aredia.
The mean baseline serum alkaline phosphatase levels were 1409 U/L, 983 U/L, and 1085 U/L, and the
mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and 0.19 for the 15-mg, 45-mg, and
90-mg groups, respectively.
The effects of Aredia on serum alkaline phosphatase (SAP) and urine hydroxy-proline/creatinine ratios
(UOHP/C) are summarized in the following table:
Percent of Patients With
Significant % Decreases in SAP and UOHP/C
SAP
UOHP/C
% Decrease
15 mg
45 mg
90 mg
15 mg
45 mg
90 mg
≥50
26
33
60
15
47
72
≥30
40
65
83
35
57
85
The median maximum percent decreases from baseline in serum alkaline phosphatase and urine
hydroxyproline/creatinine ratios were 25%, 41%, and 57%, and 25%, 47%, and 61% for the 15-mg, 45-mg,
and 90-mg groups, respectively. The median time to response (≥50% decrease) for serum alkaline
phosphatase was approximately 1 month for the 90-mg group, and the response duration ranged from 1 to
372 days.
No statistically significant differences between treatment groups, or statistically significant changes from
baseline were observed for the bone pain response, mobility, and global evaluation in the 45-mg and 90-mg
groups. Improvement in radiologic lesions occurred in some patients in the 90-mg group.
Twenty-five patients who had Paget's disease were retreated with 90 mg of Aredia. Of these, 44% had a
≥50% decrease in serum alkaline phosphatase from baseline after treatment, and 39% had a ≥50% decrease
in urine hydroxyproline/creatinine ratio from baseline after treatment.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast cancer. These
cancers demonstrate a phenomenon known as osteotropism, meaning they possess an extraordinary affinity
for bone. The distribution of osteolytic bone metastases in these cancers is predominantly in the axial
skeleton, particularly the spine, pelvis, and ribs, rather than the appendicular skeleton, although lesions in
the proximal femur and humerus are not uncommon. This distribution is similar to the red bone marrow in
which slow blood flow possibly assists attachment of metastatic cells. The surface-to-volume ratio of
trabecular bone is much higher than cortical bone, and therefore disease processes tend to occur more
floridly in trabecular bone than at sites of cortical tissue.
These bone changes can result in patients having evidence of osteolytic skeletal destruction leading to
severe bone pain that requires either radiation therapy or narcotic analgesics (or both) for symptomatic
relief. These changes also cause pathologic fractures of bone in both the axial and appendicular skeleton.
Axial skeletal fractures of the vertebral bodies may lead to spinal cord compression or vertebral body
collapse with significant neurologic complications. Also, patients may experience episode(s) of
hypercalcemia.
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7
Clinical Trials
In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple myeloma were
enrolled to receive Aredia or placebo in addition to their underlying antimyeloma therapy to determine the
effect of Aredia on the occurrence of skeletal-related events (SREs). SREs were defined as episodes of
pathologic fractures, radiation therapy to bone, surgery to bone, and spinal cord compression. Patients
received either 90 mg of Aredia or placebo as a monthly 4-hour intravenous infusion for 9 months. Of the
392 patients, 377 were evaluable for efficacy (196 Aredia, 181 placebo). The proportion of patients
developing any SRE was significantly smaller in the Aredia group (24% vs 41%, P<0.001), and the mean
skeletal morbidity rate (#SRE/year) was significantly smaller for Aredia patients than for placebo patients
(mean: 1.1 vs 2.1, P<.02). The times to the first SRE occurrence, pathologic fracture, and radiation to bone
were significantly longer in the Aredia group (P=.001, .006, and .046, respectively). Moreover, fewer
Aredia patients suffered any pathologic fracture (17% vs 30%, P=.004) or needed radiation to bone (14% vs
22%, P=.049).
In addition, decreases in pain scores from baseline occurred at the last measurement for those Aredia
patients with pain at baseline (P=.026) but not in the placebo group. At the last measurement, a worsening
from baseline was observed in the placebo group for the Spitzer quality of life variable (P<.001) and ECOG
performance status (P<.011) while there was no significant deterioration from baseline in these parameters
observed in Aredia-treated patients.*
After 21 months, the proportion of patients experiencing any skeletal event remained significantly smaller in
the Aredia group than the placebo group (P=.015). In addition, the mean skeletal morbidity rate
(#SRE/year) was 1.3 vs 2.2 for Aredia patients vs placebo patients (P=.008), and time to first SRE was
significantly longer in the Aredia group compared to placebo (P=.016). Fewer Aredia patients suffered
vertebral pathologic fractures (16% vs 27%, P=.005). Survival of all patients was not different between
treatment groups.
Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of 90 mg of
Aredia infused over 2 hours every 3 to 4 weeks for 24 months to that of placebo in preventing SREs in
breast cancer patients with osteolytic bone metastases who had one or more predominantly lytic metastases
of at least 1 cm in diameter: one in patients being treated with antineoplastic chemotherapy and the second
in patients being treated with hormonal antineoplastic therapy at trial entry.
382 patients receiving chemotherapy were randomized, 185 to Aredia and 197 to placebo. 372 patients
receiving hormonal therapy were randomized, 182 to Aredia and 190 to placebo. All but three patients
were evaluable for efficacy. Patients were followed for 24 months of therapy or until patients went off
study. Median duration of follow-up was 13 months in patients receiving chemotherapy and 17 months in
patients receiving hormone therapy. Twenty five percent of the patients in the chemotherapy study and
37% of the patients in the hormone therapy study received Aredia for 24 months. The efficacy results are
shown in the table below:
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8
Breast Cancer Patients
Receiving Chemotherapy
Breast Cancer Patients
Receiving Hormonal Therapy
Any SRE
Radiation
Fractures
Any SRE
Radiation
Fractures
A
P
A
P
A
P
A
P
A
P
A
P
N
18
5
195
185
195
185
195
182
189
182
189
182
189
Skeletal
Morbidity Rate
(#SRE/Year)
Mean
2.5
3.7
0.8
1.3
1.6
2.2
2.4
3.6
0.6
1.2
1.6
2.2
P-Value
<.001
< .001†
.018†
.021
.013†
.040†
Proportion of
Patients
having
an SRE
46
%
65%
28
%
45
%
36
%
49
%
55
%
63
%
31%
40
%
45
%
55
%
P-Value
<.001
< .001†
.014†
.094
.058†
.054†
Median Time
to
SRE (months)
13.
9
7.0
NR*
*
14.2
25.
8
13.
3
10.
9
7.4
NR**
23.
4
20.
6
12.
8
P-Value
< .001
< .001†
.009†
.118
.016†
.113†
†Fractures and radiation to bone were two of several secondary endpoints. The statistical
significance of these analyses may be overestimated since numerous analyses were performed.
**NR = Not Reached
Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12 months. The complete
+ partial response rate was 33% in Aredia patients and 18% in placebo patients treated with chemotherapy
(P=.001). No difference was seen between Aredia and placebo in hormonally-treated patients.
Pain and analgesic scores, ECOG performance status and Spitzer quality of life index were measured at
baseline and periodically during the trials. The changes from baseline to the last measurement carried
forward are shown in the table below:
Mean Change (∆∆∆∆) from Baseline at Last Measurement
Breast Cancer Patients
Receiving Chemotherapy
Breast Cancer Patients
Receiving Hormonal Therapy
Aredia
Placebo
A vs P
Aredia
Placebo
A vs P
N
Mean∆
N
Mean∆
P-Value*
N
Mean∆
N
Mean∆
P-
Value*
Pain Score
175
+0.93
18
3
+1.69
.050
17
3
+0.50
17
9
+1.60
.007
Analgesic
Score
175
+0.74
18
3
+1.55
.009
17
3
+0.90
17
9
+2.28
< .001
ECOG PS
178
+0.81
18
6
+1.19
.002
17
5
+0.95
18
2
+0.90
.773
Spitzer QOL
177
-1.76
18
-2.21
.103
17
-1.86
18
-2.05
.409
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9
5
3
1
Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an
improvement from baseline.
*The statistical significance of analyses of these secondary endpoints of pain, quality of life, and
performance status in all three trials may be overestimated since numerous analyses were
performed.
INDICATIONS AND USAGE
Hypercalcemia of Malignancy
Aredia, in conjunction with adequate hydration, is indicated for the treatment of moderate or severe
hypercalcemia associated with malignancy, with or without bone metastases. Patients who have either
epidermoid or non-epidermoid tumors respond to treatment with Aredia. Vigorous saline hydration, an
integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to
restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may
be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients
should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who
have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of
hypovolemia. The safety and efficacy of Aredia in the treatment of hypercalcemia associated with
hyperparathyroidism or with other non-tumor-related conditions has not been established.
Paget's Disease
Aredia is indicated for the treatment of patients with moderate to severe Paget's disease of bone. The
effectiveness of Aredia was demonstrated primarily in patients with serum alkaline phosphatase ≥3 times
the upper limit of normal. Aredia therapy in patients with Paget's disease has been effective in reducing
serum alkaline phosphatase and urinary hydroxyproline levels by ≥50% in at least 50% of patients, and by
≥30% in at least 80% of patients. Aredia therapy has also been effective in reducing these biochemical
markers in patients with Paget's disease who failed to respond, or no longer responded to other treatments.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
Aredia is indicated, in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone
metastases of breast cancer and osteolytic lesions of multiple myeloma. The Aredia treatment effect
appeared to be smaller in the study of breast cancer patients receiving hormonal therapy than in the study of
those receiving chemotherapy, however, overall evidence of clinical benefit has been demonstrated (see
CLINICAL PHARMACOLOGY, Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma, Clinical Trials section.)
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other
bisphosphonates.
WARNINGS
In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration
of Aredia.
Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia was given for 1, 4, or 24
hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3
mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when
administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal
tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second
study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional
findings included elevated BUN levels in several treated animals and renal tubular dilation and/or
inflammation at ≥1 mg/kg after each infusion time.
Aredia was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as a 1-
hour infusion, once a week, for 3 months followed by a 1-month recovery period. In rats, nephrotoxicity
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10
was observed at ≥6 mg/kg and included increased BUN and creatinine levels and tubular degeneration and
necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs,
moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and
creatinine levels at ≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were
partially reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects was
considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).
Patients who receive an intravenous infusion of Aredia should have periodic evaluations of standard
laboratory and clinical parameters of renal function.
Studies conducted in young rats have reported the disruption of dental dentine formation following single-
and multi-dose administration of bisphosphonates. The clinical significance of these findings is unknown.
PRECAUTIONS
General
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate,
magnesium, and potassium, should be carefully monitored following initiation of therapy with Aredia.
Cases of asymptomatic hypophosphatemia (12%), hypokalemia(7%), hypomagnesemia (11%), and
hypocalcemia (5%-12%), were reported in Aredia-treated patients. Rare cases of symptomatic
hypocalcemia (including tetany) have been reported in association with Aredia therapy. If hypocalcemia
occurs, short-term calcium therapy may be necessary. In Paget's disease of bone, 17% of patients treated
with 90 mg of Aredia showed serum calcium levels below 8 mg/dL.
Aredia has not been tested in patients who have class Dc renal impairment (creatinine >5.0 mg/dL), and in
few multiple myeloma patients with serum creatinine ≥3.0 mg/dL. (See also CLINICAL
PHARMACOLOGY, Pharmacokinetics.) Clinical judgment should determine whether the potential benefit
outweighs the potential risk in such patients.
Laboratory Tests
Serum calcium, electrolytes, phosphate, magnesium and creatinine, and CBC, differential, and
hematocrit/hemoglobin must be closely monitored in patients treated with Aredia. Patients who have
preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks
following treatment.
Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of Aredia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study (daily oral administration) in rats, there was a positive dose response
relationship for benign adrenal pheochromocytoma in males (P <0.00001). Although this condition was
also observed in females, the incidence was not statistically significant. When the dose calculations were
adjusted to account for the limited oral bioavailability of Aredia in rats, the lowest daily dose associated
with adrenal pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma was
also observed in low numbers in the control animals and is considered a relatively common spontaneous
neoplasm in the rat. Aredia (daily oral administration) was not carcinogenic in an 80-week study in mice.
Aredia was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and Escherichia/liver-
microsome test, nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test, and
micronucleus test in the rat.
In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of
Aredia orally; however, this occurred only when animals were mated with members of the same dose
group. Aredia has not been administered intravenously in such a study.
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia produces maternal toxicity
and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest
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11
recommended human dose for a single intravenous infusion. As it has been shown that Aredia can cross the
placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and
rabbits, it should not be given to women during pregnancy.
Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when Aredia is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Aredia in pediatric patients have not been established.
ADVERSE REACTIONS
Clinical Studies
Hypercalcemia of Malignancy
Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of
Aredia in 34% of patients in clinical trials. In the saline trial, 18% of patients had a temperature elevation
of at least 1°C 24 to 48 hours after treatment.
Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of
catheter insertion were most common in patients treated with 90 mg of Aredia. Symptomatic treatment
resulted in rapid resolution in all patients.
Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis, and
one case of uveitis upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the four U.S. controlled hypercalcemia clinical
studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the
seizures were considered to be drug-related by the investigators. However, a possible relationship between
the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm 1
patient (4%) had a seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90 mg Aredia over 24 hours to 2
hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical
trials suggests that the overall safety profile in patients who received 90 mg Aredia over 24 hours is similar
to those who received 90 mg Aredia over 2 hours.. The only notable differences observed were an increase
in the proportion of patients in the Aredia 24 hour group who experienced fluid overload and
electrolyte/mineral abnormalities.”
At least 15% of patients treated with Aredia for hypercalcemia of malignancy also experienced the
following adverse events during a clinical trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting
Genitourinary: Urinary tract infection
Musculoskeletal: Bone pain
Laboratory abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia
Many of these adverse experiences may have been related to the underlying disease state.
The following table lists the adverse experiences considered to be treatment-related during comparative,
controlled U.S. trials.
Treatment-Related Adverse Experiences Reported in Three U.S. Controlled
Clinical Trials
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12
Percent of Patients
Aredia
Didronel
Saline
60 mg
60 mg
90 mg
7.5 mg/kg
over 4 hr
over 24 hr over 24 hr x 3 days
n=23
n=73
n=17
n=35
n=23
General
Edema
0
1
0
0
0
Fatigue
0
0
12
0
0
Fever
26
19
18
9
0
Fluid overload
0
0
0
6
0
Infusion-site reaction
0
4
18
0
0
Moniliasis
0
0
6
0
0
Rigors
0
0
0
0
4
Gastrointestinal
Abdominal pain
0
1
0
0
0
Anorexia
4
1
12
0
0
Constipation
4
0
6
3
0
Diarrhea
0
1
0
0
0
Dyspepsia
4
0
0
0
0
Gastrointestinal
hemorrhage
0
0
6
0
0
Nausea
4
0
18
6
0
Stomatitis
0
1
0
3
0
Vomiting
4
0
0
0
0
Respiratory
Dyspnea
0
0
0
3
0
Rales
0
0
6
0
0
Rhinitis
0
0
6
0
0
Upper respiratory
infection
0
3
0
0
0
CNS
Anxiety
0
0
0
0
4
Convulsions
0
0
0
3
0
Insomnia
0
1
0
0
0
Nervousness
0
0
0
0
4
Psychosis
4
0
0
0
0
Somnolence
0
1
6
0
0
Taste perversion
0
0
0
3
0
Cardiovascular
Atrial fibrillation
0
0
6
0
4
Atrial flutter
0
1
0
0
0
Cardiac failure
0
1
0
0
0
Hypertension
0
0
6
0
4
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13
Syncope
0
0
6
0
0
Tachycardia
0
0
6
0
4
Endocrine
Hypothyroidism
0
0
6
0
0
Hemic and Lymphatic
Anemia
0
0
6
0
0
Leukopenia
4
0
0
0
0
Neutropenia
0
1
0
0
0
Thrombocytopenia
0
1
0
0
0
Musculoskeletal
Myalgia
0
1
0
0
0
Urogenital
Uremia
4
0
0
0
0
Laboratory Abnormalities
Hypocalcemia
0
1
12
0
0
Hypokalemia
4
4
18
0
0
Hypomagnesemia
4
10
12
3
4
Hypophosphatemia
0
9
18
3
0
Abnormal liver
function
0
0
0
3
0
Paget's Disease
Transient mild elevation of temperature >1°C above pretreatment baseline was noted within 48 hours after
completion of treatment in 21% of the patients treated with 90 mg of Aredia in clinical trials.
Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia,
increased sweating) were more common in patients with Paget's disease treated with 90 mg of Aredia than
in patients with hypercalcemia of malignancy treated with the same dose.
Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients with
Paget's disease treated with 90 mg of Aredia in two U.S. clinical trials, were fever, nausea, back pain, and
bone pain.
At least 10% of all Aredia-treated patients with Paget's disease also experienced the following adverse
experiences during clinical trials:
Cardiovascular: Hypertension
Musculoskeletal: Arthrosis, bone pain
Nervous system: Headache
Most of these adverse experiences may have been related to the underlying disease state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
The most commonly reported (>15%) adverse experiences occurred with similar frequencies in the Aredia
and placebo treatment groups, and most of these adverse experiences may have been related to the
underlying disease state or cancer therapy.
Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
Aredia 90 mg
over 4 hours
Placebo
Aredia 90 mg
over 2 hours
Placebo
All Aredia
90 mg
Placebo
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14
N=205
%
N=187
%
N=367
%
N=386
%
N=572
%
N=573
%
General
Asthenia
16.1
17.1
25.6
19.2
22.2
18.5
Fatigue
31.7
28.3
40.3
28.8
37.2
29.0
Fever
38.5
38.0
38.1
32.1
38.5
34.0
Metastases
1.0
3.0
31.3
24.4
20.5
17.5
Pain
13.2
11.8
15.0
18.1
14.3
16.1
Digestive System
Anorexia
17.1
17.1
31.1
24.9
26.0
22.3
Constipation
28.3
31.7
36.0
38.6
33.2
35.1
Diarrhea
26.8
26.8
29.4
30.6
28.5
29.7
Dyspepsia
17.6
13.4
18.3
15.0
22.6
17.5
Nausea
35.6
37.4
63.5
59.1
53.5
51.8
Pain Abdominal
19.5
16.0
24.3
18.1
22.6
17.5
Vomiting
16.6
19.8
46.3
39.1
35.7
32.8
Hemic and Lymphatic
Anemia
47.8
41.7
39.5
36.8
42.5
38.4
Granulocytopeni
a
20.5
15.5
19.3
20.5
19.8
18.8
Thrombocytopen
ia
16.6
17.1
12.5
14.0
14.0
15.0
Musculo-skeletal System
Arthralgias
10.7
7.0
15.3
12.7
13.6
10.8
Myalgia
25.4
15.0
26.4
22.5
26.0
20.1
Skeletal Pain
61.0
71.7
70.0
75.4
66.8
74.0
CNS
Anxiety
7.8
9.1
18.0
16.8
14.3
14.3
Headache
24.4
19.8
27.2
23.6
26.2
22.3
Insomnia
17.1
17.2
25.1
19.4
22.2
19.0
Respiratory System
Coughing
26.3
22.5
25.3
19.7
25.7
20.6
Dyspnea
22.0
21.4
35.1
24.4
30.4
23.4
Pleural Effusion
2.9
4.3
15.0
9.1
10.7
7.5
Sinusitis
14.6
16.6
16.1
10.4
15.6
12.0
Upper Resp.
Tract Infection
32.2
28.3
19.6
20.2
24.1
22.9
Urogenital System
Urinary tract
Infection
15.6
9.1
20.2
17.6
18.5
15.6
Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and anemia
were slightly more common in the Aredia patients whereas stomatitis and alopecia occurred at a frequency
similar to that in placebo patients. In the breast cancer trials, mild elevations of serum creatinine occurred
in 18.5% of Aredia patients and 12.3% of placebo patients. Mineral and electrolyte disturbances, including
hypocalcemia, were reported rarely and in similar percentages of Aredia-treated patients compared with
This label may not be the latest approved by FDA.
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15
those in the placebo group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia,
and hypomagnesemia for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively, and for
placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively. In previous hypercalcemia of
malignancy trials, patients treated with Aredia (60 or 90 mg over 24 hours) developed electrolyte
abnormalities more frequently (see ADVERSE REACTIONS, Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the Aredia group than in the placebo
group (13.6% and 26% vs 10.8% and 20.1%, respectively).
In multiple myeloma patients, there were five Aredia-related serious and unexpected adverse experiences.
Four of these were reported during the 12-month extension of the multiple myeloma trial. Three of the
reports were of worsening renal function developing in patients with progressive multiple myeloma or
multiple myeloma-associated amyloidosis. The fourth report was the adult respiratory distress syndrome
developing in a patient recovering from pneumonia and acute gangrenous cholecystitis. One Aredia-treated
patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy
throat within 24 hours after the sixth infusion.
In the breast cancer trials, there were four Aredia-related adverse experiences, all moderate in severity, that
caused a patient to discontinue participation in the trial. One was due to interstitial pneumonitis, another to
malaise and dyspnea. One Aredia patient discontinued the trial due to a symptomatic hypocalcemia.
Another Aredia patient discontinued therapy due to severe bone pain after each infusion, which the
investigator felt was trial-drug-related.
Post-Marketing Experience
Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or
angioedema, and, very rarely, anaphylactic shock. Aredia is contraindicated in patients with clinically
significant hypersensitivity to Aredia or other bisphosphonates (see CONTRAINDICATIONS).
OVERDOSAGE
There have been several cases of drug maladministration of intravenous Aredia in hypercalcemia patients
with total doses of 225 mg to 300 mg given over 2 1/2 to 4 days. All of these patients survived, but they
experienced hypocalcemia that required intravenous and/or oral administration of calcium.
In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for 3 days experienced
high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perversion,
noted about 6 hours after the first infusion. The fever and hypotension were rapidly corrected with steroids.
If overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with
short-term intravenous calcium.
DOSAGE AND ADMINISTRATION
Hypercalcemia of Malignancy
Consideration should be given to the severity of as well as the symptoms of hypercalcemia. Vigorous saline
hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia. Overhydration should be
avoided in patients who have potential for cardiac failure. In hypercalcemia associated with hematologic
malignancies, the use of glucocorticoid therapy may be helpful.
Moderate Hypercalcemia
The recommended dose of Aredia in moderate hypercalcemia (corrected serum calcium* of
approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE DOSE, intravenous infusion over 2
to 24 hours Longer infusions (i.e., > 2 hours) may reduce the risk for renal toxicity, particulary in
patients with pre-existing renal insufficiency.
Severe Hypercalcemia
The recommended dose of Aredia in severe hypercalcemia (corrected serum calcium*>13.5 mg/dL) is
90 mg given as a SINGLE DOSE, intravenous infusion over 2 to 24 hours.. Longer infusions (i.e., > 2
hours) may reduce the risk for renal toxicity, particularly in patients with pre-existing renal
insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).
Retreatment
A limited number of patients have received more than one treatment with Aredia for hypercalcemia.
Retreatment with Aredia, in patients who show complete or partial response initially, may be carried out if
serum calcium does not return to normal or remain normal after initial treatment. It is recommended that
a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. The dose
and manner of retreatment is identical to that of the initial therapy.
Paget's Disease
The recommended dose of Aredia in patients with moderate to severe Paget's disease of bone is 30 mg
daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.
Retreatment
A limited number of patients with Paget's disease have received more than one treatment of Aredia in
clinical trials. When clinically indicated, patients should be retreated at the dose of initial therapy.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of Aredia in patients with osteolytic bone lesions of multiple myeloma is 90
mg administered as a 4-hour infusion given on a monthly basis.
Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to
Aredia infusion.
Limited information is available on the use of Aredia in multiple myeloma patients with a serum creatinine
≥3.0 mg/dL.
The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final
analysis after 21 months demonstrated overall benefit (see CLINICAL TRIALS section).
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg administered
over a 2-hour infusion given every 3-4 weeks.
Aredia has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate,
mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen.
It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.
The optimal duration of therapy is not known, however, in two breast cancer studies, final analyses
performed after 24 months of therapy demonstrated overall benefit (see CLINICAL TRIALS section).
Preparation of Solution
Reconstitution
Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial, resulting in a
solution of 30 mg/10 mL, 60 mg/10 mL, or 90 mg/10 mL. The pH of the reconstituted solution is 6.0 - 7.4.
The drug should be completely dissolved before the solution is withdrawn.
Hypercalcemia of Malignancy
The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60-mg
and90-mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium
Chloride, USP, or 5% Dextrose Injection, USP. This infusion solution is stable for up to 24 hours at room
temperature.
Paget's Disease
The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium
Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period for 3 consecutive
days.
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% sodium chloride,
USP, or 5% dextrose injection, USP, and administered over a 2-hour period every 3-4 weeks.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride,
USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period on a monthly basis.
Aredia must not be mixed with calcium-containing infusion solutions, such as Ringer's solution, and
should be given in a single intravenous solution and line separate from all other drugs.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration at 36°-46°F (2°-8°C)
for up to 24 hours.
HOW SUPPLIED
Vials - 30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and
470 mg of mannitol, USP.
Carton of 4 vials.................................................................................................................. NDC 0083-2601-04
Vials - 90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and
375 mg of mannitol, USP.
Carton of 1 vial................................................................................................................... NDC 0083-2609-01
Do not store above 86°F (30°C).
REV: AUGUST 2001 Printed in U.S.A. T2001-xx
xxxxxx
Novartis Pharmaceutical Corporation
East Hanover, New Jersey 07936
©1999 Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:31.365430
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20036s24lbl.pdf', 'application_number': 20036, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
12,153
|
Aredia®
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor available in 30-mg or
90-mg vials for intravenous administration. Each 30-mg, and 90-mg vial contains, respectively,
30 mg and 90 mg of sterile, lyophilized pamidronate disodium and 470 mg and 375 mg of
mannitol, USP. The pH of a 1% solution of pamidronate disodium in distilled water is
approximately 8.3. Aredia, a member of the group of chemical compounds known as
bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated
chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt,
pentahydrate, (APD), and its structural formula is
Pamidronate disodium is a white-to-practically-white powder. It is soluble in water and in
2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and
practically insoluble in organic solvents. Its molecular formula is C3H9NO7P2Na2•5H2O and its
molecular weight is 369.1.
Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5 prior to
lyophilization).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the
mechanism of antiresorptive action is not completely understood, several factors are thought
to contribute to this action. Aredia adsorbs to calcium phosphate (hydroxyapatite) crystals in
bone and may directly block dissolution of this mineral component of bone. In vitro studies
also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption.
In animal studies, at doses recommended for the treatment of hypercalcemia, Aredia inhibits
bone resorption apparently without inhibiting bone formation and mineralization. Of relevance
to the treatment of hypercalcemia of malignancy is the finding that Aredia inhibits the accelerated
bone resorption that results from osteoclast hyperactivity induced by various tumors in animal
studies.
Pharmacokinetics
Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous
infusion of 30, 60, or 90 mg of Aredia over 4 hours and 90 mg of Aredia over 24 hours
(Table 1).
Distribution
The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose
over 120 hours.
Metabolism
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Excretion
After administration of 30, 60, and 90 mg of Aredia over 4 hours, and 90 mg of Aredia over
24 hours, an overall mean ± SD of 46 ± 16% of the drug was excreted unchanged in the urine
within 120 hours. Cumulative urinary excretion was linearly related to dose. The mean ± SD
elimination half-life is 28 ± 7 hours. Mean ± SD total and renal clearances of pamidronate
were 107 ± 50 mL/min and 49 ± 28 mL/min, respectively. The rate of elimination from bone
has not been determined.
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of
pamidronate.
Pediatric
Pamidronate is not labeled for use in the pediatric population.
Renal Insufficiency
The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and
varying degrees of renal impairment. Each patient received a single 90-mg dose of Aredia
infused over 4 hours. The renal clearance of pamidronate in patients was found to closely
correlate with creatinine clearance (see Figure 1). A trend toward a lower percentage of drug
excreted unchanged in urine was observed in renally impaired patients. Adverse experiences
noted were not found to be related to changes in renal clearance of pamidronate. Given the
recommended dose, 90 mg infused over 4 hours, excessive accumulation of pamidronate in
renally impaired patients is not anticipated if Aredia is administered on a monthly basis.
Figure 1: Pamidronate renal clearance as a function of creatinine
clearance in patients with normal and impaired renal function.
The lines are the mean prediction line and 95% confidence intervals.
Hepatic Insufficiency
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone
metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction
(n=7). Each patient received a single 90-mg dose of Aredia infused over 4 hours. Although
there was a statistically significant difference in the pharmacokinetics between patients with
normal and impaired hepatic function, the difference was not considered clinically relevant.
Patients with hepatic impairment exhibited higher mean AUC (53%) and Cmax (29%), and
decreased plasma clearance (33%) values. Nevertheless, pamidronate was still rapidly
cleared from the plasma. Drug levels were not detectable in patients by 12 to 36 hours after
drug infusion. Because Aredia is administered on a monthly basis, drug accumulation is not
expected. No changes in Aredia dosing regimen are recommended for patients with mild to
moderate abnormal hepatic function. Aredia has not been studied in patients with severe
hepatic impairment.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
Table 1
Mean (SD, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients
(n=6 for each group)
Maximum
Percent
Total
Renal
Dose
Concentration
of dose
Clearance
Clearance
(infusion rate)
(µg/mL)
excreted in urine
(mL/min)
(mL/min)
30 mg
0.73
43.9
136
58
(4 hrs)
(0.14, 19.1%)
(14.0, 31.9%)
(44, 32.4%)
(27, 46.5%)
60 mg
1.44
47.4
88
42
(4 hrs)
(0.57, 39.6%)
(47.4, 54.4%)
(56, 63.6%)
(28, 66.7%)
90 mg
2.61
45.3
103
44
(4 hrs)
(0.74, 28.3%)
(25.8, 56.9%)
(37, 35.9%)
(16, 36.4%)
90 mg
1.38
47.5
101
52
(24 hrs)
(1.97, 142.7%)
(10.2, 21.5%)
(58, 57.4%)
(42, 80.8%)
After intravenous administration of radiolabeled pamidronate in rats, approximately
50%-60% of the compound was rapidly adsorbed by bone and slowly eliminated from the
body by the kidneys. In rats given 10 mg/kg bolus injections of radiolabeled Aredia, approxi-
mately 30% of the compound was found in the liver shortly after administration and was then
redistributed to bone or eliminated by the kidneys over 24-48 hours. Studies in rats injected
with radiolabeled Aredia showed that the compound was rapidly cleared from the circulation
and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage. Radioactivity was
eliminated from most soft tissues within 1-4 days; was detectable in liver and spleen for
1 and 3 months, respectively; and remained high in bones, trachea, and teeth for 6 months
after dosing. Bone uptake occurred preferentially in areas of high bone turnover. The terminal
phase of elimination half-life in bone was estimated to be approximately 300 days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia, presum-
ably because of decreased release of phosphate from bone and increased renal excretion as
parathyroid hormone levels, which are usually suppressed in hypercalcemia associated with
malignancy, return toward normal. Phosphate therapy was administered in 30% of the
patients in response to a decrease in serum phosphate levels. Phosphate levels usually
returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usu-
ally return to within or below normal after treatment with Aredia. These changes occur within
the first week after treatment, as do decreases in serum calcium levels, and are consistent
with an antiresorptive pharmacologic action.
Hypercalcemia of Malignancy
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysi-
ologic derangement in metastatic bone disease and hypercalcemia of malignancy. Excessive
release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal
disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in
turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic
hypercalcemia. Correction of excessive bone resorption and adequate fluid administration to
correct volume deficits are therefore essential to the management of hypercalcemia.
Most cases of hypercalcemia associated with malignancy occur in patients who have
breast cancer; squamous-cell tumors of the lung or head and neck; renal-cell carcinoma; and
certain hematologic malignancies, such as multiple myeloma and some types of lymphomas.
A few less-common malignancies, including vasoactive intestinal-peptide-producing tumors
and cholangiocarcinoma, have a high incidence of hypercalcemia as a metabolic complica-
tion. Patients who have hypercalcemia of malignancy can generally be divided into two
groups, according to the pathophysiologic mechanism involved.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by
factors such as parathyroid-hormone-related protein, which are elaborated by the tumor and
circulate systemically. Humoral hypercalcemia usually occurs in squamous-cell malignancies
of the lung or head and neck or in genitourinary tumors such as renal-cell carcinoma or ovari-
an cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local
tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated
with locally mediated hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not
reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly pre-
sent. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic
conditions; however, these are not commonly or rapidly available in many clinical situations.
Therefore, adjustment of the total serum calcium value for differences in albumin levels is
often used in place of measurement of ionized calcium; several nomograms are in use for this
type of calculation (see DOSAGE AND ADMINISTRATION).
Clinical Trials
In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were
enrolled to receive 30 mg, 60 mg, or 90 mg of Aredia as a single 24-hour intravenous infusion
if their corrected serum calcium levels were ≥12.0 mg/dL after 48 hours of saline hydration.
The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups
were 13.8 mg/dL,13.8 mg/dL, and 13.3 mg/dL, respectively.
The majority of patients (64%) had decreases in albumin-corrected serum calcium levels
by 24 hours after initiation of treatment. Mean-corrected serum calcium levels at days 2-7
after initiation of treatment with Aredia were significantly reduced from baseline in all three
dosage groups. As a result, by 7 days after initiation of treatment with Aredia, 40%, 61%, and
100% of the patients receiving 30 mg, 60 mg, and 90 mg of Aredia, respectively, had normal-
corrected serum calcium levels. Many patients (33%-53%) in the 60-mg and 90-mg dosage
groups continued to have normal-corrected serum calcium levels, or a partial response (≥15%
decrease of corrected serum calcium from baseline), at day 14.
In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected
serum calcium levels of ≥12.0 mg/dL after at least 24 hours of saline hydration were random-
ized to receive either 60 mg of Aredia as a single 24-hour intravenous infusion or 7.5 mg/kg of
etidronate disodium as a 2-hour intravenous infusion daily for 3 days. Thirty patients were
randomized to receive Aredia and 35 to receive etidronate disodium.
The mean baseline-corrected serum calcium for the Aredia 60-mg and etidronate disodium
groups were 14.6 mg/dL and 13.8 mg/dL, respectively.
By day 7, 70% of the patients in the Aredia group and 41% of the patients in the
etidronate disodium group had normal-corrected serum calcium levels (P<0.05). When partial
responders (≥15% decrease of serum calcium from baseline) were also included, the
response rates were 97% for the Aredia group and 65% for the etidronate disodium group
(P<0.01). Mean-corrected serum calcium for the Aredia and etidronate disodium groups
decreased from baseline values to 10.4 and 11.2 mg/dL, respectively, on day 7. At day 14,
43% of patients in the Aredia group and 18% of patients in the etidronate disodium group still
had normal-corrected serum calcium levels, or maintenance of a partial response. For
responders in the Aredia and etidronate disodium groups, the median duration of response
was similar (7 and 5 days, respectively). The time course of effect on corrected serum calci-
um is summarized in the following table.
Change in Corrected Serum Calcium by Time
from Initiation of Treatment
Time
Mean Change from Baseline in Corrected Serum Calcium (mg/dL)
(hr)
Aredia®
Etidronate Disodium
P-Value1
Baseline
14.6
13.8
24
-0.3
-0.5
48
-1.5
-1.1
72
-2.6
-2.0
96
-3.5
-2.0
<0.01
168
-4.1
-2.5
<0.01
1Comparison between treatment groups
In a third multicenter, randomized, parallel double-blind trial, a group of 69 cancer
patients with hypercalcemia was enrolled to receive 60 mg of Aredia as a 4- or 24-hour infu-
sion, which was compared to a saline treatment group. Patients who had a corrected serum
calcium level of ≥12.0 mg/dL after 24 hours of saline hydration were eligible for this trial.
The mean baseline-corrected serum calcium levels for Aredia 60-mg 4-hour infusion,
Aredia 60-mg 24-hour infusion, and saline infusion were 14.2 mg/dL, 13.7 mg/dL, and
13.7 mg/dL, respectively.
By day 7 after initiation of treatment, 78%, 61%, and 22% of the patients had normal-
corrected serum calcium levels for the 60-mg 4-hour infusion, 60-mg 24-hour infusion, and
saline infusion, respectively. At day 14, 39% of the patients in the Aredia 60-mg 4-hour infu-
sion group and 26% of the patients in the Aredia 60-mg 24-hour infusion group had normal-
corrected serum calcium levels or maintenance of a partial response.
For responders, the median duration of complete responses was 4 days and 6.5 days for
Aredia 60-mg 4-hour infusion and Aredia 60-mg 24-hour infusion, respectively.
In all three trials, patients treated with Aredia had similar response rates in the presence
or absence of bone metastases. Concomitant administration of furosemide did not affect
response rates.
Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were
given a second course of 60 mg of Aredia over a 4- or 24-hour period. Of these, 41% showed
a complete response and 16% showed a partial response to the retreatment, and these
responders had about a 3-mg/dL fall in mean-corrected serum calcium levels 7 days after
retreatment.
In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and
hypercalcemia (corrected serum calcium ≥12.0 mg/dL) received 90 mg of Aredia as a 2-hour
infusion. The mean baseline corrected serum calcium was 14.0 mg/dL. Patients were not
required to receive IV hydration prior to drug administration, but all subjects did receive at
least 500 mL of IV saline hydration concomitantly with the pamidronate infusion. By Day 10
after drug infusion, 70% of patients had normal corrected serum calcium levels (<10.8 mg/dL).
Paget’s Disease
Paget’s disease of bone (osteitis deformans) is an idiopathic disease characterized by chron-
ic, focal areas of bone destruction complicated by concurrent excessive bone repair, affecting
one or more bones. These changes result in thickened but weakened bones that may
fracture or bend under stress. Signs and symptoms may be bone pain, deformity, fractures,
neurological disorders resulting from cranial and spinal nerve entrapment and from spinal
cord and brain stem compression, increased cardiac output to the involved bone, increased
serum alkaline phosphatase levels (reflecting increased bone formation) and/or urine
hydroxyproline excretion (reflecting increased bone resorption).
Clinical Trials
In one double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone
were enrolled to receive 5 mg, 15 mg, or 30 mg of Aredia as a single 4-hour infusion on
3 consecutive days, for total doses of 15 mg, 45 mg, and 90 mg of Aredia.
The mean baseline serum alkaline phosphatase levels were 1409 U/L, 983 U/L, and
1085 U/L, and the mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and
0.19 for the 15-mg, 45-mg, and 90-mg groups, respectively.
The effects of Aredia on serum alkaline phosphatase (SAP) and urine hydroxyproline/
creatinine ratios (UOHP/C) are summarized in the following table:
Percent of Patients With
Significant % Decreases in SAP and UOHP/C
SAP
UOHP/C
% Decrease
15 mg
45 mg
90 mg
15 mg
45 mg
90 mg
≥50
26
33
60
15
47
72
≥30
40
65
83
35
57
85
The median maximum percent decreases from baseline in serum alkaline phosphatase
and urine hydroxyproline/creatinine ratios were 25%, 41%, and 57%, and 25%, 47%, and
61% for the 15-mg, 45-mg, and 90-mg groups, respectively. The median time to response
(≥50% decrease) for serum alkaline phosphatase was approximately 1 month for the 90-mg
group, and the response duration ranged from 1 to 372 days.
No statistically significant differences between treatment groups, or statistically significant
changes from baseline were observed for the bone pain response, mobility, and global evalu-
ation in the 45-mg and 90-mg groups. Improvement in radiologic lesions occurred in some
patients in the 90-mg group.
Twenty-five patients who had Paget’s disease were retreated with 90 mg of Aredia. Of
these, 44% had a ≥50% decrease in serum alkaline phosphatase from baseline after treat-
ment, and 39% had a ≥50% decrease in urine hydroxyproline/creatinine ratio from baseline
after treatment.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple
Myeloma
Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast can-
cer. These cancers demonstrate a phenomenon known as osteotropism, meaning they pos-
sess an extraordinary affinity for bone. The distribution of osteolytic bone metastases in these
cancers is predominantly in the axial skeleton, particularly the spine, pelvis, and ribs, rather
than the appendicular skeleton, although lesions in the proximal femur and humerus are not
uncommon. This distribution is similar to the red bone marrow in which slow blood flow possi-
bly assists attachment of metastatic cells. The surface-to-volume ratio of trabecular bone is
much higher than cortical bone, and therefore disease processes tend to occur more floridly
in trabecular bone than at sites of cortical tissue.
These bone changes can result in patients having evidence of osteolytic skeletal destruc-
tion leading to severe bone pain that requires either radiation therapy or narcotic analgesics
(or both) for symptomatic relief. These changes also cause pathologic fractures of bone in
both the axial and appendicular skeleton. Axial skeletal fractures of the vertebral bodies may
lead to spinal cord compression or vertebral body collapse with significant neurologic compli-
cations. Also, patients may experience episode(s) of hypercalcemia.
Clinical Trials
In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple
myeloma were enrolled to receive Aredia or placebo in addition to their underlying antimyeloma
therapy to determine the effect of Aredia on the occurrence of skeletal-related events (SREs).
SREs were defined as episodes of pathologic fractures, radiation therapy to bone, surgery to
bone, and spinal cord compression. Patients received either 90 mg of Aredia or placebo as a
monthly 4-hour intravenous infusion for 9 months. Of the 392 patients, 377 were evaluable for
efficacy (196 Aredia, 181 placebo). The proportion of patients developing any SRE was signif-
icantly smaller in the Aredia group (24% vs 41%, P<0.001), and the mean skeletal morbidity
rate (#SRE/year) was significantly smaller for Aredia patients than for placebo patients (mean:
1.1 vs 2.1, P<.02). The times to the first SRE occurrence, pathologic fracture, and radiation to
bone were significantly longer in the Aredia group (P=.001, .006, and .046, respectively).
Moreover, fewer Aredia patients suffered any pathologic fracture (17% vs 30%, P=.004) or
needed radiation to bone (14% vs 22%, P=.049).
In addition, decreases in pain scores from baseline occurred at the last measurement for
those Aredia patients with pain at baseline (P=.026) but not in the placebo group. At the last
measurement, a worsening from baseline was observed in the placebo group for the Spitzer
quality of life variable (P<.001) and ECOG performance status (P<.011) while there was no
significant deterioration from baseline in these parameters observed in Aredia-treated
patients.*
After 21 months, the proportion of patients experiencing any skeletal event remained
significantly smaller in the Aredia group than the placebo group (P=.015). In addition, the
mean skeletal morbidity rate (#SRE/year) was 1.3 vs 2.2 for Aredia patients vs placebo
patients (P=.008), and time to first SRE was significantly longer in the Aredia group compared
to placebo (P=.016). Fewer Aredia patients suffered vertebral pathologic fractures (16% vs
27%, P=.005). Survival of all patients was not different between treatment groups.
Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy
of 90 mg of Aredia infused over 2 hours every 3 to 4 weeks for 24 months to that of placebo
in preventing SREs in breast cancer patients with osteolytic bone metastases who had one or
more predominantly lytic metastases of at least 1 cm in diameter: one in patients being treat-
ed with antineoplastic chemotherapy and the second in patients being treated with hormonal
antineoplastic therapy at trial entry.
382 patients receiving chemotherapy were randomized, 185 to Aredia and 197 to placebo.
372 patients receiving hormonal therapy were randomized, 182 to Aredia and 190 to placebo.
All but three patients were evaluable for efficacy. Patients were followed for 24 months of
therapy or until they went off study. Median duration of follow-up was 13 months in patients
receiving chemotherapy and 17 months in patients receiving hormone therapy. Twenty-five
percent of the patients in the chemotherapy study and 37% of the patients in the hormone
therapy study received Aredia for 24 months. The efficacy results are shown in the table
below:
Breast Cancer Patients
Breast Cancer Patients
Receiving Chemotherapy
Receiving Hormonal Therapy
Any SRE
Radiation
Fractures
Any SRE
Radiation
Fractures
A
P
A
P
A
P
A
P
A
P
A
P
N
185 195
185
195 185
195
182
189
182
189
182 189
Skeletal
Morbidity Rate
(#SRE/year)
Mean
2.5
3.7
0.8
1.3
1.6
2.2
2.4
3.6
0.6
1.2
1.6
2.2
P-Value
<.001
<.001†
.018†
.021
.013†
.040†
Proportion of
patients having
an SRE
46% 65%
28%
45% 36%
49%
55%
63%
31%
40%
45% 55%
P-Value
<.001
<.001†
.014†
.094
.058†
.054†
Median Time to
SRE (months)
13.9 7.0
NR** 14.2 25.8 13.3
10.9
7.4
NR** 23.4
20.6 12.8
P-Value
<.001
<.001†
.009†
.118
.016†
.113†
†Fractures and radiation to bone were two of several secondary endpoints. The statistical sig-
nificance of these analyses may be overestimated since numerous analyses were performed.
**NR = Not Reached.
Bone lesion response was radiographically assessed at baseline and at 3, 6, and
12 months. The complete + partial response rate was 33% in Aredia patients and 18% in
placebo patients treated with chemotherapy (P=.001). No difference was seen between
Aredia and placebo in hormonally-treated patients.
Pain and analgesic scores, ECOG performance status and Spitzer quality of life index
were measured at baseline and periodically during the trials. The changes from baseline to
the last measurement carried forward are shown in the following table:
Mean Change (∆) from Baseline at Last Measurement
Breast Cancer Patients
Breast Cancer Patients
Receiving Chemotherapy
Receiving Hormonal Therapy
Aredia®
Placebo
A vs P
Aredia®
Placebo
A vs P
N
Mean ∆
N
Mean ∆
P-Value* N
Mean ∆
N
Mean ∆
P-Value*
Pain Score 175
+0.93
183
+1.69
.050
173
+0.50
179
+1.60
.007
Analgesic
Score
175
+0.74
183
+1.55
.009
173
+0.90
179
+2.28
<.001
ECOG PS 178
+0.81
186
+1.19
.002
175
+0.95
182
+0.90
.773
Spitzer
QOL
177
-1.76
185
-2.21
.103
173
-1.86
181
-2.05
.409
Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an
improvement from baseline.
*The statistical significance of analyses of these secondary endpoints of pain, quality of
life, and performance status in all three trials may be overestimated since numerous analyses
were performed.
INDICATIONS AND USAGE
Hypercalcemia of Malignancy
Aredia, in conjunction with adequate hydration, is indicated for the treatment of moderate or
severe hypercalcemia associated with malignancy, with or without bone metastases. Patients
who have either epidermoid or non-epidermoid tumors respond to treatment with Aredia.
Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated
promptly and an attempt should be made to restore the urine output to about 2 L/day
throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative
measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated
adequately throughout the treatment, but overhydration, especially in those patients who have
cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction
of hypovolemia. The safety and efficacy of Aredia in the treatment of hypercalcemia associated
with hyperparathyroidism or with other non-tumor-related conditions has not been established.
Paget’s Disease
Aredia is indicated for the treatment of patients with moderate to severe Paget’s disease of
bone. The effectiveness of Aredia was demonstrated primarily in patients with serum alkaline
phosphatase ≥3 times the upper limit of normal. Aredia therapy in patients with Paget’s
disease has been effective in reducing serum alkaline phosphatase and urinary hydroxypro-
line levels by ≥50% in at least 50% of patients, and by ≥30% in at least 80% of patients.
Aredia therapy has also been effective in reducing these biochemical markers in patients with
Paget’s disease who failed to respond, or no longer responded to other treatments.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple
Myeloma
Aredia is indicated, in conjunction with standard antineoplastic therapy, for the treatment of
osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. The
Aredia treatment effect appeared to be smaller in the study of breast cancer patients receiv-
ing hormonal therapy than in the study of those receiving chemotherapy, however,
overall evidence of clinical benefit has been demonstrated (see CLINICAL PHARMACOLOGY,
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma,
Clinical Trials section).
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or
other bisphosphonates.
WARNINGS
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNC-
TION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA
SHOULD NOT EXCEED 90 MG (see DOSAGE AND ADMINISTRATION for appropriate
infusion durations).
Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as
deterioration of renal function and potential renal failure.
Patients who receive Aredia should have serum creatinine assessed prior to each treat-
ment. Patients treated with Aredia for bone metastases should have the dose withheld if renal
function has deteriorated. (See DOSAGE AND ADMINISTRATION.)
In both rats and dogs, nephropathy has been associated with intravenous (bolus and infu-
sion) administration of Aredia.
Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia was
given for 1, 4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the com-
pound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD] for a
single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as
elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was
infused for 1 hour and at doses of ≥10 mg/kg. In the second study, slight renal tubular necrosis
was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included ele-
vated BUN levels in several treated animals and renal tubular dilation and/or inflammation at
≥1 mg/kg after each infusion time.
Aredia was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6,
and 20 mg/kg as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery
period. In rats, nephrotoxicity was observed at ≥6 mg/kg and included increased BUN and
creatinine levels and tubular degeneration and necrosis. These findings were still present at
20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity
occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at
≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially
reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects
was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).
PREGNANCY: AREDIA SHOULD NOT BE USED DURING PREGNANCY
Aredia may cause fetal harm when administered to a pregnant woman. (See PRECAUTIONS,
Pregnancy Category D.)
There are no studies in pregnant women using Aredia. If the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential harm to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant.
Studies conducted in young rats have reported the disruption of dental dentine formation
following single- and multi-dose administration of bisphosphonates. The clinical significance of
these findings is unknown.
PRECAUTIONS
General
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium,
phosphate, magnesium, and potassium, should be carefully monitored following initiation of
therapy with Aredia. Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%),
hypomagnesemia (11%), and hypocalcemia (5%-12%), were reported in Aredia-treated
patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in
association with Aredia therapy. If hypocalcemia occurs, short-term calcium therapy may be
necessary. In Paget’s disease of bone, 17% of patients treated with 90 mg of Aredia showed
serum calcium levels below 8 mg/dL.
Renal Insufficiency
Aredia is excreted intact primarily via the kidney, and the risk of renal adverse reactions may
be greater in patients with impaired renal function. Patients who receive Aredia should have
serum creatinine assessed prior to each treatment. In patients receiving Aredia for bone
metastases, who show evidence of deterioration in renal function, Aredia treatment should be
withheld until renal function returns to baseline (see WARNINGS and DOSAGE AND
ADMINISTRATION).
Aredia has not been tested in patients who have class Dc renal impairment (creatinine
>5.0 mg/dL), and has been tested in few multiple myeloma patients with serum creatinine
≥3.0 mg/dL. (See also CLINICAL PHARMACOLOGY, Pharmacokinetics.) For the treatment of
bone metastases, the use of Aredia in patients with severe renal impairment is not recom-
mended. In other indications, clinical judgment should determine whether the potential benefit
outweighs the potential risk in such patients.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment
regimens including bisphosphonates. Many of these patients were also receiving chemothera-
py and corticosteroids. The majority of reported cases have been associated with dental pro-
cedures such as tooth extraction. Many had signs of local infection including osteomyelitis.
A dental examination with appropriate preventive dentistry should be considered prior to
-20
0
50
0
100
150
20
40
60
80
100
120
140
160
Pamidronate Renal CL vs CLcr
Renal CL (mL/min)
CLcr (mL/min)
Observed
Predicted
Lower 95% CI
Upper 95% CI
• 5H2O
PO3HNa
NH2 - CH2 - CH2 - C - OH
PO3HNa
©Novartis
T2004-70
FPO
FPO
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer,
chemotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For
patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate
the condition. For patients requiring dental procedures, there are no data available to suggest
whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judg-
ment of the treating physician should guide the management plan of each patient based on
individual benefit/risk assessment.
Laboratory Tests
Patients who receive Aredia should have serum creatinine assessed prior to each treatment.
Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and
hematocrit/hemoglobin must be closely monitored in patients treated with Aredia. Patients
who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully
in the first 2 weeks following treatment.
Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of
Aredia.
Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study (daily oral administration) in rats, there was a positive
dose response relationship for benign adrenal pheochromocytoma in males (P <0.00001).
Although this condition was also observed in females, the incidence was not statistically
significant. When the dose calculations were adjusted to account for the limited oral
bioavailability of Aredia in rats, the lowest daily dose associated with adrenal pheochromocy-
toma was similar to the intended clinical dose. Adrenal pheochromocytoma was also
observed in low numbers in the control animals and is considered a relatively common
spontaneous neoplasm in the rat. Aredia (daily oral administration) was not carcinogenic in an
80-week study in mice.
Aredia was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and
Escherichia/ liver-microsome test, nucleus-anomaly test, sister-chromatid-exchange study,
point-mutation test, and micronucleus test in the rat.
In rats, decreased fertility occurred in first-generation offspring of parents who had
received 150 mg/kg of Aredia orally; however, this occurred only when animals were mated
with members of the same dose group. Aredia has not been administered intravenously in
such a study.
Pregnancy Category D (See WARNINGS)
There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia produces
maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to
8.3 times the highest recommended human dose for a single intravenous infusion. As it has
been shown that Aredia can cross the placenta in rats and has produced marked maternal
and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women
during pregnancy.
Bisphosphonates are incorporated into the bone matrix, from where they are gradually
released over periods of weeks to years. The extent of bisphosphonate incorporation into
adult bone, and hence, the amount available for release back into the systemic circulation, is
directly related to the total dose and duration of bisphosphonate use. Although there are no
data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal
data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal
bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormali-
ties) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The
impact of variables such as time between cessation of bisphosphonate therapy to conception,
the particular bisphosphonate used, and the route of administration (intravenous versus oral)
on this risk has not been established.
Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when Aredia is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Aredia in pediatric patients have not been established.
ADVERSE REACTIONS
Clinical Studies
Hypercalcemia of Malignancy
Transient mild elevation of temperature by at least 1 °C was noted 24 to 48 hours after
administration of Aredia in 34% of patients in clinical trials. In the saline trial, 18% of patients
had a temperature elevation of at least 1 °C 24 to 48 hours after treatment.
Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on
palpation) at the site of catheter insertion were most common in patients treated with
90 mg of Aredia. Symptomatic treatment resulted in rapid resolution in all patients.
Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one
case of scleritis, and one case of uveitis upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the four U.S. controlled hypercal-
cemia clinical studies were reported to have had seizures, 2 of whom had preexisting seizure
disorders. None of the seizures were considered to be drug-related by the investigators.
However, a possible relationship between the drug and the occurrence of seizures cannot be
ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90 mg Aredia
over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a compari-
son of data from separate clinical trials suggests that the overall safety profile in patients who
received 90 mg Aredia over 24 hours is similar to those who received 90 mg Aredia over
2 hours. The only notable differences observed were an increase in the proportion of patients in
the Aredia 24 hour group who experienced fluid overload and electrolyte/mineral abnormalities.
At least 15% of patients treated with Aredia for hypercalcemia of malignancy also experi-
enced the following adverse events during a clinical trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting
Genitourinary: Urinary tract infection
Musculoskeletal: Bone pain
Laboratory abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia
Many of these adverse experiences may have been related to the underlying disease state.
The following table lists the adverse experiences considered to be treatment-related during
comparative, controlled U.S. trials.
Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical
Trials
Percent of Patients
Etidronate
Aredia®
Disodium
Saline
60 mg
60 mg
90 mg
7.5 mg/kg
over 4 hr
over 24 hr
over 24 hr
x 3 days
n=23
n=73
n=17
n=35
n=23
General
Edema
0
1
0
0
0
Fatigue
0
0
12
0
0
Fever
26
19
18
9
0
Fluid overload
0
0
0
6
0
Infusion-site reaction
0
4
18
0
0
Moniliasis
0
0
6
0
0
Rigors
0
0
0
0
4
Gastrointestinal
Abdominal pain
0
1
0
0
0
Anorexia
4
1
12
0
0
Constipation
4
0
6
3
0
Diarrhea
0
1
0
0
0
Dyspepsia
4
0
0
0
0
Gastrointestinal
hemorrhage
0
0
6
0
0
Nausea
4
0
18
6
0
Stomatitis
0
1
0
3
0
Vomiting
4
0
0
0
0
Respiratory
Dyspnea
0
0
0
3
0
Rales
0
0
6
0
0
Rhinitis
0
0
6
0
0
Upper respiratory
infection
0
3
0
0
0
CNS
Anxiety
0
0
0
0
4
Convulsions
0
0
0
3
0
Insomnia
0
1
0
0
0
Nervousness
0
0
0
0
4
Psychosis
4
0
0
0
0
Somnolence
0
1
6
0
0
Taste perversion
0
0
0
3
0
Cardiovascular
Atrial fibrillation
0
0
6
0
4
Atrial flutter
0
1
0
0
0
Cardiac failure
0
1
0
0
0
Hypertension
0
0
6
0
4
Syncope
0
0
6
0
0
Tachycardia
0
0
6
0
4
Endocrine
Hypothyroidism
0
0
6
0
0
Hemic and Lymphatic
Anemia
0
0
6
0
0
Leukopenia
4
0
0
0
0
Neutropenia
0
1
0
0
0
Thrombocytopenia
0
1
0
0
0
Musculoskeletal
Myalgia
0
1
0
0
0
Urogenital
Uremia
4
0
0
0
0
Laboratory Abnormalities
Hypocalcemia
0
1
12
0
0
Hypokalemia
4
4
18
0
0
Hypomagnesemia
4
10
12
3
4
Hypophosphatemia
0
9
18
3
0
Abnormal liver
function
0
0
0
3
0
Paget’s Disease
Transient mild elevation of temperature >1°C above pretreatment baseline was noted within
48 hours after completion of treatment in 21% of the patients treated with 90 mg of Aredia in
clinical trials.
Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache,
paresthesia, increased sweating) were more common in patients with Paget’s disease treated
with 90 mg of Aredia than in patients with hypercalcemia of malignancy treated with the same
dose.
Adverse experiences considered to be related to trial drug, which occurred in at least 5%
of patients with Paget’s disease treated with 90 mg of Aredia in two U.S. clinical trials, were
fever, nausea, back pain, and bone pain.
At least 10% of all Aredia-treated patients with Paget’s disease also experienced the
following adverse experiences during clinical trials:
Cardiovascular: Hypertension
Musculoskeletal: Arthrosis, bone pain
Nervous system: Headache
Most of these adverse experiences may have been related to the underlying disease state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple
Myeloma
The most commonly reported (>15%) adverse experiences occurred with similar frequencies
in the Aredia and placebo treatment groups, and most of these adverse experiences may
have been related to the underlying disease state or cancer therapy.
Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
Aredia®
Aredia®
90 mg
90 mg
All Aredia®
over 4 hours Placebo
over 2 hours Placebo 90 mg
Placebo
N=205
N=187
N=367
N=386
N=572
N=573
%
%
%
%
%
%
General
Asthenia
16.1
17.1
25.6
19.2
22.2
18.5
Fatigue
31.7
28.3
40.3
28.8
37.2
29.0
Fever
38.5
38.0
38.1
32.1
38.5
34.0
Metastases
1.0
3.0
31.3
24.4
20.5
17.5
Pain
13.2
11.8
15.0
18.1
14.3
16.1
Digestive System
Anorexia
17.1
17.1
31.1
24.9
26.0
22.3
Constipation
28.3
31.7
36.0
38.6
33.2
35.1
Diarrhea
26.8
26.8
29.4
30.6
28.5
29.7
Dyspepsia
17.6
13.4
18.3
15.0
22.6
17.5
Nausea
35.6
37.4
63.5
59.1
53.5
51.8
Pain Abdominal
19.5
16.0
24.3
18.1
22.6
17.5
Vomiting
16.6
19.8
46.3
39.1
35.7
32.8
Hemic and Lymphatic
Anemia
47.8
41.7
39.5
36.8
42.5
38.4
Granulocytopenia
20.5
15.5
19.3
20.5
19.8
18.8
Thrombocytopenia
16.6
17.1
12.5
14.0
14.0
15.0
Musculoskeletal System
Arthralgias
10.7
7.0
15.3
12.7
13.6
10.8
Myalgia
25.4
15.0
26.4
22.5
26.0
20.1
Skeletal Pain
61.0
71.7
70.0
75.4
66.8
74.0
CNS
Anxiety
7.8
9.1
18.0
16.8
14.3
14.3
Headache
24.4
19.8
27.2
23.6
26.2
22.3
Insomnia
17.1
17.2
25.1
19.4
22.2
19.0
Respiratory System
Coughing
26.3
22.5
25.3
19.7
25.7
20.6
Dyspnea
22.0
21.4
35.1
24.4
30.4
23.4
Pleural Effusion
2.9
4.3
15.0
9.1
10.7
7.5
Sinusitis
14.6
16.6
16.1
10.4
15.6
12.0
Upper Respiratory Tract
Infection
32.2
28.3
19.6
20.2
24.1
22.9
Urogenital System
Urinary Tract Infection
15.6
9.1
20.2
17.6
18.5
15.6
Of the toxicities commonly associated with chemotherapy, the frequency of vomiting,
anorexia, and anemia were slightly more common in the Aredia patients whereas stomatitis
and alopecia occurred at a frequency similar to that in placebo patients. In the breast cancer
trials, mild elevations of serum creatinine occurred in 18.5% of Aredia patients and 12.3% of
placebo patients. Mineral and electrolyte disturbances, including hypocalcemia, were reported
rarely and in similar percentages of Aredia-treated patients compared with those in the placebo
group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia, and
hypomagnesemia for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively,
and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively. In previous
hypercalcemia of malignancy trials, patients treated with Aredia (60 or 90 mg over 24 hours)
developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS,
Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the Aredia group than in
the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively).
In multiple myeloma patients, there were five Aredia-related serious and unexpected
adverse experiences. Four of these were reported during the 12-month extension of the
multiple myeloma trial. Three of the reports were of worsening renal function developing in
patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The
fourth report was the adult respiratory distress syndrome developing in a patient recovering
from pneumonia and acute gangrenous cholecystitis. One Aredia-treated patient experienced
an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat
within 24 hours after the sixth infusion.
In the breast cancer trials, there were four Aredia-related adverse experiences, all moderate
in severity, that caused a patient to discontinue participation in the trial. One was due to
interstitial pneumonitis, another to malaise and dyspnea. One Aredia patient discontinued the
trial due to a symptomatic hypocalcemia. Another Aredia patient discontinued therapy due to
severe bone pain after each infusion, which the investigator felt was trial-drug-related.
Renal Toxicity
In a study of the safety and efficacy of Aredia 90 mg (2 hour infusion) versus Zometa 4 mg
(15 minute infusion) in bone metastases patients with multiple myeloma or breast cancer,
renal deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for patients
with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an
abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal
deterioration in patients in this trial. See Table below.
Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer
Patients with Normal and Abnormal Serum Creatinine at Baseline*
Patient Population/Baseline Creatinine
Aredia® 90 mg/2 hours
Zometa® 4 mg/15 minutes
n/N
(%)
n/N
(%)
Normal
20/246
(8.1%)
23/246
(9.3%)
Abnormal
2/22
(9.1%)
1/26
(3.8%)
Total
22/268
(8.2%)
24/272
(8.8%)
*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.
Post-Marketing Experience
Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or
angioedema, and, very rarely, anaphylactic shock. Aredia is contraindicated in patients with clini-
cally significant hypersensitivity to Aredia or other bisphosphonates (see CONTRAINDICATIONS).
Cases of osteonecrosis (primarily of the jaws) have been reported since market introduc-
tion. Osteonecrosis of the jaws has other well documented multiple risk factors. It is not
possible to determine if these events are related to Aredia or other bisphosphonates, to con-
comitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to
patient’s underlying disease, or to other comorbid risk factors (e.g., anemia, infection,
preexisting oral disease). (See PRECAUTIONS.)
OVERDOSAGE
There have been several cases of drug maladministration of intravenous Aredia in hypercal-
cemia patients with total doses of 225 mg to 300 mg given over 2 1/2 to 4 days. All of these
patients survived, but they experienced hypocalcemia that required intravenous and/or oral
administration of calcium. Single doses of Aredia should not exceed 90 mg and the dura-
tion of the intravenous infusion should be no less than 2 hours. (See WARNINGS.)
In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for
3 days experienced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg),
and transient taste perversion, noted about 6 hours after the first infusion. The fever and
hypotension were rapidly corrected with steroids.
If overdosage occurs, symptomatic hypocalcemia could also result; such patients should
be treated with short-term intravenous calcium.
DOSAGE AND ADMINISTRATION
Hypercalcemia of Malignancy
Consideration should be given to the severity of as well as the symptoms of hypercalcemia.
Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic hypercal-
cemia. Overhydration should be avoided in patients who have potential for cardiac failure. In
hypercalcemia associated with hematologic malignancies, the use of glucocorticoid therapy
may be helpful.
Moderate Hypercalcemia
The recommended dose of Aredia in moderate hypercalcemia (corrected serum
calcium* of approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE,
intravenous infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce
the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.
Severe Hypercalcemia
The recommended dose of Aredia in severe hypercalcemia (corrected serum
calcium*>13.5 mg/dL) is 90 mg given as a SINGLE-DOSE, intravenous infusion over
2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity,
particularly in patients with preexisting renal insufficiency.
*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum
albumin, g/dL).
Retreatment
A limited number of patients have received more than one treatment with Aredia for hypercal-
cemia. Retreatment with Aredia, in patients who show complete or partial response initially,
may be carried out if serum calcium does not return to normal or remain normal after initial
treatment. It is recommended that a minimum of 7 days elapse before retreatment, to
allow for full response to the initial dose. The dose and manner of retreatment is identical
to that of the initial therapy.
Paget’s Disease
The recommended dose of Aredia in patients with moderate to severe Paget’s disease
of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a
total dose of 90 mg.
Retreatment
A limited number of patients with Paget’s disease have received more than one treatment of
Aredia in clinical trials. When clinically indicated, patients should be retreated at the dose of
initial therapy.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of Aredia in patients with osteolytic bone lesions of multiple
myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.
Patients with marked Bence-Jones proteinuria and dehydration should receive adequate
hydration prior to Aredia infusion.
Limited information is available on the use of Aredia in multiple myeloma patients with a
serum creatinine ≥3.0 mg/dL.
Patients who receive Aredia should have serum creatinine assessed prior to each treat-
ment. Treatment should be withheld for renal deterioration. In a clinical study, renal deteriora-
tion was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned to
within 10% of the baseline value.
The optimal duration of therapy is not yet known, however, in a study of patients with
myeloma, final analysis after 21 months demonstrated overall benefits (see CLINICAL
TRIALS section).
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg
administered over a 2-hour infusion given every 3-4 weeks.
Aredia has been frequently used with doxorubicin, fluorouracil, cyclophosphamide,
methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine,
megesterol, and tamoxifen. It has been given less frequently with etoposide, cisplatin,
cytarabine, paclitaxel, and aminoglutethimide.
Patients who receive Aredia should have serum creatinine assessed prior to each treat-
ment. Treatment should be withheld for renal deterioration. In a clinical study, renal deteriora-
tion was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned to
within 10% of the baseline value.
The optimal duration of therapy is not known, however, in two breast cancer studies, final
analyses performed after 24 months of therapy demonstrated overall benefits (see CLINICAL
TRIALS section).
Preparation of Solution
Reconstitution
Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial,
resulting in a solution of 30 mg/10 mL or 90 mg/10 mL. The pH of the reconstituted solution is
6.0-7.4. The drug should be completely dissolved before the solution is withdrawn.
Method of Administration
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNC-
TION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA
SHOULD NOT EXCEED 90 MG. (SEE WARNINGS.)
There must be strict adherence to the intravenous administration recommendations for
Aredia in order to decrease the risk of deterioration in renal function.
Hypercalcemia of Malignancy
The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours
for the 60-mg and 90-mg doses. The recommended dose should be diluted in 1000 mL of
sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. This infusion
solution is stable for up to 24 hours at room temperature.
Paget’s Disease
The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period
for 3 consecutive days.
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 2-hour period
every 3-4 weeks.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period
on a monthly basis.
Aredia must not be mixed with calcium-containing infusion solutions, such as
Ringer’s solution, and should be given in a single intravenous solution and line
separate from all other drugs.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration at
2°C-8°C (36°F-46°F) for up to 24 hours.
HOW SUPPLIED
Vials - 30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and
470 mg of mannitol, USP.
Carton of 4 vials.....................................................................................NDC 0083-2601-04
Vials - 90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and
375 mg of mannitol, USP.
Carton of 1 vial.......................................................................................NDC 0083-2609-01
Do not store above 30°C (86°F).
T2004-70
REV: AUGUST 2004 Printed in U.S.A.
5000083
5000084
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Aredia® pamidronate disodium for injection
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:46:31.821880
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20036s030lbl.pdf', 'application_number': 20036, 'submission_type': 'SUPPL ', 'submission_number': 30}
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12,155
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T2005-27
Aredia
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor available in 30-mg or
90-mg vials for intravenous administration. Each 30-mg, and 90-mg vial contains,
respectively, 30 mg and 90 mg of sterile, lyophilized pamidronate disodium and 470 mg and
375 mg of mannitol, USP. The pH of a 1% solution of pamidronate disodium in distilled
water is approximately 8.3. Aredia, a member of the group of chemical compounds known as
bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated
chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt,
pentahydrate, (APD), and its structural formula is
Pamidronate disodium is a white-to-practically-white powder. It is soluble in water and
in 2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid,
and practically insoluble in organic solvents. Its molecular formula is C3H9NO7P2Na2•5H2O
and its molecular weight is 369.1.
Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5
prior to lyophilization).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the
mechanism of antiresorptive action is not completely understood, several factors are thought
to contribute to this action. Aredia adsorbs to calcium phosphate (hydroxyapatite) crystals in
bone and may directly block dissolution of this mineral component of bone. In vitro studies
also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption.
In animal studies, at doses recommended for the treatment of hypercalcemia, Aredia inhibits
bone resorption apparently without inhibiting bone formation and mineralization. Of relevance
to the treatment of hypercalcemia of malignancy is the finding that Aredia inhibits the
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Page 2
accelerated bone resorption that results from osteoclast hyperactivity induced by various
tumors in animal studies.
Pharmacokinetics
Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous
infusion of 30, 60, or 90 mg of Aredia over 4 hours and 90 mg of Aredia over 24 hours
(Table 1).
Distribution
The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose over
120 hours.
Metabolism
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Excretion
After administration of 30, 60, and 90 mg of Aredia over 4 hours, and 90 mg of Aredia over
24 hours, an overall mean ± SD of 46 ± 16% of the drug was excreted unchanged in the urine
within 120 hours. Cumulative urinary excretion was linearly related to dose. The mean ± SD
elimination half-life is 28 ± 7 hours. Mean ± SD total and renal clearances of pamidronate
were 107 ± 50 mL/min and 49 ± 28 mL/min, respectively. The rate of elimination from bone
has not been determined.
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of
pamidronate.
Pediatric
Pamidronate is not labeled for use in the pediatric population.
Renal Insufficiency
The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and
varying degrees of renal impairment. Each patient received a single 90-mg dose of Aredia
infused over 4 hours. The renal clearance of pamidronate in patients was found to closely
correlate with creatinine clearance (see Figure 1). A trend toward a lower percentage of drug
excreted unchanged in urine was observed in renally impaired patients. Adverse experiences
noted were not found to be related to changes in renal clearance of pamidronate. Given the
recommended dose, 90 mg infused over 4 hours, excessive accumulation of pamidronate in
renally impaired patients is not anticipated if Aredia is administered on a monthly basis.
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Figure 1: Pamidronate renal clearance as a function of creatinine
clearance in patients with normal and impaired renal function.
The lines are the mean prediction line and 95% confidence intervals.
Hepatic Insufficiency
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone
metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction
(n=7). Each patient received a single 90-mg dose of Aredia infused over 4 hours. Although
there was a statistically significant difference in the pharmacokinetics between patients with
normal and impaired hepatic function, the difference was not considered clinically relevant.
Patients with hepatic impairment exhibited higher mean AUC (53%) and Cmax (29%), and
decreased plasma clearance (33%) values. Nevertheless, pamidronate was still rapidly cleared
from the plasma. Drug levels were not detectable in patients by 12 to 36 hours after drug
infusion. Because Aredia is administered on a monthly basis, drug accumulation is not
expected. No changes in Aredia dosing regimen are recommended for patients with mild to
moderate abnormal hepatic function. Aredia has not been studied in patients with severe
hepatic impairment.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
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Table 1
Mean (SD, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients
(n=6 for each group)
Maximum
Percent
Total
Renal
Dose
Concentration
of dose
Clearance
Clearance
(infusion rate)
(µg/mL)
excreted in urine
(mL/min)
(mL/min)
30 mg
0.73
43.9
136
58
(4 hrs)
(0.14, 19.1%)
(14.0, 31.9%)
(44, 32.4%)
(27, 46.5%)
60 mg
1.44
47.4
88
42
(4 hrs)
(0.57, 39.6%)
(47.4, 54.4%)
(56, 63.6%)
(28, 66.7%)
90 mg
2.61
45.3
103
44
(4 hrs)
(0.74, 28.3%)
(25.8, 56.9%)
(37, 35.9%)
(16, 36.4%)
90 mg
1.38
47.5
101
52
(24 hrs)
(1.97, 142.7%)
(10.2, 21.5%)
(58, 57.4%)
(42, 80.8%)
After intravenous administration of radiolabeled pamidronate in rats, approximately
50%-60% of the compound was rapidly adsorbed by bone and slowly eliminated from the
body by the kidneys. In rats given 10 mg/kg bolus injections of radiolabeled Aredia,
approximately 30% of the compound was found in the liver shortly after administration and
was then redistributed to bone or eliminated by the kidneys over 24-48 hours. Studies in rats
injected with radiolabeled Aredia showed that the compound was rapidly cleared from the
circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage.
Radioactivity was eliminated from most soft tissues within 1-4 days; was detectable in liver
and spleen for 1 and 3 months, respectively; and remained high in bones, trachea, and teeth for
6 months after dosing. Bone uptake occurred preferentially in areas of high bone turnover. The
terminal phase of elimination half-life in bone was estimated to be approximately 300 days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia,
presumably because of decreased release of phosphate from bone and increased renal
excretion as parathyroid hormone levels, which are usually suppressed in hypercalcemia
associated with malignancy, return toward normal. Phosphate therapy was administered in
30% of the patients in response to a decrease in serum phosphate levels. Phosphate levels
usually returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and
usually return to within or below normal after treatment with Aredia. These changes occur
within the first week after treatment, as do decreases in serum calcium levels, and are
consistent with an antiresorptive pharmacologic action.
Hypercalcemia of Malignancy
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying
pathophysiologic derangement in metastatic bone disease and hypercalcemia of malignancy.
Excessive release of calcium into the blood as bone is resorbed results in polyuria and
gastrointestinal disturbances, with progressive dehydration and decreasing glomerular
filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle
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Page 5
of worsening systemic hypercalcemia. Correction of excessive bone resorption and adequate
fluid administration to correct volume deficits are therefore essential to the management of
hypercalcemia.
Most cases of hypercalcemia associated with malignancy occur in patients who have
breast cancer; squamous-cell tumors of the lung or head and neck; renal-cell carcinoma; and
certain hematologic malignancies, such as multiple myeloma and some types of lymphomas.
A few less-common malignancies, including vasoactive intestinal-peptide-producing tumors
and cholangiocarcinoma, have a high incidence of hypercalcemia as a metabolic complication.
Patients who have hypercalcemia of malignancy can generally be divided into two groups,
according to the pathophysiologic mechanism involved.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated
by factors such as parathyroid-hormone-related protein, which are elaborated by the tumor and
circulate systemically. Humoral hypercalcemia usually occurs in squamous-cell malignancies
of the lung or head and neck or in genitourinary tumors such as renal-cell carcinoma or
ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local
tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated
with locally mediated hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not
reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly
present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic
conditions; however, these are not commonly or rapidly available in many clinical situations.
Therefore, adjustment of the total serum calcium value for differences in albumin levels is
often used in place of measurement of ionized calcium; several nomograms are in use for this
type of calculation (see DOSAGE AND ADMINISTRATION).
Clinical Trials
In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were
enrolled to receive 30 mg, 60 mg, or 90 mg of Aredia as a single 24-hour intravenous infusion
if their corrected serum calcium levels were ≥12.0 mg/dL after 48 hours of saline hydration.
The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups
were 13.8 mg/dL,13.8 mg/dL, and 13.3 mg/dL, respectively.
The majority of patients (64%) had decreases in albumin-corrected serum calcium
levels by 24 hours after initiation of treatment. Mean-corrected serum calcium levels at days
2-7 after initiation of treatment with Aredia were significantly reduced from baseline in all
three dosage groups. As a result, by 7 days after initiation of treatment with Aredia, 40%,
61%, and 100% of the patients receiving 30 mg, 60 mg, and 90 mg of Aredia, respectively,
had normal-corrected serum calcium levels. Many patients (33%-53%) in the 60-mg and
90-mg dosage groups continued to have normal-corrected serum calcium levels, or a partial
response (≥15% decrease of corrected serum calcium from baseline), at Day 14.
In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected
serum calcium levels of ≥12.0 mg/dL after at least 24 hours of saline hydration were
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randomized to receive either 60 mg of Aredia as a single 24-hour intravenous infusion or
7.5 mg/kg of etidronate disodium as a 2-hour intravenous infusion daily for 3 days. Thirty
patients were randomized to receive Aredia and 35 to receive etidronate disodium.
The mean baseline-corrected serum calcium for the Aredia 60-mg and etidronate
disodium groups were 14.6 mg/dL and 13.8 mg/dL, respectively.
By Day 7, 70% of the patients in the Aredia group and 41% of the patients in the
etidronate disodium group had normal-corrected serum calcium levels (P<0.05). When partial
responders (≥15% decrease of serum calcium from baseline) were also included, the response
rates were 97% for the Aredia group and 65% for the etidronate disodium group (P<0.01).
Mean-corrected serum calcium for the Aredia and etidronate disodium groups decreased from
baseline values to 10.4 and 11.2 mg/dL, respectively, on Day 7. At Day 14, 43% of patients in
the Aredia group and 18% of patients in the etidronate disodium group still had normal-
corrected serum calcium levels, or maintenance of a partial response. For responders in the
Aredia and etidronate disodium groups, the median duration of response was similar (7 and 5
days, respectively). The time course of effect on corrected serum calcium is summarized in the
following table.
Change in Corrected Serum Calcium by Time
from Initiation of Treatment
Time
Mean Change from Baseline in Corrected Serum Calcium (mg/dL)
(hr)
Aredia®
Etidronate Disodium
P-Value1
Baseline
14.6
13.8
24
-0.3
-0.5
48
-1.5
-1.1
72
-2.6
-2.0
96
-3.5
-2.0
<0.01
168
-4.1
-2.5
<0.01
1Comparison between treatment groups
In a third multicenter, randomized, parallel double-blind trial, a group of 69 cancer
patients with hypercalcemia was enrolled to receive 60 mg of Aredia as a 4- or 24-hour
infusion, which was compared to a saline treatment group. Patients who had a corrected serum
calcium level of ≥12.0 mg/dL after 24 hours of saline hydration were eligible for this trial.
The mean baseline-corrected serum calcium levels for Aredia 60-mg 4-hour infusion,
Aredia 60-mg 24-hour infusion, and saline infusion were 14.2 mg/dL, 13.7 mg/dL, and
13.7 mg/dL, respectively.
By Day 7 after initiation of treatment, 78%, 61%, and 22% of the patients had normal-
corrected serum calcium levels for the 60-mg 4-hour infusion, 60-mg 24-hour infusion, and
saline infusion, respectively. At Day 14, 39% of the patients in the Aredia 60-mg 4-hour
infusion group and 26% of the patients in the Aredia 60-mg 24-hour infusion group had
normal-corrected serum calcium levels or maintenance of a partial response.
For responders, the median duration of complete responses was 4 days and 6.5 days for
Aredia 60-mg 4-hour infusion and Aredia 60-mg 24-hour infusion, respectively.
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In all three trials, patients treated with Aredia had similar response rates in the
presence or absence of bone metastases. Concomitant administration of furosemide did not
affect response rates.
Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were
given a second course of 60 mg of Aredia over a 4- or 24-hour period. Of these, 41% showed
a complete response and 16% showed a partial response to the retreatment, and these
responders had about a 3-mg/dL fall in mean-corrected serum calcium levels 7 days after
retreatment.
In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and
hypercalcemia (corrected serum calcium ≥12.0 mg/dL) received 90 mg of Aredia as a 2-hour
infusion. The mean baseline corrected serum calcium was 14.0 mg/dL. Patients were not
required to receive IV hydration prior to drug administration, but all subjects did receive at
least 500 mL of IV saline hydration concomitantly with the pamidronate infusion. By Day 10
after drug infusion, 70% of patients had normal corrected serum calcium levels
(<10.8 mg/dL).
Paget’s Disease
Paget’s disease of bone (osteitis deformans) is an idiopathic disease characterized by chronic,
focal areas of bone destruction complicated by concurrent excessive bone repair, affecting one
or more bones. These changes result in thickened but weakened bones that may fracture or
bend under stress. Signs and symptoms may be bone pain, deformity, fractures, neurological
disorders resulting from cranial and spinal nerve entrapment and from spinal cord and brain
stem compression, increased cardiac output to the involved bone, increased serum alkaline
phosphatase levels (reflecting increased bone formation) and/or urine hydroxyproline
excretion (reflecting increased bone resorption).
Clinical Trials
In one double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone
were enrolled to receive 5 mg, 15 mg, or 30 mg of Aredia as a single 4-hour infusion on 3
consecutive days, for total doses of 15 mg, 45 mg, and 90 mg of Aredia.
The mean baseline serum alkaline phosphatase levels were 1,409 U/L, 983 U/L, and
1,085 U/L, and the mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and
0.19 for the 15-mg, 45-mg, and 90-mg groups, respectively.
The effects of Aredia on serum alkaline phosphatase (SAP) and urine
hydroxyproline/creatinine ratios (UOHP/C) are summarized in the following table:
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Percent of Patients With
Significant % Decreases in SAP and UOHP/C
SAP
UOHP/C
% Decrease
15 mg
45 mg
90 mg
15 mg
45 mg
90 mg
≥50
26
33
60
15
47
72
≥30
40
65
83
35
57
85
The median maximum percent decreases from baseline in serum alkaline phosphatase
and urine hydroxyproline/creatinine ratios were 25%, 41%, and 57%, and 25%, 47%, and 61%
for the 15-mg, 45-mg, and 90-mg groups, respectively. The median time to response (≥50%
decrease) for serum alkaline phosphatase was approximately 1 month for the 90-mg group,
and the response duration ranged from 1 to 372 days.
No statistically significant differences between treatment groups, or statistically
significant changes from baseline were observed for the bone pain response, mobility, and
global evaluation in the 45-mg and 90-mg groups. Improvement in radiologic lesions occurred
in some patients in the 90-mg group.
Twenty-five patients who had Paget’s disease were retreated with 90 mg of Aredia. Of
these, 44% had a ≥50% decrease in serum alkaline phosphatase from baseline after treatment,
and 39% had a ≥50% decrease in urine hydroxyproline/creatinine ratio from baseline after
treatment.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma
Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast
cancer. These cancers demonstrate a phenomenon known as osteotropism, meaning they
possess an extraordinary affinity for bone. The distribution of osteolytic bone metastases in
these cancers is predominantly in the axial skeleton, particularly the spine, pelvis, and ribs,
rather than the appendicular skeleton, although lesions in the proximal femur and humerus are
not uncommon. This distribution is similar to the red bone marrow in which slow blood flow
possibly assists attachment of metastatic cells. The surface-to-volume ratio of trabecular bone
is much higher than cortical bone, and therefore disease processes tend to occur more floridly
in trabecular bone than at sites of cortical tissue.
These bone changes can result in patients having evidence of osteolytic skeletal
destruction leading to severe bone pain that requires either radiation therapy or narcotic
analgesics (or both) for symptomatic relief. These changes also cause pathologic fractures of
bone in both the axial and appendicular skeleton. Axial skeletal fractures of the vertebral
bodies may lead to spinal cord compression or vertebral body collapse with significant
neurologic complications. Also, patients may experience episode(s) of hypercalcemia.
Clinical Trials
In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple
myeloma were enrolled to receive Aredia or placebo in addition to their underlying
antimyeloma therapy to determine the effect of Aredia on the occurrence of skeletal-related
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events (SREs). SREs were defined as episodes of pathologic fractures, radiation therapy to
bone, surgery to bone, and spinal cord compression. Patients received either 90 mg of Aredia
or placebo as a monthly 4-hour intravenous infusion for 9 months. Of the 392 patients, 377
were evaluable for efficacy (196 Aredia, 181 placebo). The proportion of patients developing
any SRE was significantly smaller in the Aredia group (24% vs 41%, P<0.001), and the mean
skeletal morbidity rate (#SRE/year) was significantly smaller for Aredia patients than for
placebo patients (mean: 1.1 vs 2.1, P<.02). The times to the first SRE occurrence, pathologic
fracture, and radiation to bone were significantly longer in the Aredia group (P=.001, .006,
and .046, respectively). Moreover, fewer Aredia patients suffered any pathologic fracture
(17% vs 30%, P=.004) or needed radiation to bone (14% vs 22%, P=.049).
In addition, decreases in pain scores from baseline occurred at the last measurement
for those Aredia patients with pain at baseline (P=.026) but not in the placebo group. At the
last measurement, a worsening from baseline was observed in the placebo group for the
Spitzer quality of life variable (P<.001) and ECOG performance status (P<.011) while there
was no significant deterioration from baseline in these parameters observed in Aredia-treated
patients.*
After 21 months, the proportion of patients experiencing any skeletal event remained
significantly smaller in the Aredia group than the placebo group (P=.015). In addition, the
mean skeletal morbidity rate (#SRE/year) was 1.3 vs 2.2 for Aredia patients versus placebo
patients (P=.008), and time to first SRE was significantly longer in the Aredia group compared
to placebo (P=.016). Fewer Aredia patients suffered vertebral pathologic fractures (16% vs
27%, P=.005). Survival of all patients was not different between treatment groups.
Two double-blind, randomized, placebo-controlled trials compared the safety and
efficacy of 90 mg of Aredia infused over 2 hours every 3 to 4 weeks for 24 months to that of
placebo in preventing SREs in breast cancer patients with osteolytic bone metastases who had
one or more predominantly lytic metastases of at least 1 cm in diameter: one in patients being
treated with antineoplastic chemotherapy and the second in patients being treated with
hormonal antineoplastic therapy at trial entry.
382 patients receiving chemotherapy were randomized, 185 to Aredia and 197 to
placebo. 372 patients receiving hormonal therapy were randomized, 182 to Aredia and 190 to
placebo. All but three patients were evaluable for efficacy. Patients were followed for 24
months of therapy or until they went off study. Median duration of follow-up was 13 months
in patients receiving chemotherapy and 17 months in patients receiving hormone therapy.
Twenty-five percent of the patients in the chemotherapy study and 37% of the patients in the
hormone therapy study received Aredia for 24 months. The efficacy results are shown in the
table below:
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Breast Cancer Patients
Breast Cancer Patients
Receiving Chemotherapy
Receiving Hormonal Therapy
Any SRE
Radiation
Fractures
Any SRE
Radiation
Fractures
A
P
A
P
A
P
A
P
A
P
A
P
N
185
195
185
195
185
195
182 189
182
189
182
189
Skeletal Morbidity Rate
(#SRE/year)
Mean
2.5
3.7
0.8
1.3
1.6
2.2
2.4
3.6
0.6
1.2
1.6
2.2
P-Value
<.001
<.001†
.018†
.021
.013†
.040†
Proportion of
patients having
an SRE
46% 65% 28% 45% 36% 49%
55% 63%
31% 40% 45% 55%
P-Value
<.001
<.001†
.014†
.094
.058†
.054†
Median Time to
SRE (months)
13.9 7.0
NR** 14.2 25.8 13.3
10.9 7.4
NR** 23.4
20.6 12.8
P-Value
<.001
<.001†
.009†
.118
.016†
.113†
†Fractures and radiation to bone were two of several secondary endpoints. The statistical significance of these
analyses may be overestimated since numerous analyses were performed.
**NR = Not Reached.
Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12
months. The complete + partial response rate was 33% in Aredia patients and 18% in placebo
patients treated with chemotherapy (P=.001). No difference was seen between Aredia and
placebo in hormonally-treated patients.
Pain and analgesic scores, ECOG performance status and Spitzer quality of life index
were measured at baseline and periodically during the trials. The changes from baseline to the
last measurement carried forward are shown in the following table:
Mean Change (∆) from Baseline at Last Measurement
Breast Cancer Patients
Breast Cancer Patients
Receiving Chemotherapy
Receiving Hormonal Therapy
Aredia
Placebo
A vs P
Aredia
Placebo
A vs P
N
Mean ∆
N
Mean ∆
P-Value*
N Mean ∆
N
Mean ∆
P-Value*
Pain Score
175
+0.93 183
+1.69
.050
173
+0.50
179
+1.60
.007
Analgesic
Score
175
+0.74 183
+1.55
.009
173
+0.90
179
+2.28
<.001
ECOG PS
178
+0.81 186
+1.19
.002
175
+0.95
182
+0.90
.773
Spitzer
QOL
177
-1.76 185
-2.21
.103
173
-1.86
181
-2.05
.409
Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an improvement from
baseline.
__________________________________
*The statistical significance of analyses of these secondary endpoints of pain, quality of life, and
performance status in all three trials may be overestimated since numerous analyses were performed.
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INDICATIONS AND USAGE
Hypercalcemia of Malignancy
Aredia, in conjunction with adequate hydration, is indicated for the treatment of moderate or
severe hypercalcemia associated with malignancy, with or without bone metastases. Patients
who have either epidermoid or non-epidermoid tumors respond to treatment with Aredia.
Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated
promptly and an attempt should be made to restore the urine output to about 2 L/day
throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative
measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated
adequately throughout the treatment, but overhydration, especially in those patients who have
cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction
of hypovolemia. The safety and efficacy of Aredia in the treatment of hypercalcemia
associated with hyperparathyroidism or with other non-tumor-related conditions has not been
established.
Paget’s Disease
Aredia is indicated for the treatment of patients with moderate to severe Paget’s disease of
bone. The effectiveness of Aredia was demonstrated primarily in patients with serum alkaline
phosphatase ≥3 times the upper limit of normal. Aredia therapy in patients with Paget’s
disease has been effective in reducing serum alkaline phosphatase and urinary hydroxyproline
levels by ≥50% in at least 50% of patients, and by ≥30% in at least 80% of patients. Aredia
therapy has also been effective in reducing these biochemical markers in patients with Paget’s
disease who failed to respond, or no longer responded to other treatments.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma
Aredia is indicated, in conjunction with standard antineoplastic therapy, for the treatment of
osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. The
Aredia treatment effect appeared to be smaller in the study of breast cancer patients receiving
hormonal therapy than in the study of those receiving chemotherapy, however, overall
evidence of clinical benefit has been demonstrated (see CLINICAL PHARMACOLOGY,
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma,
Clinical Trials section).
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or
other bisphosphonates.
WARNINGS
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN
RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE
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DOSES OF AREDIA SHOULD NOT EXCEED 90 MG (see DOSAGE AND
ADMINISTRATION for appropriate infusion durations).
Bisphosphonates, including Aredia, have been associated with renal toxicity
manifested as deterioration of renal function and potential renal failure.
Patients who receive Aredia should have serum creatinine assessed prior to each
treatment. Patients treated with Aredia for bone metastases should have the dose withheld if
renal function has deteriorated. (See DOSAGE AND ADMINISTRATION.)
In both rats and dogs, nephropathy has been associated with intravenous (bolus and
infusion) administration of Aredia.
Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia was
given for 1, 4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the
compound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD]
for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such
as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was
infused for 1 hour and at doses of ≥10 mg/kg. In the second study, slight renal tubular necrosis
was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included
elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation
at ≥1 mg/kg after each infusion time.
Aredia was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6,
and 20 mg/kg as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery
period. In rats, nephrotoxicity was observed at ≥6 mg/kg and included increased BUN and
creatinine levels and tubular degeneration and necrosis. These findings were still present at
20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity
occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at
≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially
reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects
was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).
PREGNANCY: AREDIA SHOULD NOT BE USED DURING
PREGNANCY
Aredia may cause fetal harm when administered to a pregnant woman. (See PRECAUTIONS,
Pregnancy Category D.)
There are no studies in pregnant women using Aredia. If the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential harm to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant.
Studies conducted in young rats have reported the disruption of dental dentine
formation following single- and multi-dose administration of bisphosphonates. The clinical
significance of these findings is unknown.
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PRECAUTIONS
General
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium,
phosphate, magnesium, and potassium, should be carefully monitored following initiation of
therapy with Aredia. Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%),
hypomagnesemia (11%), and hypocalcemia (5%-12%), were reported in Aredia-treated
patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in
association with Aredia therapy. If hypocalcemia occurs, short-term calcium therapy may be
necessary. In Paget’s disease of bone, 17% of patients treated with 90 mg of Aredia showed
serum calcium levels below 8 mg/dL.
Renal Insufficiency
Aredia is excreted intact primarily via the kidney, and the risk of renal adverse reactions may
be greater in patients with impaired renal function. Patients who receive Aredia should have
serum creatinine assessed prior to each treatment. In patients receiving Aredia for bone
metastases, who show evidence of deterioration in renal function, Aredia treatment should be
withheld until renal function returns to baseline (see WARNINGS and DOSAGE AND
ADMINISTRATION).
Aredia has not been tested in patients who have class Dc renal impairment (creatinine
>5.0 mg/dL), and has been tested in few multiple myeloma patients with serum creatinine
≥3.0 mg/dL. (See also CLINICAL PHARMACOLOGY, Pharmacokinetics.) For the treatment
of bone metastases, the use of Aredia in patients with severe renal impairment is not
recommended. In other indications, clinical judgment should determine whether the potential
benefit outweighs the potential risk in such patients.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment
regimens including bisphosphonates. Many of these patients were also receiving
chemotherapy and corticosteroids. The majority of reported cases have been associated with
dental procedures such as tooth extraction. Many had signs of local infection including
osteomyelitis.
A dental examination with appropriate preventive dentistry should be considered prior
to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer,
chemotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible.
For patients who develop ONJ while on bisphosphonate therapy, dental surgery may
exacerbate the condition. For patients requiring dental procedures, there are no data available
to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ.
Clinical judgment of the treating physician should guide the management plan of each patient
based on individual benefit/risk assessment.
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Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or
muscle pain has been reported in patients taking bisphosphonates. However, such reports have
been infrequent. This category of drugs includes Aredia (pamidronate disodium for injection).
The time to onset of symptoms varied from one day to several months after starting the drug.
Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms
when rechallenged with the same drug or another bisphosphonate.
Laboratory Tests
Patients who receive Aredia should have serum creatinine assessed prior to each treatment.
Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and
hematocrit/hemoglobin must be closely monitored in patients treated with Aredia. Patients
who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully
in the first 2 weeks following treatment.
Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of
Aredia.
Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study (daily oral administration) in rats, there was a positive
dose response relationship for benign adrenal pheochromocytoma in males (P <0.00001).
Although this condition was also observed in females, the incidence was not statistically
significant. When the dose calculations were adjusted to account for the limited oral
bioavailability of Aredia in rats, the lowest daily dose associated with adrenal
pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma was
also observed in low numbers in the control animals and is considered a relatively common
spontaneous neoplasm in the rat. Aredia (daily oral administration) was not carcinogenic in an
80-week study in mice.
Aredia was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and
Escherichia/ liver-microsome test, nucleus-anomaly test, sister-chromatid-exchange study,
point-mutation test, and micronucleus test in the rat.
In rats, decreased fertility occurred in first-generation offspring of parents who had
received 150 mg/kg of Aredia orally; however, this occurred only when animals were mated
with members of the same dose group. Aredia has not been administered intravenously in such
a study.
Pregnancy Category D (See WARNINGS)
There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia
produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses
of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As
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it has been shown that Aredia can cross the placenta in rats and has produced marked maternal
and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women
during pregnancy.
Bisphosphonates are incorporated into the bone matrix, from where they are gradually
released over periods of weeks to years. The extent of bisphosphonate incorporation into adult
bone, and hence, the amount available for release back into the systemic circulation, is directly
related to the total dose and duration of bisphosphonate use. Although there are no data on
fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest
that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore,
there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman
becomes pregnant after completing a course of bisphosphonate therapy. The impact of
variables such as time between cessation of bisphosphonate therapy to conception, the
particular bisphosphonate used, and the route of administration (intravenous versus oral) on
this risk has not been established.
Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when Aredia is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Aredia in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects in clinical studies of Aredia, approximately 20% were 65 and
over, while approximately 15% were 75 and over. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing
range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function , and of
concomitant disease or other drug therapy.
ADVERSE REACTIONS
Clinical Studies
Hypercalcemia of Malignancy
Transient mild elevation of temperature by at least 1 °C was noted 24 to 48 hours after
administration of Aredia in 34% of patients in clinical trials. In the saline trial, 18% of patients
had a temperature elevation of at least 1 °C 24 to 48 hours after treatment.
Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on
palpation) at the site of catheter insertion were most common in patients treated with 90 mg of
Aredia. Symptomatic treatment resulted in rapid resolution in all patients.
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Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one
case of scleritis, and one case of uveitis upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the four U.S. controlled
hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting
seizure disorders. None of the seizures were considered to be drug-related by the investigators.
However, a possible relationship between the drug and the occurrence of seizures cannot be
ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90-mg
Aredia over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a
comparison of data from separate clinical trials suggests that the overall safety profile in
patients who received 90-mg Aredia over 24 hours is similar to those who received 90-mg
Aredia over 2 hours. The only notable differences observed were an increase in the proportion
of patients in the Aredia 24-hour group who experienced fluid overload and
electrolyte/mineral abnormalities.
At least 15% of patients treated with Aredia for hypercalcemia of malignancy also
experienced the following adverse events during a clinical trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting
Genitourinary: Urinary tract infection
Musculoskeletal: Bone pain
Laboratory
Abnormality:
Anemia,
hypokalemia,
hypomagnesemia,
hypophosphatemia
Many of these adverse experiences may have been related to the underlying disease
state. The following table lists the adverse experiences considered to be treatment-related
during comparative, controlled U.S. trials.
Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials
Percent of Patients
Aredia®
Etidronate Disodium
Saline
60 mg
60 mg
90 mg
7.5 mg/kg
over 4 hr
over 24 hr
over 24 hr
x 3 days
n=23
n=73
n=17
n=35
n=23
General
Edema
0
1
0
0
0
Fatigue
0
0
12
0
0
Fever
26
19
18
9
0
Fluid overload
0
0
0
6
0
Infusion-site reaction
0
4
18
0
0
Moniliasis
0
0
6
0
0
Rigors
0
0
0
0
4
Gastrointestinal
Abdominal pain
0
1
0
0
0
Anorexia
4
1
12
0
0
Constipation
4
0
6
3
0
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Diarrhea
0
1
0
0
0
Dyspepsia
4
0
0
0
0
Gastrointestinal
hemorrhage
0
0
6
0
0
Nausea
4
0
18
6
0
Stomatitis
0
1
0
3
0
Vomiting
4
0
0
0
0
Respiratory
Dyspnea
0
0
0
3
0
Rales
0
0
6
0
0
Rhinitis
0
0
6
0
0
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Upper respiratory
infection
0
3
0
0
0
CNS
Anxiety
0
0
0
0
4
Convulsions
0
0
0
3
0
Insomnia
0
1
0
0
0
Nervousness
0
0
0
0
4
Psychosis
4
0
0
0
0
Somnolence
0
1
6
0
0
Taste perversion
0
0
0
3
0
Cardiovascular
Atrial fibrillation
0
0
6
0
4
Atrial flutter
0
1
0
0
0
Cardiac failure
0
1
0
0
0
Hypertension
0
0
6
0
4
Syncope
0
0
6
0
0
Tachycardia
0
0
6
0
4
Endocrine
Hypothyroidism
0
0
6
0
0
Hemic and Lymphatic
Anemia
0
0
6
0
0
Leukopenia
4
0
0
0
0
Neutropenia
0
1
0
0
0
Thrombocytopenia
0
1
0
0
0
Musculoskeletal
Myalgia
0
1
0
0
0
Urogenital
Uremia
4
0
0
0
0
Laboratory Abnormalities
Hypocalcemia
0
1
12
0
0
Hypokalemia
4
4
18
0
0
Hypomagnesemia
4
10
12
3
4
Hypophosphatemia
0
9
18
3
0
Abnormal liver
function
0
0
0
3
0
Paget’s Disease
Transient mild elevation of temperature >1 °C above pretreatment baseline was noted within
48 hours after completion of treatment in 21% of the patients treated with 90 mg of Aredia in
clinical trials.
Drug-related musculoskeletal pain and nervous system symptoms (dizziness,
headache, paresthesia, increased sweating) were more common in patients with Paget’s
disease treated with 90 mg of Aredia than in patients with hypercalcemia of malignancy
treated with the same dose.
Adverse experiences considered to be related to trial drug, which occurred in at least
5% of patients with Paget’s disease treated with 90 mg of Aredia in two U.S. clinical trials,
were fever, nausea, back pain, and bone pain.
At least 10% of all Aredia-treated patients with Paget’s disease also experienced the
following adverse experiences during clinical trials:
Cardiovascular: Hypertension
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Musculoskeletal: Arthrosis, bone pain
Nervous system: Headache
Most of these adverse experiences may have been related to the underlying disease
state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma
The most commonly reported (>15%) adverse experiences occurred with similar frequencies
in the Aredia- and placebo-treatment groups, and most of these adverse experiences may have
been related to the underlying disease state or cancer therapy.
Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
Aredia®
Aredia®
All
90 mg
90 mg
Aredia®
over 4 hours
Placebo
over 2 hours
Placebo
90 mg
Placebo
N=205
N=187
N=367
N=386
N=572
N=573
%
%
%
%
%
%
General
Asthenia
16.1
17.1
25.6
19.2
22.2
18.5
Fatigue
31.7
28.3
40.3
28.8
37.2
29.0
Fever
38.5
38.0
38.1
32.1
38.5
34.0
Metastases
1.0
3.0
31.3
24.4
20.5
17.5
Pain
13.2
11.8
15.0
18.1
14.3
16.1
Digestive System
Anorexia
17.1
17.1
31.1
24.9
26.0
22.3
Constipation
28.3
31.7
36.0
38.6
33.2
35.1
Diarrhea
26.8
26.8
29.4
30.6
28.5
29.7
Dyspepsia
17.6
13.4
18.3
15.0
22.6
17.5
Nausea
35.6
37.4
63.5
59.1
53.5
51.8
Pain Abdominal
19.5
16.0
24.3
18.1
22.6
17.5
Vomiting
16.6
19.8
46.3
39.1
35.7
32.8
Hemic and Lymphatic
Anemia
47.8
41.7
39.5
36.8
42.5
38.4
Granulocytopenia
20.5
15.5
19.3
20.5
19.8
18.8
Thrombocytopenia
16.6
17.1
12.5
14.0
14.0
15.0
Musculoskeletal System
Arthralgias
10.7
7.0
15.3
12.7
13.6
10.8
Myalgia
25.4
15.0
26.4
22.5
26.0
20.1
Skeletal Pain
61.0
71.7
70.0
75.4
66.8
74.0
CNS
Anxiety
7.8
9.1
18.0
16.8
14.3
14.3
Headache
24.4
19.8
27.2
23.6
26.2
22.3
Insomnia
17.1
17.2
25.1
19.4
22.2
19.0
Respiratory System
Coughing
26.3
22.5
25.3
19.7
25.7
20.6
Dyspnea
22.0
21.4
35.1
24.4
30.4
23.4
Pleural Effusion
2.9
4.3
15.0
9.1
10.7
7.5
Sinusitis
14.6
16.6
16.1
10.4
15.6
12.0
Upper Respiratory Tract
Infection
32.2
28.3
19.6
20.2
24.1
22.9
Urogenital System
Urinary Tract Infection
15.6
9.1
20.2
17.6
18.5
15.6
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Page 20
Of the toxicities commonly associated with chemotherapy, the frequency of vomiting,
anorexia, and anemia were slightly more common in the Aredia patients whereas stomatitis
and alopecia occurred at a frequency similar to that in placebo patients. In the breast cancer
trials, mild elevations of serum creatinine occurred in 18.5% of Aredia patients and 12.3% of
placebo patients. Mineral and electrolyte disturbances, including hypocalcemia, were reported
rarely and in similar percentages of Aredia-treated patients compared with those in the placebo
group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia, and
hypomagnesemia for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively,
and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively. In previous
hypercalcemia of malignancy trials, patients treated with Aredia (60 or 90 mg over 24 hours)
developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS,
Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the Aredia group
than in the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively).
In multiple myeloma patients, there were five Aredia-related serious and unexpected
adverse experiences. Four of these were reported during the 12-month extension of the
multiple myeloma trial. Three of the reports were of worsening renal function developing in
patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The
fourth report was the adult respiratory distress syndrome developing in a patient recovering
from pneumonia and acute gangrenous cholecystitis. One Aredia-treated patient experienced
an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat
within 24 hours after the sixth infusion.
In the breast cancer trials, there were four Aredia-related adverse experiences, all
moderate in severity, that caused a patient to discontinue participation in the trial. One was
due to interstitial pneumonitis, another to malaise and dyspnea. One Aredia patient
discontinued the trial due to a symptomatic hypocalcemia. Another Aredia patient
discontinued therapy due to severe bone pain after each infusion, which the investigator felt
was trial-drug-related.
Renal Toxicity
In a study of the safety and efficacy of Aredia 90 mg (2-hour infusion) versus Zometa 4 mg
(15-minute infusion) in bone metastases patients with multiple myeloma or breast cancer,
renal deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for patients
with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an
abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal
deterioration in patients in this trial. See Table below.
Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer
Patients with Normal and Abnormal Serum Creatinine at Baseline*
Patient Population/Baseline Creatinine
Aredia
® 90 mg/2 hours
Zometa
® 4 mg/15 minutes
n/N
(%)
n/N
(%)
Normal
20/246
(8.1%)
23/246
(9.3%)
Abnormal
2/22
(9.1%)
1/26
(3.8%)
Total
22/268
(8.2%)
24/272
(8.8%)
*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.
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Page 21
Post-Marketing Experience
Rare instances of allergic manifestations have been reported, including hypotension, dyspnea,
or angioedema, and, very rarely, anaphylactic shock. Aredia is contraindicated in patients with
clinically
significant
hypersensitivity
to
Aredia
or
other
bisphosphonates
(see
CONTRAINDICATIONS).
Cases of osteonecrosis (primarily of the jaws) have been reported since market introduction.
Osteonecrosis of the jaws has other well documented multiple risk factors. It is not possible to
determine if these events are related to Aredia or other bisphosphonates, to concomitant drugs
or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to patient’s underlying
disease, or to other comorbid risk factors (e.g., anemia, infection, preexisting oral disease).
(See PRECAUTIONS.)
OVERDOSAGE
There have been several cases of drug maladministration of intravenous Aredia in
hypercalcemia patients with total doses of 225 mg to 300 mg given over 2 ½ to 4 days. All of
these patients survived, but they experienced hypocalcemia that required intravenous and/or
oral administration of calcium. Single doses of Aredia should not exceed 90 mg and the
duration of the intravenous infusion should be no less than 2 hours. (See WARNINGS.)
In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for
3 days experienced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg),
and transient taste perversion, noted about 6 hours after the first infusion. The fever and
hypotension were rapidly corrected with steroids.
If overdosage occurs, symptomatic hypocalcemia could also result; such patients
should be treated with short-term intravenous calcium.
DOSAGE AND ADMINISTRATION
Hypercalcemia of Malignancy
Consideration should be given to the severity of as well as the symptoms of hypercalcemia.
Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic
hypercalcemia. Overhydration should be avoided in patients who have potential for cardiac
failure. In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid
therapy may be helpful.
Moderate Hypercalcemia
The recommended dose of Aredia in moderate hypercalcemia (corrected serum calcium*
of approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE, intravenous
infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal
toxicity, particularly in patients with preexisting renal insufficiency.
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Page 22
Severe Hypercalcemia
The recommended dose of Aredia in severe hypercalcemia (corrected serum
calcium*>13.5 mg/dL) is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2
to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity,
particularly in patients with preexisting renal insufficiency.
___________________________
*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8
(4.0-serum albumin, g/dL).
Retreatment
A limited number of patients have received more than one treatment with Aredia for
hypercalcemia. Retreatment with Aredia, in patients who show complete or partial response
initially, may be carried out if serum calcium does not return to normal or remain normal after
initial treatment. It is recommended that a minimum of 7 days elapse before retreatment,
to allow for full response to the initial dose. The dose and manner of retreatment is
identical to that of the initial therapy.
Paget’s Disease
The recommended dose of Aredia in patients with moderate to severe Paget’s disease of
bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total
dose of 90 mg.
Retreatment
A limited number of patients with Paget’s disease have received more than one treatment of
Aredia in clinical trials. When clinically indicated, patients should be retreated at the dose of
initial therapy.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of Aredia in patients with osteolytic bone lesions of multiple
myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.
Patients with marked Bence-Jones proteinuria and dehydration should receive
adequate hydration prior to Aredia infusion.
Limited information is available on the use of Aredia in multiple myeloma patients
with a serum creatinine ≥3.0 mg/dL.
Patients who receive Aredia should have serum creatinine assessed prior to each
treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal
deterioration was defined as follows:
• For patients with normal baseline creatinine, increase of 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned
to within 10% of the baseline value.
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Page 23
The optimal duration of therapy is not yet known, however, in a study of patients with
myeloma, final analysis after 21 months demonstrated overall benefits (see CLINICAL
TRIALS section).
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg
administered over a 2-hour infusion given every 3-4 weeks.
Aredia has been frequently used with doxorubicin, fluorouracil, cyclophosphamide,
methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine,
megesterol, and tamoxifen. It has been given less frequently with etoposide, cisplatin,
cytarabine, paclitaxel, and aminoglutethimide.
Patients who receive Aredia should have serum creatinine assessed prior to each
treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal
deterioration was defined as follows:
• For patients with normal baseline creatinine, increase of 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned
to within 10% of the baseline value.
The optimal duration of therapy is not known, however, in two breast cancer studies,
final analyses performed after 24 months of therapy demonstrated overall benefits (see
CLINICAL TRIALS section).
Preparation of Solution
Reconstitution
Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial,
resulting in a solution of 30 mg/10 mL or 90 mg/10 mL. The pH of the reconstituted solution
is 6.0 - 7.4. The drug should be completely dissolved before the solution is withdrawn.
Method of Administration
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN
RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE
DOSES OF AREDIA SHOULD NOT EXCEED 90 MG. (SEE WARNINGS.)
There must be strict adherence to the intravenous administration recommendations for
Aredia in order to decrease the risk of deterioration in renal function.
Hypercalcemia of Malignancy
The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for
the 60-mg and 90-mg doses. The recommended dose should be diluted in 1000 mL of sterile
0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. This infusion solution
is stable for up to 24 hours at room temperature.
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Page 24
Paget’s Disease
The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour
period for 3 consecutive days.
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 2-hour
period every 3-4 weeks.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour
period on a monthly basis.
Aredia must not be mixed with calcium-containing infusion solutions, such as
Ringer’s solution, and should be given in a single intravenous solution and line separate
from all other drugs.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration
at 2 °C-8 °C (36 °F-46 °F) for up to 24 hours.
HOW SUPPLIED
Vials - 30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and
470 mg of mannitol, USP.
Carton of 4 vials .................................................................................NDC 0083-2601-04
Vials - 90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and
375 mg of mannitol, USP.
Carton of 1 vial...................................................................................NDC 0083-2609-01
Do not store above 30 °C (86 °F).
T2005-27
REV: APRIL 2005
Printed in U.S.A.
5000347
5000348
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:32.092390
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020036s032lbl.pdf', 'application_number': 20036, 'submission_type': 'SUPPL ', 'submission_number': 32}
|
12,156
|
T2007-98
Aredia®
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor available in 30-mg or
90-mg vials for intravenous administration. Each 30-mg and 90-mg vial contains,
respectively, 30 mg and 90 mg of sterile, lyophilized pamidronate disodium and 470 mg and
375 mg of mannitol, USP. The pH of a 1% solution of pamidronate disodium in distilled
water is approximately 8.3. Aredia, a member of the group of chemical compounds known as
bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated
chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt,
pentahydrate, (APD), and its structural formula is
Pamidronate disodium is a white-to-practically-white powder. It is soluble in water
and in 2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic
acid, and practically insoluble in organic solvents. Its molecular formula is
C3H9NO7P2Na2•5H2O and its molecular weight is 369.1.
Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5
prior to lyophilization).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the
mechanism of antiresorptive action is not completely understood, several factors are thought
to contribute to this action. Aredia adsorbs to calcium phosphate (hydroxyapatite) crystals in
bone and may directly block dissolution of this mineral component of bone. In vitro studies
also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption.
In animal studies, at doses recommended for the treatment of hypercalcemia, Aredia inhibits
bone resorption apparently without inhibiting bone formation and mineralization. Of
relevance to the treatment of hypercalcemia of malignancy is the finding that Aredia inhibits
the accelerated bone resorption that results from osteoclast hyperactivity induced by various
tumors in animal studies.
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Pharmacokinetics
Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous
infusion of 30, 60, or 90 mg of Aredia over 4 hours and 90 mg of Aredia over 24 hours
(Table 1).
Distribution
The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose over
120 hours.
Metabolism
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Excretion
After administration of 30, 60, and 90 mg of Aredia over 4 hours, and 90 mg of Aredia over
24 hours, an overall mean ± SD of 46 ± 16% of the drug was excreted unchanged in the urine
within 120 hours. Cumulative urinary excretion was linearly related to dose. The mean ± SD
elimination half-life is 28 ± 7 hours. Mean ± SD total and renal clearances of pamidronate
were 107 ± 50 mL/min and 49 ± 28 mL/min, respectively. The rate of elimination from bone
has not been determined.
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of
pamidronate.
Pediatric
Pamidronate is not labeled for use in the pediatric population.
Renal Insufficiency
The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and
varying degrees of renal impairment. Each patient received a single 90-mg dose of Aredia
infused over 4 hours. The renal clearance of pamidronate in patients was found to closely
correlate with creatinine clearance (see Figure 1). A trend toward a lower percentage of drug
excreted unchanged in urine was observed in renally impaired patients. Adverse experiences
noted were not found to be related to changes in renal clearance of pamidronate. Given the
recommended dose, 90 mg infused over 4 hours, excessive accumulation of pamidronate in
renally impaired patients is not anticipated if Aredia is administered on a monthly basis.
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Page 3
Figure 1: Pamidronate renal clearance as a function of creatinine
clearance in patients with normal and impaired renal function.
The lines are the mean prediction line and 95% confidence intervals.
Hepatic Insufficiency
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone
metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction
(n=7). Each patient received a single 90-mg dose of Aredia infused over 4 hours. Although
there was a statistically significant difference in the pharmacokinetics between patients with
normal and impaired hepatic function, the difference was not considered clinically relevant.
Patients with hepatic impairment exhibited higher mean AUC (53%) and Cmax (29%), and
decreased plasma clearance (33%) values. Nevertheless, pamidronate was still rapidly cleared
from the plasma. Drug levels were not detectable in patients by 12 to 36 hours after drug
infusion. Because Aredia is administered on a monthly basis, drug accumulation is not
expected. No changes in Aredia dosing regimen are recommended for patients with mild to
moderate abnormal hepatic function. Aredia has not been studied in patients with severe
hepatic impairment.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
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Page 4
Table 1
Mean (SD, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients
(n=6 for each group)
Dose
(infusion rate)
Maximum
Concentration
(µg/mL)
Percent
of dose
excreted in urine
Total
Clearance
(mL/min)
Renal
Clearance
(mL/min)
30 mg
(4 hrs)
0.73
(0.14, 19.1%)
43.9
(14.0, 31.9%)
136
(44, 32.4%)
58
(27, 46.5%)
60 mg
(4 hrs)
1.44
(0.57, 39.6%)
47.4
(47.4, 54.4%)
88
(56, 63.6%)
42
(28, 66.7%)
90 mg
(4 hrs)
2.61
(0.74, 28.3%)
45.3
(25.8, 56.9%)
103
(37, 35.9%)
44
(16, 36.4%)
90 mg
(24 hrs)
1.38
(1.97, 142.7%)
47.5
(10.2, 21.5%)
101
(58, 57.4%)
52
(42, 80.8%)
After intravenous administration of radiolabeled pamidronate in rats, approximately
50%-60% of the compound was rapidly adsorbed by bone and slowly eliminated from the
body by the kidneys. In rats given 10 mg/kg bolus injections of radiolabeled Aredia,
approximately 30% of the compound was found in the liver shortly after administration and
was then redistributed to bone or eliminated by the kidneys over 24-48 hours. Studies in rats
injected with radiolabeled Aredia showed that the compound was rapidly cleared from the
circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage.
Radioactivity was eliminated from most soft tissues within 1-4 days; was detectable in liver
and spleen for 1 and 3 months, respectively; and remained high in bones, trachea, and teeth
for 6 months after dosing. Bone uptake occurred preferentially in areas of high bone turnover.
The terminal phase of elimination half-life in bone was estimated to be approximately 300
days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia,
presumably because of decreased release of phosphate from bone and increased renal
excretion as parathyroid hormone levels, which are usually suppressed in hypercalcemia
associated with malignancy, return toward normal. Phosphate therapy was administered in
30% of the patients in response to a decrease in serum phosphate levels. Phosphate levels
usually returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and
usually return to within or below normal after treatment with Aredia. These changes occur
within the first week after treatment, as do decreases in serum calcium levels, and are
consistent with an antiresorptive pharmacologic action.
Hypercalcemia of Malignancy
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying
pathophysiologic derangement in metastatic bone disease and hypercalcemia of malignancy.
Excessive release of calcium into the blood as bone is resorbed results in polyuria and
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Page 5
gastrointestinal disturbances, with progressive dehydration and decreasing glomerular
filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle
of worsening systemic hypercalcemia. Correction of excessive bone resorption and adequate
fluid administration to correct volume deficits are therefore essential to the management of
hypercalcemia.
Most cases of hypercalcemia associated with malignancy occur in patients who have
breast cancer; squamous-cell tumors of the lung or head and neck; renal-cell carcinoma; and
certain hematologic malignancies, such as multiple myeloma and some types of lymphomas.
A few less-common malignancies, including vasoactive intestinal-peptide-producing tumors
and cholangiocarcinoma, have a high incidence of hypercalcemia as a metabolic complication.
Patients who have hypercalcemia of malignancy can generally be divided into two groups,
according to the pathophysiologic mechanism involved.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated
by factors such as parathyroid-hormone-related protein, which are elaborated by the tumor
and circulate systemically. Humoral hypercalcemia usually occurs in squamous-cell
malignancies of the lung or head and neck or in genitourinary tumors such as renal-cell
carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local
tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated
with locally mediated hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may
not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly
present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic
conditions; however, these are not commonly or rapidly available in many clinical situations.
Therefore, adjustment of the total serum calcium value for differences in albumin levels is
often used in place of measurement of ionized calcium; several nomograms are in use for this
type of calculation (see DOSAGE AND ADMINISTRATION).
Clinical Trials
In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were
enrolled to receive 30 mg, 60 mg, or 90 mg of Aredia as a single 24-hour intravenous infusion
if their corrected serum calcium levels were ≥12.0 mg/dL after 48 hours of saline hydration.
The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups
were 13.8 mg/dL,13.8 mg/dL, and 13.3 mg/dL, respectively.
The majority of patients (64%) had decreases in albumin-corrected serum calcium
levels by 24 hours after initiation of treatment. Mean-corrected serum calcium levels at days
2-7 after initiation of treatment with Aredia were significantly reduced from baseline in all
three dosage groups. As a result, by 7 days after initiation of treatment with Aredia, 40%,
61%, and 100% of the patients receiving 30 mg, 60 mg, and 90 mg of Aredia, respectively,
had normal-corrected serum calcium levels. Many patients (33%-53%) in the 60-mg and
90-mg dosage groups continued to have normal-corrected serum calcium levels, or a partial
response (≥15% decrease of corrected serum calcium from baseline), at Day 14.
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In a second double-blind, controlled clinical trial, 65 cancer patients who had
corrected serum calcium levels of ≥12.0 mg/dL after at least 24 hours of saline hydration were
randomized to receive either 60 mg of Aredia as a single 24-hour intravenous infusion or
7.5 mg/kg of etidronate disodium as a 2-hour intravenous infusion daily for 3 days. Thirty
patients were randomized to receive Aredia and 35 to receive etidronate disodium.
The mean baseline-corrected serum calcium for the Aredia 60-mg and etidronate
disodium groups were 14.6 mg/dL and 13.8 mg/dL, respectively.
By Day 7, 70% of the patients in the Aredia group and 41% of the patients in the
etidronate disodium group had normal-corrected serum calcium levels (P<0.05). When partial
responders (≥15% decrease of serum calcium from baseline) were also included, the response
rates were 97% for the Aredia group and 65% for the etidronate disodium group (P<0.01).
Mean-corrected serum calcium for the Aredia and etidronate disodium groups decreased from
baseline values to 10.4 and 11.2 mg/dL, respectively, on Day 7. At Day 14, 43% of patients in
the Aredia group and 18% of patients in the etidronate disodium group still had normal-
corrected serum calcium levels, or maintenance of a partial response. For responders in the
Aredia and etidronate disodium groups, the median duration of response was similar (7 and 5
days, respectively). The time course of effect on corrected serum calcium is summarized in
the following table.
Change in Corrected Serum Calcium by Time
from Initiation of Treatment
Time
(hr)
Mean Change from Baseline in Corrected Serum Calcium (mg/dL)
Aredia®
Etidronate Disodium
P-Value1
Baseline
14.6
13.8
24
-0.3
-0.5
48
-1.5
-1.1
72
-2.6
-2.0
96
-3.5
-2.0
<0.01
168
-4.1
-2.5
<0.01
1Comparison between treatment groups
In a third multicenter, randomized, parallel double-blind trial, a group of 69 cancer
patients with hypercalcemia was enrolled to receive 60 mg of Aredia as a 4- or 24-hour
infusion, which was compared to a saline-treatment group. Patients who had a corrected
serum calcium level of ≥12.0 mg/dL after 24 hours of saline hydration were eligible for this
trial.
The mean baseline-corrected serum calcium levels for Aredia 60-mg 4-hour infusion,
Aredia 60-mg 24-hour infusion, and saline infusion were 14.2 mg/dL, 13.7 mg/dL, and
13.7 mg/dL, respectively.
By Day 7 after initiation of treatment, 78%, 61%, and 22% of the patients had normal-
corrected serum calcium levels for the 60-mg 4-hour infusion, 60-mg 24-hour infusion, and
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saline infusion, respectively. At Day 14, 39% of the patients in the Aredia 60-mg 4-hour
infusion group and 26% of the patients in the Aredia 60-mg 24-hour infusion group had
normal-corrected serum calcium levels or maintenance of a partial response.
For responders, the median duration of complete responses was 4 days and 6.5 days
for Aredia 60-mg 4-hour infusion and Aredia 60-mg 24-hour infusion, respectively.
In all three trials, patients treated with Aredia had similar response rates in the
presence or absence of bone metastases. Concomitant administration of furosemide did not
affect response rates.
Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were
given a second course of 60 mg of Aredia over a 4- or 24-hour period. Of these, 41% showed
a complete response and 16% showed a partial response to the retreatment, and these
responders had about a 3-mg/dL fall in mean-corrected serum calcium levels 7 days after
retreatment.
In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and
hypercalcemia (corrected serum calcium ≥12.0 mg/dL) received 90 mg of Aredia as a 2-hour
infusion. The mean baseline corrected serum calcium was 14.0 mg/dL. Patients were not
required to receive IV hydration prior to drug administration, but all subjects did receive at
least 500 mL of IV saline hydration concomitantly with the pamidronate infusion. By Day 10
after drug infusion, 70% of patients had normal corrected serum calcium levels
(<10.8 mg/dL).
Paget’s Disease
Paget’s disease of bone (osteitis deformans) is an idiopathic disease characterized by chronic,
focal areas of bone destruction complicated by concurrent excessive bone repair, affecting one
or more bones. These changes result in thickened but weakened bones that may fracture or
bend under stress. Signs and symptoms may be bone pain, deformity, fractures, neurological
disorders resulting from cranial and spinal nerve entrapment and from spinal cord and brain
stem compression, increased cardiac output to the involved bone, increased serum alkaline
phosphatase levels (reflecting increased bone formation) and/or urine hydroxyproline
excretion (reflecting increased bone resorption).
Clinical Trials
In one double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone
were enrolled to receive 5 mg, 15 mg, or 30 mg of Aredia as a single 4-hour infusion on 3
consecutive days, for total doses of 15 mg, 45 mg, and 90 mg of Aredia.
The mean baseline serum alkaline phosphatase levels were 1,409 U/L, 983 U/L, and
1,085 U/L, and the mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and
0.19 for the 15-mg, 45-mg, and 90-mg groups, respectively.
The effects of Aredia on serum alkaline phosphatase (SAP) and urine
hydroxyproline/creatinine ratios (UOHP/C) are summarized in the following table.
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Percent of Patients With
Significant % Decreases in SAP and UOHP/C
SAP
UOHP/C
% Decrease
15 mg
45 mg
90 mg
15 mg
45 mg
90 mg
≥50
26
33
60
15
47
72
≥30
40
65
83
35
57
85
The median maximum percent decreases from baseline in serum alkaline phosphatase
and urine hydroxyproline/creatinine ratios were 25%, 41%, and 57%, and 25%, 47%, and
61% for the 15-mg, 45-mg, and 90-mg groups, respectively. The median time to response
(≥50% decrease) for serum alkaline phosphatase was approximately 1 month for the 90-mg
group, and the response duration ranged from 1 to 372 days.
No statistically significant differences between treatment groups, or statistically
significant changes from baseline were observed for the bone pain response, mobility, and
global evaluation in the 45-mg and 90-mg groups. Improvement in radiologic lesions occurred
in some patients in the 90-mg group.
Twenty-five patients who had Paget’s disease were retreated with 90 mg of Aredia. Of
these, 44% had a ≥50% decrease in serum alkaline phosphatase from baseline after treatment,
and 39% had a ≥50% decrease in urine hydroxyproline/creatinine ratio from baseline after
treatment.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma
Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast
cancer. These cancers demonstrate a phenomenon known as osteotropism, meaning they
possess an extraordinary affinity for bone. The distribution of osteolytic bone metastases in
these cancers is predominantly in the axial skeleton, particularly the spine, pelvis, and ribs,
rather than the appendicular skeleton, although lesions in the proximal femur and humerus are
not uncommon. This distribution is similar to the red bone marrow in which slow blood flow
possibly assists attachment of metastatic cells. The surface-to-volume ratio of trabecular bone
is much higher than cortical bone, and therefore disease processes tend to occur more floridly
in trabecular bone than at sites of cortical tissue.
These bone changes can result in patients having evidence of osteolytic skeletal
destruction leading to severe bone pain that requires either radiation therapy or narcotic
analgesics (or both) for symptomatic relief. These changes also cause pathologic fractures of
bone in both the axial and appendicular skeleton. Axial skeletal fractures of the vertebral
bodies may lead to spinal cord compression or vertebral body collapse with significant
neurologic complications. Also, patients may experience episode(s) of hypercalcemia.
Clinical Trials
In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple
myeloma were enrolled to receive Aredia or placebo in addition to their underlying
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antimyeloma therapy to determine the effect of Aredia on the occurrence of skeletal-related
events (SREs). SREs were defined as episodes of pathologic fractures, radiation therapy to
bone, surgery to bone, and spinal cord compression. Patients received either 90 mg of Aredia
or placebo as a monthly 4-hour intravenous infusion for 9 months. Of the 392 patients, 377
were evaluable for efficacy (196 Aredia, 181 placebo). The proportion of patients developing
any SRE was significantly smaller in the Aredia group (24% vs 41%, P<0.001), and the mean
skeletal morbidity rate (#SRE/year) was significantly smaller for Aredia patients than for
placebo patients (mean: 1.1 vs 2.1, P<.02). The times to the first SRE occurrence, pathologic
fracture, and radiation to bone were significantly longer in the Aredia group (P=.001, .006,
and .046, respectively). Moreover, fewer Aredia patients suffered any pathologic fracture
(17% vs 30%, P=.004) or needed radiation to bone (14% vs 22%, P=.049).
In addition, decreases in pain scores from baseline occurred at the last measurement
for those Aredia patients with pain at baseline (P=.026) but not in the placebo group. At the
last measurement, a worsening from baseline was observed in the placebo group for the
Spitzer quality of life variable (P<.001) and ECOG performance status (P<.011) while there
was no significant deterioration from baseline in these parameters observed in Aredia-treated
patients.*
After 21 months, the proportion of patients experiencing any skeletal event remained
significantly smaller in the Aredia group than the placebo group (P=.015). In addition, the
mean skeletal morbidity rate (#SRE/year) was 1.3 vs 2.2 for Aredia patients vs placebo
patients (P=.008), and time to first SRE was significantly longer in the Aredia group
compared to placebo (P=.016). Fewer Aredia patients suffered vertebral pathologic fractures
(16% vs 27%, P=.005). Survival of all patients was not different between treatment groups.
Two double-blind, randomized, placebo-controlled trials compared the safety and
efficacy of 90 mg of Aredia infused over 2 hours every 3 to 4 weeks for 24 months to that of
placebo in preventing SREs in breast cancer patients with osteolytic bone metastases who had
one or more predominantly lytic metastases of at least 1 cm in diameter: one in patients being
treated with antineoplastic chemotherapy and the second in patients being treated with
hormonal antineoplastic therapy at trial entry.
382 patients receiving chemotherapy were randomized, 185 to Aredia and 197 to
placebo. 372 patients receiving hormonal therapy were randomized, 182 to Aredia and 190 to
placebo. All but three patients were evaluable for efficacy. Patients were followed for 24
months of therapy or until they went off study. Median duration of follow-up was 13 months
in patients receiving chemotherapy and 17 months in patients receiving hormone therapy.
Twenty-five percent of the patients in the chemotherapy study and 37% of the patients in the
hormone therapy study received Aredia for 24 months. The efficacy results are shown in the
table below:
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Breast Cancer Patients
Receiving Chemotherapy
Breast Cancer Patients
Receiving Hormonal Therapy
Any SRE
Radiation
Fractures
Any SRE
Radiation
Fractures
A
P
A
P
A
P
A
P
A
P
A
P
N
185
195
185
195
185
195
182
189
182
189
182
189
Skeletal Morbidity
Rate
(#SRE/year)
Mean
2.5
3.7
0.8
1.3
1.6
2.2
2.4
3.6
0.6
1.2
1.6
2.2
P-Value
<.001
<.001†
.018†
.021
.013†
.040†
Proportion of
patients having
an SRE
46%
65%
28%
45%
36%
49%
55%
63%
31%
40%
45%
55%
P-Value
<.001
<.001†
.014†
.094
.058†
.054†
Median Time to
SRE (months)
13.9
7.0
NR**
14.2
25.8
13.3
10.9
7.4
NR**
23.4
20.6
12.8
P-Value
<.001
<.001†
.009†
.118
.016†
.113†
†Fractures and radiation to bone were two of several secondary endpoints. The statistical significance of these
analyses may be overestimated since numerous analyses were performed.
**NR = Not Reached.
Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12
months. The complete + partial response rate was 33% in Aredia patients and 18% in placebo
patients treated with chemotherapy (P=.001). No difference was seen between Aredia and
placebo in hormonally-treated patients.
Pain and analgesic scores, ECOG performance status and Spitzer quality of life index
were measured at baseline and periodically during the trials. The changes from baseline to the
last measurement carried forward are shown in the following table:
Mean Change (∆) from Baseline at Last Measurement
Breast Cancer Patients
Receiving Chemotherapy
Breast Cancer Patients
Receiving Hormonal Therapy
Aredia®
Placebo
A vs P
Aredia®
Placebo
A vs P
N
Mean ∆
N
Mean Δ
P-Value*
N
Mean ∆
N
Mean Δ
P-Value*
Pain Score
175
+0.93
183
+1.69
.050
173
+0.50
179
+1.60
.007
Analgesic
Score
175
+0.74
183
+1.55
.009
173
+0.90
179
+2.28
<.001
ECOG PS
178
+0.81
186
+1.19
.002
175
+0.95
182
+0.90
.773
Spitzer
QOL
177
-1.76
185
-2.21
.103
173
-1.86
181
-2.05
.409
Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an improvement from
baseline.
*The statistical significance of analyses of these secondary endpoints of pain, quality of life, and
performance status in all three trials may be overestimated since numerous analyses were performed.
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INDICATIONS AND USAGE
Hypercalcemia of Malignancy
Aredia, in conjunction with adequate hydration, is indicated for the treatment of moderate or
severe hypercalcemia associated with malignancy, with or without bone metastases. Patients
who have either epidermoid or non-epidermoid tumors respond to treatment with Aredia.
Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated
promptly and an attempt should be made to restore the urine output to about 2 L/day
throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative
measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated
adequately throughout the treatment, but overhydration, especially in those patients who have
cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction
of hypovolemia. The safety and efficacy of Aredia in the treatment of hypercalcemia
associated with hyperparathyroidism or with other non-tumor-related conditions has not been
established.
Paget’s Disease
Aredia is indicated for the treatment of patients with moderate to severe Paget’s disease of
bone. The effectiveness of Aredia was demonstrated primarily in patients with serum alkaline
phosphatase ≥3 times the upper limit of normal. Aredia therapy in patients with Paget’s
disease has been effective in reducing serum alkaline phosphatase and urinary hydroxyproline
levels by ≥50% in at least 50% of patients, and by ≥30% in at least 80% of patients. Aredia
therapy has also been effective in reducing these biochemical markers in patients with Paget’s
disease who failed to respond, or no longer responded to other treatments.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma
Aredia is indicated, in conjunction with standard antineoplastic therapy, for the treatment of
osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. The
Aredia treatment effect appeared to be smaller in the study of breast cancer patients receiving
hormonal therapy than in the study of those receiving chemotherapy, however, overall
evidence of clinical benefit has been demonstrated (see CLINICAL PHARMACOLOGY,
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma,
Clinical Trials section).
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or
other bisphosphonates.
WARNINGS
Deterioration in Renal Function
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Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as
deterioration of renal function and potential renal failure.
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN
RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE
DOSES OF AREDIA SHOULD NOT EXCEED 90 MG (see DOSAGE AND
ADMINISTRATION for appropriate infusion durations). Renal deterioration,
progression to renal failure, and dialysis have been reported in patients after the initial
or a single dose of Aredia.
Focal segmental glomerulosclerosis (including the collapsing variant) with or without
nephrotic syndrome, which may lead to renal failure, has been reported in Aredia-treated
patients, particularly in the setting of multiple myeloma and breast cancer. Some of these
patients had gradual improvement in renal status after Aredia was discontinued.
Patients who receive Aredia should have serum creatinine assessed prior to each
treatment. Patients treated with Aredia for bone metastases should have the dose withheld if
renal function has deteriorated. (See DOSAGE AND ADMINISTRATION.)
PREGNANCY: AREDIA SHOULD NOT BE USED DURING
PREGNANCY
Aredia may cause fetal harm when administered to a pregnant woman. (See PRECAUTIONS,
Pregnancy Category D.)
There are no studies in pregnant women using Aredia. If the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential harm to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant.
Studies conducted in young rats have reported the disruption of dental dentine
formation following single- and multi-dose administration of bisphosphonates. The clinical
significance of these findings is unknown.
PRECAUTIONS
General
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium,
phosphate, magnesium, and potassium, should be carefully monitored following initiation of
therapy with Aredia. Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%),
hypomagnesemia (11%), and hypocalcemia (5%-12%), were reported in Aredia-treated
patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in
association with Aredia therapy. If hypocalcemia occurs, short-term calcium therapy may be
necessary. In Paget’s disease of bone, 17% of patients treated with 90 mg of Aredia showed
serum calcium levels below 8 mg/dL.
Patients with a history of thyroid surgery may have relative hypoparathyroidism that
may predispose to hypocalcemia with Aredia.
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Renal Insufficiency
Aredia is excreted intact primarily via the kidney, and the risk of renal adverse reactions may
be greater in patients with impaired renal function. Patients who receive Aredia should have
serum creatinine assessed prior to each treatment. In patients receiving Aredia for bone
metastases, who show evidence of deterioration in renal function, Aredia treatment should be
withheld until renal function returns to baseline (see WARNINGS and DOSAGE AND
ADMINISTRATION).
In clinical trials, patients with real impairment (serum creatinine >3.0 mg/dL) have not
been studied. Limited pharmacokinetic data exist in patients with creatinine clearance <30
ml/min (See Clinical Pharmacology, Pharmacokinetics.) For the treatment of bone
metastases, the use of Aredia in patients with severe renal impairment is not recommended. In
other indications, clinical judgment should determine whether the potential benefit outweighs
the potential risk in such patients.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients with cancer receiving treatment
regimens including bisphosphonates. Many of these patients were also receiving
chemotherapy and corticosteroids. The majority of reported cases have been associated with
dental procedures such as tooth extraction. Many had signs of local infection including
osteomyelitis.
A dental examination with appropriate preventive dentistry should be considered prior
to treatment with bisphosphonates in patients with concomitant risk factors (e.g., cancer,
chemotherapy, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible.
For patients who develop ONJ while on bisphosphonate therapy, dental surgery may
exacerbate the condition. For patients requiring dental procedures, there are no data available
to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ.
Clinical judgment of the treating physician should guide the management plan of each patient
based on individual benefit/risk assessment.
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or
muscle pain has been reported in patients taking bisphosphonates. However, such reports have
been infrequent. This category of drugs includes Aredia (pamidronate disodium for injection).
The time to onset of symptoms varied from one day to several months after starting the drug.
Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms
when rechallenged with the same drug or another bisphosphonate.
Laboratory Tests
Patients who receive Aredia should have serum creatinine assessed prior to each treatment.
Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and
hematocrit/hemoglobin must be closely monitored in patients treated with Aredia. Patients
who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully
in the first 2 weeks following treatment.
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Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of
Aredia.
Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when
Aredia is used in combination with thalidomide.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study (daily oral administration) in rats, there was a positive
dose response relationship for benign adrenal pheochromocytoma in males (P<0.00001).
Although this condition was also observed in females, the incidence was not statistically
significant. When the dose calculations were adjusted to account for the limited oral
bioavailability of Aredia in rats, the lowest daily dose associated with adrenal
pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma
was also observed in low numbers in the control animals and is considered a relatively
common spontaneous neoplasm in the rat. Aredia (daily oral administration) was not
carcinogenic in an 80-week study in mice.
Aredia was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and
Escherichia/ liver-microsome test, nucleus-anomaly test, sister-chromatid-exchange study,
point-mutation test, and micronucleus test in the rat.
In rats, decreased fertility occurred in first-generation offspring of parents who had
received 150 mg/kg of Aredia orally; however, this occurred only when animals were mated
with members of the same dose group. Aredia has not been administered intravenously in
such a study.
Animal Toxicology
In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion)
administration of Aredia.
Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia
was given for 1, 4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the
compound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD]
for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such
as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was
infused for 1 hour and at doses of ≥10 mg/kg. In the second study, slight renal tubular necrosis
was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included
elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation
at ≥1 mg/kg after each infusion time.
Aredia was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6,
and 20 mg/kg as a 1-hour infusion, once a week, for 3 months followed by a 1-month
recovery period. In rats, nephrotoxicity was observed at ≥6 mg/kg and included increased
BUN and creatinine levels and tubular degeneration and necrosis. These findings were still
present at 20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal
toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at
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≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially
reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects
was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).
Pregnancy Category D (See WARNINGS)
There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia
produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses
of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As
it has been shown that Aredia can cross the placenta in rats and has produced marked maternal
and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women
during pregnancy.
Bisphosphonates are incorporated into the bone matrix, from where they are gradually
released over periods of weeks to years. The extent of bisphosphonate incorporation into adult
bone, and hence, the amount available for release back into the systemic circulation, is
directly related to the total dose and duration of bisphosphonate use. Although there are no
data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data
suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone.
Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a
woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of
variables such as time between cessation of bisphosphonate therapy to conception, the
particular bisphosphonate used, and the route of administration (intravenous vs oral) on this
risk has not been established.
Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when Aredia is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Aredia in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects in clinical studies of Aredia, approximately 20% were 65 and
over, while approximately 15% were 75 and over. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out. In
general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
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ADVERSE REACTIONS
Clinical Studies
Hypercalcemia of Malignancy
Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after
administration of Aredia in 34% of patients in clinical trials. In the saline trial, 18% of
patients had a temperature elevation of at least 1°C 24 to 48 hours after treatment.
Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on
palpation) at the site of catheter insertion were most common in patients treated with 90 mg of
Aredia. Symptomatic treatment resulted in rapid resolution in all patients.
Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one
case of scleritis, and one case of uveitis upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the four U.S. controlled
hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting
seizure disorders. None of the seizures were considered to be drug-related by the
investigators. However, a possible relationship between the drug and the occurrence of
seizures cannot be ruled out. It should be noted that in the saline arm 1 patient (4%) had a
seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90-mg
Aredia over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a
comparison of data from separate clinical trials suggests that the overall safety profile in
patients who received 90-mg Aredia over 24 hours is similar to those who received 90-mg
Aredia over 2 hours. The only notable differences observed were an increase in the proportion
of patients in the Aredia 24-hour group who experienced fluid overload and
electrolyte/mineral abnormalities.
At least 15% of patients treated with Aredia for hypercalcemia of malignancy also
experienced the following adverse events during a clinical trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting
Genitourinary: Urinary tract infection
Musculoskeletal: Bone pain
Laboratory Abnormality: Anemia, hypokalemia, hypomagnesemia,
hypophosphatemia
Many of these adverse experiences may have been related to the underlying disease
state. The following table lists the adverse experiences considered to be treatment-related
during comparative, controlled U.S. trials.
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Treatment-Related Adverse Experiences Reported in Three U.S. Controlled
Clinical Trials
Percent of Patients
Aredia®
Etidronate Disodium
Saline
60 mg
over 4 hr
n=23
60 mg
over 24 hr
n=73
90 mg
over 24 hr
n=17
7.5 mg/kg
x 3 days
n=35
n=23
General
Edema
0
1
0
0
0
Fatigue
0
0
12
0
0
Fever
26
19
18
9
0
Fluid overload
0
0
0
6
0
Infusion-site reaction
0
4
18
0
0
Moniliasis
0
0
6
0
0
Rigors
0
0
0
0
4
Gastrointestinal
Abdominal pain
0
1
0
0
0
Anorexia
4
1
12
0
0
Constipation
4
0
6
3
0
Diarrhea
0
1
0
0
0
Dyspepsia
4
0
0
0
0
Gastrointestinal hemorrhage
0
0
6
0
0
Nausea
4
0
18
6
0
Stomatitis
0
1
0
3
0
Vomiting
4
0
0
0
0
Respiratory
Dyspnea
0
0
0
3
0
Rales
0
0
6
0
0
Rhinitis
0
0
6
0
0
Upper respiratory infection
0
3
0
0
0
CNS
Anxiety
0
0
0
0
4
Convulsions
0
0
0
3
0
Insomnia
0
1
0
0
0
Nervousness
0
0
0
0
4
Psychosis
4
0
0
0
0
Somnolence
0
1
6
0
0
Taste perversion
0
0
0
3
0
Cardiovascular
Atrial fibrillation
0
0
6
0
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 18
Atrial flutter
0
1
0
0
0
Cardiac failure
0
1
0
0
0
Hypertension
0
0
6
0
4
Syncope
0
0
6
0
0
Tachycardia
0
0
6
0
4
Endocrine
Hypothyroidism
0
0
6
0
0
Hemic and Lymphatic
Anemia
0
0
6
0
0
Leukopenia
4
0
0
0
0
Neutropenia
0
1
0
0
0
Thrombocytopenia
0
1
0
0
0
Musculoskeletal
Myalgia
0
1
0
0
0
Urogenital
Uremia
4
0
0
0
0
Laboratory Abnormalities
Hypocalcemia
0
1
12
0
0
Hypokalemia
4
4
18
0
0
Hypomagnesemia
4
10
12
3
4
Hypophosphatemia
0
9
18
3
0
Abnormal liver function
0
0
0
3
0
Paget’s Disease
Transient mild elevation of temperature >1°C above pretreatment baseline was noted within
48 hours after completion of treatment in 21% of the patients treated with 90 mg of Aredia in
clinical trials.
Drug-related musculoskeletal pain and nervous system symptoms (dizziness,
headache, paresthesia, increased sweating) were more common in patients with Paget’s
disease treated with 90 mg of Aredia than in patients with hypercalcemia of malignancy
treated with the same dose.
Adverse experiences considered to be related to trial drug, which occurred in at least
5% of patients with Paget’s disease treated with 90 mg of Aredia in two U.S. clinical trials,
were fever, nausea, back pain, and bone pain.
At least 10% of all Aredia-treated patients with Paget’s disease also experienced the
following adverse experiences during clinical trials:
Cardiovascular: Hypertension
Musculoskeletal: Arthrosis, bone pain
Nervous system: Headache
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 19
Most of these adverse experiences may have been related to the underlying disease
state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma
The most commonly reported (>15%) adverse experiences occurred with similar frequencies
in the Aredia- and placebo-treatment groups, and most of these adverse experiences may have
been related to the underlying disease state or cancer therapy.
Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical
Trials
Aredia®
90 mg
over 4 hours
N=205
%
Placebo
N=187
%
Aredia®
90 mg
over 2 hours
N=367
%
Placebo
N=386
%
All
Aredia®
90 mg
N=572
%
Placebo
N=573
%
General
Asthenia
16.1
17.1
25.6
19.2
22.2
18.5
Fatigue
31.7
28.3
40.3
28.8
37.2
29.0
Fever
38.5
38
38.1
32.1
38.5
34
Metastases
1.0
3.0
31.3
24.4
20.5
17.5
Pain
13.2
11.8
15.0
18.1
14.3
16.1
Digestive System
Anorexia
17.1
17.1
31.1
24.9
26.0
22.3
Constipation
28.3
31.7
36.0
38.6
33.2
35.1
Diarrhea
26.8
26.8
29.4
30.6
28.5
29.7
Dyspepsia
17.6
13.4
18.3
15.0
22.6
17.5
Nausea
35.6
37.4
63.5
59.1
53.5
51.8
Pain Abdominal
19.5
16.0
24.3
18.1
22.6
17.5
Vomiting
16.6
19.8
46.3
39.1
35.7
32.8
Hemic and Lymphatic
Anemia
47.8
41.7
39.5
36.8
42.5
38.4
Granulocytopenia
20.5
15.5
19.3
20.5
19.8
18.8
Thrombocytopenia
16.6
17.1
12.5
14.0
14.0
15.0
Musculoskeletal
System
Arthralgias
10.7
7.0
15.3
12.7
13.6
10.8
Myalgia
25.4
15.0
26.4
22.5
26
20.1
Skeletal Pain
61.0
71.7
70.0
75.4
66.8
74
CNS
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 20
Anxiety
7.8
9.1
18.0
16.8
14.3
14.3
Headache
24.4
19.8
27.2
23.6
26.2
22.3
Insomnia
17.1
17.2
25.1
19.4
22.2
19.0
Respiratory System
Coughing
26.3
22.5
25.3
19.7
25.7
20.6
Dyspnea
22.0
21.4
35.1
24.4
30.4
23.4
Pleural Effusion
2.9
4.3
15.0
9.1
10.7
7.5
Sinusitis
14.6
16.6
16.1
10.4
15.6
12.0
Upper Respiratory Tract
Infection
32.2
28.3
19.6
20.2
24.1
22.9
Urogenital System
Urinary Tract Infection
15.6
9.1
20.2
17.6
18.5
15.6
Of the toxicities commonly associated with chemotherapy, the frequency of vomiting,
anorexia, and anemia were slightly more common in the Aredia patients whereas stomatitis
and alopecia occurred at a frequency similar to that in placebo patients. In the breast cancer
trials, mild elevations of serum creatinine occurred in 18.5% of Aredia patients and 12.3% of
placebo patients. Mineral and electrolyte disturbances, including hypocalcemia, were reported
rarely and in similar percentages of Aredia-treated patients compared with those in the
placebo group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia,
and hypomagnesemia for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%,
respectively, and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively.
In previous hypercalcemia of malignancy trials, patients treated with Aredia (60 or 90 mg
over 24 hours) developed electrolyte abnormalities more frequently (see ADVERSE
REACTIONS, Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the Aredia group
than in the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively).
In multiple myeloma patients, there were five Aredia-related serious and unexpected
adverse experiences. Four of these were reported during the 12-month extension of the
multiple myeloma trial. Three of the reports were of worsening renal function developing in
patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The
fourth report was the adult respiratory distress syndrome developing in a patient recovering
from pneumonia and acute gangrenous cholecystitis. One Aredia-treated patient experienced
an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat
within 24 hours after the sixth infusion.
In the breast cancer trials, there were four Aredia-related adverse experiences, all
moderate in severity, that caused a patient to discontinue participation in the trial. One was
due to interstitial pneumonitis, another to malaise and dyspnea. One Aredia patient
discontinued the trial due to a symptomatic hypocalcemia. Another Aredia patient
discontinued therapy due to severe bone pain after each infusion, which the investigator felt
was trial-drug-related.
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Page 21
Renal Toxicity
In a study of the safety and efficacy of Aredia 90 mg (2-hour infusion) vs Zometa 4 mg (15-
minute infusion) in bone metastases patients with multiple myeloma or breast cancer, renal
deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for patients with
normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an
abnormal baseline creatinine (≥1.4 mg/dL). The following are data on the incidence of renal
deterioration in patients in this trial. See table below.
Incidence of Renal Function Deterioration in Multiple Myeloma and Breast
Cancer Patients with Normal and Abnormal Serum Creatinine at Baseline*
Patient Population/Baseline Creatinine
Aredia® 90 mg/2 hours
Zometa® 4 mg/15 minutes
n/N
(%)
n/N
(%)
Normal
20/246
(8.1%)
23/246
(9.3%)
Abnormal
2/22
(9.1%)
1/26
(3.8%)
Total
22/268
(8.2%)
24/272
(8.8%)
*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.
Post-Marketing Experience
The following adverse reactions have been reported in post-marketing use: General:
reactivation of Herpes simplex and Herpes zoster, influenza-like symptoms; CNS: confusion
and visual hallucinations, sometimes in the presence of electrolyte imbalance; Skin: rash,
pruritus; Special senses:conjunctivitis; Renal: focal segmental glomerulosclerosis including
the collapsing variant, nephrotic syndrome; Laboratory abnormalities: hyperkalemia,
hypernatremia, hematuria. Rare instances of allergic manifestations have been reported,
including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock. Aredia
is contraindicated in patients with clinically significant hypersensitivity to Aredia or other
bisphosphonates (see CONTRAINDICATIONS).
Cases of osteonecrosis (primarily of the jaws) have been reported since market
introduction. Osteonecrosis of the jaws has other well documented multiple risk factors. It is
not possible to determine if these events are related to Aredia or other bisphosphonates, to
concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to
patient’s underlying disease, or to other comorbid risk factors (e.g., anemia, infection,
preexisting oral disease). (See PRECAUTIONS.)
OVERDOSAGE
There have been several cases of drug maladministration of intravenous Aredia in
hypercalcemia patients with total doses of 225 mg to 300 mg given over 2 ½ to 4 days. All of
these patients survived, but they experienced hypocalcemia that required intravenous and/or
oral administration of calcium. Single doses of Aredia should not exceed 90 mg and the
duration of the intravenous infusion should be no less than 2 hours. (See WARNINGS.)
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Page 22
In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for
3 days experienced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg),
and transient taste perversion, noted about 6 hours after the first infusion. The fever and
hypotension were rapidly corrected with steroids.
If overdosage occurs, symptomatic hypocalcemia could also result; such patients
should be treated with short-term intravenous calcium.
DOSAGE AND ADMINISTRATION
Hypercalcemia of Malignancy
Consideration should be given to the severity of as well as the symptoms of hypercalcemia.
Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic
hypercalcemia. Overhydration should be avoided in patients who have potential for cardiac
failure. In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid
therapy may be helpful.
Moderate Hypercalcemia
The recommended dose of Aredia in moderate hypercalcemia (corrected serum
calcium* of approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE,
intravenous infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the
risk for renal toxicity, particularly in patients with preexisting renal insufficiency.
Severe Hypercalcemia
The recommended dose of Aredia in severe hypercalcemia (corrected serum
calcium*>13.5 mg/dL) is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2
to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity,
particularly in patients with preexisting renal insufficiency.
___________________________
*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8
(4.0-serum albumin, g/dL).
Retreatment
A limited number of patients have received more than one treatment with Aredia for
hypercalcemia. Retreatment with Aredia, in patients who show complete or partial response
initially, may be carried out if serum calcium does not return to normal or remain normal after
initial treatment. It is recommended that a minimum of 7 days elapse before retreatment,
to allow for full response to the initial dose. The dose and manner of retreatment is
identical to that of the initial therapy.
Paget’s Disease
The recommended dose of Aredia in patients with moderate to severe Paget’s disease of
bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total
dose of 90 mg.
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Page 23
Retreatment
A limited number of patients with Paget’s disease have received more than one treatment of
Aredia in clinical trials. When clinically indicated, patients should be retreated at the dose of
initial therapy.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of Aredia in patients with osteolytic bone lesions of multiple
myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.
Patients with marked Bence-Jones proteinuria and dehydration should receive
adequate hydration prior to Aredia infusion.
Limited information is available on the use of Aredia in multiple myeloma patients
with a serum creatinine ≥3.0 mg/dL.
Patients who receive Aredia should have serum creatinine assessed prior to each
treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal
deterioration was defined as follows:
• For patients with normal baseline creatinine, increase of 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned
to within 10% of the baseline value.
The optimal duration of therapy is not yet known, however, in a study of patients with
myeloma, final analysis after 21 months demonstrated overall benefits (see CLINICAL
TRIALS section).
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg
administered over a 2-hour infusion given every 3-4 weeks.
Aredia has been frequently used with doxorubicin, fluorouracil, cyclophosphamide,
methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine,
megesterol, and tamoxifen. It has been given less frequently with etoposide, cisplatin,
cytarabine, paclitaxel, and aminoglutethimide.
Patients who receive Aredia should have serum creatinine assessed prior to each
treatment. Treatment should be withheld for renal deterioration. In a clinical study, renal
deterioration was defined as follows:
• For patients with normal baseline creatinine, increase of 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned
to within 10% of the baseline value.
The optimal duration of therapy is not known, however, in two breast cancer studies,
final analyses performed after 24 months of therapy demonstrated overall benefits (see
CLINICAL TRIALS section).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 24
Calcium and Vitamin D Supplementation
In the absence of hypercalcemia, patients with predominantly lytic bone metastases or
multiple myeloma, who are at risk of calcium or vitamin D deficiency, and patients with
Paget’s disease of the bone, should be given oral calcium and vitamin D supplementation in
order to minimize the risk of hypocalcemia.
Preparation of Solution
Reconstitution
Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial,
resulting in a solution of 30 mg/10 mL or 90 mg/10 mL. The pH of the reconstituted solution
is 6.0-7.4. The drug should be completely dissolved before the solution is withdrawn.
Method of Administration
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN
RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE
DOSES OF AREDIA SHOULD NOT EXCEED 90 MG. (SEE WARNINGS.)
There must be strict adherence to the intravenous administration recommendations for
Aredia in order to decrease the risk of deterioration in renal function.
Hypercalcemia of Malignancy
The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for
the 60-mg and 90-mg doses. The recommended dose should be diluted in 1000 mL of sterile
0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. This infusion solution
is stable for up to 24 hours at room temperature.
Paget’s Disease
The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour
period for 3 consecutive days.
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 2-hour
period every 3-4 weeks.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9%
Sodium Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour
period on a monthly basis.
Aredia must not be mixed with calcium-containing infusion solutions, such as
Ringer’s solution, and should be given in a single intravenous solution and line separate
from all other drugs.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 25
Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration
at 2°C-8°C (36°F-46°F) for up to 24 hours.
HOW SUPPLIED
Vials - 30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and
470 mg of mannitol, USP.
Carton of 4 vials .................................................................................NDC 0078-0463-91
Vials - 90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and
375 mg of mannitol, USP.
Carton of 1 vial...................................................................................NDC 0078-0464-61
Do not store above 30°C (86°F).
T2007-98
REV: November 2007
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:32.182807
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020036s034lbl.pdf', 'application_number': 20036, 'submission_type': 'SUPPL ', 'submission_number': 34}
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NDA 20-037/S-014
Page 3
VOLTAREN OPHTHALMIC®
(diclofenac sodium ophthalmic solution) 0.1%
Sterile Ophthalmic Solution
Prescribing Information
DESCRIPTION
Voltaren Ophthalmic (diclofenac sodium ophthalmic solution) 0.1% solution is a sterile, topical,
nonsteroidal, anti-inflammatory product for ophthalmic use. Diclofenac sodium is designated
chemically as 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt, with an empirical
formula of C14H10Cl2NO2Na. The structural formula of diclofenac sodium is:
[Structural formula]
Voltaren Ophthalmic is available as a sterile solution which contains diclofenac sodium 0.1%
(1mg/mL).
Inactive Ingredients: polyoxyl 35 castor oil, Boric acid, tromethamine, sorbic acid (2 mg/mL), edetate
disodium (1 mg/mL), and purified water.
Diclofenac sodium is a faintly yellow-white to light-beige, slightly hygroscopic crystalline powder. It
is freely soluble in methanol, sparingly soluble in water, very slightly soluble in acetonitrile, and
insoluble in chloroform and in 0.1N hydrochloric acid. Its molecular weight is 318.14. Voltaren
Ophthalmic 0.1% is an iso-osmotic solution with an osmolality of about 300 mOsmol/1000 g, buffered
at approximately pH 7.2. Voltaren Ophthalmic solution has a faint characteristic odor of castor oil.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Diclofenac sodium is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and
analgesic properties in pharmacological studies. It is thought to inhibit the enzyme cyclooxygenase,
which is essential in the biosynthesis of prostaglandins.
Animal Studies
Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular
inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce
disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability,
leukocytosis, and increased intraocular pressure.
Pharmacokinetics
Results from a bioavailability study established that plasma levels of diclofenac following ocular
instillation of two drops of Voltaren Ophthalmic to each eye were below the limit of quantification (10
ng/mL) over a 4-hour period. This study suggests that limited, if any, systemic absorption occurs with
Voltaren Ophthalmic.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-037/S-014
Page 4
Clinical Trials
Postoperative Anti-Inflammatory Effects:
In two double-masked, controlled, efficacy studies of postoperative inflammation, a total of 206
cataract patients were treated with Voltaren Ophthalmic and 103 patients were treated with vehicle
placebo. Voltaren Ophthalmic was favored over vehicle placebo over a 2-week period for the clinical
assessments of inflammation as measured by anterior chamber cells and flare.
In double-masked, controlled studies of corneal refractive surgery (radial keratotomy (RK) and laser
photorefractive keratectomy (PRK)) patients were treated with Voltaren Ophthalmic and/or vehicle
placebo. The efficacy of Voltaren Ophthalmic given before and shortly after surgery was favored over
vehicle placebo during the 6-hour period following surgery for the clinical assessments of pain and
photophobia. Patients were permitted to use a hydrogel soft contact lens with Voltaren Ophthalmic for
up to three days after PRK.
INDICATIONS AND USAGE
Voltaren Ophthalmic is indicated for the treatment of postoperative inflammation in patients who have
undergone cataract extraction and for the temporary relief of pain and photophobia in patients
undergoing corneal refractive surgery.
CONTRAINDICATIONS
Voltaren Ophthalmic is contraindicated in patients who are hypersensitive to any component of the
medication.
WARNINGS
The refractive stability of patients undergoing corneal refractive procedures and treated with Voltaren
has not been established. Patients should be monitored for a year following use in this setting.
With some nonsteroidal anti-inflammatory drugs, there exists the potential for increased bleeding time
due to interference with thrombocyte aggregation. There have been reports that ocularly applied
nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including
hyphemas) in conjunction with ocular surgery.
There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and
other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating
individuals who have previously exhibited sensitivities to these drugs.
PRECAUTIONS
General
All topical nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay healing. Topical
corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and
topical steroids may increase the potential for healing problems.
Use of topical NSAIDs may result in keratitis. In some susceptible patients continued use of topical
NSAIDs may result in epithelial breakdown, corneal thinning, corneal infiltrates, corneal erosion,
corneal ulceration, and corneal perforation. These events may be sight threatening. Patients with
evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and
should be closely monitored for corneal health.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-037/S-014
Page 5
Postmarketing experience with topical NSAIDs suggests that patients experiencing complicated ocular
surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface disease (e.g.,
dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period-of-time may
be at increased risk for corneal adverse events, which may become sight threatening. Topical NSAIDs
should be used with caution in these patients.
Postmarketing experience with topical NSAIDs also suggests that use more than 24 hours prior to
surgery or use beyond 14 days post surgery may increase patient risk for occurrence and severity of
corneal adverse events.
It is recommended that Voltaren Ophthalmic, like other NSAIDs, be used with caution in patients with
known bleeding tendencies or who are receiving other medications which may prolong bleeding time.
Results from clinical studies indicate that Voltaren Ophthalmic has no significant effect upon ocular
pressure. However, elevations in intraocular pressure may occur following cataract surgery.
Information for Patients
Except for the use of a bandage hydrogel soft contact lens during the first 3 days following refractive
surgery, Voltaren Ophthalmic should not be used by patients currently wearing soft contact lenses due
to adverse events that have occurred in other circumstances.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies in rats given Voltaren in oral doses up to 2 mg/kg/day
(approximately 500 times the human topical ophthalmic dose) revealed no significant increases in
tumor incidence. A 2-year carcinogenicity study conducted in mice employing oral Voltaren up to 2
mg/kg/day did not reveal any oncogenic potential. Voltaren did not show mutagenic potential in
various mutagenicity studies including the Ames test. Voltaren administered to male and female rats at
4 mg/kg/day (approximately 1000 times the human topical ophthalmic dose) did not affect fertility.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger adult
patients.
PREGNANCY
Teratogenic Effects
Pregnancy Category C. Reproduction studies performed in mice at oral doses up to 5,000 times (20
mg/kg/day) and in rats and rabbits at oral doses up to 2,500 times (10 mg/kg/day) the human topical
dose have revealed no evidence of teratogenicity due to Voltaren despite the induction of maternal
toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged
gestation, reduced fetal weights and growth, and reduced fetal survival. Voltaren has been shown to
cross the placental barrier in mice and rats.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-037/S-014
Page 6
Non-teratogenic Effects
Because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular
system (closure of ductus arteriosus), the use of Voltaren Ophthalmic during late pregnancy should be
avoided.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Clinical Practice: The following events have been identified during postmarketing use of topical
diclofenac sodium ophthalmic solution, 0.1% in clinical practice. Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. The events, which have
been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal
connection to topical diclofenac sodium ophthalmic solution, 0.1%, or a combination of these factors,
include corneal erosion, corneal infiltrates, corneal perforation, corneal thinning, corneal ulceration,
epithelial breakdown, and superficial punctate keratitis, (see PRECAUTIONS, General).
Ocular: Transient burning and stinging were reported in approximately 15% of patients across studies
with the use of Voltaren Ophthalmic. In cataract surgery studies, keratitis was reported in up to 28% of
patients receiving Voltaren Ophthalmic, although in many of these cases keratitis was initially noted
prior to the initiation of treatment. Elevated intraocular pressure following cataract surgery was
reported in approximately 15% of patients undergoing cataract surgery. Lacrimation complaints were
reported in approximately 30% of case studies undergoing incisional refractive surgery.
The following adverse reactions were reported in approximately 5% or less of the patients: abnormal
vision, acute elevated IOP, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal
opacity, corneal lesions, discharge, eyelid swelling, injection, iritis, irritation, itching, lacrimation
disorder and ocular allergy.
Systemic: The following adverse reactions were reported in 3% or less of the patients: abdominal pain,
asthenia, chills, dizziness, facial edema, fever, headache, insomnia, nausea, pain, rhinitis, viral
infection, and vomiting.
OVERDOSAGE
Overdosage will not ordinarily cause acute problems. If Voltaren Ophthalmic is accidentally ingested,
fluids should be taken to dilute the medication.
DOSAGE AND ADMINISTRATION
Cataract Surgery: One drop of Voltaren Ophthalmic should be applied to the affected eye, 4 times
daily beginning 24 hours after cataract surgery and continuing throughout the first 2 weeks of the post
operative period.
Corneal Refractive Surgery: One or two drops of Voltaren Ophthalmic should be applied to the
operative eye within the hour prior to corneal refractive surgery. Within 15 minutes after surgery, one
or two drops should be applied to the operative eye and continued 4 times daily for up to 3 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-037/S-014
Page 7
HOW SUPPLIED
Voltaren Ophthalmic 0.1% (1 mg/mL) Sterile Solution is supplied in a low density polyethylene
(LDPE) white bottle with a LDPE Dropper Tip and Polypropylene grey closure. The 2.5 mL fill is
supplied in a 7.5 mL size bottle. The 5.0 mL fill is supplied in a 10.0 mL size bottle.
Bottles of 2.5 mL NDC 58768-100-02
Bottles of 5 mL NDC 58768-100-05
Store at 15°C to 25°C (59° to 77°F).
Dispense in original, unopened container only.
Printed in Canada
Made in Canada. Manufactured for:
Novartis Ophthalmics, Duluth, Georgia 30097
CS 665635G
Novartis ® September, 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:32.669657
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020037s014lbl.pdf', 'application_number': 20037, 'submission_type': 'SUPPL ', 'submission_number': 14}
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AREDIA - pamidronate disodium injection, powder, lyophilized, for solution
Novartis Pharmaceuticals Corporation
Aredia®
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor available in 30-mg or 90-mg vials for intravenous administration.
Each 30-mg and 90-mg vial contains, respectively, 30 mg and 90 mg of sterile, lyophilized pamidronate disodium and 470 mg and 375
mg of mannitol, USP. The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Aredia, a member
of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated
chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD), and its structural formula is Chemical Structure
Pamidronate disodium is a white-to-practically-white powder. It is soluble in water and in 2N sodium hydroxide, sparingly
soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in organic solvents. Its molecular formula is
C3H9NO7P2Na2•5H2O and its molecular weight is 369.1.
Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5 prior to lyophilization).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the mechanism of antiresorptive action is not
completely understood, several factors are thought to contribute to this action. Aredia adsorbs to calcium phosphate (hydroxyapatite)
crystals in bone and may directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition
of osteoclast activity contributes to inhibition of bone resorption. In animal studies, at doses recommended for the treatment of
hypercalcemia, Aredia inhibits bone resorption apparently without inhibiting bone formation and mineralization. Of relevance to
the treatment of hypercalcemia of malignancy is the finding that Aredia inhibits the accelerated bone resorption that results from
osteoclast hyperactivity induced by various tumors in animal studies.
Pharmacokinetics
Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous infusion of 30, 60, or 90 mg of Aredia
over 4 hours and 90 mg of Aredia over 24 hours (Table 1).
Distribution
The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose over 120 hours.
Metabolism
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Excretion
After administration of 30, 60, and 90 mg of Aredia over 4 hours, and 90 mg of Aredia over 24 hours, an overall mean ± SD of 46 ±
16% of the drug was excreted unchanged in the urine within 120 hours. Cumulative urinary excretion was linearly related to dose. The
mean ± SD elimination half-life is 28 ± 7 hours. Mean ± SD total and renal clearances of pamidronate were 107 ± 50 mL/min and 49
± 28 mL/min, respectively. The rate of elimination from bone has not been determined.
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.
Pediatric
Pamidronate is not labeled for use in the pediatric population.
page 1 of 16
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Renal Insufficiency
The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying degrees of renal impairment.
Each patient received a single 90-mg dose of Aredia infused over 4 hours. The renal clearance of pamidronate in patients was found
to closely correlate with creatinine clearance (see Figure 1). A trend toward a lower percentage of drug excreted unchanged in urine
was observed in renally impaired patients. Adverse experiences noted were not found to be related to changes in renal clearance of
pamidronate. Given the recommended dose, 90 mg infused over 4 hours, excessive accumulation of pamidronate in renally impaired
patients is not anticipated if Aredia is administered on a monthly basis. Graph
Figure 1: Pamidronate renal clearance as a function of creatinine clearance in patients with normal and impaired renal function. The
lines are the mean prediction line and 95% confidence intervals.
Hepatic Insufficiency
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases with normal hepatic function
(n=6) and mild to moderate hepatic dysfunction (n=7). Each patient received a single 90-mg dose of Aredia infused over 4 hours.
Although there was a statistically significant difference in the pharmacokinetics between patients with normal and impaired hepatic
function, the difference was not considered clinically relevant. Patients with hepatic impairment exhibited higher mean AUC (53%)
and Cmax (29%), and decreased plasma clearance (33%) values. Nevertheless, pamidronate was still rapidly cleared from the plasma.
Drug levels were not detectable in patients by 12 to 36 hours after drug infusion. Because Aredia is administered on a monthly
basis, drug accumulation is not expected. No changes in Aredia dosing regimen are recommended for patients with mild to moderate
abnormal hepatic function. Aredia has not been studied in patients with severe hepatic impairment.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
Table 1 Mean (SD, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients(n=6 for each group)
Dose
(infusion rate)
30 mg
Maximum
Concentration
(µg/mL)
0.73
Percent
of dose
excreted in urine
43.9
Total
Clearance
(mL/min)
136
Renal
Clearance
(mL/min)
58
page 2 of 16
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(4 hrs)
(0.14, 19.1%)
(14.0, 31.9%)
(44, 32.4%)
(27, 46.5%)
60 mg
1.44
47.4
88
42
(4 hrs)
(0.57, 39.6%)
(47.4, 54.4%)
(56, 63.6%)
(28, 66.7%)
90 mg
2.61
45.3
103
44
(4 hrs)
(0.74, 28.3%)
(25.8, 56.9%)
(37, 35.9%)
(16, 36.4%)
90 mg
1.38
47.5
101
52
(24 hrs)
(1.97, 142.7%)
(10.2, 21.5%)
(58, 57.4%)
(42, 80.8%)
After intravenous administration of radiolabeled pamidronate in rats, approximately 50%-60% of the compound was rapidly
adsorbed by bone and slowly eliminated from the body by the kidneys. In rats given 10 mg/kg bolus injections of radiolabeled
Aredia, approximately 30% of the compound was found in the liver shortly after administration and was then redistributed to bone or
eliminated by the kidneys over 24-48 hours. Studies in rats injected with radiolabeled Aredia showed that the compound was rapidly
cleared from the circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage. Radioactivity was eliminated
from most soft tissues within 1-4 days; was detectable in liver and spleen for 1 and 3 months, respectively; and remained high in
bones, trachea, and teeth for 6 months after dosing. Bone uptake occurred preferentially in areas of high bone turnover. The terminal
phase of elimination half-life in bone was estimated to be approximately 300 days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia, presumably because of decreased release of
phosphate from bone and increased renal excretion as parathyroid hormone levels, which are usually suppressed in hypercalcemia
associated with malignancy, return toward normal. Phosphate therapy was administered in 30% of the patients in response to a
decrease in serum phosphate levels. Phosphate levels usually returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to within or below normal
after treatment with Aredia. These changes occur within the first week after treatment, as do decreases in serum calcium levels, and
are consistent with an antiresorptive pharmacologic action.
Hypercalcemia of Malignancy
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in metastatic bone
disease and hypercalcemia of malignancy. Excessive release of calcium into the blood as bone is resorbed results in polyuria and
gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased
renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Correction of excessive bone resorption and
adequate fluid administration to correct volume deficits are therefore essential to the management of hypercalcemia.
Most cases of hypercalcemia associated with malignancy occur in patients who have breast cancer; squamous-cell tumors of the
lung or head and neck; renal-cell carcinoma; and certain hematologic malignancies, such as multiple myeloma and some types of
lymphomas. A few less-common malignancies, including vasoactive intestinal-peptide-producing tumors and cholangiocarcinoma,
have a high incidence of hypercalcemia as a metabolic complication. Patients who have hypercalcemia of malignancy can generally be
divided into two groups, according to the pathophysiologic mechanism involved.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid-hormone
related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous-
cell malignancies of the lung or head and neck or in genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal
metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone
resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple
myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia,
since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow
hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment
of the total serum calcium value for differences in albumin levels is often used in place of measurement of ionized calcium; several
nomograms are in use for this type of calculation (see DOSAGE AND ADMINISTRATION).
Clinical Trials
In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were enrolled to receive 30 mg, 60 mg, or 90 mg
of Aredia as a single 24-hour intravenous infusion if their corrected serum calcium levels were ≥12.0 mg/dL after 48 hours of saline
hydration.
The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups were 13.8 mg/dL,13.8 mg/dL, and 13.3 mg/
dL, respectively.
The majority of patients (64%) had decreases in albumin-corrected serum calcium levels by 24 hours after initiation of treatment.
Mean-corrected serum calcium levels at days 2-7 after initiation of treatment with Aredia were significantly reduced from baseline in
page 3 of 16
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all three dosage groups. As a result, by 7 days after initiation of treatment with Aredia, 40%, 61%, and 100% of the patients receiving
30 mg, 60 mg, and 90 mg of Aredia, respectively, had normal-corrected serum calcium levels. Many patients (33%-53%) in the 60-mg
and 90-mg dosage groups continued to have normal-corrected serum calcium levels, or a partial response (≥15% decrease of corrected
serum calcium from baseline), at Day 14.
In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium levels of ≥12.0 mg/dL after
at least 24 hours of saline hydration were randomized to receive either 60 mg of Aredia as a single 24-hour intravenous infusion or
7.5 mg/kg of etidronate disodium as a 2-hour intravenous infusion daily for 3 days. Thirty patients were randomized to receive Aredia
and 35 to receive etidronate disodium.
The mean baseline-corrected serum calcium for the Aredia 60-mg and etidronate disodium groups were 14.6 mg/dL and 13.8 mg/
dL, respectively.
By Day 7, 70% of the patients in the Aredia group and 41% of the patients in the etidronate disodium group had normal-corrected
serum calcium levels (P<0.05). When partial responders (≥15% decrease of serum calcium from baseline) were also included, the
response rates were 97% for the Aredia group and 65% for the etidronate disodium group (P<0.01). Mean-corrected serum calcium for
the Aredia and etidronate disodium groups decreased from baseline values to 10.4 and 11.2 mg/dL, respectively, on Day 7. At Day 14,
43% of patients in the Aredia group and 18% of patients in the etidronate disodium group still had normal-corrected serum calcium
levels, or maintenance of a partial response. For responders in the Aredia and etidronate disodium groups, the median duration
of response was similar (7 and 5 days, respectively). The time course of effect on corrected serum calcium is summarized in the
following table.
Change in Corrected Serum Calcium by Time
from Initiation of Treatment
Time
Mean Change from Baseline in Corrected Serum Calcium (mg/dL)
(hr)
Aredia®
Etidronate Disodium
P-Value1
Baseline
14.6
13.8
24
-0.3
-0.5
48
-1.5
-1.1
72
-2.6
-2.0
96
-3.5
-2.0
<0.01
168
-4.1
-2.5
<0.01
1Comparison between treatment groups
In a third multicenter, randomized, parallel double-blind trial, a group of 69 cancer patients with hypercalcemia was enrolled to
receive 60 mg of Aredia as a 4- or 24-hour infusion, which was compared to a saline-treatment group. Patients who had a corrected
serum calcium level of ≥12.0 mg/dL after 24 hours of saline hydration were eligible for this trial.
The mean baseline-corrected serum calcium levels for Aredia 60-mg 4-hour infusion, Aredia 60-mg 24-hour infusion, and saline
infusion were 14.2 mg/dL, 13.7 mg/dL, and 13.7 mg/dL, respectively.
By Day 7 after initiation of treatment, 78%, 61%, and 22% of the patients had normal-corrected serum calcium levels for the 60
mg 4-hour infusion, 60-mg 24-hour infusion, and saline infusion, respectively. At Day 14, 39% of the patients in the Aredia 60-mg 4
hour infusion group and 26% of the patients in the Aredia 60-mg 24-hour infusion group had normal-corrected serum calcium levels
or maintenance of a partial response.
For responders, the median duration of complete responses was 4 days and 6.5 days for Aredia 60-mg 4-hour infusion and Aredia
60-mg 24-hour infusion, respectively.
In all three trials, patients treated with Aredia had similar response rates in the presence or absence of bone metastases.
Concomitant administration of furosemide did not affect response rates.
Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were given a second course of 60 mg of Aredia
over a 4- or 24-hour period. Of these, 41% showed a complete response and 16% showed a partial response to the retreatment, and
these responders had about a 3-mg/dL fall in mean-corrected serum calcium levels 7 days after retreatment.
page 4 of 16
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In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia (corrected serum calcium
≥12.0 mg/dL) received 90 mg of Aredia as a 2-hour infusion. The mean baseline corrected serum calcium was 14.0 mg/dL. Patients
were not required to receive IV hydration prior to drug administration, but all subjects did receive at least 500 mL of IV saline
hydration concomitantly with the pamidronate infusion. By Day 10 after drug infusion, 70% of patients had normal corrected serum
calcium levels (<10.8 mg/dL).
Paget’s Disease
Paget’s disease of bone (osteitis deformans) is an idiopathic disease characterized by chronic, focal areas of bone destruction
complicated by concurrent excessive bone repair, affecting one or more bones. These changes result in thickened but weakened
bones that may fracture or bend under stress. Signs and symptoms may be bone pain, deformity, fractures, neurological disorders
resulting from cranial and spinal nerve entrapment and from spinal cord and brain stem compression, increased cardiac output to
the involved bone, increased serum alkaline phosphatase levels (reflecting increased bone formation) and/or urine hydroxyproline
excretion (reflecting increased bone resorption).
Clinical Trials
In one double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone were enrolled to receive 5 mg, 15 mg, or
30 mg of Aredia as a single 4-hour infusion on 3 consecutive days, for total doses of 15 mg, 45 mg, and 90 mg of Aredia.
The mean baseline serum alkaline phosphatase levels were 1,409 U/L, 983 U/L, and 1,085 U/L, and the mean baseline urine
hydroxyproline/creatinine ratios were 0.25, 0.19, and 0.19 for the 15-mg, 45-mg, and 90-mg groups, respectively.
The effects of Aredia on serum alkaline phosphatase (SAP) and urine hydroxyproline/creatinine ratios (UOHP/C) are summarized
in the following table.
Percent of Patients With Significant % Decreases in SAP and UOHP/C
SAP
UOHP/C
% Decrease
15 mg
45 mg
90 mg
15 mg
45 mg
90 mg
≥50
26
33
60
15
47
72
≥30
40
65
83
35
57
85
The median maximum percent decreases from baseline in serum alkaline phosphatase and urine hydroxyproline/creatinine ratios
were 25%, 41%, and 57%, and 25%, 47%, and 61% for the 15-mg, 45-mg, and 90-mg groups, respectively. The median time to
response (≥50% decrease) for serum alkaline phosphatase was approximately 1 month for the 90-mg group, and the response duration
ranged from 1 to 372 days.
No statistically significant differences between treatment groups, or statistically significant changes from baseline were observed
for the bone pain response, mobility, and global evaluation in the 45-mg and 90-mg groups. Improvement in radiologic lesions
occurred in some patients in the 90-mg group.
Twenty-five patients who had Paget’s disease were retreated with 90 mg of Aredia. Of these, 44% had a ≥50% decrease in serum
alkaline phosphatase from baseline after treatment, and 39% had a ≥50% decrease in urine hydroxyproline/creatinine ratio from
baseline after treatment.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast cancer. These cancers demonstrate a
phenomenon known as osteotropism, meaning they possess an extraordinary affinity for bone. The distribution of osteolytic bone
metastases in these cancers is predominantly in the axial skeleton, particularly the spine, pelvis, and ribs, rather than the appendicular
skeleton, although lesions in the proximal femur and humerus are not uncommon. This distribution is similar to the red bone marrow
in which slow blood flow possibly assists attachment of metastatic cells. The surface-to-volume ratio of trabecular bone is much
higher than cortical bone, and therefore disease processes tend to occur more floridly in trabecular bone than at sites of cortical tissue.
These bone changes can result in patients having evidence of osteolytic skeletal destruction leading to severe bone pain that
requires either radiation therapy or narcotic analgesics (or both) for symptomatic relief. These changes also cause pathologic
fractures of bone in both the axial and appendicular skeleton. Axial skeletal fractures of the vertebral bodies may lead to spinal
cord compression or vertebral body collapse with significant neurologic complications. Also, patients may experience episode(s) of
hypercalcemia.
Clinical Trials
In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple myeloma were enrolled to receive Aredia
or placebo in addition to their underlying antimyeloma therapy to determine the effect of Aredia on the occurrence of skeletal-related
page 5 of 16
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events (SREs). SREs were defined as episodes of pathologic fractures, radiation therapy to bone, surgery to bone, and spinal cord
compression. Patients received either 90 mg of Aredia or placebo as a monthly 4-hour intravenous infusion for 9 months. Of the 392
patients, 377 were evaluable for efficacy (196 Aredia, 181 placebo). The proportion of patients developing any SRE was significantly
smaller in the Aredia group (24% vs 41%, P<0.001), and the mean skeletal morbidity rate (#SRE/year) was significantly smaller for
Aredia patients than for placebo patients (mean: 1.1 vs 2.1, P<.02). The times to the first SRE occurrence, pathologic fracture, and
radiation to bone were significantly longer in the Aredia group (P=.001, .006, and .046, respectively). Moreover, fewer Aredia patients
suffered any pathologic fracture (17% vs 30%, P=.004) or needed radiation to bone (14% vs 22%, P=.049).
In addition, decreases in pain scores from baseline occurred at the last measurement for those Aredia patients with pain at baseline
(P=.026) but not in the placebo group. At the last measurement, a worsening from baseline was observed in the placebo group for the
Spitzer quality of life variable (P<.001) and ECOG performance status (P<.011) while there was no significant deterioration from
baseline in these parameters observed in Aredia-treated patients.*
After 21 months, the proportion of patients experiencing any skeletal event remained significantly smaller in the Aredia group than
the placebo group (P=.015). In addition, the mean skeletal morbidity rate (#SRE/year) was 1.3 vs 2.2 for Aredia patients vs placebo
patients (P=.008), and time to first SRE was significantly longer in the Aredia group compared to placebo (P=.016). Fewer Aredia
patients suffered vertebral pathologic fractures (16% vs 27%, P=.005). Survival of all patients was not different between treatment
groups.
Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of 90 mg of Aredia infused over 2
hours every 3 to 4 weeks for 24 months to that of placebo in preventing SREs in breast cancer patients with osteolytic bone metastases
who had one or more predominantly lytic metastases of at least 1 cm in diameter: one in patients being treated with antineoplastic
chemotherapy and the second in patients being treated with hormonal antineoplastic therapy at trial entry.
382 patients receiving chemotherapy were randomized, 185 to Aredia and 197 to placebo. 372 patients receiving hormonal therapy
were randomized, 182 to Aredia and 190 to placebo. All but three patients were evaluable for efficacy. Patients were followed for
24 months of therapy or until they went off study. Median duration of follow-up was 13 months in patients receiving chemotherapy
and 17 months in patients receiving hormone therapy. Twenty-five percent of the patients in the chemotherapy study and 37% of the
patients in the hormone therapy study received Aredia for 24 months. The efficacy results are shown in the table below:
N
Breast Cancer Patients
Receiving Chemotherapy
Any SRE
Radiation
Fractures
A
P
A
P
A
P
185
195
185
195
185
195
Breast Cancer Patients
Receiving Hormonal Therapy
Any SRE
Radiation
Fractures
A
P
A
P
A
P
182
189
182
189
182
189
Skeletal Morbidity
Rate
(#SRE/year)
Mean
2.5
3.7
0.8
1.3
1.6
2.2
2.4
3.6
0.6
1.2
1.6
2.2
P-Value
<.001
<.001†
.018†
.021
.013†
.040†
Proportion of
patients having
an SRE
46%
65%
28%
45%
36%
49%
55%
63%
31%
40%
45%
55%
P-Value
<.001
<.001†
.014†
.094
.058†
.054†
Median Time to
SRE (months)
13.9
7.0
NR**
14.2
25.8
13.3
10.9
7.4
NR**
23.4
20.6
12.8
P-Value
<.001
<.001†
.009†
.118
.016†
.113†
†Fractures and radiation to bone were two of several secondary endpoints. The statistical significance of these analyses may be
overestimated since numerous analyses were performed.
**NR = Not Reached.
Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12 months. The complete + partial response rate
was 33% in Aredia patients and 18% in placebo patients treated with chemotherapy (P=.001). No difference was seen between Aredia
and placebo in hormonally-treated patients.
page 6 of 16
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Pain and analgesic scores, ECOG performance status and Spitzer quality of life index were measured at baseline and periodically
during the trials. The changes from baseline to the last measurement carried forward are shown in the following table:
Mean Change (#) from Baseline at Last Measurement
Breast Cancer Patients
Receiving Chemotherapy
Aredia®
Placebo
A vs P
Breast Cancer Patients
Receiving Hormonal Therapy
Aredia®
Placebo
A vs P
N
Mean #
N
Mean Δ
P-Value*
N
Mean #
N
Mean Δ
P-Value*
Pain Score
175
+0.93
183
+1.69
.050
Analgesic
Score
175
+0.74
183
+1.55
.009
ECOG PS
178
+0.81
186
+1.19
.002
Spitzer
QOL
177
-1.76
185
-2.21
.103
173
+0.50
179
+1.60
.007
173
+0.90
179
+2.28
<.001
175
+0.95
182
+0.90
.773
173
-1.86
181
-2.05
.409
Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an improvement from baseline.
*The statistical significance of analyses of these secondary endpoints of pain, quality of life, and performance status in all three trials
may be overestimated since numerous analyses were performed.
INDICATIONS AND USAGE
Hypercalcemia of Malignancy
Aredia, in conjunction with adequate hydration, is indicated for the treatment of moderate or severe hypercalcemia associated with
malignancy, with or without bone metastases. Patients who have either epidermoid or non-epidermoid tumors respond to treatment
with Aredia. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should
be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with
conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the
treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be
employed prior to correction of hypovolemia. The safety and efficacy of Aredia in the treatment of hypercalcemia associated with
hyperparathyroidism or with other non-tumor-related conditions has not been established.
Paget’s Disease
Aredia is indicated for the treatment of patients with moderate to severe Paget’s disease of bone. The effectiveness of Aredia was
demonstrated primarily in patients with serum alkaline phosphatase ≥3 times the upper limit of normal. Aredia therapy in patients with
Paget’s disease has been effective in reducing serum alkaline phosphatase and urinary hydroxyproline levels by ≥50% in at least 50%
of patients, and by ≥30% in at least 80% of patients. Aredia therapy has also been effective in reducing these biochemical markers in
patients with Paget’s disease who failed to respond, or no longer responded to other treatments.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
Aredia is indicated, in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone metastases of breast
cancer and osteolytic lesions of multiple myeloma. The Aredia treatment effect appeared to be smaller in the study of breast cancer
patients receiving hormonal therapy than in the study of those receiving chemotherapy, however, overall evidence of clinical benefit
has been demonstrated (see CLINICAL PHARMACOLOGY, Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of
Multiple Myeloma, Clinical Trials section).
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other bisphosphonates.
WARNINGS
Deterioration in Renal Function
Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration of renal function and potential
renal failure.
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY
PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA SHOULD NOT EXCEED 90 MG (see DOSAGE AND
ADMINISTRATION for appropriate infusion durations). Renal deterioration, progression to renal failure, and dialysis have
been reported in patients after the initial or a single dose of Aredia.
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Focal segmental glomerulosclerosis (including the collapsing variant) with or without nephrotic syndrome, which may lead to
renal failure, has been reported in Aredia-treated patients, particularly in the setting of multiple myeloma and breast cancer. Some of
these patients had gradual improvement in renal status after Aredia was discontinued.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Patients treated with Aredia for bone
metastases should have the dose withheld if renal function has deteriorated. (See DOSAGE AND ADMINISTRATION.)
PREGNANCY: AREDIA SHOULD NOT BE USED DURING PREGNANCY
Aredia may cause fetal harm when administered to a pregnant woman. (See PRECAUTIONS, Pregnancy Category D.)
There are no studies in pregnant women using Aredia. If the patient becomes pregnant while taking this drug, the patient should be
apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Studies conducted in young rats have reported the disruption of dental dentine formation following single- and multi-dose
administration of bisphosphonates. The clinical significance of these findings is unknown.
PRECAUTIONS
General
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium, and potassium, should
be carefully monitored following initiation of therapy with Aredia. Cases of asymptomatic hypophosphatemia (12%), hypokalemia
(7%), hypomagnesemia (11%), and hypocalcemia (5%-12%), were reported in Aredia-treated patients. Rare cases of symptomatic
hypocalcemia (including tetany) have been reported in association with Aredia therapy. If hypocalcemia occurs, short-term calcium
therapy may be necessary. In Paget’s disease of bone, 17% of patients treated with 90 mg of Aredia showed serum calcium levels
below 8 mg/dL.
Patients with a history of thyroid surgery may have relative hypoparathyroidism that may predispose to hypocalcemia with Aredia.
Renal Insufficiency
Aredia is excreted intact primarily via the kidney, and the risk of renal adverse reactions may be greater in patients with impaired
renal function. Patients who receive Aredia should have serum creatinine assessed prior to each treatment. In patients receiving Aredia
for bone metastases, who show evidence of deterioration in renal function, Aredia treatment should be withheld until renal function
returns to baseline (see WARNINGS and DOSAGE AND ADMINISTRATION).
In clinical trials, patients with renal impairment (serum creatinine >3.0 mg/dL) have not been studied. Limited
pharmacokinetic data exist in patients with creatinine clearance <30 ml/min (See Clinical Pharmacology, Pharmacokinetics.)
For the treatment of bone metastases, the use of Aredia in patients with severe renal impairment is not recommended. In other
indications, clinical judgment should determine whether the potential benefit outweighs the potential risk in such patients.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates,
including Aredia. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ.
Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast
cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures).
Many reports of ONJ involved patients with signs of local infection including osteomyelitis.
Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to
treatment with bisphosphonates.
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on
bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data
available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating
physician should guide the management plan of each patient based on individual benefit/risk assessment (See Adverse Reactions).
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients
taking bisphosphonates. However, such reports have been infrequent. This category of drugs includes Aredia (pamidronate disodium
for injection). The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of
symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
Laboratory Tests
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Serum calcium, electrolytes, phosphate,
magnesium, and CBC, differential, and hematocrit/hemoglobin must be closely monitored in patients treated with Aredia. Patients
who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks following treatment.
Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of Aredia.
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Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal dysfunction may be increased when Aredia is used in combination with
thalidomide.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study (daily oral administration) in rats, there was a positive dose response relationship for benign
adrenal pheochromocytoma in males (P<0.00001). Although this condition was also observed in females, the incidence was not
statistically significant. When the dose calculations were adjusted to account for the limited oral bioavailability of Aredia in rats, the
lowest daily dose associated with adrenal pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma
was also observed in low numbers in the control animals and is considered a relatively common spontaneous neoplasm in the rat.
Aredia (daily oral administration) was not carcinogenic in an 80-week study in mice.
Aredia was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and Escherichia/ liver-microsome test, nucleus-
anomaly test, sister-chromatid-exchange study, point-mutation test, and micronucleus test in the rat.
In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of Aredia orally; however,
this occurred only when animals were mated with members of the same dose group. Aredia has not been administered intravenously in
such a study.
Animal Toxicology
In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of Aredia.
Two 7-day intravenous infusion studies were conducted in the dog wherein Aredia was given for 1, 4, or 24 hours at doses of
1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3 mg/kg (1.7 x highest recommended human
dose [HRHD] for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as elevated BUN and
creatinine levels and renal tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second
study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included elevated
BUN levels in several treated animals and renal tubular dilation and/or inflammation at ≥1 mg/kg after each infusion time.
Aredia was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as a 1-hour infusion, once a
week, for 3 months followed by a 1-month recovery period. In rats, nephrotoxicity was observed at ≥6 mg/kg and included increased
BUN and creatinine levels and tubular degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the
recovery period. In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and
creatinine levels at ≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially reversible at 6 mg/kg. In
both studies, the dose level that produced no adverse renal effects was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous
infusion).
Pregnancy Category D (See WARNINGS)
There are no adequate and well-controlled studies in pregnant women.
Bolus intravenous studies conducted in rats and rabbits determined that Aredia produces maternal toxicity and embryo/fetal effects
when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion.
As it has been shown that Aredia can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal
effects in rats and rabbits, it should not be given to women during pregnancy.
Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years.
The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic
circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans,
bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater
than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman
becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of
bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous vs oral) on this
risk has not been established.
Nursing Mothers
It is not known whether Aredia is excreted in human milk. Because many drugs are excreted in human milk, caution should be
exercised when Aredia is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Aredia in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects in clinical studies of Aredia, approximately 20% were 65 and over, while approximately 15% were
75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other
reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at
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the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
ADVERSE REACTIONS
Clinical Studies
Hypercalcemia of Malignancy
Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of Aredia in 34% of patients in
clinical trials. In the saline trial, 18% of patients had a temperature elevation of at least 1°C 24 to 48 hours after treatment.
Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of catheter insertion
were most common in patients treated with 90 mg of Aredia. Symptomatic treatment resulted in rapid resolution in all patients.
Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis, and one case of uveitis
upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the four U.S. controlled hypercalcemia clinical studies were reported
to have had seizures, 2 of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the
investigators. However, a possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted
that in the saline arm 1 patient (4%) had a seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90-mg Aredia over 24 hours to 2 hours in patients with
hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in
patients who received 90-mg Aredia over 24 hours is similar to those who received 90-mg Aredia over 2 hours. The only notable
differences observed were an increase in the proportion of patients in the Aredia 24-hour group who experienced fluid overload and
electrolyte/mineral abnormalities.
At least 15% of patients treated with Aredia for hypercalcemia of malignancy also experienced the following adverse events
during a clinical trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting
Genitourinary: Urinary tract infection
Musculoskeletal: Bone pain
Laboratory Abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia
Many of these adverse experiences may have been related to the underlying disease state.
The following table lists the adverse
experiences considered to be treatment-related during comparative, controlled U.S. trials.
Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials
Percent of Patients
Aredia®
Etidronate Disodium
Saline
60 mg
60 mg
90 mg
7.5 mg/kg
over 4 hr
over 24 hr
over 24 hr
x 3 days
n=23
n=73
n=17
n=35
n=23
General
Edema
0
1
0
0
0
Fatigue
0
0
12
0
0
Fever
26
19
18
9
0
Fluid overload
0
0
0
6
0
Infusion-site reaction
0
4
18
0
0
Moniliasis
0
0
6
0
0
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Rigors
0
0
0
0
4
Gastrointestinal
Abdominal pain
0
1
0
0
0
Anorexia
4
1
12
0
0
Constipation
4
0
6
3
0
Diarrhea
0
1
0
0
0
Dyspepsia
4
0
0
0
0
Gastrointestinal hemorrhage
0
0
6
0
0
Nausea
4
0
18
6
0
Stomatitis
0
1
0
3
0
Vomiting
4
0
0
0
0
Respiratory
Dyspnea
0
0
0
3
0
Rales
0
0
6
0
0
Rhinitis
0
0
6
0
0
Upper respiratory infection
0
3
0
0
0
CNS
Anxiety
0
0
0
0
4
Convulsions
0
0
0
3
0
Insomnia
0
1
0
0
0
Nervousness
0
0
0
0
4
Psychosis
4
0
0
0
0
Somnolence
0
1
6
0
0
Taste perversion
0
0
0
3
0
Cardiovascular
Atrial fibrillation
0
0
6
0
4
Atrial flutter
0
1
0
0
0
Cardiac failure
0
1
0
0
0
Hypertension
0
0
6
0
4
Syncope
0
0
6
0
0
Tachycardia
0
0
6
0
4
Endocrine
Hypothyroidism
0
0
6
0
0
Hemic and Lymphatic
Anemia
0
0
6
0
0
Leukopenia
4
0
0
0
0
Neutropenia
0
1
0
0
0
Thrombocytopenia
0
1
0
0
0
Musculoskeletal
Myalgia
0
1
0
0
0
Urogenital
Uremia
4
0
0
0
0
Laboratory Abnormalities
Hypocalcemia
0
1
12
0
0
Hypokalemia
4
4
18
0
0
Hypomagnesemia
4
10
12
3
4
Hypophosphatemia
0
9
18
3
0
Abnormal liver function
0
0
0
3
0
Paget’s Disease
Transient mild elevation of temperature >1°C above pretreatment baseline was noted within 48 hours after completion of treatment in
21% of the patients treated with 90 mg of Aredia in clinical trials.
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Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia, increased sweating) were
more common in patients with Paget’s disease treated with 90 mg of Aredia than in patients with hypercalcemia of malignancy treated
with the same dose.
Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients with Paget’s disease treated
with 90 mg of Aredia in two U.S. clinical trials, were fever, nausea, back pain, and bone pain.
At least 10% of all Aredia-treated patients with Paget’s disease also experienced the following adverse experiences during clinical
trials:
Cardiovascular: Hypertension
Musculoskeletal: Arthrosis, bone pain
Nervous system: Headache
Most of these adverse experiences may have been related to the underlying disease state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma
The most commonly reported (>15%) adverse experiences occurred with similar frequencies in the Aredia- and placebo-treatment
groups, and most of these adverse experiences may have been related to the underlying disease state or cancer therapy.
Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
Aredia®
Aredia®
All
90 mg
90 mg
Aredia®
over 4 hours
Placebo
over 2 hours
Placebo
90 mg
Placebo
N=205
N=187
N=367
N=386
N=572
N=573
%
%
%
%
%
%
General
Asthenia
16.1
17.1
25.6
19.2
22.2
18.5
Fatigue
31.7
28.3
40.3
28.8
37.2
29.0
Fever
38.5
38
38.1
32.1
38.5
34
Metastases
1.0
3.0
31.3
24.4
20.5
17.5
Pain
13.2
11.8
15.0
18.1
14.3
16.1
Digestive System
Anorexia
17.1
17.1
31.1
24.9
26.0
22.3
Constipation
28.3
31.7
36.0
38.6
33.2
35.1
Diarrhea
26.8
26.8
29.4
30.6
28.5
29.7
Dyspepsia
17.6
13.4
18.3
15.0
22.6
17.5
Nausea
35.6
37.4
63.5
59.1
53.5
51.8
Pain Abdominal
19.5
16.0
24.3
18.1
22.6
17.5
Vomiting
16.6
19.8
46.3
39.1
35.7
32.8
Hemic and Lymphatic
Anemia
47.8
41.7
39.5
36.8
42.5
38.4
Granulocytopenia
20.5
15.5
19.3
20.5
19.8
18.8
Thrombocytopenia
16.6
17.1
12.5
14.0
14.0
15.0
Musculoskeletal System
Arthralgias
10.7
7.0
15.3
12.7
13.6
10.8
Myalgia
25.4
15.0
26.4
22.5
26
20.1
Skeletal Pain
61.0
71.7
70.0
75.4
66.8
74
CNS
Anxiety
7.8
9.1
18.0
16.8
14.3
14.3
Headache
24.4
19.8
27.2
23.6
26.2
22.3
Insomnia
17.1
17.2
25.1
19.4
22.2
19.0
Respiratory System
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Coughing
26.3
22.5
25.3
19.7
25.7
20.6
Dyspnea
22.0
21.4
35.1
24.4
30.4
23.4
Pleural Effusion
2.9
4.3
15.0
9.1
10.7
7.5
Sinusitis
14.6
16.6
16.1
10.4
15.6
12.0
Upper Respiratory Tract
Infection
32.2
28.3
19.6
20.2
24.1
22.9
Urogenital System
Urinary Tract Infection
15.6
9.1
20.2
17.6
18.5
15.6
Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and anemia were slightly more
common in the Aredia patients whereas stomatitis and alopecia occurred at a frequency similar to that in placebo patients. In the breast
cancer trials, mild elevations of serum creatinine occurred in 18.5% of Aredia patients and 12.3% of placebo patients. Mineral and
electrolyte disturbances, including hypocalcemia, were reported rarely and in similar percentages of Aredia-treated patients compared
with those in the placebo group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia, and hypomagnesemia
for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively, and for placebo-treated patients were 1.2%, 12%, 1.7%,
and 4.5%, respectively. In previous hypercalcemia of malignancy trials, patients treated with Aredia (60 or 90 mg over 24 hours)
developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS, Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the Aredia group than in the placebo group (13.6% and 26% vs
10.8% and 20.1%, respectively).
In multiple myeloma patients, there were five Aredia-related serious and unexpected adverse experiences. Four of these were
reported during the 12-month extension of the multiple myeloma trial. Three of the reports were of worsening renal function
developing in patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The fourth report was the
adult respiratory distress syndrome developing in a patient recovering from pneumonia and acute gangrenous cholecystitis. One
Aredia-treated patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat within
24 hours after the sixth infusion.
In the breast cancer trials, there were four Aredia-related adverse experiences, all moderate in severity, that caused a patient to
discontinue participation in the trial. One was due to interstitial pneumonitis, another to malaise and dyspnea. One Aredia patient
discontinued the trial due to a symptomatic hypocalcemia. Another Aredia patient discontinued therapy due to severe bone pain after
each infusion, which the investigator felt was trial-drug-related.
Renal Toxicity
In a study of the safety and efficacy of Aredia 90 mg (2-hour infusion) vs Zometa 4 mg (15-minute infusion) in bone metastases
patients with multiple myeloma or breast cancer, renal deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for
patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine
(≥1.4 mg/dL). The following are data on the incidence of renal deterioration in patients in this trial. See table below.
Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer Patients with Normal and Abnormal
Serum Creatinine at Baseline*
Patient Population/Baseline Creatinine
Aredia® 90 mg/2 hours
Zometa® 4 mg/15 minutes
n/N
(%)
n/N
(%)
Normal
20/246
(8.1%)
23/246
(9.3%)
Abnormal
2/22
(9.1%)
1/26
(3.8%)
Total
22/268
(8.2%)
24/272
(8.8%)
*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.
Post-Marketing Experience
The following adverse reactions have been reported in post-marketing use: General: reactivation of Herpes simplex and Herpes
zoster, influenza-like symptoms; CNS: confusion and visual hallucinations, sometimes in the presence of electrolyte imbalance; Skin:
rash, pruritus; Special senses:conjunctivitis; Renal: focal segmental glomerulosclerosis including the collapsing variant, nephrotic
syndrome; Laboratory abnormalities: hyperkalemia, hypernatremia, hematuria. Rare instances of allergic manifestations have been
reported, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock. Aredia is contraindicated in patients
with clinically significant hypersensitivity to Aredia or other bisphosphonates (see CONTRAINDICATIONS).
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___________________________
Cases of osteonecrosis (primarily involving the jaw) have been reported predominantly in cancer patients treated with intravenous
bisphosphonates, including Aredia. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk
factors for ONJ. Data suggest a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple
myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is
therefore prudent to avoid invasive dental procedures as recovery may be prolonged.(See PRECAUTIONS.)
OVERDOSAGE
There have been several cases of drug maladministration of intravenous Aredia in hypercalcemia patients with total doses of 225 mg
to 300 mg given over 2 ½ to 4 days. All of these patients survived, but they experienced hypocalcemia that required intravenous and/
or oral administration of calcium. Single doses of Aredia should not exceed 90 mg and the duration of the intravenous infusion
should be no less than 2 hours. (See WARNINGS.)
In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for 3 days experienced high fever (39.5°C),
hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perversion, noted about 6 hours after the first infusion. The
fever and hypotension were rapidly corrected with steroids.
If overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with short-term intravenous
calcium.
DOSAGE AND ADMINISTRATION
Hypercalcemia of Malignancy
Consideration should be given to the severity of as well as the symptoms of hypercalcemia. Vigorous saline hydration alone may be
sufficient for treating mild, asymptomatic hypercalcemia. Overhydration should be avoided in patients who have potential for cardiac
failure. In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid therapy may be helpful.
Moderate Hypercalcemia
The recommended dose of Aredia in moderate hypercalcemia (corrected serum calcium* of approximately 12-13.5 mg/dL) is
60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce
the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.
Severe Hypercalcemia
The recommended dose of Aredia in severe hypercalcemia (corrected serum calcium*>13.5 mg/dL) is 90 mg given as a
SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal
toxicity, particularly in patients with preexisting renal insufficiency.
*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).
Retreatment
A limited number of patients have received more than one treatment with Aredia for hypercalcemia. Retreatment with Aredia, in
patients who show complete or partial response initially, may be carried out if serum calcium does not return to normal or remain
normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response
to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy.
Paget’s Disease
The recommended dose of Aredia in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a
4-hour infusion on 3 consecutive days for a total dose of 90 mg.
Retreatment
A limited number of patients with Paget’s disease have received more than one treatment of Aredia in clinical trials. When clinically
indicated, patients should be retreated at the dose of initial therapy.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of Aredia in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4
hour infusion given on a monthly basis.
Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to Aredia infusion.
Limited information is available on the use of Aredia in multiple myeloma patients with a serum creatinine ≥3.0 mg/dL.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal
deterioration. In a clinical study, renal deterioration was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
page 14 of 16
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In this clinical study, Aredia treatment was resumed only when the creatinine returned to within 10% of the baseline value.
The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final analysis after 21 months
demonstrated overall benefits (see CLINICAL TRIALS section).
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion
given every 3-4 weeks.
Aredia has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate, mitoxantrone, vinblastine,
dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen. It has been given less frequently with etoposide,
cisplatin, cytarabine, paclitaxel, and aminoglutethimide.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal
deterioration. In a clinical study, renal deterioration was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned to within 10% of the baseline value.
The optimal duration of therapy is not known, however, in two breast cancer studies, final analyses performed after 24 months of
therapy demonstrated overall benefits (see CLINICAL TRIALS section).
Calcium and Vitamin D Supplementation
In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium
or vitamin D deficiency, and patients with Paget’s disease of the bone, should be given oral calcium and vitamin D supplementation in
order to minimize the risk of hypocalcemia.
Preparation of Solution
Reconstitution
Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial, resulting in a solution of 30 mg/10 mL or 90
mg/10 mL. The pH of the reconstituted solution is 6.0-7.4. The drug should be completely dissolved before the solution is withdrawn.
Method of Administration
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY
PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA SHOULD NOT EXCEED 90 MG. (SEE WARNINGS.)
There must be strict adherence to the intravenous administration recommendations for Aredia in order to decrease the risk of
deterioration in renal function.
Hypercalcemia of Malignancy
The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60-mg and 90-mg doses. The
recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.
This infusion solution is stable for up to 24 hours at room temperature.
Paget’s Disease
The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose
Injection, USP, and administered over a 4-hour period for 3 consecutive days.
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose
Injection, USP, and administered over a 2-hour period every 3-4 weeks.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride, USP, or 5% Dextrose
Injection, USP, and administered over a 4-hour period on a monthly basis.
Aredia must not be mixed with calcium-containing infusion solutions, such as Ringer’s solution, and should be given in a
single intravenous solution and line separate from all other drugs.
Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
whenever solution and container permit.
Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration at 2°C-8°C (36°F-46°F) for up to 24 hours.
page 15 of 16
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HOW SUPPLIED
Vials -
30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and
470 mg of mannitol, USP.
Carton of 4 vials………………………………………………NDC 0078-0463-91
Vials -
90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and
375 mg of mannitol, USP.
Carton of 1 vial………………………………………………NDC 0078-0464-61
Do not store above 30°C (86°F).
T2008-43
REV:
November 2008
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
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custom-source
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2025-02-12T13:46:32.709376
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020036s035lbl.pdf', 'application_number': 20036, 'submission_type': 'SUPPL ', 'submission_number': 35}
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Aredia
pamidronate disodium for injection
For Intravenous Infusion
Rx only
Prescribing Information
DESCRIPTION
Aredia, pamidronate disodium (APD), is a bisphosphonate available in 30-mg or 90-mg vials for
intravenous administration. Each 30-mg and 90-mg vial contains, respectively, 30 mg and 90 mg of
sterile, lyophilized pamidronate disodium and 470 mg and 375 mg of mannitol, USP. The pH of a 1%
solution of pamidronate disodium in distilled water is approximately 8.3. Aredia, a member of the group
of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium
is designated chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt,
pentahydrate, (APD), and its structural formula is structural formula
Pamidronate disodium is a white-to-practically-white powder. It is soluble in water and in 2N sodium
hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble
in organic solvents. Its molecular formula is C3H9NO7P2Na2•5H2O and its molecular weight is 369.1.
Inactive Ingredients. Mannitol, USP, and phosphoric acid (for adjustment to pH 6.5 prior to
lyophilization).
CLINICAL PHARMACOLOGY
The principal pharmacologic action of Aredia is inhibition of bone resorption. Although the mechanism of
antiresorptive action is not completely understood, several factors are thought to contribute to this action.
Aredia adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution
of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity
contributes to inhibition of bone resorption. In animal studies, at doses recommended for the treatment of
hypercalcemia, Aredia inhibits bone resorption apparently without inhibiting bone formation and
mineralization. Of relevance to the treatment of hypercalcemia of malignancy is the finding that Aredia
inhibits the accelerated bone resorption that results from osteoclast hyperactivity induced by various
tumors in animal studies.
Pharmacokinetics
Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous infusion of
30, 60, or 90 mg of Aredia over 4 hours and 90 mg of Aredia over 24 hours (Table 1).
Distribution
The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose over 120 hours.
Reference ID: 3138612
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Metabolism
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Excretion
After administration of 30, 60, and 90 mg of Aredia over 4 hours, and 90 mg of Aredia over 24 hours, an
overall mean ± SD of 46 ± 16% of the drug was excreted unchanged in the urine within 120 hours.
Cumulative urinary excretion was linearly related to dose. The mean ± SD elimination half-life is 28 ± 7
hours. Mean ± SD total and renal clearances of pamidronate were 107 ± 50 mL/min and 49 ± 28 mL/min,
respectively. The rate of elimination from bone has not been determined.
Special Populations
There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.
Pediatric
Pamidronate is not labeled for use in the pediatric population.
Renal Insufficiency
The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying
degrees of renal impairment. Each patient received a single 90-mg dose of Aredia infused over 4 hours.
The renal clearance of pamidronate in patients was found to closely correlate with creatinine clearance
(see Figure 1). A trend toward a lower percentage of drug excreted unchanged in urine was observed in
renally impaired patients. Adverse experiences noted were not found to be related to changes in renal
clearance of pamidronate. Given the recommended dose, 90 mg infused over 4 hours, excessive
accumulation of pamidronate in renally impaired patients is not anticipated if Aredia is administered on a
monthly basis.
Figure 1: Pamidronate renal clearance as a function of creatinine
clearance in patients with normal and impaired renal function.
The lines are the mean prediction line and 95% confidence intervals. graph
Reference ID: 3138612
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Hepatic Insufficiency
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases
with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=7). Each patient received
a single 90-mg dose of Aredia infused over 4 hours. Although there was a statistically significant
difference in the pharmacokinetics between patients with normal and impaired hepatic function, the
difference was not considered clinically relevant. Patients with hepatic impairment exhibited higher mean
AUC (53%) and Cmax (29%), and decreased plasma clearance (33%) values. Nevertheless, pamidronate
was still rapidly cleared from the plasma. Drug levels were not detectable in patients by 12 to 36 hours
after drug infusion. Because Aredia is administered on a monthly basis, drug accumulation is not
expected. No changes in Aredia dosing regimen are recommended for patients with mild to moderate
abnormal hepatic function. Aredia has not been studied in patients with severe hepatic impairment.
Drug-Drug Interactions
There are no human pharmacokinetic data for drug interactions with Aredia.
Table 1
Mean (SD, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients
(n=6 for each group)
Dose
(infusion rate)
Maximum
Concentration
(µg/mL)
Percent
of dose
excreted in urine
Total
Clearance
(mL/min)
Renal
Clearance
(mL/min)
30 mg
(4 hrs)
0.73
(0.14, 19.1%)
43.9
(14.0, 31.9%)
136
(44, 32.4%)
58
(27, 46.5%)
60 mg
(4 hrs)
1.44
(0.57, 39.6%)
47.4
(47.4, 54.4%)
88
(56, 63.6%)
42
(28, 66.7%)
90 mg
(4 hrs)
2.61
(0.74, 28.3%)
45.3
(25.8, 56.9%)
103
(37, 35.9%)
44
(16, 36.4%)
90 mg
(24 hrs)
1.38
(1.97, 142.7%)
47.5
(10.2, 21.5%)
101
(58, 57.4%)
52
(42, 80.8%)
After intravenous administration of radiolabeled pamidronate in rats, approximately 50%-60% of the
compound was rapidly adsorbed by bone and slowly eliminated from the body by the kidneys. In rats
given 10 mg/kg bolus injections of radiolabeled Aredia, approximately 30% of the compound was found
in the liver shortly after administration and was then redistributed to bone or eliminated by the kidneys
over 24-48 hours. Studies in rats injected with radiolabeled Aredia showed that the compound was rapidly
cleared from the circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage.
Radioactivity was eliminated from most soft tissues within 1-4 days; was detectable in liver and spleen
for 1 and 3 months, respectively; and remained high in bones, trachea, and teeth for 6 months after dosing.
Bone uptake occurred preferentially in areas of high bone turnover. The terminal phase of elimination
half-life in bone was estimated to be approximately 300 days.
Pharmacodynamics
Serum phosphate levels have been noted to decrease after administration of Aredia, presumably because
of decreased release of phosphate from bone and increased renal excretion as parathyroid hormone levels,
which are usually suppressed in hypercalcemia associated with malignancy, return toward normal.
Phosphate therapy was administered in 30% of the patients in response to a decrease in serum phosphate
levels. Phosphate levels usually returned toward normal within 7-10 days.
Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to
within or below normal after treatment with Aredia. These changes occur within the first week after
Reference ID: 3138612
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treatment, as do decreases in serum calcium levels, and are consistent with an antiresorptive
pharmacologic action.
Hypercalcemia of Malignancy
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic
derangement in metastatic bone disease and hypercalcemia of malignancy. Excessive release of calcium
into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive
dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of
calcium, setting up a cycle of worsening systemic hypercalcemia. Correction of excessive bone resorption
and adequate fluid administration to correct volume deficits are therefore essential to the management of
hypercalcemia.
Most cases of hypercalcemia associated with malignancy occur in patients who have breast cancer;
squamous-cell tumors of the lung or head and neck; renal-cell carcinoma; and certain hematologic
malignancies, such as multiple myeloma and some types of lymphomas. A few less-common
malignancies, including vasoactive intestinal-peptide-producing tumors and cholangiocarcinoma, have a
high incidence of hypercalcemia as a metabolic complication. Patients who have hypercalcemia of
malignancy can generally be divided into two groups, according to the pathophysiologic mechanism
involved.
In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as
parathyroid-hormone-related protein, which are elaborated by the tumor and circulate systemically.
Humoral hypercalcemia usually occurs in squamous-cell malignancies of the lung or head and neck or in
genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal metastases may be absent or
minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products
that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated
hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity
of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium
levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly
or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value
for differences in albumin levels is often used in place of measurement of ionized calcium; several
nomograms are in use for this type of calculation (see DOSAGE AND ADMINISTRATION).
Clinical Trials
In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy were enrolled to
receive 30 mg, 60 mg, or 90 mg of Aredia as a single 24-hour intravenous infusion if their corrected
serum calcium levels were ≥12.0 mg/dL after 48 hours of saline hydration.
The mean baseline-corrected serum calcium for the 30-mg, 60-mg, and 90-mg groups were 13.8
mg/dL,13.8 mg/dL, and 13.3 mg/dL, respectively.
The majority of patients (64%) had decreases in albumin-corrected serum calcium levels by 24 hours after
initiation of treatment. Mean-corrected serum calcium levels at days 2-7 after initiation of treatment with
Aredia were significantly reduced from baseline in all three dosage groups. As a result, by 7 days after
initiation of treatment with Aredia, 40%, 61%, and 100% of the patients receiving 30 mg, 60 mg, and 90
mg of Aredia, respectively, had normal-corrected serum calcium levels. Many patients (33%-53%) in the
60-mg and 90-mg dosage groups continued to have normal-corrected serum calcium levels, or a partial
response (≥15% decrease of corrected serum calcium from baseline), at Day 14.
Reference ID: 3138612
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In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium
levels of ≥12.0 mg/dL after at least 24 hours of saline hydration were randomized to receive either 60 mg
of Aredia as a single 24-hour intravenous infusion or 7.5 mg/kg of etidronate disodium as a 2-hour
intravenous infusion daily for 3 days. Thirty patients were randomized to receive Aredia and 35 to receive
etidronate disodium.
The mean baseline-corrected serum calcium for the Aredia 60-mg and etidronate disodium groups were
14.6 mg/dL and 13.8 mg/dL, respectively.
By Day 7, 70% of the patients in the Aredia group and 41% of the patients in the etidronate disodium
group had normal-corrected serum calcium levels (P<0.05). When partial responders (≥15% decrease of
serum calcium from baseline) were also included, the response rates were 97% for the Aredia group and
65% for the etidronate disodium group (P<0.01). Mean-corrected serum calcium for the Aredia and
etidronate disodium groups decreased from baseline values to 10.4 and 11.2 mg/dL, respectively, on Day
7. At Day 14, 43% of patients in the Aredia group and 18% of patients in the etidronate disodium group
still had normal-corrected serum calcium levels, or maintenance of a partial response. For responders in
the Aredia and etidronate disodium groups, the median duration of response was similar (7 and 5 days,
respectively). The time course of effect on corrected serum calcium is summarized in the following table.
Change in Corrected Serum Calcium by Time
from Initiation of Treatment
Time
Mean Change from Baseline in Corrected Serum Calcium (mg/dL)
(hr)
Aredia®
Etidronate Disodium
P-Value1
Baseline
14.6
13.8
24
-0.3
-0.5
48
-1.5
-1.1
72
-2.6
-2.0
96
-3.5
-2.0
<0.01
168
-4.1
-2.5
<0.01
1Comparison between treatment groups
In a third multicenter, randomized, parallel double-blind trial, a group of 69 cancer patients with
hypercalcemia was enrolled to receive 60 mg of Aredia as a 4- or 24-hour infusion, which was compared
to a saline-treatment group. Patients who had a corrected serum calcium level of ≥12.0 mg/dL after 24
hours of saline hydration were eligible for this trial.
The mean baseline-corrected serum calcium levels for Aredia 60-mg 4-hour infusion, Aredia 60-mg 24
hour infusion, and saline infusion were 14.2 mg/dL, 13.7 mg/dL, and 13.7 mg/dL, respectively.
By Day 7 after initiation of treatment, 78%, 61%, and 22% of the patients had normal-corrected serum
calcium levels for the 60-mg 4-hour infusion, 60-mg 24-hour infusion, and saline infusion, respectively.
At Day 14, 39% of the patients in the Aredia 60-mg 4-hour infusion group and 26% of the patients in the
Aredia 60-mg 24-hour infusion group had normal-corrected serum calcium levels or maintenance of a
partial response.
For responders, the median duration of complete responses was 4 days and 6.5 days for Aredia 60-mg 4
hour infusion and Aredia 60-mg 24-hour infusion, respectively.
In all three trials, patients treated with Aredia had similar response rates in the presence or absence of
bone metastases. Concomitant administration of furosemide did not affect response rates.
Reference ID: 3138612
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Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were given a second
course of 60 mg of Aredia over a 4- or 24-hour period. Of these, 41% showed a complete response and
16% showed a partial response to the retreatment, and these responders had about a 3-mg/dL fall in mean-
corrected serum calcium levels 7 days after retreatment.
In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia
(corrected serum calcium ≥12.0 mg/dL) received 90 mg of Aredia as a 2-hour infusion. The mean
baseline corrected serum calcium was 14.0 mg/dL. Patients were not required to receive IV hydration
prior to drug administration, but all subjects did receive at least 500 mL of IV saline hydration
concomitantly with the pamidronate infusion. By Day 10 after drug infusion, 70% of patients had normal
corrected serum calcium levels (<10.8 mg/dL).
Paget’s Disease
Paget’s disease of bone (osteitis deformans) is an idiopathic disease characterized by chronic, focal areas
of bone destruction complicated by concurrent excessive bone repair, affecting one or more bones. These
changes result in thickened but weakened bones that may fracture or bend under stress. Signs and
symptoms may be bone pain, deformity, fractures, neurological disorders resulting from cranial and spinal
nerve entrapment and from spinal cord and brain stem compression, increased cardiac output to the
involved bone, increased serum alkaline phosphatase levels (reflecting increased bone formation) and/or
urine hydroxyproline excretion (reflecting increased bone resorption).
Clinical Trials
In one double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone were
enrolled to receive 5 mg, 15 mg, or 30 mg of Aredia as a single 4-hour infusion on 3 consecutive days, for
total doses of 15 mg, 45 mg, and 90 mg of Aredia.
The mean baseline serum alkaline phosphatase levels were 1,409 U/L, 983 U/L, and 1,085 U/L, and the
mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and 0.19 for the 15-mg, 45-mg, and
90-mg groups, respectively.
The effects of Aredia on serum alkaline phosphatase (SAP) and urine hydroxyproline/creatinine ratios
(UOHP/C) are summarized in the following table.
Percent of Patients With
Significant % Decreases in SAP and UOHP/C
SAP
UOHP/C
% Decrease
15 mg
45 mg
90 mg
15 mg
45 mg
90 mg
≥50
26
33
60
15
47
72
≥30
40
65
83
35
57
85
The median maximum percent decreases from baseline in serum alkaline phosphatase and urine
hydroxyproline/creatinine ratios were 25%, 41%, and 57%, and 25%, 47%, and 61% for the 15-mg, 45
mg, and 90-mg groups, respectively. The median time to response (≥50% decrease) for serum alkaline
phosphatase was approximately 1 month for the 90-mg group, and the response duration ranged from 1 to
372 days.
No statistically significant differences between treatment groups, or statistically significant changes from
baseline were observed for the bone pain response, mobility, and global evaluation in the 45-mg and 90
mg groups. Improvement in radiologic lesions occurred in some patients in the 90-mg group.
Reference ID: 3138612
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Twenty-five patients who had Paget’s disease were retreated with 90 mg of Aredia. Of these, 44% had a
≥50% decrease in serum alkaline phosphatase from baseline after treatment, and 39% had a ≥50%
decrease in urine hydroxyproline/creatinine ratio from baseline after treatment.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple
Myeloma
Osteolytic bone metastases commonly occur in patients with multiple myeloma or breast cancer. These
cancers demonstrate a phenomenon known as osteotropism, meaning they possess an extraordinary
affinity for bone. The distribution of osteolytic bone metastases in these cancers is predominantly in the
axial skeleton, particularly the spine, pelvis, and ribs, rather than the appendicular skeleton, although
lesions in the proximal femur and humerus are not uncommon. This distribution is similar to the red bone
marrow in which slow blood flow possibly assists attachment of metastatic cells. The surface-to-volume
ratio of trabecular bone is much higher than cortical bone, and therefore disease processes tend to occur
more floridly in trabecular bone than at sites of cortical tissue.
These bone changes can result in patients having evidence of osteolytic skeletal destruction leading to
severe bone pain that requires either radiation therapy or narcotic analgesics (or both) for symptomatic
relief. These changes also cause pathologic fractures of bone in both the axial and appendicular skeleton.
Axial skeletal fractures of the vertebral bodies may lead to spinal cord compression or vertebral body
collapse with significant neurologic complications. Also, patients may experience episode(s) of
hypercalcemia.
Clinical Trials
In a double-blind, randomized, placebo-controlled trial, 392 patients with advanced multiple myeloma
were enrolled to receive Aredia or placebo in addition to their underlying antimyeloma therapy to
determine the effect of Aredia on the occurrence of skeletal-related events (SREs). SREs were defined as
episodes of pathologic fractures, radiation therapy to bone, surgery to bone, and spinal cord compression.
Patients received either 90 mg of Aredia or placebo as a monthly 4-hour intravenous infusion for 9
months. Of the 392 patients, 377 were evaluable for efficacy (196 Aredia, 181 placebo). The proportion of
patients developing any SRE was significantly smaller in the Aredia group (24% vs 41%, P<0.001), and
the mean skeletal morbidity rate (#SRE/year) was significantly smaller for Aredia patients than for
placebo patients (mean: 1.1 vs 2.1, P<.02). The times to the first SRE occurrence, pathologic fracture,
and radiation to bone were significantly longer in the Aredia group (P=.001, .006, and .046, respectively).
Moreover, fewer Aredia patients suffered any pathologic fracture (17% vs 30%, P=.004) or needed
radiation to bone (14% vs 22%, P=.049).
In addition, decreases in pain scores from baseline occurred at the last measurement for those Aredia
patients with pain at baseline (P=.026) but not in the placebo group. At the last measurement, a worsening
from baseline was observed in the placebo group for the Spitzer quality of life variable (P<.001) and
ECOG performance status (P<.011) while there was no significant deterioration from baseline in these
parameters observed in Aredia-treated patients.*
After 21 months, the proportion of patients experiencing any skeletal event remained significantly smaller
in the Aredia group than the placebo group (P=.015). In addition, the mean skeletal morbidity rate
(#SRE/year) was 1.3 vs 2.2 for Aredia patients vs placebo patients (P=.008), and time to first SRE was
significantly longer in the Aredia group compared to placebo (P=.016). Fewer Aredia patients suffered
vertebral pathologic fractures (16% vs 27%, P=.005). Survival of all patients was not different between
treatment groups.
Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of 90 mg of
Aredia infused over 2 hours every 3 to 4 weeks for 24 months to that of placebo in preventing SREs in
breast cancer patients with osteolytic bone metastases who had one or more predominantly lytic
Reference ID: 3138612
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metastases of at least 1 cm in diameter: one in patients being treated with antineoplastic chemotherapy
and the second in patients being treated with hormonal antineoplastic therapy at trial entry.
382 patients receiving chemotherapy were randomized, 185 to Aredia and 197 to placebo. 372 patients
receiving hormonal therapy were randomized, 182 to Aredia and 190 to placebo. All but three patients
were evaluable for efficacy. Patients were followed for 24 months of therapy or until they went off study.
Median duration of follow-up was 13 months in patients receiving chemotherapy and 17 months in
patients receiving hormone therapy. Twenty-five percent of the patients in the chemotherapy study and
37% of the patients in the hormone therapy study received Aredia for 24 months. The efficacy results are
shown in the table below:
N
Breast Cancer Patients
Receiving Chemotherapy
Any SRE
Radiation
Fractures
A
P
A
P
A
P
185
195
185
195
185
195
Breast Cancer Patients
Receiving Hormonal Therapy
Any SRE
Radiation
Fractures
A
P
A
P
A
P
182
189
182
189
182
189
Skeletal Morbidity
Rate
(#SRE/year)
Mean
2.5
3.7
0.8
1.3
1.6
2.2
2.4
3.6
0.6
1.2
1.6
2.2
P-Value
<.001
<.001†
.018†
.021
.013†
.040†
Proportion of
patients having
an SRE
46%
65%
28%
45%
36%
49%
55%
63%
31%
40%
45%
55%
P-Value
<.001
<.001†
.014†
.094
.058†
.054†
Median Time to
SRE (months)
13.9
7.0
NR**
14.2
25.8
13.3
10.9
7.4
NR**
23.4
20.6
12.8
P-Value
<.001
<.001†
.009†
.118
.016†
.113†
†Fractures and radiation to bone were two of several secondary endpoints. The statistical significance of these analyses may be
overestimated since numerous analyses were performed.
**NR = Not Reached.
Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12 months. The complete
+ partial response rate was 33% in Aredia patients and 18% in placebo patients treated with chemotherapy
(P=.001). No difference was seen between Aredia and placebo in hormonally-treated patients.
Pain and analgesic scores, ECOG performance status and Spitzer quality of life index were measured at
baseline and periodically during the trials. The changes from baseline to the last measurement carried
forward are shown in the following table:
Mean Change (∆) from Baseline at Last Measurement
Breast Cancer Patients
Receiving Chemotherapy
Aredia®
Placebo
A vs P
N
Mean ∆
N
Mean Δ
P-Value*
Pain Score
175
+0.93
183
+1.69
Analgesic
Score
175
+0.74
183
+1.55
ECOG PS
178
+0.81
186
+1.19
Spitzer QOL
177
-1.76
185
-2.21
.050
173
+0.50
179
+1.60
.007
.009
173
+0.90
179
+2.28
<.001
.002
175
+0.95
182
+0.90
.773
.103
173
-1.86
181
-2.05
.409
Breast Cancer Patients
Receiving Hormonal Therapy
Aredia®
Placebo
A vs P
N
Mean ∆
N
Mean Δ
P-Value*
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Decreases in pain, analgesic scores and ECOG PS, and increases in Spitzer QOL indicate an improvement from
baseline.
*The statistical significance of analyses of these secondary endpoints of pain, quality of life, and performance
status in all three trials may be overestimated since numerous analyses were performed.
INDICATIONS AND USAGE
Hypercalcemia of Malignancy
Aredia, in conjunction with adequate hydration, is indicated for the treatment of moderate or severe
hypercalcemia associated with malignancy, with or without bone metastases. Patients who have either
epidermoid or non-epidermoid tumors respond to treatment with Aredia. Vigorous saline hydration, an
integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to
restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may
be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients
should be hydrated adequately throughout the treatment, but overhydration, especially in those patients
who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of
hypovolemia. The safety and efficacy of Aredia in the treatment of hypercalcemia associated with
hyperparathyroidism or with other non-tumor-related conditions has not been established.
Paget’s Disease
Aredia is indicated for the treatment of patients with moderate to severe Paget’s disease of bone. The
effectiveness of Aredia was demonstrated primarily in patients with serum alkaline phosphatase ≥3 times
the upper limit of normal. Aredia therapy in patients with Paget’s disease has been effective in reducing
serum alkaline phosphatase and urinary hydroxyproline levels by ≥50% in at least 50% of patients, and by
≥30% in at least 80% of patients. Aredia therapy has also been effective in reducing these biochemical
markers in patients with Paget’s disease who failed to respond, or no longer responded to other
treatments.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple
Myeloma
Aredia is indicated, in conjunction with standard antineoplastic therapy, for the treatment of osteolytic
bone metastases of breast cancer and osteolytic lesions of multiple myeloma. The Aredia treatment effect
appeared to be smaller in the study of breast cancer patients receiving hormonal therapy than in the study
of those receiving chemotherapy, however, overall evidence of clinical benefit has been demonstrated
(see CLINICAL PHARMACOLOGY, Osteolytic Bone Metastases of Breast Cancer and Osteolytic
Lesions of Multiple Myeloma, Clinical Trials section).
CONTRAINDICATIONS
Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other
bisphosphonates.
WARNINGS
Deterioration in Renal Function
Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration
of renal function and potential renal failure.
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL
FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA
SHOULD NOT EXCEED 90 MG (see DOSAGE AND ADMINISTRATION for appropriate
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infusion durations). Renal deterioration, progression to renal failure, and dialysis have been
reported in patients after the initial or a single dose of Aredia.
Focal segmental glomerulosclerosis (including the collapsing variant) with or without nephrotic
syndrome, which may lead to renal failure, has been reported in Aredia-treated patients, particularly in the
setting of multiple myeloma and breast cancer. Some of these patients had gradual improvement in renal
status after Aredia was discontinued.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Patients
treated with Aredia for bone metastases should have the dose withheld if renal function has deteriorated.
(See DOSAGE AND ADMINISTRATION.)
PREGNANCY:
Bisphosphonates, such as Aredia, are incorporated into the bone matrix, from where they are gradually
released over periods of weeks to years. Aredia may cause fetal harm when administered to a pregnant
woman. In reproductive studies in rats and rabbits, pamidronate doses equivalent to 0.6 to 8.3 times the
highest human recommended dose resulted in maternal toxicity and embryo/fetal effects. There are no
adequate and well-controlled studies of Aredia in pregnant women. If this drug is used during pregnancy,
or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the
fetus (See PRECAUTIONS, Pregnancy Category D).
PRECAUTIONS
General
Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate,
magnesium, and potassium, should be carefully monitored following initiation of therapy with Aredia.
Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%), hypomagnesemia (11%), and
hypocalcemia (5%-12%), were reported in Aredia-treated patients. Rare cases of symptomatic
hypocalcemia (including tetany) have been reported in association with Aredia therapy. If hypocalcemia
occurs, short-term calcium therapy may be necessary. In Paget’s disease of bone, 17% of patients treated
with 90 mg of Aredia showed serum calcium levels below 8 mg/dL.
Patients with a history of thyroid surgery may have relative hypoparathyroidism that may predispose to
hypocalcemia with Aredia.
Renal Insufficiency
Aredia is excreted intact primarily via the kidney, and the risk of renal adverse reactions may be greater in
patients with impaired renal function. Patients who receive Aredia should have serum creatinine assessed
prior to each treatment. In patients receiving Aredia for bone metastases, who show evidence of
deterioration in renal function, Aredia treatment should be withheld until renal function returns to baseline
(see WARNINGS and DOSAGE AND ADMINISTRATION).
In clinical trials, patients with renal impairment (serum creatinine >3.0 mg/dL) have not been
studied. Limited pharmacokinetic data exist in patients with creatinine clearance <30 ml/min (See
Clinical Pharmacology, Pharmacokinetics.) For the treatment of bone metastases, the use of Aredia in
patients with severe renal impairment is not recommended. In other indications, clinical judgment should
determine whether the potential benefit outweighs the potential risk in such patients.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with
intravenous bisphosphonates, including Aredia. Many of these patients were also receiving
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chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the
literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer,
multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including
poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including
osteomyelitis.
Cancer patients should maintain good oral hygiene and should have a dental examination with preventive
dentistry prior to treatment with bisphosphonates.
While on treatment, these patients should avoid invasive dental procedures if possible. For patients who
develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients
requiring dental procedures, there are no data available to suggest whether discontinuation of
bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should
guide the management plan of each patient based on individual benefit/risk assessment (See Adverse
Reactions).
Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has
been reported in patients taking bisphosphonates.. This category of drugs includes Aredia (pamidronate
disodium for injection). The time to onset of symptoms varied from one day to several months after
starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of
symptoms when rechallenged with the same drug or another bisphosphonate.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving
bisphosphonate therapy, including Aredia. These fractures can occur anywhere in the femoral shaft from
just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in
orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients
may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture.
Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate
treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been
reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids
(such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has
not been established.
Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the
absence of trauma should be suspected of having an atypical fracture and should be evaluated.
Discontinuation of Aredia therapy in patients suspected to have an atypical femur fracture should be
considered pending evaluation of the patient, based on an individual benefit risk assessment. It is
unknown whether the risk of atypical femur fracture continues after stopping therapy.
Laboratory Tests
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Serum
calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin must be
closely monitored in patients treated with Aredia. Patients who have preexisting anemia, leukopenia, or
thrombocytopenia should be monitored carefully in the first 2 weeks following treatment. Patients
receiving Aredia may be at risk for anemia, leukopenia or thrombocytopenia and should have regular
hematology assessments.
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Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of Aredia.
Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.
In multiple myeloma patients, the risk of renal function deterioration may be increased when Aredia is
used in combination with thalidomide.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104-week carcinogenicity study with daily oral administration of pamidronate in rats, there was a
positive dose response relationship for benign adrenal pheochromocytoma in males (P<0.00001).
Although this condition was also observed in females, the incidence was not statistically significant.
When the dose calculations were adjusted to account for the limited oral bioavailability of pamidronate in
rats, systemic exposure with the lowest daily dose associated with adrenal pheochromocytoma resulted in
systemic exposures that were similar to the systemic exposure achieved at the intended clinical dose.
Adrenal pheochromocytoma was also observed in low numbers in the control animals and is considered a
relatively common spontaneous neoplasm in the rat. Pamidronate given daily by oral administration was
not carcinogenic in an 80-week study in mice.
Pamidronate was nonmutagenic in six mutagenicity assays, including: the Ames bacterial mutagenicity
assay, (with and without metabolic activation), nucleus-anomaly test, sister-chromatid-exchange study,
point-mutation test, and micronucleus test in the rat.
In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of
pamidronate orally; however, this occurred only when animals were mated with members of the same
dose group. Pamidronate has not been administered intravenously in such a study.
Animal Toxicology
In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion)
administration of pamidronate.
Two 7-day intravenous infusion studies were conducted in the dog wherein pamidronate was given for 1,
4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated
at 3 mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when
administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal
tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second
study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours.
Additional findings included elevated BUN levels in several treated animals and renal tubular dilation
and/or inflammation at ≥1 mg/kg after each infusion time.
Pamidronate was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg
as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery period. In rats,
nephrotoxicity was observed at ≥6 mg/kg and included increased BUN and creatinine levels and tubular
degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period.
In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated
BUN and creatinine levels at ≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes
were partially reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects
was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).
Pregnancy Category D (See WARNINGS)
There are no adequate and well-controlled studies in pregnant women. Aredia may cause fetal harm when
administered to a pregnant woman. Bisphosphonates, such as Aredia, are incorporated into the bone
matrix, from where they are gradually released over periods of weeks to years. The extent of
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bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the
systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although
there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data
suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there
is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant
after completing a course of bisphosphonate therapy. The impact of variables such as time between
cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of
administration (intravenous versus oral) on this risk has not been established. If Aredia is used during
pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be
apprised of the potential hazard to the fetus.
Intravenous bolus dosing of pregnant rats and rabbits with pamidronate resulted in maternal toxicity and
embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest
recommended human dose for a single intravenous infusion. Pamidronate can cross the placenta in rats,
and has produced marked maternal and nonteratogenic embryo/fetal effects in both rats and rabbits.
Nursing Mothers
It is not known whether pamidronate is excreted in human milk. Because many drugs are excreted in
human milk, and because of the potential for serious adverse reactions in nursing infants from Aredia, a
decision should be made to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of Aredia in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects in clinical studies of Aredia, approximately 20% were 65 and over, while
approximately 15% were 75 and over. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
Clinical Studies
Hypercalcemia of Malignancy
Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of
Aredia in 34% of patients in clinical trials. In the saline trial, 18% of patients had a temperature elevation
of at least 1°C 24 to 48 hours after treatment.
Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site
of catheter insertion were most common in patients treated with 90 mg of Aredia. Symptomatic treatment
resulted in rapid resolution in all patients.
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Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis,
and one case of uveitis upon separate rechallenges.
Five of 231 patients (2%) who received Aredia during the four U.S. controlled hypercalcemia clinical
studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the
seizures were considered to be drug-related by the investigators. However, a possible relationship
between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline
arm 1 patient (4%) had a seizure.
There are no controlled clinical trials comparing the efficacy and safety of 90-mg Aredia over 24 hours to
2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate
clinical trials suggests that the overall safety profile in patients who received 90-mg Aredia over 24 hours
is similar to those who received 90-mg Aredia over 2 hours. The only notable differences observed were
an increase in the proportion of patients in the Aredia 24-hour group who experienced fluid overload and
electrolyte/mineral abnormalities.
At least 15% of patients treated with Aredia for hypercalcemia of malignancy also experienced the
following adverse events during a clinical trial:
General: Fluid overload, generalized pain
Cardiovascular: Hypertension
Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting
Genitourinary: Urinary tract infection
Musculoskeletal: Bone pain
Laboratory Abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia
Many of these adverse experiences may have been related to the underlying disease state.
The following table lists the adverse experiences considered to be treatment-related during comparative,
controlled U.S. trials.
Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials
Percent of Patients
Aredia®
Etidronate Disodium
Saline
60 mg
60 mg
90 mg
7.5 mg/kg
over 4 hr
over 24 hr
over 24 hr
x 3 days
n=23
n=73
n=17
n=35
n=23
General
Edema
0
1
0
0
0
Fatigue
0
0
12
0
0
Fever
26
19
18
9
0
Fluid overload
0
0
0
6
0
Infusion-site reaction
0
4
18
0
0
Moniliasis
0
0
6
0
0
Rigors
0
0
0
0
4
Gastrointestinal
Abdominal pain
0
1
0
0
0
Anorexia
4
1
12
0
0
Constipation
4
0
6
3
0
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Diarrhea
0
1
0
0
0
Dyspepsia
Gastrointestinal hemorrhage
Nausea
4
0
4
0
0
0
0
6
18
0
0
6
0
0
0
Stomatitis
0
1
0
3
0
Vomiting
Respiratory
Dyspnea
Rales
4
0
0
0
0
0
0
0
6
0
3
0
0
0
0
Rhinitis
0
0
6
0
0
Upper respiratory infection
CNS
0
3
0
0
0
Anxiety
Convulsions
0
0
0
0
0
0
0
3
4
0
Insomnia
0
1
0
0
0
Nervousness
0
0
0
0
4
Psychosis
Somnolence
4
0
0
1
0
6
0
0
0
0
Taste perversion
Cardiovascular
0
0
0
3
0
Atrial fibrillation
0
0
6
0
4
Atrial flutter
0
1
0
0
0
Cardiac failure
0
1
0
0
0
Hypertension
Syncope
Tachycardia
Endocrine
0
0
0
0
0
0
6
6
6
0
0
0
4
0
4
Hypothyroidism
Hemic and Lymphatic
Anemia
0
0
0
0
6
6
0
0
0
0
Leukopenia
Neutropenia
Thrombocytopenia
Musculoskeletal
4
0
0
0
1
1
0
0
0
0
0
0
0
0
0
Myalgia
Urogenital
Uremia
0
4
1
0
0
0
0
0
0
0
Laboratory Abnormalities
Hypocalcemia
Hypokalemia
Hypomagnesemia
Hypophosphatemia
0
4
4
0
1
4
10
9
12
18
12
18
0
0
3
3
0
0
4
0
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Abnormal liver function
0
0
0
3
0
Paget’s Disease
Transient mild elevation of temperature >1°C above pretreatment baseline was noted within 48 hours
after completion of treatment in 21% of the patients treated with 90 mg of Aredia in clinical trials.
Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia,
increased sweating) were more common in patients with Paget’s disease treated with 90 mg of Aredia
than in patients with hypercalcemia of malignancy treated with the same dose.
Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients with
Paget’s disease treated with 90 mg of Aredia in two U.S. clinical trials, were fever, nausea, back pain, and
bone pain.
At least 10% of all Aredia-treated patients with Paget’s disease also experienced the following adverse
experiences during clinical trials:
Cardiovascular: Hypertension
Musculoskeletal: Arthrosis, bone pain
Nervous system: Headache
Most of these adverse experiences may have been related to the underlying disease state.
Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple
Myeloma
The most commonly reported (>15%) adverse experiences occurred with similar frequencies in the
Aredia- and placebo-treatment groups, and most of these adverse experiences may have been related to
the underlying disease state or cancer therapy.
Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
Aredia®
90 mg
over 4 hours
N=205
%
Placebo
N=187
%
Aredia®
90 mg
over 2 hours
N=367
%
Placebo
N=386
%
All
Aredia®
90 mg
N=572
%
Placebo
N=573
%
General
Asthenia
16.1
17.1
25.6
19.2
22.2
18.5
Fatigue
Fever
31.7
38.5
28.3
38
40.3
38.1
28.8
32.1
37.2
38.5
29.0
34
Metastases
1.0
3.0
31.3
24.4
20.5
17.5
Pain
13.2
11.8
15.0
18.1
14.3
16.1
Digestive System
Anorexia
17.1
17.1
31.1
24.9
26.0
22.3
Constipation
Diarrhea
28.3
26.8
31.7
26.8
36.0
29.4
38.6
30.6
33.2
28.5
35.1
29.7
Dyspepsia
Nausea
17.6
35.6
13.4
37.4
18.3
63.5
15.0
59.1
22.6
53.5
17.5
51.8
Pain Abdominal
19.5
16.0
24.3
18.1
22.6
17.5
Vomiting
16.6
19.8
46.3
39.1
35.7
32.8
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Hemic and Lymphatic
Anemia
47.8
41.7
39.5
36.8
42.5
38.4
Granulocytopenia
20.5
15.5
19.3
20.5
19.8
18.8
Thrombocytopenia
16.6
17.1
12.5
14.0
14.0
15.0
Musculoskeletal
System
Arthralgias
10.7
7.0
15.3
12.7
13.6
10.8
Myalgia
25.4
15.0
26.4
22.5
26
20.1
Skeletal Pain
61.0
71.7
70.0
75.4
66.8
74
CNS
Anxiety
7.8
9.1
18.0
16.8
14.3
14.3
Headache
24.4
19.8
27.2
23.6
26.2
22.3
Insomnia
17.1
17.2
25.1
19.4
22.2
19.0
Respiratory System
Coughing
26.3
22.5
25.3
19.7
25.7
20.6
Dyspnea
22.0
21.4
35.1
24.4
30.4
23.4
Pleural Effusion
2.9
4.3
15.0
9.1
10.7
7.5
Sinusitis
14.6
16.6
16.1
10.4
15.6
12.0
Upper Respiratory Tract
Infection
32.2
28.3
19.6
20.2
24.1
22.9
Urogenital System
Urinary Tract Infection
15.6
9.1
20.2
17.6
18.5
15.6
Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and
anemia were slightly more common in the Aredia patients whereas stomatitis and alopecia occurred at a
frequency similar to that in placebo patients. In the breast cancer trials, mild elevations of serum
creatinine occurred in 18.5% of Aredia patients and 12.3% of placebo patients. Mineral and electrolyte
disturbances, including hypocalcemia, were reported rarely and in similar percentages of Aredia-treated
patients compared with those in the placebo group. The reported frequencies of hypocalcemia,
hypokalemia, hypophosphatemia, and hypomagnesemia for Aredia-treated patients were 3.3%, 10.5%,
1.7%, and 4.4%, respectively, and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%,
respectively. In previous hypercalcemia of malignancy trials, patients treated with Aredia (60 or 90 mg
over 24 hours) developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS,
Hypercalcemia of Malignancy).
Arthralgias and myalgias were reported slightly more frequently in the Aredia group than in the placebo
group (13.6% and 26% vs 10.8% and 20.1%, respectively).
In multiple myeloma patients, there were five Aredia-related serious and unexpected adverse experiences.
Four of these were reported during the 12-month extension of the multiple myeloma trial. Three of the
reports were of worsening renal function developing in patients with progressive multiple myeloma or
multiple myeloma-associated amyloidosis. The fourth report was the adult respiratory distress syndrome
developing in a patient recovering from pneumonia and acute gangrenous cholecystitis. One Aredia
treated patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and
scratchy throat within 24 hours after the sixth infusion.
In the breast cancer trials, there were four Aredia-related adverse experiences, all moderate in severity,
that caused a patient to discontinue participation in the trial. One was due to interstitial pneumonitis,
another to malaise and dyspnea. One Aredia patient discontinued the trial due to a symptomatic
Reference ID: 3138612
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For current labeling information, please visit https://www.fda.gov/drugsatfda
hypocalcemia. Another Aredia patient discontinued therapy due to severe bone pain after each infusion,
which the investigator felt was trial-drug-related.
Renal Toxicity
In a study of the safety and efficacy of Aredia 90 mg (2-hour infusion) vs Zometa 4 mg (15-minute
infusion) in bone metastases patients with multiple myeloma or breast cancer, renal deterioration was
defined as an increase in serum creatinine of 0.5 mg/dL for patients with normal baseline creatinine (<1.4
mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥1.4 mg/dL). The
following are data on the incidence of renal deterioration in patients in this trial. See table below.
Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer Patients with
Normal and Abnormal Serum Creatinine at Baseline*
Patient Population/Baseline Creatinine
Aredia® 90 mg/2 hours
Zometa® 4 mg/15 minutes
n/N
(%)
n/N
(%)
Normal
20/246
(8.1%)
23/246
(9.3%)
Abnormal
2/22
(9.1%)
1/26
(3.8%)
Total
22/268
(8.2%)
24/272
(8.8%)
*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.
Post-Marketing Experience
The following adverse reactions have been reported during post-approval use of Aredia. Because these
reports are from a population of uncertain size and are subject to confounding factors, it is not possible to
reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been reported in post-marketing use: General: reactivation of
Herpes simplex and Herpes zoster, influenza-like symptoms; CNS: confusion and visual hallucinations,
sometimes in the presence of electrolyte imbalance; Skin: rash, pruritus; Special senses: conjunctivitis,
orbital inflammation; Renal and urinary disorders: focal segmental glomerulosclerosis including the
collapsing variant, nephrotic syndrome; renal tubular disorders (RTD); tubulointerstitial nephritis, and
glomerulonephropathies. Laboratory abnormalities: hyperkalemia, hypernatremia, hematuria. Rare
instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema,
and, very rarely, anaphylactic shock. Aredia is contraindicated in patients with clinically significant
hypersensitivity to Aredia or other bisphosphonates (see CONTRAINDICATIONS). Respiratory,
thoracic and mediastinal disorders: adult respiratory distress syndrome (ARDS), interstitial lung disease
(ILD). Musculoskeletal and connective tissue disorders: severe and occasionally incapacitating
bone, joint, and/or muscle pain.
Cases of osteonecrosis (primarily involving the jaw) have been reported predominantly in cancer patients
treated with intravenous bisphosphonates, including Aredia. Many of these patients were also receiving
chemotherapy and corticosteroids which may be risk factors for ONJ. Data suggest a greater frequency of
reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of
the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It
is therefore prudent to avoid invasive dental procedures as recovery may be prolonged. (See
PRECAUTIONS.)
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate
therapy, including Aredia. (See PRECAUTIONS.)
Reference ID: 3138612
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___________________________
OVERDOSAGE
There have been several cases of drug maladministration of intravenous Aredia in hypercalcemia patients
with total doses of 225 mg to 300 mg given over 2 ½ to 4 days. All of these patients survived, but they
experienced hypocalcemia that required intravenous and/or oral administration of calcium. Single doses
of Aredia should not exceed 90 mg and the duration of the intravenous infusion should be no less
than 2 hours. (See WARNINGS.)
In addition, one obese woman (95 kg) who was treated with 285 mg of Aredia/day for 3 days experienced
high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perversion,
noted about 6 hours after the first infusion. The fever and hypotension were rapidly corrected with
steroids.
If overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with
short-term intravenous calcium.
DOSAGE AND ADMINISTRATION
Hypercalcemia of Malignancy
Consideration should be given to the severity of as well as the symptoms of hypercalcemia. Vigorous
saline hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia. Overhydration
should be avoided in patients who have potential for cardiac failure. In hypercalcemia associated with
hematologic malignancies, the use of glucocorticoid therapy may be helpful.
Moderate Hypercalcemia
The recommended dose of Aredia in moderate hypercalcemia (corrected serum calcium* of
approximately 12-13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over
2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in
patients with preexisting renal insufficiency.
Severe Hypercalcemia
The recommended dose of Aredia in severe hypercalcemia (corrected serum calcium*>13.5 mg/dL)
is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e.,
>2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal
insufficiency.
*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum
albumin, g/dL).
Retreatment
A limited number of patients have received more than one treatment with Aredia for hypercalcemia.
Retreatment with Aredia, in patients who show complete or partial response initially, may be carried out if
serum calcium does not return to normal or remain normal after initial treatment. It is recommended that
a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. The
dose and manner of retreatment is identical to that of the initial therapy.
Paget’s Disease
The recommended dose of Aredia in patients with moderate to severe Paget’s disease of bone is 30
mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.
Reference ID: 3138612
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Retreatment
A limited number of patients with Paget’s disease have received more than one treatment of Aredia in
clinical trials. When clinically indicated, patients should be retreated at the dose of initial therapy.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of Aredia in patients with osteolytic bone lesions of multiple myeloma is 90
mg administered as a 4-hour infusion given on a monthly basis.
Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to
Aredia infusion.
Limited information is available on the use of Aredia in multiple myeloma patients with a serum
creatinine ≥3.0 mg/dL.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment
should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned to within 10% of
the baseline value.
The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final
analysis after 21 months demonstrated overall benefits (see CLINICAL TRIALS section).
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of Aredia in patients with osteolytic bone metastases is 90 mg administered
over a 2-hour infusion given every 3-4 weeks.
Aredia has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate,
mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen.
It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.
Patients who receive Aredia should have serum creatinine assessed prior to each treatment. Treatment
should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:
•
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
•
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL.
In this clinical study, Aredia treatment was resumed only when the creatinine returned to within 10% of
the baseline value.
The optimal duration of therapy is not known, however, in two breast cancer studies, final analyses
performed after 24 months of therapy demonstrated overall benefits (see CLINICAL TRIALS section).
Calcium and Vitamin D Supplementation
In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma,
who are at risk of calcium or vitamin D deficiency, and patients with Paget’s disease of the bone, should
be given oral calcium and vitamin D supplementation in order to minimize the risk of hypocalcemia.
Reference ID: 3138612
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Preparation of Solution
Reconstitution
Aredia is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial, resulting in a
solution of 30 mg/10 mL or 90 mg/10 mL. The pH of the reconstituted solution is 6.0-7.4. The drug
should be completely dissolved before the solution is withdrawn.
Method of Administration
DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL
FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF AREDIA
SHOULD NOT EXCEED 90 MG. (SEE WARNINGS.)
There must be strict adherence to the intravenous administration recommendations for Aredia in order to
decrease the risk of deterioration in renal function.
Hypercalcemia of Malignancy
The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60-mg
and 90-mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium
Chloride, USP, or 5% Dextrose Injection, USP. This infusion solution is stable for up to 24 hours at room
temperature.
Paget’s Disease
The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium
Chloride, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period for 3 consecutive
days.
Osteolytic Bone Metastases of Breast Cancer
The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% Sodium Chloride,
USP, or 5% Dextrose Injection, USP, and administered over a 2-hour period every 3-4 weeks.
Osteolytic Bone Lesions of Multiple Myeloma
The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride,
USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period on a monthly basis.
Aredia must not be mixed with calcium-containing infusion solutions, such as Ringer’s solution, and
should be given in a single intravenous solution and line separate from all other drugs.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Aredia reconstituted with Sterile Water for Injection may be stored under refrigeration at 2°C-8°C (36°F
46°F) for up to 24 hours.
HOW SUPPLIED
Vials -30 mg - each contains 30 mg of sterile, lyophilized pamidronate disodium and 470 mg of mannitol,
USP.
Carton of 4 vials................................................................................. NDC 0078-0463-91
Vials - 90 mg - each contains 90 mg of sterile, lyophilized pamidronate disodium and 375 mg of mannitol,
USP.
Carton of 1 vial .................................................................................. NDC 0078-0464-61
Reference ID: 3138612
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not store above 30°C (86°F). company logo
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Novartis
T2012-XX
05/2012
Reference ID: 3138612
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:32.933385
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020036s041lbl.pdf', 'application_number': 20036, 'submission_type': 'SUPPL ', 'submission_number': 41}
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NDA 20-038/S-031
Page 3
Fludara®
(fludarabine phosphate)
FOR INJECTION
FOR INTRAVENOUS USE ONLY
Rx Only
WARNING: FLUDARA FOR INJECTION should be administered under the supervision of a qualified
physician experienced in the use of antineoplastic therapy. FLUDARA FOR INJECTION can severely
suppress bone marrow function. When used at high doses in dose-ranging studies in patients with
acute leukemia, FLUDARA FOR INJECTION was associated with severe neurologic effects, including
blindness, coma, and death. This severe central nervous system toxicity occurred in 36% of patients
treated with doses approximately four times greater (96 mg/m2/day for 5-7 days) than the
recommended dose. Similar severe central nervous system toxicity has been rarely (≤0.2%) reported
in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia.
Instances of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia,
autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evan’s syndrome, and acquired
hemophilia have been reported to occur after one or more cycles of treatment with FLUDARA FOR
INJECTION. Patients undergoing treatment with FLUDARA FOR INJECTION should be evaluated
and closely monitored for hemolysis.
In a clinical investigation using FLUDARA FOR INJECTION in combination with pentostatin
(deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL), there was an
unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of FLUDARA FOR
INJECTION in combination with pentostatin is not recommended.
DESCRIPTION
FLUDARA FOR INJECTION contains fludarabine phosphate, a fluorinated nucleotide analog of the
antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A) that is relatively resistant to
deamination by adenosine deaminase. Each vial of sterile lyophilized solid cake contains 50 mg of the
active ingredient fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7.
The pH range for the final product is 7.2-8.2. Reconstitution with 2 mL of Sterile Water for Injection
USP results in a solution containing 25 mg/mL of fludarabine phosphate intended for intravenous
administration.
The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-β-D-
arabino-furanosyl) (2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is
C10H13FN5O7P (MW 365.2) and the structure is:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-038/S-031
Page 4
CLINICAL PHARMACOLOGY
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated
intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite
appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus
inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely
characterized and may be multi-faceted.
Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the
active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical
pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of
25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations
show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough
levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as
approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and
29%.
A correlation was noted between the degree of absolute granulocyte count nadir and increased area
under the concentration x time curve (AUC).
Special Populations
Pediatric Patients
Limited pharmacokinetic data for FLUDARA FOR INJECTION are available from a published study of
children (ages 1-21 years) with refractory acute leukemias or solid tumors (Children’s Cancer Group
Study 0971). When FLUDARA FOR INJECTION was administered as a loading dose over 10 minutes
immediately followed by a 5-day continuous infusion, steady-state conditions were reached early.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-038/S-031
Page 5
Patients with Renal Impairment
The total body clearance of the principal metabolite 2-fluoro-ara-A correlated with the creatinine
clearance, indicating the importance of the renal excretion pathway for the elimination of the drug.
Renal clearance represents approximately 40% of the total body clearance. Patients with moderate
renal impairment (17 - 41 mL/min/m2) receiving 20% reduced Fludara dose had a similar exposure
(AUC; 21 versus 20 nM●h/mL) compared to patients with normal renal function receiving the
recommended dose. The mean total body clearance was 172 mL/min for normal and 124 mL/min for
patients with moderately impaired renal function.
Clinical Studies
Two single-arm open-label studies of FLUDARA FOR INJECTION have been conducted in adult
patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In a
study conducted by M.D. Anderson Cancer Center (MDAH), 48 patients were treated with a dose of
22-40 mg/m2 daily for 5 days every 28 days. Another study conducted by the Southwest Oncology
Group (SWOG) involved 31 patients treated with a dose of 15-25 mg/m2 daily for 5 days every 28
days. The overall objective response rates were 48% and 32% in the MDAH and SWOG studies,
respectively. The complete response rate in both studies was 13%; the partial response rate was 35%
in the MDAH study and 19% in the SWOG study. These response rates were obtained using
standardized response criteria developed by the National Cancer Institute CLL Working Group3and
were achieved in heavily pre-treated patients. The ability of FLUDARA FOR INJECTION to induce a
significant rate of response in refractory patients suggests minimal cross-resistance with commonly
used anti-CLL agents.
The median time to response in the MDAH and SWOG studies was 7 weeks (range of 1 to 68 weeks)
and 21 weeks (range of 1 to 53 weeks) respectively. The median duration of disease control was 91
weeks (MDAH) and 65 weeks (SWOG). The median survival of all refractory CLL patients treated with
FLUDARA FOR INJECTION was 43 weeks and 52 weeks in the MDAH and SWOG studies,
respectively.
Rai stage improved to Stage II or better in 7 of 12 MDAH responders (58%) and in 5 of 7 SWOG
responders (71%) who were Stage III or IV at baseline. In the combined studies, mean hemoglobin
concentration improved from 9.0 g/dL at baseline to 11.8 g/dL at the time of response in a subgroup of
anemic patients. Similarly, average platelet count improved from 63,500/mm3 to 103,300/mm3 at the
time of response in a subgroup of patients who were thrombocytopenic at baseline.
INDICATIONS AND USAGE
FLUDARA FOR INJECTION is indicated for the treatment of adult patients with B-cell chronic
lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during
treatment with at least one standard alkylating-agent containing regimen. The safety and
effectiveness of FLUDARA FOR INJECTION in previously untreated or non-refractory patients with
CLL have not been established.
CONTRAINDICATIONS
FLUDARA FOR INJECTION is contraindicated in those patients who are hypersensitive to this drug or
its components.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-038/S-031
Page 6
WARNINGS
(See BOXED WARNINGS)
There are clear dose dependent toxic effects seen with FLUDARA FOR INJECTION. Dose levels
approximately 4 times greater (96 mg/m2/day for 5 to 7 days) than that recommended for CLL (25
mg/m2/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma
and death. Symptoms appeared from 21 to 60 days following the last dose. Thirteen of 36 patients
(36%) who received FLUDARA FOR INJECTION at high doses (96 mg/m2/day for 5 to 7 days)
developed this severe neurotoxicity. This syndrome has been reported rarely in patients treated with
doses in the range of the recommended CLL dose of 25 mg/m2/day for 5 days every 28 days. The
effect of chronic administration of FLUDARA FOR INJECTION on the central nervous system is
unknown, however, patients have received the recommended dose for up to 15 courses of therapy.
Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been
reported in patients treated with FLUDARA FOR INJECTION. In a Phase I study in adult solid tumor
patients, the median time to nadir counts was 13 days (range, 3-25 days) for granulocytes and 16
days (range, 2-32) for platelets. Most patients had hematologic impairment at baseline either as a
result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may
be seen. While chemotherapy-induced myelosuppression is often reversible, administration of
FLUDARA FOR INJECTION requires careful hematologic monitoring.
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia,
sometimes resulting in death, have been reported in adult patients. The duration of clinically
significant cytopenia in the reported cases has ranged from approximately 2 months to approximately
1 year. These episodes have occurred both in previously treated or untreated patients.
Instances of life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia,
autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evan’s syndrome, and acquired
hemophilia have been reported to occur after one or more cycles of treatment with FLUDARA FOR
INJECTION in patients with or without a previous history of autoimmune hemolytic anemia or a
positive Coombs’ test and who may or may not be in remission from their disease. Steroids may or
may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged
with FLUDARA FOR INJECTION developed a recurrence in the hemolytic process. The
mechanism(s) which predispose patients to the development of this complication has not been
identified. Patients undergoing treatment with FLUDARA FOR INJECTION should be evaluated and
closely monitored for hemolysis. Discontinuation of therapy with Fludara is recommended in case of
hemolysis.
Transfusion-associated graft-versus-host disease has been observed after transfusion of non-
irradiated blood in FLUDARA FOR INJECTION treated patients. Fatal outcome as a consequence of
this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-
host disease, patients who require blood transfusion and who are undergoing, or who have received,
treatment with FLUDARA FOR INJECTION should receive irradiated blood only.
In a clinical investigation using FLUDARA FOR INJECTION in combination with pentostatin
(deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults, there
was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of FLUDARA FOR
INJECTION in combination with pentostatin is not recommended.
Of the 133 adult CLL patients in the two trials, there were 29 fatalities during study. Approximately
50% of the fatalities were due to infection and 25% due to progressive disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-038/S-031
Page 7
Pregnancy Category D: FLUDARA FOR INJECTION may cause fetal harm when administered to a
pregnant woman. Fludarabine phosphate was teratogenic in rats and in rabbits. Fludarabine
phosphate was administered intravenously at doses of 0, 1, 10 or 30 mg/kg/day to pregnant rats on
days 6 to 15 of gestation. At 10 and 30 mg/kg/day in rats, there was an increased incidence of various
skeletal malformations. Fludarabine phosphate was administered intravenously at doses of 0, 1, 5 or
8 mg/kg/day to pregnant rabbits on days 6 to 15 of gestation. Dose-related teratogenic effects
manifested by external deformities and skeletal malformations were observed in the rabbits at 5 and 8
mg/kg/day. Drug-related deaths or toxic effects on maternal and fetal weights were not observed.
There are no adequate and well-controlled studies in pregnant women.
If FLUDARA FOR INJECTION is used during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of
childbearing potential or fertile males must take contraceptive measures during and at least for 6
months after cessation of therapy.
PRECAUTIONS
General
FLUDARA FOR INJECTION is a potent antineoplastic agent with potentially significant toxic side
effects. Patients undergoing therapy should be closely observed for signs of hematologic and
nonhematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect
the development of anemia, neutropenia and thrombocytopenia.
Tumor lysis syndrome associated with FLUDARA FOR INJECTION treatment has been reported in
CLL patients with large tumor burdens. Since FLUDARA FOR INJECTION can induce a response as
early as the first week of treatment, precautions should be taken in those patients at risk of developing
this complication.
In patients with impaired state of health, FLUDARA FOR INJECTION should be given with caution
and after careful risk/benefit consideration. This applies especially for patients with severe impairment
of bone marrow function (thrombocytopenia, anemia, and/or granulocytopenia), immunodeficiency or
with a history of opportunistic infection. Prophylactic treatment should be considered in patients at
increased risk of developing opportunistic infections.
There are inadequate data on dosing of patients with renal insufficiency. FLUDARA FOR INJECTION
must be administered cautiously in patients with renal insufficiency. The total body clearance of 2-
fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with
moderate impairment of renal function (creatinine clearance 30-70 mL/min/1.73 m2) should have their
Fludara dose reduced by 20% and be monitored closely. FLUDARA FOR INJECTION is not
recommended for patients with severely impaired renal function (creatinine clearance less than 30
mL/min/1.73 m2).
Fludara may reduce the ability to drive or use machines, since fatigue, weakness and visual
disturbances have been observed.
Laboratory Tests
During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be
monitored regularly to determine the degree of hematopoietic suppression.
Drug Interactions
The use of FLUDARA FOR INJECTION in combination with pentostatin is not recommended due to
the risk of severe pulmonary toxicity (see WARNINGS section).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-038/S-031
Page 8
Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic efficacy of
FLUDARA FOR INJECTION.
Carcinogenesis
No animal carcinogenicity studies with FLUDARA FOR INJECTION have been conducted.
Mutagenesis
Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells (HGRPT assay
in Chinese hamster ovary cells) either in the presence or absence of metabolic activation.
Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome
aberrations in the presence of metabolic activation) and induced sister chromatid exchanges both with
and without metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse
micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice).
Impairment of Fertility
Studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male
reproductive system. Observations consisted of a decrease in mean testicular weights in mice and
rats with a trend toward decreased testicular weights in dogs and degeneration and necrosis of
spermatogenic epithelium of the testes in mice, rats and dogs. The possible adverse effects on fertility
in humans have not been adequately evaluated.
Pregnancy
Pregnancy Category D: (See WARNINGS section).
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk and because of the potential for serious adverse reactions in nursing infants from
FLUDARA FOR INJECTION, a decision should be made to discontinue nursing or discontinue the
drug, taking into account the importance of the drug for the mother.
Pediatric Use
Data submitted to the FDA was insufficient to establish efficacy in any childhood malignancy.
Fludarabine was evaluated in 62 pediatric patients (median age 10, range 1-21) with refractory acute
leukemia (45 patients) or solid tumors (17 patients). The fludarabine regimen tested for pediatric acute
lymphocytic leukemia (ALL) patients was a loading bolus of 10.5 mg/m2/day followed by a continuous
infusion of 30.5 mg/m2/day for 5 days. In 12 pediatric patients with solid tumors, dose-limiting
myelosuppression was observed with a loading dose of 8 mg/m2/day followed by a continuous
infusion of 23.5 mg/m2/day for 5 days. The maximum tolerated dose was a loading dose of 7
mg/m2/day followed by a continuous infusion of 20 mg/m2/day for 5 days. Treatment toxicity included
bone marrow suppression. Platelet counts appeared to be more sensitive to the effects of fludarabine
than hemoglobin and white blood cell counts. Other adverse events included fever, chills, asthenia,
rash, nausea, vomiting, diarrhea, and infection. There were no reported occurrences of peripheral
neuropathy or pulmonary hypersensitivity reaction.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-038/S-031
Page 9
Vaccination
During and after treatment with FLUDARA FOR INJECTION, vaccination with live vaccines should be
avoided.
Disease Progression
Disease progression and transformation (e.g. Richter’s syndrome) have been reported in CLL
patients.
ADVERSE REACTIONS
The most common adverse events include myelosuppression (neutropenia, thrombocytopenia and
anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events
include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in
CLL patients treated with FLUDARA FOR INJECTION. Adverse events, and those reactions which
are more clearly related to the drug are arranged below according to body system.
Hematopoietic Systems: Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were
reported in the majority of CLL patients treated with FLUDARA FOR INJECTION. During FLUDARA
FOR INJECTION treatment of 133 patients with CLL, the absolute neutrophil count decreased to less
than 500/mm3 in 59% of patients, hemoglobin decreased from pretreatment values by at least 2
grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in
55%. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow
fibrosis occurred in one CLL patient treated with FLUDARA FOR INJECTION.
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia,
sometimes resulting in death, have been reported in postmarketing surveillance. The duration of
clinically significant cytopenia in the reported cases has ranged from approximately 2 months to
approximately 1 year. These episodes have occurred both in previously treated or untreated patients.
Life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia,
autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evan’s syndrome, and acquired
hemophilia have been reported to occur in patients receiving FLUDARA FOR INJECTION (see
WARNINGS section). The majority of patients rechallenged with FLUDARA FOR INJECTION
developed a recurrence in the hemolytic process.
In post-marketing experience, rare cases of myelodysplastic syndrome and acute myeloid leukemia
associated with prior, concomitant or subsequent treatment with alkylating agents or irradiation have
been reported.
Infections: Serious, and sometimes fatal infections, including opportunistic infections and
reactivations of latent viral infections such as VZV (Herpes zoster), Epstein-Barr virus and JC virus
(progressive multifocal leukoencephalopathy)) have been reported in patients treated with FLUDARA
FOR INJECTION.
Rare cases of Epstein Barr Virus (EBV) associated lymphoproliferative disorders have been reported
in patients treated with FLUDARA FOR INJECTION.
Metabolic: Tumor lysis syndrome has been reported in CLL patients treated with FLUDARA FOR
INJECTION. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia,
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NDA 20-038/S-031
Page 10
metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this
syndrome may be heralded by flank pain and hematuria.
Nervous System: Nervous System: (See WARNINGS section) Objective weakness, agitation,
confusion, visual disturbances, optic neuritis, optic neuropathy, blindness and coma have occurred in
CLL patients treated with FLUDARA FOR INJECTION at the recommended dose. Peripheral
neuropathy has been observed in patients treated with FLUDARA FOR INJECTION and one case of
wrist-drop was reported.
In post-marketing experience, cases of progressive multifocal leukoencephalopaty have been
reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or
concurrent chemotherapy. The time to onset has ranged from a few weeks to approximately one year
after initiating treatment.
Pulmonary System: Pneumonia, a frequent manifestation of infection in CLL patients, occurred in
16%, and 22% of those treated with FLUDARA FOR INJECTION in the MDAH and SWOG studies,
respectively. Pulmonary hypersensitivity reactions to FLUDARA FOR INJECTION characterized by
dyspnea, cough and interstitial pulmonary infiltrate have been observed.
In post-marketing experience, cases of severe pulmonary toxicity have been observed with Fludara
use which resulted in ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and
respiratory failure. After an infectious origin has been excluded, some patients experienced symptom
improvement with corticosteroids.
Gastrointestinal System: Gastrointestinal disturbances such as nausea and vomiting, anorexia,
diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with
FLUDARA FOR INJECTION.
Cardiovascular: Edema has been frequently reported. One patient developed a pericardial effusion
possibly related to treatment with FLUDARA FOR INJECTION. No other severe cardiovascular events
were considered to be drug related.
Genitourinary System: Rare cases of hemorrhagic cystitis have been reported in patients treated
with FLUDARA FOR INJECTION.
Skin: Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with
FLUDARA FOR INJECTION.
Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and pemphigus have
been reported, with fatal outcomes in some cases.
Worsening or flare up of pre-existing skin cancer lesions, as well as new onset of skin cancer, has
been reported in patients during or after treatment with FLUDARA FOR INJECTION.
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NDA 20-038/S-031
Page 11
Data in the following table are derived from the 133 patients with CLL who received FLUDARA FOR
INJECTION in the MDAH and SWOG studies.
PERCENT OF CLL PATIENTS REPORTING
NON-HEMATOLOGIC ADVERSE EVENTS
ADVERSE EVENTS
MDAH (N=101) SWOG (N=32)
ANY ADVERSE EVENT
88%
91%
BODY AS A WHOLE
72
84
FEVER
60
69
CHILLS
11
19
FATIGUE
10
38
INFECTION
33
44
PAIN
20
22
MALAISE
8
6
DIAPHORESIS
1
13
ALOPECIA
0
3
ANAPHYLAXIS
1
0
HEMORRHAGE
1
0
HYPERGLYCEMIA
1
6
DEHYDRATION
1
0
NEUROLOGICAL
21
69
WEAKNESS
9
65
PARESTHESIA
4
12
HEADACHE
3
0
VISUAL DISTURBANCE
3
15
HEARING LOSS
2
6
SLEEP DISORDER
1
3
DEPRESSION
1
0
CEREBELLAR SYNDROME
1
0
IMPAIRED MENTATION
1
0
PULMONARY
35
69
COUGH
10
44
PNEUMONIA
16
22
DYSPNEA
9
22
SINUSITIS
5
0
PHARYNGITIS
0
9
UPPER RESPIRATORY INFECTION
2
16
ALLERGIC PNEUMONITIS
0
6
EPISTAXIS
1
0
HEMOPTYSIS
1
6
BRONCHITIS
1
0
HYPOXIA
1
0
GASTROINTESTINAL
46
63
NAUSEA/VOMITING
36
31
DIARRHEA
15
13
ANOREXIA
7
34
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NDA 20-038/S-031
Page 12
PERCENT OF CLL PATIENTS REPORTING
NON-HEMATOLOGIC ADVERSE EVENTS
ADVERSE EVENTS
MDAH (N=101) SWOG (N=32)
STOMATITIS
9
0
GI BLEEDING
3
13
ESOPHAGITIS
3
0
MUCOSITIS
2
0
LIVER FAILURE
1
0
ABNORMAL LIVER FUNCTION TEST
1
3
CHOLELITHIASIS
0
3
CONSTIPATION
1
3
DYSPHAGIA
1
0
CUTANEOUS
17
18
RASH
15
15
PRURITUS
1
3
SEBORRHEA
1
0
GENITOURINARY
12
22
DYSURIA
4
3
URINARY INFECTION
2
15
HEMATURIA
2
3
RENAL FAILURE
1
0
ABNORMAL RENAL FUNCTION TEST
1
0
PROTEINURIA
1
0
HESITANCY
0
3
CARDIOVASCULAR
12
38
EDEMA
8
19
ANGINA
0
6
CONGESTIVE HEART FAILURE
0
3
ARRHYTHMIA
0
3
SUPRAVENTRICULAR TACHYCARDIA
0
3
MYOCARDIAL INFARCTION
0
3
DEEP VENOUS THROMBOSIS
1
3
PHLEBITIS
1
3
TRANSIENT ISCHEMIC ATTACK
1
0
ANEURYSM
1
0
CEREBROVASCULAR ACCIDENT
0
3
MUSCULOSKELETAL
7
16
MYALGIA
4
16
OSTEOPOROSIS
2
0
ARTHRALGIA
1
0
TUMOR LYSIS SYNDROME
1
0
More than 3000 adult patients received FLUDARA FOR INJECTION in studies of other leukemias,
lymphomas, and other solid tumors. The spectrum of adverse effects reported in these studies was
consistent with the data presented above.
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NDA 20-038/S-031
Page 13
OVERDOSAGE
High doses of FLUDARA FOR INJECTION (see WARNINGS section) have been associated with an
irreversible central nervous system toxicity characterized by delayed blindness, coma and death.
High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow
suppression. There is no known specific antidote for FLUDARA FOR INJECTION overdosage.
Treatment consists of drug discontinuation and supportive therapy.
DOSAGE AND ADMINISTRATION
Usual Dose:
The recommended adult dose of FLUDARA FOR INJECTION is 25 mg/m2 administered intravenously
over a period of approximately 30 minutes daily for five consecutive days. Each 5 day course of
treatment should commence every 28 days. Dosage may be decreased or delayed based on
evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or
discontinuing the drug if neurotoxicity occurs.
A number of clinical settings may predispose to increased toxicity from FLUDARA FOR INJECTION.
These include advanced age, renal insufficiency, and bone marrow impairment. Such patients should
be monitored closely for excessive toxicity and the dose modified accordingly.
The optimal duration of treatment has not been clearly established. It is recommended that three
additional cycles of FLUDARA FOR INJECTION be administered following the achievement of a
maximal response and then the drug should be discontinued.
Renal Insufficiency
Adult patients with moderate impairment of renal function (creatinine clearance 30-70 mL/min/1.73
m2) should have a 20% dose reduction of FLUDARA FOR INJECTION. FLUDARA FOR INJECTION
should not be administered to patients with severely impaired renal function (creatinine clearance less
than 30 mL/min/1.73 m2).
Preparation of Solutions:
FLUDARA FOR INJECTION should be prepared for parenteral use by aseptically adding Sterile
Water for Injection USP. When reconstituted with 2mL of Sterile Water for Injection, USP, the solid
cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg
of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH
range for the final product is 7.2-8.2. In clinical studies, the product has been diluted in 100 cc or 125
cc of 5% Dextrose Injection USP or 0.9% Sodium Chloride USP.
Reconstituted FLUDARA FOR INJECTION contains no antimicrobial preservative and thus should be
used within 8 hours of reconstitution. Care must be taken to assure the sterility of prepared solutions.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
FLUDARA FOR INJECTION should not be mixed with other drugs.
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NDA 20-038/S-031
Page 14
Handling and Disposal:
Procedures for proper handling and disposal should be considered. Consideration should be given to
handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this
subject have been published. 2-9 1-8 There is no general agreement that all of the procedures
recommended in the guidelines are necessary or appropriate.
Caution should be exercised in the handling and preparation of FLUDARA FOR INJECTION solution.
The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of
the vial or other accidental spillage. If the solution contacts the skin or mucous membranes, wash
thoroughly with soap and water; rinse eyes thoroughly with plain water. Avoid exposure by inhalation
or by direct contact of the skin or mucous membranes.
FLUDARA FOR INJECTION should not be handled by pregnant staff.
HOW SUPPLIED
FLUDARA FOR INJECTION is supplied as a white, lyophilized solid cake. Each vial contains 50 mg of
fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range
for the final product is 7.2-8.2. Store under refrigeration, between 2º-8ºC (36º-46ºF).
FLUDARA FOR INJECTION is supplied in a clear glass single dose vial (6mL capacity) and packaged
in a single dose vial carton in a shelf pack of five.
NDC 50419-511-06
Manufactured by: Ben Venue Laboratories, Bedford, OH 44146
Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470
U.S. Patent Number: 4,357,324
REFERENCES
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for
Practice. Pittsburgh, Pa: Oncology Nursing Society. 1999:32-41.
2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC;
Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National
Institute of Health; 1992. US Department of Health and Human Services, Public Health Service
Publication NIH 92-2621.
3. AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985;
253:1590-1591.
4. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic
Agents. 1987. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on
Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood
Avenue, Boston, MA 02115.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-038/S-031
Page 15
5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of
Antineoplastic Agents. Med J Australia. 1983;1:426-428.
6. Jones, R.B, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the
Mount Sinai Medical Center. CA Cancer J Clin. 1983; 33:258-263.
7. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling
Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
8. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am J
Health-Syst Pharm. 1996;53:1669-1685.
1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care
Settings. NIOSH Alert 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational
Exposure to Hazardous Drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs.
Am J Health-Syst Pharm. 2006: 63: 1172-1193.
4. Polovich, M., White, J.M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines
and recommendations for practice (2nd ed.). Pittsburgh, PA: Oncology Nursing Society
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:46:32.983509
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020038s031lbl.pdf', 'application_number': 20038, 'submission_type': 'SUPPL ', 'submission_number': 31}
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12,161
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Dextrose Injection, USP
in AVIVA Plastic Container
DESCRIPTION
Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid replenishment and
caloric supply in single dose containers for intravenous administration. It contains no
antimicrobial agents. Composition, osmolarity, pH, and caloric content are shown in
Table 1.
Table 1
Size
(mL)
*Dextrose
Hydrous,
USP (g/L)
Osmolarity
(mOsmol/L)
(calc.)
pH
nominal
(range)
Caloric
Content
(kcal/L)
5% Dextrose
Injection, USP
250
500
1000
50
252
4.5
(3.2 to 6.5)
170
10% Dextrose
Injection, USP
250
500
1000
100
505
4.5
(3.2 to 6.5)
340
The flexible container is made with non-latex plastic materials specially designed for a
wide range of parenteral drugs including those requiring delivery in containers made of
polyolefins or polypropylene. For example, the AVIVA container system is compatible
with and appropriate for use in the admixture and administration of paclitaxel. In
addition, the AVIVA container system is compatible with and appropriate for use in the
admixture and administration of all drugs deemed compatible with existing polyvinyl
chloride container systems. The solution contact materials do not contain PVC, DEHP,
or other plasticizers.
Reference ID: 3677008
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The suitability of the container materials has been established through biological
evaluations, which have shown the container passes Class VI U.S. Pharmacopeia (USP)
testing for plastic containers. These tests confirm the biological safety of the container
system.
The flexible container is a closed system, and air is prefilled in the container to facilitate
drainage. The container does not require entry of external air during administration.
The container has two ports: one is the administration outlet port for attachment of an
intravenous administration set and the other port has a medication site for addition of
supplemental medication (see DIRECTIONS FOR USE). The primary function of the
overwrap is to protect the container from the physical environment.
CLINICAL PHARMACOLOGY
Dextrose Injection, USP has value as a source of water and calories. It is capable of
inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Dextrose Injection, USP is indicated as a source of water and calories.
CONTRAINDICATIONS
Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products.
WARNINGS
Dextrose Injection, USP should not be administered simultaneously with blood through
the same administration set because of the possibility of pseudoagglutination or
hemolysis.
The intravenous administration of these solutions can cause fluid and/or solute
overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutive states is inversely proportional
to the electrolyte concentrations of the injections. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injections.
Excessive administration of dextrose injections may result in significant hypokalemia.
Reference ID: 3677008
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In very low birth weight infants, excessive or rapid administration of dextrose injection
may result in increased serum osmolality and possible intracerebral hemorrhage.
Clinical evaluation and periodic laboratory determinations are necessary to monitor
changes in fluid balance, electrolyte concentrations, and acid base balance during
prolonged parenteral therapy or whenever the condition of the patient warrants such
evaluation.
PRECAUTIONS
General
Do not connect flexible plastic containers in series in order to avoid air embolism due to
possible residual air contained in the primary container. Such use could result in air
embolism due to residual air being drawn from the primary container before
administration of the fluid from a secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Dextrose Injection, USP should be used with caution in patients with overt or subclinical
diabetes mellitus.
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies with Dextrose Injection, USP in
pregnant women and animal reproduction studies have not been conducted with this drug.
Therefore, it is not known whether Dextrose Injection, USP can cause fetal harm when
administered to a pregnant woman. Dextrose Injection, USP should be given during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Labor and Delivery
Intrapartum maternal intravenous infusion of glucose-containing solutions may produce
maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic
acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may
result in neonatal hypoglycemia following delivery. Consider the potential risks and
benefits for each specific patient before administering Dextrose Injection, USP.
Nursing Mothers
It is not known whether this drug is present in human milk. Because many drugs are
present in human milk, caution should be exercised when Dextrose Injection, USP is
administered to a nursing woman.
Pediatric Use
The use of Dextrose Injection, USP in pediatric patients is based on clinical practice (see
DOSAGE AND ADMINISTRATION).
Newborns – especially those born premature and with low birth weight - are at increased
risk of developing hypo- or hyperglycemia and therefore need close monitoring during
treatment with intravenous glucose solutions to ensure adequate glycemic control in order
to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause
prolonged seizures, coma and brain damage. Hyperglycemia has been associated with
intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of
prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of
hospital stay, and death.
Geriatric Use
Clinical studies of Dextrose Injection, USP did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the
elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
Reference ID: 3677008
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elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
Hypersensitivity reactions, including anaphylaxis and chills.
Reactions which may occur because of the injection or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures and save the remainder of the fluid for
examination if deemed necessary.
DOSAGE AND ADMINISTRATION
As directed by a physician. Dosage is dependent upon the age, weight and clinical
condition of the patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
final filter is recommended during administration of all parenteral solutions, where
possible.
Do not administer unless solution is clear and seal is intact.
All injections in AVIVA plastic containers are intended for intravenous administration
using sterile equipment.
The dosage selection and constant infusion rate of intravenous dextrose must be selected
with caution in pediatric patients, particularly neonates and low birth weight infants,
because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of
serum glucose concentrations is required when dextrose is prescribed to pediatric
patients, particularly neonates and low birth weight infants. The infusion rate and
volume depends on the age, weight, clinical and metabolic conditions of the patient,
concomitant therapy and should be determined by the consulting physician experienced
in pediatric intravenous fluid therapy.
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
Reference ID: 3677008
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the informed judgment of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
HOW SUPPLIED
Dextrose Injection, USP in AVIVA plastic container is available as follows:
Code
Size (ml)
NDC
Product Name
6E0062
250
0338-6346-02
5% Dextrose Injection, USP
6E0063
500
0338-6346-03
6E0064
1000
0338-6346-04
6E0162
250
0338-6347-02
10% Dextrose Injection, USP
6E0163
500
0338-6347-03
6E0164
1000
0338-6347-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25° C/ 77° F); brief
exposure up to 40° C/ 104° F does not adversely affect the product.
DIRECTIONS FOR USE OF AVIVA PLASTIC CONTAINER
For Information on Risk of Air Embolism - see PRECAUTIONS
To Open
Tear overwrap down side at slit and remove solution container. Visually inspect the
container. If the outlet port protector is damaged, detached, or not present, discard
container as solution path sterility may be impaired. Some opacity of the plastic due to
moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check
for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as
sterility may be impaired. If supplemental medication is desired, follow “To Add
Medication” directions below.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
Reference ID: 3677008
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3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
07-19-69-267
Rev. December 2014
Baxter and Aviva are trademarks of Baxter International Inc.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dextrose Injection, USP
in VIAFLEX Plastic Container
DESCRIPTION
Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid replenishment and
caloric supply in single dose containers for intravenous administration. It contains no
antimicrobial agents. Composition, osmolarity, pH, and caloric content are shown in
Table 1.
Table 1
Size (mL)
*Dextrose
Hydrous, USP
(g/L)
Osmolarity
(mOsmol/L)
(calc.)
pH
Caloric Content
(kcal/L)
5% Dextrose
Injection, USP
25
Quad pack
50
Single pack
Quad pack
Multi pack
100
Single pack
Quad pack
Multi pack
150
250
500
1000
50
252
4.0
(3.2 to 6.5)
170
10% Dextrose
Injection, USP
250
500
1000
100
505
4.0
(3.2 to 6.5)
340
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). The amount of water that can permeate from inside the
container into the overwrap is insufficient to affect the solution significantly. Solutions in
contact with the plastic container can leach out certain of its chemical components in very
small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to
5 parts per million. However, the safety of the plastic has been confirmed in tests in
animals according to USP biological test for plastic containers as well as by tissue culture
toxicity studies.
CLINICAL PHARMACOLOGY
Dextrose Injection, USP has value as a source of water and calories. It is capable of
inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Dextrose Injection, USP is indicated as a source of water and calories.
CONTRAINDICATIONS
Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products.
WARNINGS
Dextrose Injection, USP should not be administered simultaneously with blood through
the same administration set because of the possibility of pseudoagglutination or
hemolysis.
The intravenous administration of these solutions can cause fluid and/or solute
overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutive states is inversely proportional
to the electrolyte concentrations of the injections. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injections.
Excessive administration of dextrose injections may result in significant hypokalemia.
In very low birth weight infants, excessive or rapid administration of dextrose injection
may result in increased serum osmolality and possible intracerebral hemorrhage.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Monitor changes in fluid balance, electrolyte concentrations, and acid base balance
during prolonged parenteral therapy or whenever the condition of the patient warrants
such evaluation.
PRECAUTIONS
General
Do not connect flexible plastic containers in series in order to avoid air embolism due to
possible residual air contained in the primary container. Such use could result in air
embolism due to residual air being drawn from the primary container before
administration of the fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Dextrose Injection, USP should be used with caution in patients with overt or subclinical
diabetes mellitus.
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies with Dextrose Injection, USP in
pregnant women and animal reproduction studies have not been conductedwith this drug.
Therefore, it is not known whether Dextrose Injection, USP can cause fetal harm when
administered to a pregnant woman. Dextrose Injection, USP should be given during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
Intrapartum maternal intravenous infusion of glucose-containing solutions may produce
maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic
acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may
result in neonatal hypoglycemia following delivery. Consider the potential risks and
benefits for each specific patient before administering Dextrose Injection , USP.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers
It is not known whether this drug is present in human milk. Because many drugs are
present in human milk, caution should be exercised when a Dextrose Injection, USP is
administered to a nursing woman.
Pediatric Use
The use of Dextrose Injection, USP in pediatric patients is based on clinical practice (see
DOSAGE AND ADMINISTRATION).
Newborns – especially those born premature and with low birth weight - are at increased
risk of developing hypo- or hyperglycemia and therefore need close monitoring during
treatment with intravenous glucose solutions to ensure adequate glycemic control in order
to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause
prolonged seizures, coma and brain damage. Hyperglycemia has been associated with
intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of
prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of
hospital stay, and death.
Geriatric Use
Clinical studies of Dextrose Injection, USP did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the
elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
Hypersensitivity reactions, including anaphylaxis and chills.
Reference ID: 3677008
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Reactions which may occur because of the injection or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures and save the remainder of the fluid for
examination if deemed necessary.
DOSAGE AND ADMINISTRATION
As directed by a physician. Dosage is dependent upon the age, weight and clinical
condition of the patient as well as laboratory determinations.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
final filter is recommended during administration of all parenteral solutions, where
possible.
Do not administer unless solution is clear and seal is intact.
All injections in VIAFLEX plastic containers are intended for intravenous administration
using sterile equipment.
The dosage selection and constant infusion rate of intravenous dextrose must be selected
with caution in pediatric patients, particularly neonates and low birth weight infants,
because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of
serum glucose concentrations is required when dextrose is prescribed to pediatric
patients, particularly neonates and low birth weight infants. The infusion rate and volume
depends on the age, weight, clinical and metabolic conditions of the patient, concomitant
therapy and should be determined by the consulting physician experienced in pediatric
intravenous fluid therapy.
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
the informed judgment of the physician, it is deemed advisable to introduce additives, use
aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
HOW SUPPLIED
Dextrose Injection, USP in VIAFLEX plastic container is available as follows:
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Code
Size
(mL)
NDC
Product Name
25
2B0080
Quad pack
0338- 0017- 10
5% Dextrose Injection, USP
50
2B0086
Single pack
0338-0017-41
5% Dextrose Injection, USP
2B0081
Quad pack
0338-0017-11
2B0088
Multi pack
0338-0017-31
100
2B0087
Single pack
0338-0017-48
5% Dextrose Injection, USP
2B0082
Quad pack
0338-0017-18
2B0089
Multi pack
0338-0017-38
2B0061
150
0338- 0017-01
2B0062
250
0338- 0017-02
2B0063
500
0338- 0017-03
2B0064
1000
0338- 0017-04
2B0162
250
0338- 0023-02
10% Dextrose Injection, USP
2B0163
500
0338- 0023-03
2B0164
1000
0338- 0023-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C/77°F); brief exposure
up to 40°C/104°F does not adversely affect the product.
DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER
For Information on Risk of Air Embolism - see PRECAUTIONS
To Open
Tear overwrap down side at slit and remove solution container. Visually inspect the
container. If the outlet port protector is damaged, detached, or not present, discard
container as solution path sterility may be impaired. Some opacity of the plastic due to
moisture absorption during the sterilization process may be observed. This is normal and
does not affect the solution quality or safety. The opacity will diminish gradually. Check
for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as
sterility may be impaired. If supplemental medication is desired, follow “To Add
Medication” directions below.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Additives may be incompatible.
To add medication before solution administration
1. Prepare medication site.
2. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
3. Mix solution and medication thoroughly. For high density medication such as
potassium chloride, squeeze ports while ports are upright and mix thoroughly.
To add medication during solution administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port
and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in-use position and continue administration.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
07-19-69-268
Rev. December 2014
Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
70% Dextrose Injection, USP
in VIAFLEX Plastic Container
A Parenteral Nutrient
DESCRIPTION
Dextrose Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid
replenishment and caloric supply in single dose container for intravenous administration
after compounding. It contains no antimicrobial agents. Composition, osmolarity, pH,
and caloric content are shown in Table 1.
Table 1
Composition
Osmolarity
(mOsmol/L) (calc.)
pH
Caloric Content (kcal/L)
How Supplied
Dextrose Hydrous, USP
(g/L)
Size
500 mL in 1000 mL container
Code and NDC
70% Dextrose
Injection, USP
700
3530
4.0
(3.2 to 6.5)
2390
2B0114
NDC 0338-0719-13
The structural formula of Dextrose Hydrous, USP is:
The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). Exposure to temperatures above 25ºC/77ºF during transport
and storage will lead to minor losses in moisture content. Higher temperatures lead to
greater losses. It is unlikely that these minor losses will lead to clinically significant
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
changes within the expiration period. The amount of water that can permeate from inside
the container into the overwrap is insufficient to affect the solution significantly.
Solutions in contact with the plastic container may leach out certain chemical
components from the plastic in very small amounts; however, biological testing was
supportive of the safety of the plastic container materials.
CLINICAL PHARMACOLOGY
Dextrose Injection, USP have value as a source of water and calories. They are capable of
inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Dextrose Injection, USP are indicated as a caloric component in a parenteral nutrition
regimen. They are used with an appropriate protein (nitrogen) source in the prevention of
nitrogen loss or in the treatment of negative nitrogen balance in patients where: (1) the
alimentary tract cannot or should not be used, (2) gastrointestinal absorption of protein is
impaired, or (3) metabolic requirements for protein are substantially increased, as with
extensive burns.
CONTRAINDICATIONS
The infusion of hypertonic dextrose injection is contraindicated in patients having
intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, in
patients who are anuric, and in patients in hepatic coma.
Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products.
WARNINGS
Dilute before use to a concentration which will, when administered with an amino acid
(nitrogen) source, result in an appropriate calorie to gram of nitrogen ratio and which has
an osmolarity consistent with the route of administration.
Unless appropriately diluted, the infusion of hypertonic dextrose injection into a
peripheral vein may result in vein irritation, vein damage, and thrombosis. Strongly
hypertonic nutrient solutions should only be administered through an indwelling
intravenous catheter with the tip located in a large central vein such as the superior vena
cava.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In very low birth weight infants, excessive or rapid administration of dextrose injection
may result in increased serum osmolality and possible intracerebral hemorrhage.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach
toxic levels with prolonged parenteral administration if kidney function is impaired.
Premature neonates are particularly at risk because their kidneys are immature, and they
require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature
neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day
accumulate aluminum at levels associated with central nervous system and bone toxicity.
Tissue loading may occur at even lower rates of administration.
Monitor changes in fluid balance, electrolyte concentrations, and acid base balance
during prolonged parenteral therapy or whenever the condition of the patient warrants
such evaluation.
PRECAUTIONS
General
Do not connect flexible plastic containers in series in order to avoid air embolism due to
possible residual air contained in the primary container.
Such use could result in air embolism due to residual air being drawn from the primary
container before administration of the fluid from the secondary container is completed.
Pressurizing intravenous solutions contained in flexible plastic containers to increase
flow rates can result in air embolism if the residual air in the container is not fully
evacuated prior to administration.
Use of a vented intravenous administration set with the vent in the open position could
result in air embolism. Vented intravenous administration sets with the vent in the open
position should not be used with flexible plastic containers.
Administration of hypertonic dextrose and amino acid solutions via central venous
catheter may be associated with complications which can be prevented or minimized by
careful attention to all aspects of the procedure. This includes attention to solution
preparation, administration and patient monitoring.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
It is essential that a carefully prepared protocol, based upon current medical
practice, be followed, preferably by an experienced medical team. The package insert
of the protein (nitrogen) source should be consulted for dosage and all precautionary
information.
Care should be taken to avoid circulatory overload, particularly in patients with cardiac
insufficiency.
Caution must be exercised in the administration of these injections to patients receiving
corticosteroids or corticotropin.
These injections should be used with caution in patients with overt or subclinical diabetes
mellitus.
Drug product contains no more than 25 mcg/L of aluminum.
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies with Dextrose Injections, USP in
pregnant women and animal reproduction studies have not been conducted with this drug.
Therefore, it is not known whether Dextrose Injections, USP can cause fetal harm when
administered to a pregnant woman. Dextrose Injections, USP should be given during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
Intrapartum maternal intravenous infusion of glucose-containing solutions may produce
maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic
acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may
result in neonatal hypoglycemia following delivery. Consider the potential risks and
benefits for each specific patient before administering Dextrose Injection, USP.
Nursing Mothers
It is not known if this drug is present in human milk. Because many drugs are present in
human milk, caution should be exercised when Dextrose Injection, USP, is administered
to a nursing woman.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
The use of Dextrose is in pediatric patients is based on clinical practice (see DOSAGE
AND ADMINISTRATION).Because of their hypertonicity, 70% Dextrose Injection
must be diluted prior to administration.
Newborns – especially those born premature and with low birth weight - are at increased
risk of developing hypo- or hyperglycemia and therefore need close monitoring during
treatment with intravenous glucose solutions to ensure adequate glycemic control in order
to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause
prolonged seizures, coma and brain damage. Hyperglycemia has been associated with
intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of
prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of
hospital stay, and death.
ADVERSE REACTIONS
Too rapid infusion of a hypertonic dextrose solution may result in diuresis,
hyperglycemia, glycosuria, and hyperosmolar coma. Continual clinical monitoring of the
patient is necessary in order to identify and initiate measures for these clinical conditions.
Hypersensitivity reactions, including anaphylaxis and chills.
Reactions which may occur because of the solution or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation and hypervolemia.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures, and save the remainder of the fluid for
examination if deemed necessary.
DOSAGE AND ADMINISTRATION
Following suitable admixture of prescribed drugs, the dosage is usually dependent upon
the age, weight and clinical condition of the patient as well as laboratory determinations.
See directions accompanying drugs.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
final filter is recommended during administration of all parenteral solutions, where
possible.
Do not administer unless solution is clear and seal is intact.
These admixed injections in VIAFLEX plastic containers are intended for intravenous
administration using sterile equipment.
The dosage selection and constant infusion rate of intravenous dextrose must be selected
with caution in pediatric patients, particularly neonates and low birth weight infants,
because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of
serum glucose concentrations is required when dextrose is prescribed to pediatric
patients, particularly neonates and low birth weight infants. The infusion rate and volume
depends on the age, weight, clinical and metabolic conditions of the patient, concomitant
therapy and should be determined by the consulting physician experienced in pediatric
intravenous fluid therapy.
Additives may be incompatible. Complete information is not available. Those additives
known to be incompatible should not be used. Consult with pharmacist, if available. If, in
the informed judgement of the physician, it is deemed advisable to introduce additives,
use aseptic technique. Mix thoroughly when additives have been introduced. Do not store
solutions containing additives.
HOW SUPPLIED
See Table 1.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
Protect from freezing. It is recommended the product be stored at room temperature
(25ºC/77ºF).
DIRECTIONS FOR USE OF VIAFLEX PLASTIC CONTAINER
For Information on Risk of Air Embolism - see PRECAUTIONS
Preparation for Administration
1. Tear overwrap down side at slit and remove solution container. Visually inspect
the container. If the outlet port protector is damaged, detached, or not present,
discard container as solution path sterility may be impaired. Some opacity of the
plastic due to moisture absorption during the sterilization process may be
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
observed. This is normal and does not affect the solution quality or safety. The
opacity will diminish gradually. Check for minute leaks by squeezing inner bag
firmly. If leaks are found, discard solution as sterility may be impaired.
2. Insert transfer set into prepared solution container to be transferred. Follow
directions accompanying transfer set.
3. Remove protector from extended middle port of dextrose solution container and
insert connector of transfer set.
4. Transfer solution by gravity or by using a VIAVAC unit.
5. After desired solution has been transferred, mix thoroughly and seal extension
tubing of extended middle port. Cut between seal and connector of transfer set.
6. Check for leaks.
7. Warning: Additives may be incompatible. Supplemental medication may be
added with a 19 to 22 gauge needle through the medication injection site on the
dextrose solution container. Mix solution and medication thoroughly. For high
density medications, such as potassium chloride, squeeze ports while ports are
upright and mix thoroughly.
8. Suspend container from eyelet support.
9. Remove plastic protector from outlet port at bottom of container.
10. Attach administration set. Refer to complete directions accompanying set.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
07-19-65-534
Rev. December 2014
Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50% and 70% Dextrose Injection, USP
Pharmacy Bulk Package
Not for Direct Infusion
VIAFLEX Plastic Container
A Parenteral Nutrient
DESCRIPTION
Dextrose Injections, USP are sterile, nonpyrogenic hypertonic solutions for fluid
replenishment and caloric supply in Pharmacy Bulk Package. A Pharmacy Bulk Package
is a container of sterile preparation for parenteral use that contains many single doses.
The contents are intended for use in a pharmacy admixture program and are restricted to
the preparation of admixtures for intravenous infusion. They contain no antimicrobial
agents. Composition, osmolarity, pH, and caloric content are shown below.
Table 1.
Composition
Osmolarity
(mOsmol/L) (calc.)
pH
Caloric Content (kcal/L)
How Supplied
Dextrose Hydrous, USP
(g/L)
Size, code, NDC
2000 mL unit
50% Dextrose
Injection, USP
500
2520
4.0
(3.2 to 6.5)
1710
2B0256
NDC 0338-0031-06
70% Dextrose
Injection, USP
700
3530
4.0
(3.2 to 6.5)
2390
2B0296
NDC 0338-0719-06
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The VIAFLEX plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). Exposure to temperatures above 25°C/77°F during transport
and storage will lead to minor losses in moisture content. Higher temperatures lead to
greater losses. It is unlikely that these minor losses will lead to clinically significant
changes within the expiration period. The amount of water that can permeate from inside
the container into the overwrap is insufficient to affect the solution significantly.
Solutions in contact with the plastic container can leach out certain of its chemical
components in very small amounts within the expiration period, e.g., di-2-ethylhexyl
phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been
confirmed in tests in animals according to USP biological tests for plastic containers as
well as tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Dextrose Injection, USP have value as a source of water and calories. They are capable of
inducing diuresis depending on the clinical condition of the patient.
INDICATIONS AND USAGE
Dextrose Injection, USP are indicated as a caloric component in a parenteral nutrition
regimen. They are used with an appropriate protein (nitrogen) source in the prevention of
nitrogen loss or in the treatment of negative nitrogen balance in patients where: (1) the
alimentary tract cannot or should not be used, (2) gastrointestinal absorption of protein is
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
impaired, or (3) metabolic requirements for protein are substantially increased, as with
extensive burns.
CONTRAINDICATIONS
The infusion of hypertonic dextrose injections is contraindicated in patients having
intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, in
patients who are anuric, and in patients in hepatic coma.
Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products.
WARNINGS
These injections are for compounding only, not for direct infusion.
Dilute before use to a concentration which will, when administered with an amino acid
(nitrogen) source, result in an appropriate calorie to gram of nitrogen ratio and which has
an osmolarity consistent with the route of administration.
Unless appropriately diluted, the infusion of hypertonic dextrose injection into a
peripheral vein may result in vein irritation, vein damage, and thrombosis. Strongly
hypertonic nutrient solutions should only be administered through an indwelling
intravenous catheter with the tip located in a large central vein such as the superior vena
cava.
In very low birth weight infants, excessive or rapid administration of dextrose injection
may result in increased serum osmolality and possible intracerebral hemorrhage.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach
toxic levels with prolonged parenteral administration if kidney function is impaired.
Premature neonates are particularly at risk because their kidneys are immature, and they
require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature
neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day
accumulate aluminum at levels associated with central nervous system and bone toxicity.
Tissue loading may occur at even lower rates of administration.
Administration by central venous catheter should be used only by those familiar
with this technique and its complications.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Monitor changes in fluid balance, electrolyte concentration, and acid base balance during
prolonged parenteral therapy or whenever the conditions of the patient warrants such
evaluation.
PRECAUTIONS
General
Administration of hypertonic dextrose and amino acid solutions via central venous
catheter may be associated with complications which can be prevented or minimized by
careful attention to all aspects of the procedure. This includes attention to solution
preparation, administration and patient monitoring.
It is essential that a carefully prepared protocol, based upon current medical
practice, be followed, preferably by an experienced medical team.
The package insert of the protein (nitrogen) source should be consulted for dosage and all
precautionary information.
Monitor changes in fluid balance, electrolyte concentration, and acid base balance during
prolonged parenteral therapy or whenever the conditions of the patient warrants such
evaluation.
Care should be taken to avoid circulatory overload, particularly in patients with cardiac
insufficiency.
Caution must be exercised in the administration of these injections to patients receiving
corticosteroids or corticotropin.
These injections should be used with caution in patients with overt or subclinical diabetes
mellitus.
Drug product contains no more than 25 mcg/L of aluminum.
Pregnancy
Pregnancy Category C
There are no adequate and well controlled studies with Dextrose Injections, USP in
pregnant women and animal reproduction studies have not been conducted with this drug.
Therefore, it is not known whether Dextrose Injections, USP can cause fetal harm when
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
administered to a pregnant woman. Dextrose Injections, USP should be given during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
Intrapartum maternal intravenous infusion of glucose-containing solutions may produce
maternal hyperglycemia with subsequent fetal hyperglycemia and fetal metabolic
acidosis. Fetal hyperglycemia can result in increased fetal insulin levels which may
result in neonatal hypoglycemia following delivery. Consider the potential risks and
benefits for each specific patient before administering Dextrose Injections, USP.
Nursing Mothers
It is not known whether this drug is present in human milk. Because many drugs are
present in human milk, caution should be exercised when 50% and 70% Dextrose
Injection, USP is administered to a nursing woman.
Pediatric Use
The use of Dextrose in pediatric patients is based on clinical practice (see DOSAGE
AND ADMINISTRATION). Because of their hypertonicity, 50% and 70% Dextrose
Injections must be diluted prior to administration.
Newborns – especially those born premature and with low birth weight - are at increased
risk of developing hypo- or hyperglycemia and therefore need close monitoring during
treatment with intravenous glucose solutions to ensure adequate glycemic control in order
to avoid potential long term adverse effects. Hypoglycemia in the newborn can cause
prolonged seizures, coma and brain damage. Hyperglycemia has been associated with
intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of
prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of
hospital stay, and death.
ADVERSE REACTIONS
Too rapid infusion of a hypertonic dextrose solution may result in diuresis,
hyperglycemia, glycosuria, and hyperosmolar coma. Continual clinical monitoring of the
patient is necessary in order to identify and initiate measures for these clinical conditions.
Hypersensitivity reactions, including anaphylaxis and chills.
Reference ID: 3677008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reactions which may occur because of the solution or the technique of administration
include febrile response, infection at the site of injection, venous thrombosis or phlebitis
extending from the site of injection, extravasation and hypervolemia.
If an adverse reaction does occur discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures, and save the remainder of the fluid for
examination if deemed necessary.
DOSAGE AND ADMINISTRATION
Following suitable admixture of prescribed drugs, the dosage is usually dependent upon
age, weight and clinical condition of the patient as well as laboratory determinations. See
directions accompanying drugs.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
Do not administer unless solution is clear and seal is intact.
Use of a final filter is recommended during administration of all parenteral solutions
where possible.
The dosage selection and constant infusion rate of intravenous dextrose must be selected
with caution in pediatric patients, particularly neonates and low birth weight infants,
because of the increased risk of hyperglycemia/ hypoglycemia. Frequent monitoring of
serum glucose concentrations is required when dextrose is prescribed to pediatric
patients, particularly neonates and low birth weight infants. The infusion rate and volume
depends on the age, weight, clinical and metabolic conditions of the patient, concomitant
therapy and should be determined by the consulting physician experienced in pediatric
intravenous fluid therapy.
50% and 70% Dextrose Injection, USP in the Pharmacy Bulk Package is intended for use
in the preparation of sterile, intravenous admixtures. Additives may be incompatible with
the fluid withdrawn from this container. Complete information is not available. Those
additives known to be incompatible should not be used. Consult with pharmacist, if
available. When compounding admixtures, use aseptic technique. Mix thoroughly. Do not
store any unused portion of the 50% and 70% Dextrose Injection, USP.
Reference ID: 3677008
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DIRECTIONS FOR USE OF VIAFLEX PLASTIC PHARMACY BULK
PACKAGE CONTAINER
To Open
Tear overpouch at slit and remove solution container. Visually inspect the container. If
the outlet port protector is damaged, detached, or not present, discard container as
solution path sterility may be impaired. Some opacity of the plastic due to moisture
absorption during the sterilization process may be observed. This is normal and does not
affect the solution quality or safety. The opacity will diminish gradually. Check for
minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as
sterility may be impaired.
For compounding only, not for direct infusion.
Preparation for Admixing
1. The Pharmacy Bulk Package is to be used only in a suitable work area such as a
laminar flow hood (or an equivalent clean air compounding area).
2. Suspend container from eyelet support.
3. Remove plastic protector from outlet port at bottom of container.
4. Attach solution transfer set. Refer to complete directions accompanying set.
Note: The closure shall be penetrated only one time with a suitable sterile transfer
device or dispensing set which allows measured dispensing of the contents.
5. The VIAFLEX plastic container should not be written on directly since ink migration
has not been investigated. Affix accompanying label for date and time of entry
notation.
6. Once container closure has been penetrated, withdrawal of contents should be
completed without delay. After initial entry, maintain contents at room temperature
(25°C/77°F) and dispense within 4 hours.
HOW SUPPLIED
See Table 1.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
Protect from freezing. It is recommended the product be stored at room temperature
(25°C/77°F).
Reference ID: 3677008
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
Distributed in Canada by
Baxter Corporation
Mississauga, ON L5N 0C2
Baxter, PL 146, and Viaflex are trademarks of Baxter International Inc.
07-19-69-266
Revised December 2014
Reference ID: 3677008
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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ADENOSCAN®
(adenosine injection)
FOR INTRAVENOUS INFUSION ONLY
DESCRIPTION
Adenosine is an endogenous nucleoside occurring in all cells of the body. It is chemically 6
amino-9-beta-D-ribofuranosyl-9-H-purine and has the following structural formula: structural formula
C10H13N5O4 267.24
Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol.
Solubility increases by warming and lowering the pH of the solution.
Each Adenoscan vial contains a sterile, non-pyrogenic solution of adenosine 3 mg/mL and
sodium chloride 9 mg/mL in Water for Injection, q.s. The pH of the solution is between 4.5 and
7.5.
CLINICAL PHARMACOLOGY
Mechanism of Action
Adenosine is a potent vasodilator in most vascular beds, except in renal afferent arterioles and
hepatic veins where it produces vasoconstriction. Adenosine is thought to exert its
pharmacological effects through activation of purine receptors (cell-surface A1 and A2 adenosine
receptors). Although the exact mechanism by which adenosine receptor activation relaxes
vascular smooth muscle is not known, there is evidence to support both inhibition of the slow
inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A2
receptors in smooth muscle cells. Adenosine may also lessen vascular tone by modulating
sympathetic neurotransmission. The intracellular uptake of adenosine is mediated by a specific
transmembrane nucleoside transport system. Once inside the cell, adenosine is rapidly
phosphorylated by adenosine kinase to adenosine monophosphate, or deaminated by adenosine
deaminase to inosine. These intracellular metabolites of adenosine are not vasoactive.
Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since
Adenoscan significantly increases blood flow in normal coronary arteries with little or no
Reference ID: 3430721
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
increase in stenotic arteries, Adenoscan causes relatively less thallium-201 uptake in vascular
territories supplied by stenotic coronary arteries i.e., a greater difference is seen after Adenoscan
between areas served by normal and areas served by stenotic vessels than is seen prior to
Adenoscan.
Hemodynamics
Adenosine produces a direct negative chronotropic, dromotropic and inotropic effect on the heart,
presumably due to A1-receptor agonism, and produces peripheral vasodilation, presumably due to
A2-receptor agonism. The net effect of Adenoscan in humans is typically a mild to moderate
reduction in systolic, diastolic and mean arterial blood pressure associated with a reflex increase
in heart rate. Rarely, significant hypotension and tachycardia have been observed.
Pharmacokinetics
Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake,
primarily by erythrocytes and vascular endothelial cells. This process involves a specific
transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally
symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to
adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine
deaminase in the cytosol. Since adenosine kinase has a lower Km and Vmax than adenosine
deaminase, deamination plays a significant role only when cytosolic adenosine saturates the
phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or
can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate
formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool.
While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than
10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine
deaminase. As Adenoscan requires no hepatic or renal function for its activation or inactivation,
hepatic and renal failure would not be expected to alter its effectiveness or tolerability.
Clinical Trials
In two crossover comparative studies involving 319 subjects who could exercise (including 106
healthy volunteers and 213 patients with known or suspected coronary disease), Adenoscan and
exercise thallium images were compared by blinded observers. The images were concordant for
the presence of perfusion defects in 85.5% of cases by global analysis (patient by patient) and up
to 93% of cases based on vascular territories. In these two studies, 193 patients also had recent
coronary arteriography for comparison (healthy volunteers were not catheterized). The sensitivity
(true positive Adenoscan divided by the number of patients with positive (abnormal)
angiography) for detecting angiographically significant disease (≥50% reduction in the luminal
diameter of at least one major vessel) was 64% for Adenoscan and 64% for exercise testing,
while the specificity (true negative divided by the number of patients with negative angiograms)
was 54% for Adenoscan and 65% for exercise testing. The 95% confidence limits for Adenoscan
sensitivity were 56% to 78% and for specificity were 37% to 71%.
Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous
Adenoscan of 140 mcg/kg/min produces maximum coronary hyperemia (relative to intracoronary
papaverine) in approximately 95% of cases within two to three minutes of the onset of the
infusion. Coronary blood flow velocity returns to basal levels within one to two minutes of
discontinuing the Adenoscan infusion.
INDICATIONS AND USAGE
Intravenous Adenoscan is indicated as an adjunct to thallium-201 myocardial perfusion
scintigraphy in patients unable to exercise adequately (See WARNINGS).
Reference ID: 3430721
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
Intravenous Adenoscan (adenosine injection) should not be administered to individuals with:
1. Second- or third-degree AV block (except in patients with a functioning artificial pacemaker).
2. Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in
patients with a functioning artificial pacemaker).
3. Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma).
4. Known hypersensitivity to adenosine.
WARNINGS
Fatal Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction
Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and
myocardial infarction have occurred following Adenoscan infusion. Avoid use in patients with
symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular
instability; these patients may be at greater risk of serious cardiovascular reactions to Adenoscan.
Appropriate resuscitative measures should be available.
Sinoatrial and Atrioventricular Nodal Block
Adenoscan (adenosine injection) exerts a direct depressant effect on the SA and AV nodes and
has the potential to cause first-, second- or third-degree AV block, or sinus bradycardia.
Approximately 6.3% of patients develop AV block with Adenoscan, including first-degree
(2.9%), second-degree (2.6%), and third-degree (0.8%) heart block. Adenoscan can cause sinus
bradycardia. Adenoscan should be used with caution in patients with pre-existing first-degree AV
block or bundle branch block and should be avoided in patients with high-grade AV block or
sinus node dysfunction (except in patients with a functioning artificial pacemaker). Adenoscan
should be discontinued in any patient who develops persistent or symptomatic high-grade AV
block. Sinus pause has been rarely observed with adenosine infusions.
Hypotension
Adenoscan (adenosine injection) is a potent peripheral vasodilator and can cause significant
hypotension. Patients with an intact baroreceptor reflex mechanism are able to maintain blood
pressure and tissue perfusion in response to Adenoscan by increasing heart rate and cardiac
output. However, Adenoscan should be used with caution in patients with autonomic dysfunction,
stenotic valvular heart disease, pericarditis or pericardial effusions, stenotic carotid artery disease
with cerebrovascular insufficiency, or uncorrected hypovolemia, due to the risk of hypotensive
complications in these patients. Adenoscan should be discontinued in any patient who develops
persistent or symptomatic hypotension.
Hypertension
Increases in systolic and diastolic pressure have been observed (as great as 140 mm Hg systolic in
one case) concomitant with Adenoscan infusion; most increases resolved spontaneously within
several minutes, but in some cases, hypertension lasted for several hours.
Bronchoconstriction
Adenoscan (adenosine injection) is a respiratory stimulant (probably through activation of carotid
body chemoreceptors) and intravenous administration in man has been shown to increase minute
ventilation (Ve) and reduce arterial PCO2 causing respiratory alkalosis. Approximately 28% of
Reference ID: 3430721
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients experience breathlessness (dyspnea) or an urge to breathe deeply with Adenoscan. These
respiratory complaints are transient and only rarely require intervention.
Adenosine administered by inhalation has been reported to cause bronchoconstriction in
asthmatic patients, presumably due to mast cell degranulation and histamine release. These
effects have not been observed in normal subjects. Adenoscan has been administered to a limited
number of patients with asthma and mild to moderate exacerbation of their symptoms has been
reported. Respiratory compromise has occurred during adenosine infusion in patients with
obstructive pulmonary disease. Adenoscan should be used with caution in patients with
obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis,
etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma).
Adenoscan should be discontinued in any patient who develops severe respiratory difficulties.
Atrial fibrillation
Atrial fibrillation has been reported in patients (with and without a history of atrial fibrillation)
undergoing myocardial perfusion imaging with adenosine infusion. In these cases, atrial
fibrillation began 1.5 to 3 minutes after initiation of adenosine, lasted for 15 seconds to 6 hours,
and spontaneously converted to normal sinus rhythm.
PRECAUTIONS
Drug interactions
Intravenous Adenoscan (adenosine injection) has been given with other cardioactive drugs (such
as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without
apparent adverse interactions, but its effectiveness with these agents has not been systematically
evaluated. Because of the potential for additive or synergistic depressant effects on the SA and
AV nodes, however, Adenoscan should be used with caution in the presence of these agents.
The vasoactive effects of Adenoscan are inhibited by adenosine receptor antagonists, such as
methylxanthines (e.g., caffeine and theophylline). The safety and efficacy of Adenoscan in the
presence of these agents has not been systematically evaluated.
The vasoactive effects of Adenoscan are potentiated by nucleoside transport inhibitors, such as
dipyridamole. The safety and efficacy of Adenoscan in the presence of dipyridamole has not been
systematically evaluated.
Whenever possible, drugs that might inhibit or augment the effects of adenosine should be
withheld for at least five half-lives prior to the use of Adenoscan.
Carcinogenesis, mutagenesis, impairment of fertility
Studies in animals have not been performed to evaluate the carcinogenic potential of Adenoscan
(adenosine injection). Adenosine was negative for genotoxic potential in the Salmonella (Ames
Test) and Mammalian Microsome Assay.
Adenosine, however, like other nucleosides at millimolar concentrations present for several
doubling times of cells in culture, is known to produce a variety of chromosomal alterations.
Fertility studies in animals have not been conducted with adenosine.
Pregnancy Category C
Animal reproduction studies have not been conducted with adenosine; nor have studies been
performed in pregnant women. Because it is not known whether Adenoscan can cause fetal harm
when administered to pregnant women, Adenoscan should be used during pregnancy only if
clearly needed.
Reference ID: 3430721
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric use
The safety and effectiveness of Adenoscan in patients less than 18 years of age have not been
established.
Geriatric use
Clinical studies of Adenoscan did not include sufficient numbers of subjects aged younger than
65 years to determine whether they respond differently. Other reported experience has not
revealed clinically relevant differences of the response of elderly in comparison to younger
patients. Greater sensitivity of some older individuals, however, cannot be ruled out.
ADVERSE REACTIONS
The following reactions with an incidence of at least 1% were reported with intravenous
Adenoscan among 1421 patients enrolled in controlled and uncontrolled U.S. clinical trials.
Despite the short half-life of adenosine, 10.6% of the side effects occurred not with the infusion
of Adenoscan but several hours after the infusion terminated. Also, 8.4% of the side effects that
began coincident with the infusion persisted for up to 24 hours after the infusion was complete. In
many cases, it is not possible to know whether these late adverse events are the result of
Adenoscan infusion.
Flushing
44%
Chest discomfort
40%
Dyspnea or urge to breathe deeply
28%
Headache
18%
Throat, neck or jaw discomfort
15%
Gastrointestinal discomfort
13%
Lightheadedness/dizziness
12%
Upper extremity discomfort
4%
ST segment depression
3%
First-degree AV block
3%
Second-degree AV block
3%
Paresthesia
2%
Hypotension
2%
Nervousness
2%
Arrhythmias
1%
Adverse experiences of any severity reported in less than 1% of patients include:
Body as a Whole
Back discomfort; lower extremity discomfort; weakness
Cardiovascular System
Nonfatal myocardial infarction; life-threatening ventricular arrhythmia; third-degree AV block;
bradycardia; palpitation; sinus exit block; sinus pause; sweating; T-wave changes; hypertension
(systolic blood pressure > 200 mm Hg)
Central Nervous System
Drowsiness; emotional instability; tremors
Reference ID: 3430721
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Genital/Urinary System
Vaginal pressure; urgency
Respiratory System
Cough
Special Senses
Blurred vision; dry mouth; ear discomfort; metallic taste; nasal congestion; scotomas; tongue
discomfort
Post Marketing Experience (see WARNINGS)
The following adverse events have been reported from marketing experience with Adenoscan.
Because these events are reported voluntarily from a population of uncertain size, are associated
with concomitant diseases and multiple drug therapies and surgical procedures, it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Decisions to include these events in labeling are typically based on one or more of the following
factors: (1) seriousness of the event, (2) frequency of the reporting, (3) strength of causal
connection to the drug, or a combination of these factors.
Body as a Whole
Injection site reaction
Cardiovascular System
Fatal and nonfatal cardiac arrest, myocardial infarction, ventricular arrhythmia
Central Nervous System
Seizure activity, including tonic clonic (grand mal) seizures, and loss of consciousness
Digestive
Nausea and vomiting
Respiratory
Respiratory arrest, throat tightness
OVERDOSAGE
The half-life of adenosine is less than 10 seconds and side effects of Adenoscan (when they
occur) usually resolve quickly when the infusion is discontinued, although delayed or persistent
effects have been observed. Methylxanthines, such as caffeine and theophylline, are competitive
adenosine receptor antagonists and theophylline has been used to effectively terminate persistent
side effects. In controlled U.S. clinical trials, theophylline (50-125 mg slow intravenous injection)
was needed to abort Adenoscan side effects in less than 2% of patients.
DOSAGE AND ADMINISTRATION
For intravenous infusion only.
Reference ID: 3430721
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Adenoscan should be given as a continuous peripheral intravenous infusion.
The recommended intravenous dose for adults is 140 mcg/kg/min infused for six minutes (total
dose of 0.84 mg/kg).
The required dose of thallium-201 should be injected at the midpoint of the Adenoscan infusion
(i.e., after the first three minutes of Adenoscan). Thallium-201 is physically compatible with
Adenoscan and may be injected directly into the Adenoscan infusion set.
The injection should be as close to the venous access as possible to prevent an inadvertent
increase in the dose of Adenoscan (the contents of the IV tubing) being administered.
There are no data on the safety or efficacy of alternative Adenoscan infusion protocols.
The safety and efficacy of Adenoscan administered by the intracoronary route have not been
established.
The following Adenoscan infusion nomogram may be used to determine the appropriate infusion
rate corrected for total body weight:
Patient Weight
Infusion Rate
kg
lbs
mL/min
45
99
2.1
50
110
2.3
55
121
2.6
60
132
2.8
65
143
3.0
70
154
3.3
75
165
3.5
80
176
3.8
85
187
4.0
90
198
4.2
This nomogram was derived from the following general formula: general formula
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration.
Reference ID: 3430721
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Adenoscan (adenosine injection) is supplied as 20 mL and 30 mL vials of sterile, nonpyrogenic
solution in normal saline.
NDC 0469-0871-20
Product Code 87120
60 mg/20 mL (3 mg/mL) in a 20 mL single-dose, flip-top glass vial, packaged individually
and in packages of ten.
NDC 0469-0871-30
Product Code 87130
90 mg/30 mL (3 mg/mL) in a 30 mL single-dose, flip-top glass vial, packaged individually
and in packages of ten.
Store at controlled room temperature 15°-30°C (59°-86°F)
Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals
by warming to room temperature. The solution must be clear at the time of use.
Contains no preservative. Discard unused portion.
Rx only
Product of Germany
Marketed by:
Astellas Pharma US, Inc.
Northbrook, IL 60062 USA
Manufactured by:
Hospira, Inc.
Lake Forest, IL 60045 USA
Revised October 2013
13G037-ADS
Reference ID: 3430721
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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CARDIZEM® CD
(diltiazem HCl)
Capsules
Rx only
DESCRIPTION
Cardizem (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (slow channel
blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin
4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-,
monohydrochloride,(+)-cis-. The chemical structure is: chemical structure
Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble
in water, methanol, and chloroform. It has a molecular weight of 450.98. Cardizem CD is
formulated as a once-a-day extended-release capsule containing 120 mg, 180 mg, 240 mg, 300
mg, or 360 mg diltiazem hydrochloride. The 120 mg, 180 mg, 240 mg, and 300 mg capsules
also contain: acetyl tributyl citrate, ammonio methacrylate copolymer dispersion, black iron
oxide (300 mg), castor oil, ethylcellulose, FD&C Blue #1, fumaric acid, gelatin, silicon dioxide,
simethicone, starch, stearic acid, sucrose, talc, titanium dioxide and white wax. The 360 mg
capsule also contains: acetyl tributyl citrate, ammonio methacrylate copolymer dispersion,
diethyl phthalate, FD&C Blue #1, gelatin, povidone, simethicone, sodium lauryl sulfate, starch,
sucrose, talc and titanium dioxide.
For oral administration.
CLINICAL PHARMACOLOGY
The therapeutic effects of Cardizem CD are believed to be related to its ability to inhibit the
cellular influx of calcium ions during membrane depolarization of cardiac and vascular smooth
muscle.
Mechanisms of Action
Hypertension. Cardizem CD produces its antihypertensive effect primarily by relaxation of
vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The
magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive
Reference ID: 2867302
N20062/S-040
Page 3
individuals experience an antihypertensive effect, whereas there is only a modest fall in blood
pressure in normotensives.
Angina. Cardizem CD has been shown to produce increases in exercise tolerance, probably due
to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart
rate and systemic blood pressure at submaximal and maximal work loads. Diltiazem has been
shown to be a potent dilator of coronary arteries, both epicardial and subendocardial.
Spontaneous and ergonovine-induced coronary artery spasm are inhibited by diltiazem.
In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable
tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes
in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular
smooth muscle and dilation of both large and small coronary arteries at drug levels which cause
little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial
and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-
dependent decreases in systemic blood pressure and decreases in peripheral resistance.
Hemodynamic and Electrophysiologic Effects
Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular
conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the
intact animal, prolongation of the AH interval can be seen at higher doses.
In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It
causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in
normotensive individuals and, in exercise tolerance studies in patients with ischemic heart
disease, reduces the heart rate-blood pressure product for any given work load. Studies to date,
primarily in patients with good ventricular function, have not revealed evidence of a negative
inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have
not been affected. Such data have no predictive value with respect to effects in patients with
poor ventricular function, and increased heart failure has been reported in patients with
preexisting impairment of ventricular function. There are as yet few data on the interaction of
diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is
usually slightly reduced by diltiazem.
In hypertensive patients, Cardizem CD produces antihypertensive effects both in the supine and
standing positions. In a double-blind, parallel, dose-response study utilizing doses ranging from
90 to 540 mg once daily, Cardizem CD lowered supine diastolic blood pressure in an apparent
linear manner over the entire dose range studied. The changes in diastolic blood pressure,
measured at trough, for placebo, 90 mg, 180 mg, 360 mg, and 540 mg were –2.9, –4.5, –6.1, –
9.5, and –10.5 mm Hg, respectively. Postural hypotension is infrequently noted upon suddenly
assuming an upright position. No reflex tachycardia is associated with the chronic anti
hypertensive effects. Cardizem CD decreases vascular resistance, increases cardiac output (by
increasing stroke volume), and produces a slight decrease or no change in heart rate. During
dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable
systolic pressure is usually reduced. Chronic therapy with Cardizem CD produces no change or
an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone
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axis has been observed. Cardizem CD reduces the renal and peripheral effects of angiotensin II.
Hypertensive animal models respond to diltiazem with reductions in blood pressure and
increased urinary output and natriuresis without a change in urinary sodium/potassium ratio.
In a double-blind, parallel dose-response study of doses from 60 mg to 480 mg once daily,
Cardizem CD increased time to termination of exercise in a linear manner over the entire dose
range studied. The improvement in time to termination of exercise utilizing a Bruce exercise
protocol, measured at trough, for placebo, 60 mg, 120 mg, 240 mg, 360 mg, and 480 mg was 29,
40, 56, 51, 69, and 68 seconds, respectively. As doses of Cardizem CD were increased, overall
angina frequency was decreased. Cardizem CD, 180 mg once daily, or placebo was
administered in a double-blind study to patients receiving concomitant treatment with long-
acting nitrates and/or beta-blockers. A significant increase in time to termination of exercise and
a significant decrease in overall angina frequency was observed. In this trial the overall
frequency of adverse events in the Cardizem CD treatment group was the same as the placebo
group.
Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional
and effective refractory periods by approximately 20%. In a study involving single oral doses of
300 mg of Cardizem in six normal volunteers, the average maximum PR prolongation was 14%
with no instances of greater than first-degree AV block. Diltiazem-associated prolongation of
the AH interval is not more pronounced in patients with first-degree heart block. In patients with
sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some
cases).
Chronic oral administration of Cardizem to patients in doses of up to 540 mg/day has resulted in
small increases in PR interval and on occasion produces abnormal prolongation (see
WARNINGS).
Pharmacokinetics and Metabolism
Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass
effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%.
Cardizem undergoes extensive metabolism in which only 2% to 4% of the unchanged drug
appears in the urine. Drugs which induce or inhibit hepatic microsomal enzymes may alter
diltiazem disposition.
Total radioactivity measurement following short IV administration in healthy volunteers suggests
the presence of other unidentified metabolites, which attain higher concentrations than those of
diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours
compared to 2 to 5 hours for diltiazem.
In vitro binding studies show Cardizem is 70% to 80% bound to plasma proteins. Competitive in
vitro ligand binding studies have also shown Cardizem binding is not altered by therapeutic
concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or
warfarin. The plasma elimination half-life following single or multiple drug administration is
approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of
10% to 20% of the parent drug and is 25% to 50% as potent as a coronary vasodilator as
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diltiazem. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50
to 200 ng/mL. There is a departure from linearity when dose strengths are increased; the half-
life is slightly increased with dose. A study that compared patients with normal hepatic function
to patients with cirrhosis found an increase in half-life and a 69% increase in bioavailability in
the hepatically impaired patients. A single study in nine patients with severely impaired renal
function showed no difference in the pharmacokinetic profile of diltiazem compared to patients
with normal renal function.
Cardizem CD Capsules. When compared to a regimen of Cardizem tablets at steady-state, more
than 95% of drug is absorbed from the Cardizem CD formulation. A single 360-mg dose of the
capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and
14 hours; absorption occurs throughout the dosing interval. When Cardizem CD was
coadministered with a high fat content breakfast, the extent of diltiazem absorption was not
affected. Dose-dumping does not occur. The apparent elimination half-life after single or
multiple dosing is 5 to 8 hours. A departure from linearity similar to that seen with Cardizem
tablets and Cardizem SR capsules is observed. As the dose of Cardizem CD capsules is
increased from a daily dose of 120 mg to 240 mg, there is an increase in the area-under-the-curve
of 2.7 times. When the dose is increased from 240 mg to 360 mg, there is an increase in the
area-under-the-curve of 1.6 times.
INDICATIONS AND USAGE
Cardizem CD is indicated for the treatment of hypertension. It may be used alone or in
combination with other antihypertensive medications.
Cardizem CD is indicated for the management of chronic stable angina and angina due to
coronary artery spasm.
CONTRAINDICATIONS
Cardizem is contraindicated in (1) patients with sick sinus syndrome except in the presence of a
functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in
the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90
mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5)
patients with acute myocardial infarction and pulmonary congestion documented by x-ray on
admission.
WARNINGS
1. Cardiac Conduction. Cardizem prolongs AV node refractory periods without significantly
prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect
may rarely result in abnormally slow heart rates (particularly in patients with sick sinus
syndrome) or second- or third-degree AV block (13 of 3290 patients or 0.40%). Concomitant
use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac
conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds)
after a single dose of 60 mg of diltiazem (see ADVERSE REACTIONS).
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2. Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated
animal tissue preparations, hemodynamic studies in humans with normal ventricular function
have not shown a reduction in cardiac index nor consistent negative effects on contractility
(dp/dt). An acute study of oral diltiazem in patients with impaired ventricular function
(ejection fraction 24%± 6%) showed improvement in indices of ventricular function without
significant decrease in contractile function (dp/dt). Worsening of congestive heart failure has
been reported in patients with preexisting impairment of ventricular function. Experience with
the use of Cardizem (diltiazem hydrochloride) in combination with beta-blockers in patients
with impaired ventricular function is limited. Caution should be exercised when using this
combination.
3. Hypotension. Decreases in blood pressure associated with Cardizem therapy may
occasionally result in symptomatic hypotension.
4. Acute Hepatic Injury. Mild elevations of transaminases with and without concomitant
elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such
elevations were usually transient and frequently resolved even with continued diltiazem
treatment. In rare instances, significant elevations in enzymes such as alkaline phosphatase,
LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been
noted. These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have
been reversible upon discontinuation of drug therapy. The relationship to Cardizem is
uncertain in some cases, but probable in some (see PRECAUTIONS).
PRECAUTIONS
General
Cardizem (diltiazem hydrochloride) is extensively metabolized by the liver and excreted by the
kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of
renal and hepatic function should be monitored at regular intervals. The drug should be used
with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and
rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic
damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were
associated with histological changes in the liver which were reversible when the drug was
discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however,
these changes were reversible with continued dosing.
Dermatological events (see ADVERSE REACTIONS) may be transient and may disappear
despite continued use of Cardizem. However, skin eruptions progressing to erythema
multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a
dermatologic reaction persist, the drug should be discontinued.
Drug Interactions
Due to the potential for additive effects, caution and careful titration are warranted in patients
receiving Cardizem concomitantly with other agents known to affect cardiac contractility and/or
conduction (see WARNINGS). Pharmacologic studies indicate that there may be additive
effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with
Cardizem (see WARNINGS).
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As with all drugs, care should be exercised when treating patients with multiple medications.
Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system.
Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a
significant impact on the efficacy and side effect profile of diltiazem. Patients taking other drugs
that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment,
may require dosage adjustment when starting or stopping concomitantly administered diltiazem
in order to maintain optimum therapeutic blood levels.
Anesthetics. The depression of cardiac contractility, conductivity, and automaticity as well as
the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers.
When used concomitantly, anesthetics and calcium blockers should be titrated carefully.
Benzodiazepines. Studies showed that diltiazem increased the AUC of midazolam and triazolam
by 3- to 4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of
midazolam and triazolam also increased (1.5- to 2.5-fold) during coadministration with
diltiazem. These pharmacokinetic effects seen during diltiazem coadministration can result in
increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.
Beta-blockers. Controlled and uncontrolled domestic studies suggest that concomitant use of
Cardizem and beta-blockers is usually well tolerated, but available data are not sufficient to
predict the effects of concomitant treatment in patients with left ventricular dysfunction or
cardiac conduction abnormalities.
Administration of Cardizem (diltiazem hydrochloride) concomitantly with propranolol in five
normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of
propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced
from its binding sites by diltiazem. If combination therapy is initiated or withdrawn in
conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see
WARNINGS).
Buspirone. In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC
5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax of buspirone were not
significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be
possible during concomitant administration with diltiazem. Subsequent dose adjustments may be
necessary during coadministration, and should be based on clinical assessment.
Carbamazepine. Concomitant administration of diltiazem with carbamazepine has been
reported to result in elevated serum levels of carbamazepine (40% to 72% increase), resulting in
toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a
potential drug interaction.
Cimetidine. A study in six healthy volunteers has shown a significant increase in peak diltiazem
plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200
mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant
increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome
P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients
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currently receiving diltiazem therapy should be carefully monitored for a change in
pharmacological effect when initiating and discontinuing therapy with cimetidine. An
adjustment in the diltiazem dose may be warranted.
Clonidine. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been
reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate
in patients receiving concomitant diltiazem and clonidine.
Cyclosporine. A pharmacokinetic interaction between diltiazem and cyclosporine has been
observed during studies involving renal and cardiac transplant patients. In renal and cardiac
transplant recipients, a reduction of cyclosporine dose ranging from 15% to 48% was necessary
to maintain cyclosporine trough concentrations similar to those seen prior to the addition of
diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations
should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued.
The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.
Digitalis. Administration of Cardizem with digoxin in 24 healthy male subjects increased plasma
digoxin concentrations approximately 20%. Another investigator found no increase in digoxin
levels in 12 patients with coronary artery disease. Since there have been conflicting results
regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when
initiating, adjusting, and discontinuing Cardizem therapy to avoid possible over- or under-
digitalization (see WARNINGS).
Quinidine. Diltiazem significantly increases the AUC (0 →∞) of quinidine by 51%, T1/2 by 36%,
and decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and
the dose adjusted accordingly.
Rifampin. Coadministration of rifampin with diltiazem lowered the diltiazem plasma
concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known
CYP3A4 inducer should be avoided when possible, and alternative therapy considered.
Statins. Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the
AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by
CYP3A4 may be increased with concomitant use of diltiazem. When possible, use a non
CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both
diltiazem and the statin should be considered along with close monitoring for signs and
symptoms of any statin related adverse events.
In a healthy volunteer cross-over study (N=10), co-administration of a single 20 mg dose of
simvastatin at the end of a 14 day regimen with 120 mg BID diltiazem SR resulted in a 5-fold
increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average
steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure.
Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold
mean increase in simvastatin AUC can be expected. If co-administration of simvastatin with
diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.
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In a ten-subject randomized, open label, 4-way cross-over study, co-administration of diltiazem
(120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to
4-fold increase in mean lovastatin AUC and Cmax versus lovastatin alone. In the same study,
there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem
coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or
pravastatin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at oral dosage levels of up to 100 mg/kg/day and a 21-month study in
mice at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There
was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro in
bacteria. No evidence of impaired fertility was observed in a study performed in male and
female rats at oral dosages of up to 100 mg/kg/day.
Pregnancy
Category C. Reproduction studies have been conducted in mice, rats, and rabbits.
Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily
recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some
studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies,
there was an increased incidence of stillbirths at doses of 20 times the human dose or greater.
There are no well-controlled studies in pregnant women; therefore, use Cardizem in pregnant
women only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may
approximate serum levels. If use of Cardizem is deemed essential, an alternative method of
infant feeding should be instituted.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Serious adverse reactions have been rare in studies carried out to date, but it should be
recognized that patients with impaired ventricular function and cardiac conduction abnormalities
have usually been excluded from these studies.
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The following table presents the most common adverse reactions reported in placebo-controlled
angina and hypertension trials in patients receiving Cardizem CD up to 360 mg with rates in
placebo patients shown for comparison.
Cardizem CD Capsule Placebo-Controlled Angina and Hypertension Trials Combined
Cardizem CD
Placebo
Adverse Reactions
(n=607)
(n=301)
Headache
5.4%
5.0%
Dizziness
3.0%
3.0%
Bradycardia
3.3%
1.3%
AV Block First Degree
3.3%
0.0%
Edema
2.6%
1.3%
ECG Abnormality
1.6%
2.3%
Asthenia
1.8%
1.7%
In clinical trials of Cardizem CD capsules, Cardizem tablets, and Cardizem SR capsules
involving over 3200 patients, the most common events (i.e., greater than 1%) were edema
(4.6%), headache (4.6%), dizziness (3.5%), asthenia (2.6%), first-degree AV block (2.4%),
bradycardia (1.7%), flushing (1.4%), nausea (1.4%), and rash (1.2%).
In addition, the following events were reported infrequently (less than 1%) in angina or
hypertension trials:
Cardiovascular: Angina, arrhythmia, AV block (second- or third-degree), bundle branch block,
congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia,
ventricular extrasystoles.
Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations,
insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.
Gastrointestinal: Anorexia, constipation, diarrhea, dry mouth, dysgeusia, dyspepsia, mild
elevations of SGOT, SGPT, LDH, and alkaline phosphatase (see WARNINGS, Acute Hepatic
Injury), thirst, vomiting, weight increase.
Dermatological: Petechiae, photosensitivity, pruritus, urticaria.
Other: Amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia,
hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain,
polyuria, sexual difficulties.
The following postmarketing events have been reported infrequently in patients receiving
Cardizem: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema
(including facial or periorbital edema), asystole, erythema multiforme (including Stevens-
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Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, extrapyramidal
symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia,
photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin
areas), purpura, retinopathy, myopathy, and thrombocytopenia. In addition, events such as
myocardial infarction have been observed which are not readily distinguishable from the natural
history of the disease in these patients. A number of well-documented cases of generalized rash,
some characterized as leukocytoclastic vasculitis, have been reported. However, a definitive
cause and effect relationship between these events and Cardizem therapy is yet to be established.
OVERDOSAGE
The oral LD50's in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg,
respectively. The intravenous LD50's in these species were 60 and 38 mg/kg, respectively. The
oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys
at 360 mg/kg.
The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard
dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.
There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. Of cases
with known outcome, most patients recovered and in cases with a fatal outcome, the majority
involved multiple drug ingestion.
Events observed following diltiazem overdose included bradycardia, hypotension, heart block,
and cardiac failure. Most reports of overdose described some supportive medical measure and/or
drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block,
although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors
were used to maintain blood pressure and in cases of cardiac failure, inotropic agents were
administered. In addition, some patients received treatment with ventilatory support, gastric
lavage, activated charcoal, and/or intravenous calcium.
The effectiveness of intravenous calcium administration to reverse the pharmacological effects
of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium
channel blockers associated with hypotension and bradycardia that was initially refractory to
atropine became more responsive to atropine after the patients received intravenous calcium. In
some cases, intravenous calcium has been administered (1 g calcium chloride or 3 g calcium
gluconate) over 5 minutes and repeated every 10 to 20 minutes as necessary. Calcium gluconate
has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours.
Infusions of calcium for 24 hours or more may be required. Patients should be monitored for
signs of hypercalcemia.
In the event of overdose or exaggerated response, appropriate supportive measures should be
employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be
removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal
hemoperfusion may hasten diltiazem elimination following overdose. Based on the known
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pharmacological effects of diltiazem and/or reported clinical experiences, the following
measures may be considered:
Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade,
administer isoproterenol cautiously.
High-degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be
treated with cardiac pacing.
Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and
diuretics.
Hypotension: Vasopressors (e.g., dopamine or norepinephrine).
Actual treatment and dosage should depend on the severity of the clinical situation and the
judgment and experience of the treating physician.
DOSAGE AND ADMINISTRATION
Patients controlled on diltiazem alone or in combination with other medications may be switched
to Cardizem CD capsules at the nearest equivalent total daily dose. Higher doses of Cardizem
CD may be needed in some patients. Patients should be closely monitored. Subsequent titration
to higher or lower doses may be necessary and should be initiated as clinically warranted. There
is limited general clinical experience with doses above 360 mg, but doses to 540 mg have been
studied in clinical trials. The incidence of side effects increases as the dose increases with first-
degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose.
Hypertension. Dosage needs to be adjusted by titration to individual patient needs. When used
as monotherapy, reasonable starting doses are 180 to 240 mg once daily, although some patients
may respond to lower doses. Maximum antihypertensive effect is usually observed by 14 days
of chronic therapy; therefore, dosage adjustments should be scheduled accordingly. The usual
dosage range studied in clinical trials was 240 to 360 mg once daily. Individual patients may
respond to higher doses of up to 480 mg once daily.
Angina. Dosages for the treatment of angina should be adjusted to each patient's needs, starting
with a dose of 120 or 180 mg once daily. Individual patients may respond to higher doses of up
to 480 mg once daily. When necessary, titration may be carried out over a 7- to 14-day period.
Concomitant Use With Other Cardiovascular Agents
1. Sublingual NTG. May be taken as required to abort acute anginal attacks during Cardizem
CD (diltiazem hydrochloride) therapy.
2. Prophylactic Nitrate Therapy. Cardizem CD may be safely coadministered with short- and
long-acting nitrates.
3. Beta-blockers (see WARNINGS and PRECAUTIONS).
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4. Antihypertensives. Cardizem CD has an additive antihypertensive effect when used with
other antihypertensive agents. Therefore, the dosage of Cardizem CD or the concomitant
antihypertensives may need to be adjusted when adding one to the other.
HOW SUPPLIED
Cardizem® CD
(diltiazem hydrochloride)
Capsules
Strength Quantity
NDC Number
Description
120 mg
30 btl
90 btl
100 UDIP®
64455-795-30
64455-795-42
64455-795-49
Light turquoise blue/light turquoise blue
capsule imprinted with cardizem CD and 120
mg on one end.
180 mg
30 btl
90 btl
100 UDIP®
64455-796-30
64455-796-42
64455-796-49
Light turquoise blue/blue capsule imprinted
with cardizem CD and 180 mg on one end.
240 mg
30 btl
90 btl
100 UDIP®
64455-797-30
64455-797-42
64455-797-49
Blue/blue capsule imprinted with cardizem
CD and 240 mg on one end.
300 mg
30 btl
90 btl
100 UDIP®
64455-798-30
64455-798-42
64455-798-49
Light gray/blue capsule imprinted with
cardizem CD and 300 mg on one end.
360 mg
90 btl
64455-799-42
Light blue/white capsule imprinted with
cardizem CD and 360 mg on one end.
Storage Conditions: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature]. Avoid excessive humidity.
Cardizem® is a registered trademark of Biovail Laboratories International, SRL
Manufactured by: sanofi-aventis U.S. LLC
Kansas City, MO, 64137, USA
For: BTA Pharmaceuticals, Inc.
(subsidiary of Biovail Corporation)
Bridgewater, NJ, 08807, USA
LB 0070-03
Rev. 11/09
Reference ID: 2867302
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custom-source
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2025-02-12T13:46:33.399252
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020062s040lbl.pdf', 'application_number': 20062, 'submission_type': 'SUPPL ', 'submission_number': 40}
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