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6000
PRODUCT
6200
INFORMATION
PROGLYCEM®
brand of diazoxide
Capsules
Suspension, USP
FOR ORAL ADMINISTRATION
Rx Only
DESCRIPTION
PROGLYCEM® (diazoxide) is a nondiuretic benzothiadiazine derivative taken orally for the
management of symptomatic hypoglycemia. PROGLYCEM® Capsules contain 50 mg diazoxide,
USP. The Suspension contains 50 mg of diazoxide, USP in each milliliter and has a chocolate-
mint flavor; alcohol content is approximately 7.25%. Other ingredients: Sorbitol solution,
chocolate cream flavor, propylene glycol, magnesium aluminum silicate, carboxymethycellulose
sodium, mint flavor, sodium benzoate, methylparaben, poloxamer 188, propylparaben, and
purified water. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
Diazoxide has the following structural formula:
Diazoxide is 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide with the empirical
formula C8H7CIN2O2S and the molecular weight 230.7. It is a white powder practically insoluble
to sparingly soluble in water.
CLINICAL PHARMACOLOGY
Diazoxide administered orally produces a prompt dose-related increase in blood glucose level,
due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic
effect.
The hyperglycemic effect begins within an hour and generally lasts no more than eight hours in
the presence of normal renal function.
PROGLYCEM® decreases the excretion of sodium and water, resulting in fluid retention which
may be clinically significant.
The hypotensive effect of diazoxide on blood pressure is usually not marked with the oral
preparation. This contrasts with the intravenous preparation of diazoxide (see ADVERSE
REACTIONS).
Other pharmacologic actions of PROGLYCEM® include increased pulse rate; increased serum
uric acid levels due to decreased excretion; increased serum levels of free fatty acids’ decreased
chloride excretion; decreased para-aminohippuric acid; (PAH) clearance with no appreciable
effect on glomerular filtration rate.
1
Reference ID: 3822049
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The concomitant administration of a benzothiazide diuretic may intensify the hyperglycemic and
hyperuricemic effects of PROGLYCEM®. In the presence of hypokalemia, hyperglycemic
effects are also potentiated.
PROGLYCEM®-induced hyperglycemia is reversed by the administration of insulin or
tolbutamide. The inhibition of insulin release by PROGLYCEM® is antagonized by alpha
adrenergic blocking agents.
PROGLYCEM® is extensively bound (more than 90%) to serum proteins, and is excreted in the
kidneys. The plasma half-life following I.V. administration is 28 ± 8.3 hours. Limited data on
oral administration revealed a half-life of 24 and 36 hours in two adults. In four children aged
four months to six years, the plasma half-life varied from 9.5 to 24 hours on long-term oral
administration. The half-life may be prolonged following overdosage, and in patients with
impaired renal function.
INDICATIONS AND USAGE
PROGLYCEM® (ORAL DIAZOXIDE) is useful in the management of hypoglycemia due to
hyperinsulinism associated with the following conditions:
Adults: Inoperable islet cell adenoma or carcinoma, or extrapancreatic malignancy.
Infants and Children: Leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic
malignancy, islet cell adenoma, or adenomatosis. PROGLYCEM® may be used preoperatively
as a temporary measure, and postoperatively, if hypoglycemia persists.
PROGLYCEM® should be used only after a diagnosis of hypoglycemia due to one of the above
conditions has been definitely established. When other specific medical therapy or surgical
management either has been unsuccessful or is not feasible, treatment with PROGLYCEM®
should be considered.
CONTRAINDICATIONS
The use of PROGLYCEM® for functional hypoglycemia is contraindicated. The drug should not
be used in patients hypersensitive to diazoxide or to other thiazides unless the potential benefits
outweigh the possible risks.
WARNINGS
The antidiuretic property of diazoxide may lead to significant fluid retention, which in patients
with compromised cardiac reserve, may precipitate congestive heart failure. The fluid retention
will respond to conventional therapy with diuretics.
It should be noted that concomitantly administered thiazides may potentiate the hyperglycemic
and hyperuricemic actions of diazoxide (See DRUG INTERACTIONS and ANIMAL
PHARMACOLOGY AND/OR TOXICOLOGY).
Ketoacidosis and nonketotic hyperosmolar coma have been reported in patients treated with
recommended doses of PROGLYCEM® usually during intercurrent illness. Prompt recognition
and treatment are essential (See OVERDOSAGE), and prolonged surveillance following the
acute episode is necessary because of the long drug half-life of approximately 30 hours. The
occurrence of these serious events may be reduced by careful education of patients regarding the
need for monitoring the urine for sugar and ketones and for prompt reporting of abnormal
2
Reference ID: 3822049
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For current labeling information, please visit https://www.fda.gov/drugsatfda
findings and unusual symptoms to the physician. Transient cataracts occurred in association with
hyperosmolar coma in an infant, and subsided on correction of the hyper-osmolarity. Cataracts
have been observed in several animals receiving daily doses of intravenous or oral diazoxide.
The development of abnormal facial features in four children treated chronically (>4 years) with
PROGLYCEM® for hypoglycemia hyperinsulinism in the same clinic has been reported.
Pulmonary Hypertension in Neonates and Infants
There have been postmarketing reports of pulmonary hypertension occurring in infants and
neonates treated with diazoxide. The cases were reversible upon discontinuation of the drug.
Monitor patients, especially those with risk factors for pulmonary hypertension, for respiratory
distress and discontinue diazoxide if pulmonary hypertension is suspected.
PRECAUTIONS
General:
Treatment with PROGLYCEM® should be initiated under close clinical supervision, with careful
monitoring of blood glucose and clinical response until the patient’s condition has stabilized.
This usually requires several days. If not effective in two to three weeks, the drug should be
discontinued.
Prolonged treatment requires regular monitoring of the urine for sugar and ketones, especially
under stress conditions, with prompt reporting of any abnormalities to the physician.
Additionally, blood sugar levels should be monitored periodically by the physician to determine
the need for dose adjustment.
The effects of diazoxide on the hematopoietic system and the level of serum uric acid should be
kept in mind; the latter should be considered particularly in patients with hyperuricemia or a
history of gout.
In some patients, higher blood levels have been observed with the oral suspension than with the
capsule formulation of PROGLYCEM®. Dosage should be adjusted as necessary in individual
patients if changed from one formulation to the other.
Since the plasma half-life of diazoxide is prolonged in patients with impaired renal function, a
reduced dosage should be considered. Serum electrolyte levels should also be evaluated for such
patients.
The antihypertensive effect of other drugs may be enhanced by PROGLYCEM®, and this should
be kept in mind when administering it concomitantly with antihypertensive agents.
Because of the protein binding, administration of PROGLYCEM® with coumarin or its
derivatives may require reduction in the dosage of the anticoagulant, although there has been no
reported evidence of excessive anticoagulant effect. In addition, PROGLYCEM® may possibly
displace bilirubin from albumin; this should be kept in mind particularly when treating newborns
with increased bilirubinemia.
Pulmonary hypertension has been reported in neonates and young infants treated with diazoxide.
(see WARNINGS)
Information for Patients:
3
Reference ID: 3822049
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During treatment with PROGLYCEM® the patient should be advised to consult regularly with
the physician and to cooperate in the periodic monitoring of his condition by laboratory tests. In
addition, the patient should be advised:
• to take the drug on a regular schedule as prescribed, not to skip doses, not to take
extra doses;
• not to use this drug with other medications unless this is done with the physician’s
advice;
• not to allow anyone else to take this medication;
• to follow dietary instructions;
• to report promptly any adverse effects (i.e., increased urinary frequency, increased
thirst, fruity breath odor);
• to report pregnancy or to discuss plans for pregnancy.
Laboratory tests:
The following procedures may be especially important in patient monitoring (not necessarily
inclusive); blood glucose determinations (recommended at periodic intervals in patients taking
diazoxide orally for treatment of hypoglycemia, until stabilized); blood urea nitrogen (BUN)
determinations and creatinine clearance determinations; hematocrit determinations; platelet count
determinations; total and differential leukocyte counts; serum aspartate aminotransferase (AST)
level determinations; serum uric acid level determinations; and urine testing for glucose and
ketones (in patients being treated with diazoxide for hypoglycemia, semiquantitative estimation
of sugar and ketones in serum performed by the patient and reported to the physician provides
frequent and relatively inexpensive monitoring of the condition).
Drug Interactions:
Since diazoxide is highly bound to serum proteins, it may displace other substances which are
also bound to protein, such as bilirubin or coumarin and its derivatives, resulting in higher blood
levels of these substances. Concomitant administration of oral diazoxide and diphenylhydantoin
may result in a loss of seizure control. These potential interactions must be considered when
administering PROGLYCEM® Capsules or Suspension.
The concomitant administration of thiazides or other commonly used diuretics may potentiate the
hyperglycemic and hyperuricemic effects of diazoxide.
Drug/Laboratory Test Interactions:
The hyperglycemic and hyperuricemic effects of diazoxide preclude proper assessment of these
metabolic states. Increased renin secretion, IgG concentrations and decreased cortisol secretions
have also been noted. Diazoxide inhibits glucagon-stimulated insulin release and causes a false-
negative insulin response to glucagon.
Carcinogenesis, mutagenesis, impairment of fertility:
No long-term animal dosing study has been done to evaluate the carcinogenic potential of
diazoxide. No laboratory study of mutagenic potential or animal study of effects on fertility has
been done.
4
Reference ID: 3822049
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy Category C:
Reproduction studies using the oral preparation in rats have revealed increased fetal resorptions
and delayed parturition, as well as fetal skeletal anomalies; evidence of skeletal and cardiac
teratogenic effects in rabbits has been noted with intravenous administration. The drug has also
been demonstrated to cross the placental barrier in animals and to cause degeneration of the fetal
pancreatic beta cells (See ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY). Since
there are no adequate data on fetal effects of this drug when given to pregnant women, safety in
pregnancy has not been established. When the use of PROGLYCEM® is considered, the
indications should be limited to those specified above for adults (See INDICATIONS AND
USAGE), and the potential benefits to the mother must be weighed against possible harmful
effects to the fetus.
Non-teratogenic effects:
Diazoxide crosses the placental barrier and appears in cord blood. When given to the mother
prior to delivery of the infant, the drug may produce fetal or neonatal hyperbilirubinemia,
thrombocytopenia, altered carbohydrate metabolism, and possibly other side effects that have
occurred in adults.
Alopecia and hypertrichosis lanuginosa have occurred in infants whose mothers received oral
diazoxide during the last 19 to 60 days of pregnancy.
Labor and delivery:
Since intravenous administration of the drug during labor may cause cessation of uterine
contractions, and administration of oxytocic agents may be required to reinstate labor, caution is
advised in administering PROGLYCEM® at that time.
Nursing mothers:
Information is not available concerning the passage of diazoxide in breast milk. Because many
drugs are excreted in human milk and because of the potential for adverse reactions from
diazoxide 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:
(See INDICATIONS AND USAGE).
ADVERSE REACTIONS:
Frequent and Serious:
Sodium and fluid retention is most common in young infants and in adults and may precipitate
congestive heart failure in patients with compromised cardiac reserve. It usually responds to
diuretic therapy (See DRUG INTERACTIONS).
Infrequent but Serious:
Diabetic ketoacidosis and hyperosmolar nonketotic coma may develop very rapidly.
Conventional therapy with insulin and restoration of fluid and electrolyte balance is usually
effective if instituted promptly. Prolonged surveillance is essential in view of the long half-life of
PROGLYCEM® (See OVERDOSAGE).
5
Reference ID: 3822049
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Other frequent adverse reactions:
Hirsutism of the lanugo type, mainly on the forehead, back and limbs, occurs most commonly in
children and women and may be cosmetically unacceptable. It subsides on discontinuation of the
drug.
Hyperglycemia or glycosuria may require reduction in dosage in order to avoid progression to
ketoacidosis or hyperosmolar coma.
Gastrointestinal intolerance may include anorexia, nausea, vomiting, abdominal pain, ileus,
diarrhea, transient loss of taste.
Tachycardia, palpitations, increased levels of serum uric acid are common.
Thrombocytopenia with or without purpura may require discontinuation of the drug. Neutropenia
is transient, is not associated with increased susceptibility to infection, and ordinarily does not
require discontinuation of the drug. Skin rash, headache, weakness, and malaise may also occur.
Other adverse reactions which have been observed are:
Cardiovascular: hypotension occurs occasionally, which may be augmented by thiazide diuretics
given concurrently. A few cases of transient hypertension, for which no explanation is apparent,
have been noted. Chest pain has been reported rarely. Pulmonary hypertension has been reported
in neonates and young infants (see WARNINGS).
Hematologic: eosinophilia; decreased hemoglobin / hematocrit; excessive bleeding, decreased
IgG.
Hepato-renal: increased AST, alkaline phosphatase; azotemia, decreased creatinine clearance,
reversible nephrotic syndrome, decreased urinary output, hematuria, albuminuria. Neurologic:
anxiety, dizziness, insomnia, polyneuritis, paresthesia, pruritus, extrapyramidal signs.
Ophthalmologic: transient cataracts, subconjunctival hemorrhage, ring scotoma, blurred vision,
diplopia, lacrimation. Skeletal, integumentary; monilial dermatitis, herpes, advance in bone age;
loss of scalp hair. Systemic: fever, lymphadenopathy. Other; gout acute pancreatitis/pancreatic
necrosis, galactorrhea, enlargement of lump in breast.
OVERDOSAGE
An overdosage of PROGLYCEM® causes marked hyperglycemia which may be associated with
ketoacidosis. It will respond to prompt insulin administration and restoration of fluid and
electrolyte balance. Because of the drug’s long half-life (approximately 30 hours), the symptoms
of overdosage require prolonged surveillance for periods up to seven days until the blood sugar
level stabilizes within the normal range. One investigator reported successful lowering of
diazoxide blood levels by peritoneal dialysis in one patient and by hemodialysis in another.
DOSAGE AND ADMINISTRATION
Patients should be under close clinical observation when treatment with PROGLYCEM® is
initiated. The clinical response and blood glucose level should be carefully monitored until the
patient’s condition has stabilized satisfactory; in most instances, this may be accomplished in
several days. If administration of PROGLYCEM® is not effective after two or three weeks, the
drug should be discontinued.
6
Reference ID: 3822049
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The dosage of PROGLYCEM® must be individualized based on the severity of the
hypoglycemic condition and the blood glucose level and clinical response of the patient. The
dosage should be adjusted until the desired clinical and laboratory effects are produced with the
least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and
young children.
Adults and children:
The usual daily dosage is 3 to 8 mg/kg, divided into two or three equal doses every 8 or 12 hours.
In certain instances, patients with refractory hypoglycemia may require higher dosages.
Ordinarily, an appropriate starting dosage is 3 mg/kg/day, divided into three equal doses every 8
hours. Thus an average adult would receive a starting dosage of approximately 200 mg daily.
Infants and newborns:
The usual daily dosage is 8 to 15 mg/kg divided into two or three equal doses every 8 to 12
hours. An appropriate starting dosage is 10 mg/kg/day, divided into three equal doses every 8
hours.
ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY
Oral diazoxide in the mouse, rat, rabbit, dog, pig, and monkey produces a rapid and transient rise
in blood glucose levels. In dogs, increased blood glucose is accompanied by increased free fatty
acids, lactate, and pyruvate in the serum. In mice, a marked decrease in liver glycogen and an
increase in the blood urea nitrogen level occur.
In acute toxicity studies the LD50 for oral diazoxide suspension is >5000 mg/kg in the rat, >522
mg/kg in the neonatal rat, between 1900 and 2572 mg/kg in the mouse, and 219 mg/kg in the
guinea pig. Although the oral LD50 was not determined in the dog, a dosage of up to 500 mg/kg
was well tolerated.
In subacute oral toxicity studies, diazoxide at 400 mg/kg in the rat produced growth retardation,
edema, increases in liver and kidney weights, and adrenal hypertrophy. Daily dosages up to 1080
mg/kg for three months produced hyperglycemia, an increase in liver weight and an increase in
mortality. In dogs given oral diazoxide at approximately 40 mg/kg/day for one month, no
biologically significant gross or microscopic abnormalities were observed. Cataracts, attributed
to markedly disturbed carbohydrate metabolism, have been observed in a few dogs given
repeated daily doses of oral or intravenous diazoxide. The lenticular changes resembled those
which occur experimentally in animals with increased blood glucose levels. In chronic toxicity
studies, rats given a daily dose of 200 mg/kg diazoxide for 52 weeks had a decrease in weight
gain and an increase in heart, liver, adrenal and thyroid weights. Mortality in drug-treated and
control groups was not different. Dogs treated with diazoxide at dosages of 50, l00, and 200
mg/kg/day for 82 weeks had higher blood glucose levels than controls. Mild bone marrow
stimulation and increased pancreas weights were evident in the drug-treated dogs; several
developed inguinal hernias, one had a testicular seminoma, and another had a mass near the
penis. Two females had inguinal mammary swellings. The etiology of these changes was not
established. There was no difference in mortality between drug-treated and control groups. In a
second chronic oral toxicity study, dogs given milled diazoxide at 50, l00, and 200 mg/kg/day
had anorexia and sever weight loss, causing death in a few. Hematologic, biochemical, and
7
Reference ID: 3822049
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For current labeling information, please visit https://www.fda.gov/drugsatfda
histologic examination did not indicate any cause of death other than inanition. After one year of
treatment, there is no evidence of herniation or tissue swelling in any of the dogs.
When diazoxide was administered at high dosages concomitantly with either chlorothiazide to
rats or trichlormethiazide to dogs, increased toxicity was observed. In rats, the combination was
nephrotoxic; epithelial hyperplasia was observed in the collecting tubules. In dogs, a diabetic
syndrome was produced which resulted in ketosis and death. Neither of the drugs given alone
produced these effects.
Although the data are inconclusive, reproduction and teratology studies in several species of
animals indicate that diazoxide, when administered during the critical period of embryo
formation, may interfere with normal fetal development, possibly through altered glucose
metabolism. Parturition was occasionally prolonged in animals treated at term. Intravenous
administration of diazoxide to pregnant sheep, goats, and swine produced in the fetus an
appreciable increase in blood glucose level and degeneration of the beta cells of the Islets of
Langerhans. The reversibility of these effects was not studied.
HOW SUPPLIED
PROGLYCEM® (diazoxide capsules, USP), 50 mg, half opaque orange and half clear capsules,
branded in black with BNP 6000: bottle of 100 (NDC 0575-6000-01).
PROGLYCEM® suspension, 50 mg/mL, a chocolate-mint flavored suspension; bottle of 30 ml
(NDC 0575-6200-30), with dropper calibrated to deliver 10, 20, 30, 40 and 50 mg diazoxide.
Shake well before each use. Protect from light. Store in carton until contents are used.
Store in light resistant container as defined in the USP. Store PROGLYCEM® Capsules
and Suspension at 25°C (77°F) excursions permitted 15°-30°C (59-86°F). [See USP
Controlled Room Temperature].
Rx only
Distributed by:
Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454
Rev. 9/2015
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|
custom-source
|
2025-02-12T13:44:10.670713
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017425s016lbl.pdf', 'application_number': 17425, 'submission_type': 'SUPPL ', 'submission_number': 16}
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NDA 17407/S-036
Page 4
CATAPRES - clonidine hydrochloride tablet
Boehringer Ingelheim Pharmaceuticals Inc.
Catapres
(clonidine hydrochloride, USP)
Oral Antihypertensive
Tablets of 0.1, 0.2 and 0.3 mg
Prescribing Information
DESCRIPTION
Catapres (clonidine hydrochloride, USP) is a centrally acting alpha-agonist hypotensive agent
available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg.
The 0.1 mg tablet is equivalent to 0.087 mg of the free base.
The inactive ingredients are colloidal silicon dioxide, corn starch, dibasic calcium phosphate,
FD&C Yellow No. 6, gelatin, glycerin, lactose, and magnesium stearate. The Catapres 0.1 mg
tablet also contains FD&C Blue No.1 and FD&C Red No.3.
Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The
chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is
the structural formula: Structural Formula
Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and
alcohol.
CLINICAL PHARMACOLOGY
Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced
sympathetic outflow from the central nervous system and in decreases in peripheral resistance,
renal vascular resistance, heart rate, and blood pressure. Catapres tablets act relatively rapidly.
The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum
decrease occurring within 2 to 4 hours. Renal blood flow and glomerular filtration rate remain
essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are
mild and infrequent.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17407/S-036
Page 5
Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction
(15% to 20%) of cardiac output in the supine position with no change in the peripheral
resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral
resistance. During long term therapy, cardiac output tends to return to control values, while
peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most
patients given clonidine, but the drug does not alter normal hemodynamic response to exercise.
Tolerance to the antihypertensive effect may develop in some patients, necessitating a
reevaluation of therapy.
Other studies in patients have provided evidence of a reduction in plasma renin activity and in
the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic
actions to the antihypertensive effect of clonidine has not been fully elucidated.
Clonidine acutely stimulates growth hormone release in both children and adults, but does not
produce a chronic elevation of growth hormone with long-term use.
Pharmacokinetics
The plasma level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life
ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe
impairment of renal function. Following oral administration about 40-60% of the absorbed dose
is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is
metabolized in the liver. Neither food nor the race of the patient influences the pharmacokinetics
of clonidine.
INDICATIONS AND USAGE
Catapres (clonidine hydrochloride, USP) tablets are indicated in the treatment of hypertension.
Catapres tablets may be employed alone or concomitantly with other antihypertensive agents.
CONTRAINDICATIONS
Catapres tablets should not be used in patients with known hypersensitivity to clonidine (see
PRECAUTIONS).
WARNINGS
Withdrawal
Patients should be instructed not to discontinue therapy without consulting their physician.
Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as
nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood
pressure and elevated catecholamine concentrations in the plasma. The likelihood of such
reactions to discontinuation of clonidine therapy appears to be greater after administration of
higher doses or continuation of concomitant beta-blocker treatment and special caution is
therefore advised in these situations. Rare instances of hypertensive encephalopathy,
cerebrovascular accidents and death have been reported after clonidine withdrawal. When
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17407/S-036
Page 6
discontinuing therapy with Catapres (clonidine hydrochloride, USP) tablets, the physician should
reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology.
An excessive rise in blood pressure following discontinuation of Catapres tablets therapy can be
reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If
therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the
beta-blocker should be withdrawn several days before the gradual discontinuation of Catapres
tablets.
Because children commonly have gastrointestinal illnesses that lead to vomiting, they may
be particularly susceptible to hypertensive episodes resulting from abrupt inability to take
medication.
PRECAUTIONS
General
In patients who have developed localized contact sensitization to Catapres-TTS (clonidine),
continuation of Catapres-TTS or substitution of oral clonidine hydrochloride therapy may be
associated with the development of a generalized skin rash.
In patients who develop an allergic reaction to Catapres-TTS, substitution of oral clonidine
hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or
angioedema).
Catapres tablets should be used with caution in patients with severe coronary insufficiency,
conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal
failure.
Perioperative Use
Administration of Catapres tablets should be continued to within four hours of surgery and
resumed as soon as possible thereafter. Blood pressure should be carefully monitored during
surgery and additional measures to control blood pressure should be available if required.
Information for Patients
Patients should be cautioned against interruption of Catapres tablets therapy without their
physician's advice.
Patients who engage in potentially hazardous activities, such as operating machinery or driving,
should be advised of a possible sedative effect of clonidine. They should also be informed that
this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other
sedating drugs.
Patients who wear contact lenses should be cautioned that treatment with Catapres tablets may
cause dryness of eyes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17407/S-036
Page 7
Drug Interactions
Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating
drugs. If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the
hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose.
Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect
sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers, and beta-
blockers. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been
reported in association with the use of clonidine concomitantly with diltiazem or verapamil.
Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats
(see Toxicology).
Toxicology
In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence
and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or
longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in
the choroid.
In view of the retinal degeneration seen in rats, eye examinations were performed during clinical
trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these
908 patients, the eye examinations were carried out over periods of 24 months or longer. Except
for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded
and, according to specialized tests such as electroretinography and macular dazzle, retinal
function was unchanged.
In combination with amitriptyline, clonidine hydrochloride administration led to the
development of corneal lesions in rats within 5 days.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78
weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human
dose as mg/kg (9 or 6 times the MRDHD on a mg/m basis). There was no evidence of
genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.
Fertility of male or female rats was unaffected by clonidine doses as high as 150 mcg/kg
(approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to
be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg
basis; 2 to 8 times the MRDHD on a mg/m basis).
Pregnancy
Teratogenic Effects: Pregnancy Category C.
Reproduction studies performed in rabbits at doses up to approximately 3 times the oral
maximum recommended daily human dose (MRDHD) of Catapres (clonidine hydrochloride,
USP) tablets produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats,
however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m basis) of clonidine
This label may not be the latest approved by FDA.
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NDA 17407/S-036
Page 8
were associated with increased resorptions in a study in which dams were treated continuously
from 2 months prior to mating. Increased resorptions were not associated with treatment at the
same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated
on gestation days 6-15. Increases in resorption were observed at much higher dose levels (40
times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m basis) in mice
and rats treated on gestation days 1-14 (lowest dose employed in the study was 500 mcg/kg).
No adequate, well-controlled studies have been conducted 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
As clonidine hydrochloride is excreted in human milk, caution should be exercised when
Catapres (clonidine hydrochloride, USP) tablets are administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established in adequate and well-
controlled trials (see WARNINGS, Withdrawal).
ADVERSE REACTIONS
Most adverse effects are mild and tend to diminish with continued therapy. The most frequent
(which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients;
drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10
in 100.
The following less frequent adverse experiences have also been reported in patients receiving
Catapres tablets, but in many cases patients were receiving concomitant medication and a causal
relationship has not been established.
Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also
reported were a weakly positive Coombs’ test and increased sensitivity to alcohol.
Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities
(i.e.,sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias),
orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of
sinus bradycardia and atrioventricular block have been reported, both with and without the use of
concomitant digitalis.
Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations
(including visual and auditory), insomnia, mental depression, nervousness, other behavioral
changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares.
Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria.
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NDA 17407/S-036
Page 9
Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient
abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic
pseudo-obstruction), salivary gland pain, and vomiting.
Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of
libido, nocturia, and urinary retention.
Hematologic: Thrombocytopenia.
Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase,
and weight gain.
Musculoskeletal: Leg cramps and muscle or joint pain.
Oro-otolaryngeal: Dryness of the nasal mucosa.
Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased
lacrimation, and dryness of eyes.
OVERDOSAGE
Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory
depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and
miosis. The frequency of CNS depression may be higher in children than adults. Large
overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and
seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after
exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children.
There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the
rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not
recommended. Gastric lavage may be indicated following recent and/or large ingestions.
Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may
include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for
hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the
management of clonidine-induced respiratory depression, hypotension and/or coma; blood
pressure should be monitored since the administration of naloxone has occasionally resulted in
paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not
recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination
of clonidine.
The largest overdose reported to date involved a 28-year old male who ingested 100 mg of
clonidine hydrochloride powder. This patient developed hypertension followed by hypotension,
bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The
patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/ml after 1
hour, 190 ng/ml after 1.5 hours, 370 ng/ml after 2 hours, and 120 ng/ml after 5.5 and 6.5 hours.
In mice and rats, the oral LD of clonidine is 206 and 465 mg/kg, respectively.
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______________________________________________________________________________
______________________________________________________________________________
NDA 17407/S-036
Page 10
DOSAGE AND ADMINISTRATION
Adults
The dose of Catapres (clonidine hydrochloride, USP) tablets must be adjusted according to the
patient's individual blood pressure response. The following is a general guide to its
administration.
Initial Dose
0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower
initial dose.
Maintenance Dose
Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the
desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may
minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most
commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses.
Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this
have rarely been employed.
Renal Impairment
Dosage must be adjusted according to the degree of impairment, and patients should be carefully
monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis,
there is no need to give supplemental clonidine following dialysis.
HOW SUPPLIED
Catapres (clonidine hydrochloride, USP) tablets are supplied as follows:
Dose (mg)
Color
Marking
Bottle of 100
0.1
Tan
BI 6
NDC 0597-0006-01
0.2
Orange
BI 7
NDC 0597-0007-01
0.3
Peach
BI 11
NDC 0597-0011-01
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room
Temperature].
Dispense in tight, light-resistant container.
Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Manufactured by:
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NDA 17407/S-036
Page 11
Boehringer Ingelheim Promeco S.A. de C.V.,
Mexico City, Mexico
Licensed from:
Boehringer Ingelheim
International GmbH
Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY.
©Copyright Boehringer Ingelheim International GmbH 2010
ALL RIGHTS RESERVED
Printed in USA
Rev: January 2010
OT6000GA0710
090340066/US/6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:10.707382
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017407s036lbl.pdf', 'application_number': 17407, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
10,987
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1
NSS-9A (O)
NegGram ®
Suspension1
NALIDIXIC ACID
ORAL SUSPENSION1, USP
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
NegGram (nalidixic acid, USP) and other antibacterial drugs, NegGram should be used only to
treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
NegGram, brand of nalidixic acid, is a quinolone antibacterial agent for oral
administration. Nalidixic acid is 1-ethyl-1, 4-dihydro-7-methyl-4-oxo-1, 8-naphthyridine-3-
carboxylic acid. It is a pale yellow, crystalline substance and a very weak organic acid.
Nalidixic acid has the following structural formula:
Inactive Ingredients – Carbomere 934P, FD&C Red #40, Flavor, Parabens, Purified
Water, Saccharin Sodium, Sodium Chloride, Sorbitol Solution.
CLINICAL PHARMACOLOGY
Following oral administration, NegGram is rapidly absorbed from the gastrointestinal
tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Unchanged
nalidixic acid appears in the urine along with an active metabolite, hydroxynalidixic acid, which
has antibacterial activity similar to that of nalidixic acid. Other metabolites include glucuronic
acid conjugates of nalidixic acid and hydroxy nalidixic acid, and the dicarboxylic acid derivative.
The hydroxy metabolite represents 30 percent of the biologically active drug in the blood and 85
percent in the urine. Peak serum levels of active drug average approximately 20 mcg to 40 mcg
per mL (90 percent protein bound), one to two hours after administration of a 1 g dose to a
1 Insert is being revised to make it specific to NegGram Suspension. Previously the insert applied to both NegGram
Caplets and NegGram Suspension.
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2
fasting normal individual, with a half-life of about 90 minutes. Peak urine levels of active drug
average approximately 150 mcg to 200 mcg per mL, three to four hours after administration,
with a half-life of about six hours. Approximately four percent of NegGram is excreted in the
feces. Traces of nalidixic acid were found in blood and urine of an infant whose mother had
received the drug during the last trimester of pregnancy. (See PRECAUTIONS—Drug
Interactions.)
Microbiology
NegGram has marked antibacterial activity against gram-negative bacteria including
Enterobacter species, Escherichia coli, Morganella Morganii; Proteus Mirabilis, Proteus
vulgaris, and Providencia rettgeri. Pseudomonas species are generally resistant to the drug.
NegGram is bactericidal and is effective over the entire urinary pH range. Conventional
chromosomal resistance to NegGram taken in full dosage has been reported to emerge in
approximately 2 to 14 percent of patients during treatment; however, bacterial resistance to
NegGram has not been shown to be transferable via R factor.
Susceptibility Test
Diffusion Techniques: Quantitative methods that require measurement of zone
diameters give the most precise estimates of antibacterial susceptibility. One such procedure
recommended for use with a disc containing 30 mcg of nalidixic acid is the National Committee
for Clinical Laboratory Standards (NCCLS) approved procedure. Only organisms from urinary
tract infections should be tested. Results of laboratory tests using 30 mcg nalidixic acid discs
should be interpreted using the following criteria:
Zone Diameter (mm) Interpretation
≥19
(S) Susceptible
14-18
(I) Intermediate
≤13
(R) Resistant
Dilution Techniques: Broth and agar dilution methods, such as those recommended by
the NCCLS, may be used to determine the minimum inhibitory concentration (MIC) of nalidixic
acid. MIC test results should be interpreted according to the following criteria:
MIC (mcg/mL)
Interpretation
≤16
(S) Susceptible
≥32
(R) Resistant
For any susceptibility test, a report of "susceptible" indicates that the pathogen is likely to
respond to nalidixic acid therapy. A report of "resistant" indicates that the pathogen is not likely
to respond. A report of "intermediate" generally indicates that the test result is equivocal.
The Quality Control strains should have the following assigned daily ranges for nalidixic
acid:
QC Strains
E. Coli
(ATCC 25922)
Disc Zone Diameter
22-28
MIC (mcg/mL)
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3
1.0-4.0
INDICATIONS AND USAGE
NegGram (nalidixic acid, USP) is indicated for the treatment of urinary tract infections
caused by susceptible gram-negative microorganisms, including the majority of E. Coli,
Enterobacter species, Klebsiella species, and Proteus species. Disc susceptibility testing with
the 30 mcg disc should be performed prior to administration of the drug, and during treatment if
clinical response warrants.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
NegGram and other antibacterial drugs, NegGram 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
NegGram is contraindicated in patients with known hypersensitivity to nalidixic acid or
to related compounds, infants less than three months of age, and in patients with porphyria or a
history of convulsive disorders. NegGram is contraindicated in patients undergoing concomitant
therapy with melphalan or other related cancer chemotherapeutic alkylating agents because of
serious gastrointestinal toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis.
WARNINGS
Central Nervous System (CNS) effects including convulsions, increased intracranial
pressure, and toxic psychosis have been reported with nalidixic acid therapy. Convulsive
seizures have been reported with other drugs in this class. Quinolones may also cause CNS
stimulation which may lead to tremor, restlessness, lightheadedness, confusion, and
hallucinations. Therefore, nalidixic acid should be used with caution in patients with known or
suspected CNS disorders, such as, cerebral arteriosclerosis or epilepsy, or other factors which
predispose seizures. (See ADVERSE REACTIONS.) If these reactions occur in patients
receiving nalidixic acid, the drug should be discontinued and appropriate measures instituted.
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions, some following
the first dose, have been reported in patients receiving quinolone therapy. Some reactions were
accompanied by cardiovascular collapse, loss of conscious-ness, tingling, pharyngeal or facial
edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactoid reactions required immediate emergency treatment with
epinephrine. Oxygen, intravenous steroids, and airway management, including intubation,
should be administered as indicated.
Nalidixic acid and other members of the quinolone drug class have been shown to cause
arthropathy in juvenile animals. (See PRECAUTIONS and ANIMAL PHARMACOLOGY.)
Pseudomembranous colitis has been reported with nearly all antibacterial agents,
including quinolones, and may range in severity from mild to life-threatening. Therefore, it is
important to consider this diagnosis in patients who present with diarrhea subsequent to the
administration of antibacterial agents.
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4
Treatment with antibacterial agents alters the normal flora of the colon and may permit
overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one
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 drug
discontinuation 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.
QT interval prolongation/torsades de pointes: Rare cases of torsades de pointes have
been spontaneously reported during post-marketing surveillance in patients receiving quinolones,
including nalidixic acid. These rare cases were associated with one or more of the following
factors: age over 60, female gender, underlying cardiac disease, and/or use of multiple
medications. Nalidixic acid should be avoided in patients with known prolongation of the QT
interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine,
Procainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.2
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including nalidixic acid.
Nalidixic acid should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light
touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to
prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that
required surgical repair or resulted in prolonged disability have been reported in patients
receiving quinolones, including nalidixic acid. Post-marketing surveillance reports indicate that
this risk may be increased in patients receiving concomitant corticosteroids, especially in the
elderly. Nalidixic acid 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
tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after
therapy with quinolones, including nalidixic acid.
PRECAUTIONS
General
Blood counts and renal and liver function tests should be performed periodically if
treatment is continued for more than two weeks. NegGram should be used with caution in
patients with liver disease, epilepsy, or severe cerebral arteriosclerosis. (See WARNINGS.)
While caution should be used in patients with severe renal failure, therapeutic concentrations of
NegGram in the urine, without increased toxicity due to drug accumulation in the blood, have
been observed in patients on full dosage with creatinine clearances as low as 2 mL/minute to 8
mL/minute.
2 The QT interval prolongation/torsades de pointes paragraph is being removed as allowed by the FDA per the
Quinolone Class Labeling
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5
Moderate to severe phototoxicity reactions have been observed in patients who are
exposed to direct sunlight while receiving NegGram or other members of this drug class.
Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
If bacterial resistance to NegGram emerges during treatment, it usually does so within 48
hours, permitting rapid change to another antimicrobial. Therefore, if the clinical response is
unsatisfactory or if relapse occurs, cultures and sensitivity tests should be repeated.
Underdosage with NegGram during initial treatment (with less than 4 g per day for adults) may
predispose to emergence of bacterial resistance. (See DOSAGE AND ADMINISTRATION.)
Cross-resistance between nalidixic acid and other quinolone derivatives such as oxolinic
acid and cinoxacin has been observed
Caution should be observed in patients with glucose-6-phosphate dehydrogenase
deficiency. (see ADVERSE REACTIONS).
Prescribing NegGram 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 NegGram may be taken with or without meals. Patients should
be advised to drink fluids liberally and not take antacids.
Patients should be advised that quinolones may be associated with hypersensitivity
reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash
or other allergic reactions.
Quinolones may cause dizziness and light-headedness, therefore, patients should know
how they react to NegGram before they operate an automobile or machinery or engage in
activities requiring mental alertness or coordination.
Patients should be advised that quinolones may increase the effects of theophylline and
caffeine. There is a possibility of caffeine accumulation when products containing caffeine are
consumed while taking quinolones. Patients should be advised to avoid excessive sunlight or
artificial ultraviolet light while receiving nalidixic acid and to discontinue therapy if
phototoxicity occurs.
Patients should be advised that convulsions have been reported in patients taking
quinolones, including nalidixic acid, and to notify their physician before taking this drug if there
is a history of this condition. Patients should be advised that mineral supplements, vitamins with
iron or minerals, calcium-, aluminum-, magnesium-based antacids, sucralfate or Videx® ,
(didanosine), chewable/buffered tablets of the pediatric powder for oral solution should not be
taken within the two-hour period before or within the two-hour period after taking nalidixic acid
(see Drug Interactions).
Patients should be advised:
• that nalidixic acid may cause changes in the electrocardiogram (QTc interval
prolongation)
• that nalidixic acid should be avoided in patients receiving class IA (e.g. quinidine,
Procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents
• that nalidixic acid should be used with caution in subjects receiving drugs that affect
the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic
antidepressant
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6
• to inform their physicians of any personal or family history of QTc prolongation or
proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial
ischemia
• that peripheral neuropathies have been associated with nalidixic acid use. If
symptoms of peripheral neuropathy including pain, burning, tingling, numbness,
and/or weakness develop, they should discontinue treatment and contact their
physicians.
Patients should be counseled that antibacterial drugs including NegGram should only be
used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
When NegGram 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 NegGram or other antibacterial drugs in the
future.
Drug Interactions
Elevated plasma levels of theophylline have been reported with concomitant quinolone
use. There have been reports of theophylline-related side effects in patients on concomitant
therapy with quinolones and theophylline. Therefore, monitoring of theophylline plasma levels
should be considered and dosage of theophylline adjusted, as required.
Quinolones have been shown to interfere with the metabolism of caffeine. This may lead
to reduced clearance of caffeine and the prolongation of its plasma half-life.
Quinolones, including nalidixic acid, may enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin
time or other suitable coagulation test should be closely monitored.
Since active proliferation of organisms is a necessary condition for its antibacterial
activity, the action of nalidixic acid may be inhibited by the presence of other antibacterial
substances, especially bacteriostatic agents such as tetracycline, chloramphenicol, or
nitrofurantoin, which is antagonistic to nalidixic acid in vitro.
Probenecid inhibits the tubular secretion of nalidixic acid and may reduce its efficacy in
the treatment of urinary tract infections while increasing the risk of systemic side effects.
Serious gastrointestinal toxicity has been associated with the concomitant use of nalidixic
acid and the anti-cancer drug melphalan. (see CONTRAINDICATIONS)
Antacids containing magnesium, aluminum, or calcium; sucralfate or divalent or trivalent
cations such as iron; multivitamins containing zinc; and Videx®, (Didanosine),
chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere
with the absorption of quinolones, resulting in systemic levels considerably lower than desired.
These agents should not be taken within the two-hour period before or within the two-hour
period after nalidixic acid administration.
Elevated serum levels of Cyclosporine have been reported with the concomitant use of
some quinolones and cyclosporine. Therefore, cyclosporine serum levels should be monitored
and appropriate Cyclosporine dosage adjustments made when these drugs are used
concomitantly.
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7
Drug Laboratory Test Interactions
When Benedict's or Fehling's solution or Clinitest® Reagent Tablets are used to test the
urine of patients taking NegGram, a false-positive reaction for glucose may be obtained, due to
the liberation of glucuronic acid from the metabolites excreted. However, a colorimetric test for
glucose based on an enzyme reaction (e.g., with Clinistix® Reagent Strips or Tes-Tape® ) does
not give a false-positive reaction to the liberated glucuronic acid.
Incorrect values may be obtained for urinary 17-keto and ketogenic steroids in patients
receiving NegGram, because of an interaction between the drug and the m-dinitrobenzene used
in the usual assay method. In such cases, the Porter-Silber test for 17-hydroxycorticoids may be
used.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In lifetime studies in the rat given nalidixic acid in the diet, there was an increased
incidence of preputial gland neoplasms in the treated males and clitoral gland neoplasms in the
treated females. Studies in mice in which nalidixic acid was administered in the feed for two
years, or was given in the feed for 76 weeks followed by no treatment for 9 weeks, gave
equivocal evidence of carcinogenic activity.
Nalidixic acid was tested in the Ames bacterial mutagenicity test (maximum dose 33
mcg/plate) and the mouse lymphoma assay (L5178Y/TK; maximum dose 100 mcg/mL) with and
without metabolic activation, and results were negative.
Pregnancy: Teratogenic Effects.
Pregnancy Category C
NegGram has been shown to be teratogenic and embryocidal in rats when given in oral
doses six times the human dose. NegGram also prolonged the duration of pregnancy especially
at four times the clinical dose. There are no adequate and well-controlled studies in pregnant
women. Since nalidixic acid, like other drugs in this class, causes arthropathy in immature
animals, NegGram should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. (See WARNINGS and ANIMAL PHARMACOLOGY.)
Nursing Mothers
Since nalidixic acid is excreted in breast milk, it is contraindicated during lactation.3
Because of the potential for serious adverse reactions in nursing infants from NegGram, 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 infants below the age of three months have not been
established.
Usage in Patients Under 18 Years of Age
Toxicological studies have shown that nalidixic acid and related drugs can produce
erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature
animals of most species tested. No such joint lesions have been reported in humans to date.
Nevertheless, until the significance of this finding is clarified, this drug should only be used in
3 There is evidence to show that nalidixic acid is excreted in human milk. Therefore, the revised language reflects
current knowledge on the bioavailability of the drug. See Traeger A, Peiker G. Excretion of nalidixic acid via
mother’s milk. Arch Toxicol 1980; Suppl. 4, 388-390.
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8
patients under 18 years of age when the potential benefit justifies the potential risk. If arthralgia
occurs, treatment with nalidixic acid should be stopped. (See WARNINGS and ANIMAL
PHARMACOLOGY.)
Geriatric Use
Clinical studies of NegGram® 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. Caution should therefore be observed in using nalidixic acid in elderly patients. 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 PRECAUTIONS, General.)
ADVERSE REACTIONS
Reactions reported after oral administration of NegGram include the following.
CNS effects: drowsiness, weakness, headache, and dizziness and vertigo. Reversible
subjective visual disturbances without objective findings have occurred infrequently (generally
with each dose during the first few days of treatment). These reactions include overbrightness of
lights, change in color perception, difficulty in focusing, decrease in visual acuity, and double
vision. They usually disappeared promptly when dosage was reduced or therapy was
discontinued. Toxic psychosis or brief convulsions have been reported rarely, usually following
excessive doses. In general, the convulsions have occurred in patients with predisposing factors
such as epilepsy or cerebral arteriosclerosis. In infants and children receiving therapeutic doses
of NegGram, increased intracranial pressure with bulging anterior fontanel, papilledema, and
headache has occasionally been observed. A few cases of 6th cranial nerve palsy have been
reported. Although the mechanisms of these reactions are unknown, the signs and symptoms
usually disappeared rapidly with no sequelae when treatment was discontinued.
Gastrointestinal: abdominal pain, nausea, vomiting, and diarrhea.
Allergic: rash, pruritus, urticaria, angioedema, eosinophilia, arthralgia with joint
stiffness and swelling, and anaphylactoid reaction, including anaphylactic shock. Erythema
Multiforme and Stevens-Johnson syndrome have been reported with nalidixic acid and other
drugs in this class. Rash was the most frequently reported adverse reaction. Photosensitivity
reactions consisting of erythema and bullae on exposed skin surfaces usually resolve completely
in 2 weeks to 2 months after NegGram is discontinued; however, bullae may continue to appear
with successive exposures to sunlight or with mild skin trauma for up to 3 months after
discontinuation of drug. (See PRECAUTIONS.)
Other: rarely, cholestasis, paresthesia, metabolic acidosis, thrombocytopenia,
leukopenia, or hemolytic anemia, sometimes associated with glucose 6-phosphate dehydrogenase
deficiency and peripheral neuropathy.
OVERDOSAGE
Manifestations: Toxic psychosis, convulsions, increased intracranial pressure, or
metabolic acidosis may occur in patients taking more than the recommended dosage. Vomiting,
nausea, and lethargy may also occur following overdosage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Treatment: Reactions are short-lived (two to three hours) because the drug is rapidly
excreted. If absorption has occurred, increased fluid administration is advisable and supportive
measures such as oxygen and means of artificial respiration should be available. Although
anticonvulsant therapy has not been used in the few instances of overdosage reported, it may be
indicated in a severe case.
DOSAGE AND ADMINISTRATION
Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent
cations such as iron; multivitamins containing zinc; or Videx® (Didanosine), chewable/buffered
tablets of the pediatric powder for oral solution should not be taken within the two-hour period
before or within the two-hour period after taking nalidixic acid.
Adults. The recommended dosage for initial therapy in adults is 1 g administered four
times daily for one or two weeks (total daily dose, 4 g). For prolonged therapy, the total daily
dose may be reduced to 2 g after the initial treatment period. Underdosage during initial
treatment may predispose to emergence of bacterial resistance.
Pediatric Patients. Until further experience is gained, NegGram should not be
administered to infants younger than three months. Dosage in pediatric patients 12 years of age
and under should be calculated on the basis of body weight. The recommended total daily
dosage for initial therapy is 25 mg/lb/day (55 mg/kg/day), administered in four equally divided
doses. For prolonged therapy, the total daily dose may be reduced to 15 mg/lb/day (33
mg/kg/day). NegGram Suspension or NegGram Caplets of 250 mg may be used. One 250 mg
caplet is equivalent to one teaspoon (5 mL) of the suspension.
HOW SUPPLIED
NegGram Suspension (nalidixic acid, USP) is supplied as:
Suspension (250 mg / 5 mL), raspberry flavored, bottles of 1 pint
(NDC 0024-1318-06)
Store suspension at room temperature up to 25° C (77° F).
ANIMAL PHARMACOLOGY
NegGram (nalidixic acid) and related drugs have been shown to cause arthropathy in
juvenile animals of most species tested. (See WARNINGS.)
Long-term administration of nalidixic acid to rats resulted in retinal degeneration and
cataracts.
Hydroxynalidixic acid, the principal metabolite of NegGram, did not produce any
oculotoxic effects at any dosage level in seven species of animals including three primate
species. However, oral administration of this metabolite in high doses has been shown to have
oculotoxic potential, namely in dogs and cats where it produced retinal degeneration upon
prolonged administration leading, in some cases, to blindness.
In experiments with NegGram itself, little if any such activity could be elicited in either
dogs or cats. Sensitivity to CNS side effects in these species limited the doses of NegGram that
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
could be used; this factor, together with a low conversion rate to the hydroxy metabolite in these
species, may explain the absence of these effects.
Distributed by
Sanofi-Synthelabo Inc.
New York, NY 10016
Revised June 2004
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:10.767850
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17430s028,029,030lbl.pdf', 'application_number': 17430, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
10,988
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1
NSS-9A (O)
NegGram ®
Suspension1
NALIDIXIC ACID
ORAL SUSPENSION1, USP
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
NegGram (nalidixic acid, USP) and other antibacterial drugs, NegGram should be used only to
treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
NegGram, brand of nalidixic acid, is a quinolone antibacterial agent for oral
administration. Nalidixic acid is 1-ethyl-1, 4-dihydro-7-methyl-4-oxo-1, 8-naphthyridine-3-
carboxylic acid. It is a pale yellow, crystalline substance and a very weak organic acid.
Nalidixic acid has the following structural formula:
Inactive Ingredients – Carbomere 934P, FD&C Red #40, Flavor, Parabens, Purified
Water, Saccharin Sodium, Sodium Chloride, Sorbitol Solution.
CLINICAL PHARMACOLOGY
Following oral administration, NegGram is rapidly absorbed from the gastrointestinal
tract, partially metabolized in the liver, and rapidly excreted through the kidneys. Unchanged
nalidixic acid appears in the urine along with an active metabolite, hydroxynalidixic acid, which
has antibacterial activity similar to that of nalidixic acid. Other metabolites include glucuronic
acid conjugates of nalidixic acid and hydroxy nalidixic acid, and the dicarboxylic acid derivative.
The hydroxy metabolite represents 30 percent of the biologically active drug in the blood and 85
percent in the urine. Peak serum levels of active drug average approximately 20 mcg to 40 mcg
per mL (90 percent protein bound), one to two hours after administration of a 1 g dose to a
1 Insert is being revised to make it specific to NegGram Suspension. Previously the insert applied to both NegGram
Caplets and NegGram Suspension.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
fasting normal individual, with a half-life of about 90 minutes. Peak urine levels of active drug
average approximately 150 mcg to 200 mcg per mL, three to four hours after administration,
with a half-life of about six hours. Approximately four percent of NegGram is excreted in the
feces. Traces of nalidixic acid were found in blood and urine of an infant whose mother had
received the drug during the last trimester of pregnancy. (See PRECAUTIONS—Drug
Interactions.)
Microbiology
NegGram has marked antibacterial activity against gram-negative bacteria including
Enterobacter species, Escherichia coli, Morganella Morganii; Proteus Mirabilis, Proteus
vulgaris, and Providencia rettgeri. Pseudomonas species are generally resistant to the drug.
NegGram is bactericidal and is effective over the entire urinary pH range. Conventional
chromosomal resistance to NegGram taken in full dosage has been reported to emerge in
approximately 2 to 14 percent of patients during treatment; however, bacterial resistance to
NegGram has not been shown to be transferable via R factor.
Susceptibility Test
Diffusion Techniques: Quantitative methods that require measurement of zone
diameters give the most precise estimates of antibacterial susceptibility. One such procedure
recommended for use with a disc containing 30 mcg of nalidixic acid is the National Committee
for Clinical Laboratory Standards (NCCLS) approved procedure. Only organisms from urinary
tract infections should be tested. Results of laboratory tests using 30 mcg nalidixic acid discs
should be interpreted using the following criteria:
Zone Diameter (mm) Interpretation
≥19
(S) Susceptible
14-18
(I) Intermediate
≤13
(R) Resistant
Dilution Techniques: Broth and agar dilution methods, such as those recommended by
the NCCLS, may be used to determine the minimum inhibitory concentration (MIC) of nalidixic
acid. MIC test results should be interpreted according to the following criteria:
MIC (mcg/mL)
Interpretation
≤16
(S) Susceptible
≥32
(R) Resistant
For any susceptibility test, a report of "susceptible" indicates that the pathogen is likely to
respond to nalidixic acid therapy. A report of "resistant" indicates that the pathogen is not likely
to respond. A report of "intermediate" generally indicates that the test result is equivocal.
The Quality Control strains should have the following assigned daily ranges for nalidixic
acid:
QC Strains
E. Coli
(ATCC 25922)
Disc Zone Diameter
22-28
MIC (mcg/mL)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
1.0-4.0
INDICATIONS AND USAGE
NegGram (nalidixic acid, USP) is indicated for the treatment of urinary tract infections
caused by susceptible gram-negative microorganisms, including the majority of E. Coli,
Enterobacter species, Klebsiella species, and Proteus species. Disc susceptibility testing with
the 30 mcg disc should be performed prior to administration of the drug, and during treatment if
clinical response warrants.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
NegGram and other antibacterial drugs, NegGram 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
NegGram is contraindicated in patients with known hypersensitivity to nalidixic acid or
to related compounds, infants less than three months of age, and in patients with porphyria or a
history of convulsive disorders. NegGram is contraindicated in patients undergoing concomitant
therapy with melphalan or other related cancer chemotherapeutic alkylating agents because of
serious gastrointestinal toxicity such as hemorrhagic ulcerative colitis or intestinal necrosis.
WARNINGS
Central Nervous System (CNS) effects including convulsions, increased intracranial
pressure, and toxic psychosis have been reported with nalidixic acid therapy. Convulsive
seizures have been reported with other drugs in this class. Quinolones may also cause CNS
stimulation which may lead to tremor, restlessness, lightheadedness, confusion, and
hallucinations. Therefore, nalidixic acid should be used with caution in patients with known or
suspected CNS disorders, such as, cerebral arteriosclerosis or epilepsy, or other factors which
predispose seizures. (See ADVERSE REACTIONS.) If these reactions occur in patients
receiving nalidixic acid, the drug should be discontinued and appropriate measures instituted.
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions, some following
the first dose, have been reported in patients receiving quinolone therapy. Some reactions were
accompanied by cardiovascular collapse, loss of conscious-ness, tingling, pharyngeal or facial
edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity
reactions. Serious anaphylactoid reactions required immediate emergency treatment with
epinephrine. Oxygen, intravenous steroids, and airway management, including intubation,
should be administered as indicated.
Nalidixic acid and other members of the quinolone drug class have been shown to cause
arthropathy in juvenile animals. (See PRECAUTIONS and ANIMAL PHARMACOLOGY.)
Pseudomembranous colitis has been reported with nearly all antibacterial agents,
including quinolones, and may range in severity from mild to life-threatening. Therefore, it is
important to consider this diagnosis in patients who present with diarrhea subsequent to the
administration of antibacterial agents.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Treatment with antibacterial agents alters the normal flora of the colon and may permit
overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one
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 drug
discontinuation 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.
QT interval prolongation/torsades de pointes: Rare cases of torsades de pointes have
been spontaneously reported during post-marketing surveillance in patients receiving quinolones,
including nalidixic acid. These rare cases were associated with one or more of the following
factors: age over 60, female gender, underlying cardiac disease, and/or use of multiple
medications. Nalidixic acid should be avoided in patients with known prolongation of the QT
interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine,
Procainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.2
Peripheral neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy
affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and
weakness have been reported in patients receiving quinolones, including nalidixic acid.
Nalidixic acid should be discontinued if the patient experiences symptoms of neuropathy
including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light
touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to
prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that
required surgical repair or resulted in prolonged disability have been reported in patients
receiving quinolones, including nalidixic acid. Post-marketing surveillance reports indicate that
this risk may be increased in patients receiving concomitant corticosteroids, especially in the
elderly. Nalidixic acid 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
tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after
therapy with quinolones, including nalidixic acid.
PRECAUTIONS
General
Blood counts and renal and liver function tests should be performed periodically if
treatment is continued for more than two weeks. NegGram should be used with caution in
patients with liver disease, epilepsy, or severe cerebral arteriosclerosis. (See WARNINGS.)
While caution should be used in patients with severe renal failure, therapeutic concentrations of
NegGram in the urine, without increased toxicity due to drug accumulation in the blood, have
been observed in patients on full dosage with creatinine clearances as low as 2 mL/minute to 8
mL/minute.
2 The QT interval prolongation/torsades de pointes paragraph is being removed as allowed by the FDA per the
Quinolone Class Labeling
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Moderate to severe phototoxicity reactions have been observed in patients who are
exposed to direct sunlight while receiving NegGram or other members of this drug class.
Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
If bacterial resistance to NegGram emerges during treatment, it usually does so within 48
hours, permitting rapid change to another antimicrobial. Therefore, if the clinical response is
unsatisfactory or if relapse occurs, cultures and sensitivity tests should be repeated.
Underdosage with NegGram during initial treatment (with less than 4 g per day for adults) may
predispose to emergence of bacterial resistance. (See DOSAGE AND ADMINISTRATION.)
Cross-resistance between nalidixic acid and other quinolone derivatives such as oxolinic
acid and cinoxacin has been observed
Caution should be observed in patients with glucose-6-phosphate dehydrogenase
deficiency. (see ADVERSE REACTIONS).
Prescribing NegGram 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 NegGram may be taken with or without meals. Patients should
be advised to drink fluids liberally and not take antacids.
Patients should be advised that quinolones may be associated with hypersensitivity
reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash
or other allergic reactions.
Quinolones may cause dizziness and light-headedness, therefore, patients should know
how they react to NegGram before they operate an automobile or machinery or engage in
activities requiring mental alertness or coordination.
Patients should be advised that quinolones may increase the effects of theophylline and
caffeine. There is a possibility of caffeine accumulation when products containing caffeine are
consumed while taking quinolones. Patients should be advised to avoid excessive sunlight or
artificial ultraviolet light while receiving nalidixic acid and to discontinue therapy if
phototoxicity occurs.
Patients should be advised that convulsions have been reported in patients taking
quinolones, including nalidixic acid, and to notify their physician before taking this drug if there
is a history of this condition. Patients should be advised that mineral supplements, vitamins with
iron or minerals, calcium-, aluminum-, magnesium-based antacids, sucralfate or Videx® ,
(didanosine), chewable/buffered tablets of the pediatric powder for oral solution should not be
taken within the two-hour period before or within the two-hour period after taking nalidixic acid
(see Drug Interactions).
Patients should be advised:
• that nalidixic acid may cause changes in the electrocardiogram (QTc interval
prolongation)
• that nalidixic acid should be avoided in patients receiving class IA (e.g. quinidine,
Procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents
• that nalidixic acid should be used with caution in subjects receiving drugs that affect
the QTc interval such as cisapride, erythromycin, antipsychotics, and tricyclic
antidepressant
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
• to inform their physicians of any personal or family history of QTc prolongation or
proarrhythmic conditions such as hypokalemia, bradycardia or recent myocardial
ischemia
• that peripheral neuropathies have been associated with nalidixic acid use. If
symptoms of peripheral neuropathy including pain, burning, tingling, numbness,
and/or weakness develop, they should discontinue treatment and contact their
physicians.
Patients should be counseled that antibacterial drugs including NegGram should only be
used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
When NegGram 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 NegGram or other antibacterial drugs in the
future.
Drug Interactions
Elevated plasma levels of theophylline have been reported with concomitant quinolone
use. There have been reports of theophylline-related side effects in patients on concomitant
therapy with quinolones and theophylline. Therefore, monitoring of theophylline plasma levels
should be considered and dosage of theophylline adjusted, as required.
Quinolones have been shown to interfere with the metabolism of caffeine. This may lead
to reduced clearance of caffeine and the prolongation of its plasma half-life.
Quinolones, including nalidixic acid, may enhance the effects of the oral anticoagulant
warfarin or its derivatives. When these products are administered concomitantly, prothrombin
time or other suitable coagulation test should be closely monitored.
Since active proliferation of organisms is a necessary condition for its antibacterial
activity, the action of nalidixic acid may be inhibited by the presence of other antibacterial
substances, especially bacteriostatic agents such as tetracycline, chloramphenicol, or
nitrofurantoin, which is antagonistic to nalidixic acid in vitro.
Probenecid inhibits the tubular secretion of nalidixic acid and may reduce its efficacy in
the treatment of urinary tract infections while increasing the risk of systemic side effects.
Serious gastrointestinal toxicity has been associated with the concomitant use of nalidixic
acid and the anti-cancer drug melphalan. (see CONTRAINDICATIONS)
Antacids containing magnesium, aluminum, or calcium; sucralfate or divalent or trivalent
cations such as iron; multivitamins containing zinc; and Videx®, (Didanosine),
chewable/buffered tablets or the pediatric powder for oral solution may substantially interfere
with the absorption of quinolones, resulting in systemic levels considerably lower than desired.
These agents should not be taken within the two-hour period before or within the two-hour
period after nalidixic acid administration.
Elevated serum levels of Cyclosporine have been reported with the concomitant use of
some quinolones and cyclosporine. Therefore, cyclosporine serum levels should be monitored
and appropriate Cyclosporine dosage adjustments made when these drugs are used
concomitantly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Drug Laboratory Test Interactions
When Benedict's or Fehling's solution or Clinitest® Reagent Tablets are used to test the
urine of patients taking NegGram, a false-positive reaction for glucose may be obtained, due to
the liberation of glucuronic acid from the metabolites excreted. However, a colorimetric test for
glucose based on an enzyme reaction (e.g., with Clinistix® Reagent Strips or Tes-Tape® ) does
not give a false-positive reaction to the liberated glucuronic acid.
Incorrect values may be obtained for urinary 17-keto and ketogenic steroids in patients
receiving NegGram, because of an interaction between the drug and the m-dinitrobenzene used
in the usual assay method. In such cases, the Porter-Silber test for 17-hydroxycorticoids may be
used.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In lifetime studies in the rat given nalidixic acid in the diet, there was an increased
incidence of preputial gland neoplasms in the treated males and clitoral gland neoplasms in the
treated females. Studies in mice in which nalidixic acid was administered in the feed for two
years, or was given in the feed for 76 weeks followed by no treatment for 9 weeks, gave
equivocal evidence of carcinogenic activity.
Nalidixic acid was tested in the Ames bacterial mutagenicity test (maximum dose 33
mcg/plate) and the mouse lymphoma assay (L5178Y/TK; maximum dose 100 mcg/mL) with and
without metabolic activation, and results were negative.
Pregnancy: Teratogenic Effects.
Pregnancy Category C
NegGram has been shown to be teratogenic and embryocidal in rats when given in oral
doses six times the human dose. NegGram also prolonged the duration of pregnancy especially
at four times the clinical dose. There are no adequate and well-controlled studies in pregnant
women. Since nalidixic acid, like other drugs in this class, causes arthropathy in immature
animals, NegGram should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. (See WARNINGS and ANIMAL PHARMACOLOGY.)
Nursing Mothers
Since nalidixic acid is excreted in breast milk, it is contraindicated during lactation.3
Because of the potential for serious adverse reactions in nursing infants from NegGram, 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 infants below the age of three months have not been
established.
Usage in Patients Under 18 Years of Age
Toxicological studies have shown that nalidixic acid and related drugs can produce
erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature
animals of most species tested. No such joint lesions have been reported in humans to date.
Nevertheless, until the significance of this finding is clarified, this drug should only be used in
3 There is evidence to show that nalidixic acid is excreted in human milk. Therefore, the revised language reflects
current knowledge on the bioavailability of the drug. See Traeger A, Peiker G. Excretion of nalidixic acid via
mother’s milk. Arch Toxicol 1980; Suppl. 4, 388-390.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
patients under 18 years of age when the potential benefit justifies the potential risk. If arthralgia
occurs, treatment with nalidixic acid should be stopped. (See WARNINGS and ANIMAL
PHARMACOLOGY.)
Geriatric Use
Clinical studies of NegGram® 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. Caution should therefore be observed in using nalidixic acid in elderly patients. 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 PRECAUTIONS, General.)
ADVERSE REACTIONS
Reactions reported after oral administration of NegGram include the following.
CNS effects: drowsiness, weakness, headache, and dizziness and vertigo. Reversible
subjective visual disturbances without objective findings have occurred infrequently (generally
with each dose during the first few days of treatment). These reactions include overbrightness of
lights, change in color perception, difficulty in focusing, decrease in visual acuity, and double
vision. They usually disappeared promptly when dosage was reduced or therapy was
discontinued. Toxic psychosis or brief convulsions have been reported rarely, usually following
excessive doses. In general, the convulsions have occurred in patients with predisposing factors
such as epilepsy or cerebral arteriosclerosis. In infants and children receiving therapeutic doses
of NegGram, increased intracranial pressure with bulging anterior fontanel, papilledema, and
headache has occasionally been observed. A few cases of 6th cranial nerve palsy have been
reported. Although the mechanisms of these reactions are unknown, the signs and symptoms
usually disappeared rapidly with no sequelae when treatment was discontinued.
Gastrointestinal: abdominal pain, nausea, vomiting, and diarrhea.
Allergic: rash, pruritus, urticaria, angioedema, eosinophilia, arthralgia with joint
stiffness and swelling, and anaphylactoid reaction, including anaphylactic shock. Erythema
Multiforme and Stevens-Johnson syndrome have been reported with nalidixic acid and other
drugs in this class. Rash was the most frequently reported adverse reaction. Photosensitivity
reactions consisting of erythema and bullae on exposed skin surfaces usually resolve completely
in 2 weeks to 2 months after NegGram is discontinued; however, bullae may continue to appear
with successive exposures to sunlight or with mild skin trauma for up to 3 months after
discontinuation of drug. (See PRECAUTIONS.)
Other: rarely, cholestasis, paresthesia, metabolic acidosis, thrombocytopenia,
leukopenia, or hemolytic anemia, sometimes associated with glucose 6-phosphate dehydrogenase
deficiency and peripheral neuropathy.
OVERDOSAGE
Manifestations: Toxic psychosis, convulsions, increased intracranial pressure, or
metabolic acidosis may occur in patients taking more than the recommended dosage. Vomiting,
nausea, and lethargy may also occur following overdosage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Treatment: Reactions are short-lived (two to three hours) because the drug is rapidly
excreted. If absorption has occurred, increased fluid administration is advisable and supportive
measures such as oxygen and means of artificial respiration should be available. Although
anticonvulsant therapy has not been used in the few instances of overdosage reported, it may be
indicated in a severe case.
DOSAGE AND ADMINISTRATION
Antacids containing calcium, magnesium, or aluminum; sucralfate; divalent or trivalent
cations such as iron; multivitamins containing zinc; or Videx® (Didanosine), chewable/buffered
tablets of the pediatric powder for oral solution should not be taken within the two-hour period
before or within the two-hour period after taking nalidixic acid.
Adults. The recommended dosage for initial therapy in adults is 1 g administered four
times daily for one or two weeks (total daily dose, 4 g). For prolonged therapy, the total daily
dose may be reduced to 2 g after the initial treatment period. Underdosage during initial
treatment may predispose to emergence of bacterial resistance.
Pediatric Patients. Until further experience is gained, NegGram should not be
administered to infants younger than three months. Dosage in pediatric patients 12 years of age
and under should be calculated on the basis of body weight. The recommended total daily
dosage for initial therapy is 25 mg/lb/day (55 mg/kg/day), administered in four equally divided
doses. For prolonged therapy, the total daily dose may be reduced to 15 mg/lb/day (33
mg/kg/day). NegGram Suspension or NegGram Caplets of 250 mg may be used. One 250 mg
caplet is equivalent to one teaspoon (5 mL) of the suspension.
HOW SUPPLIED
NegGram Suspension (nalidixic acid, USP) is supplied as:
Suspension (250 mg / 5 mL), raspberry flavored, bottles of 1 pint
(NDC 0024-1318-06)
Store suspension at room temperature up to 25° C (77° F).
ANIMAL PHARMACOLOGY
NegGram (nalidixic acid) and related drugs have been shown to cause arthropathy in
juvenile animals of most species tested. (See WARNINGS.)
Long-term administration of nalidixic acid to rats resulted in retinal degeneration and
cataracts.
Hydroxynalidixic acid, the principal metabolite of NegGram, did not produce any
oculotoxic effects at any dosage level in seven species of animals including three primate
species. However, oral administration of this metabolite in high doses has been shown to have
oculotoxic potential, namely in dogs and cats where it produced retinal degeneration upon
prolonged administration leading, in some cases, to blindness.
In experiments with NegGram itself, little if any such activity could be elicited in either
dogs or cats. Sensitivity to CNS side effects in these species limited the doses of NegGram that
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
could be used; this factor, together with a low conversion rate to the hydroxy metabolite in these
species, may explain the absence of these effects.
Distributed by
Sanofi-Synthelabo Inc.
New York, NY 10016
Revised June 2004
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:10.888072
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17430s028,029,030lbl.pdf', 'application_number': 17430, 'submission_type': 'SUPPL ', 'submission_number': 30}
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10,989
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Minipress®
Capsules
(prazosin hydrochloride)
For Oral Use
DESCRIPTION
MINIPRESS® (prazosin hydrochloride), a quinazoline derivative, is the first of a new
chemical class of antihypertensives. It is the hydrochloride salt of
1-(4-amino-6,7-dimethoxy- 2-quinazolinyl)-4-(2-furoyl) piperazine and its structural
formula is:
S
tr
uc
tu
ral
Formu
la
Molecular formula C19H21N5O4•HCl
It is a white, crystalline substance, slightly soluble in water and isotonic saline, and has
a molecular weight of 419.87. Each 1 mg capsule of MINIPRESS for oral use contains
drug equivalent to 1 mg free base.
Inert ingredients in the formulations are: hard gelatin capsules (which may contain
Blue 1, Red 3, Red 28, Red 40, and other inert ingredients); magnesium stearate;
sodium lauryl sulfate; starch; sucrose.
CLINICAL PHARMACOLOGY
The exact mechanism of the hypotensive action of prazosin is unknown. Prazosin
causes a decrease in total peripheral resistance and was originally thought to have a
direct relaxant action on vascular smooth muscle. Recent animal studies, however,
have suggested that the vasodilator effect of prazosin is also related to blockade of
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
postsynaptic alpha-adrenoceptors. The results of dog forelimb experiments demonstrate
that the peripheral vasodilator effect of prazosin is confined mainly to the level of the
resistance vessels (arterioles). Unlike conventional alpha-blockers, the antihypertensive
action of prazosin is usually not accompanied by a reflex tachycardia. Tolerance has not
been observed to develop in long term therapy.
Hemodynamic studies have been carried out in man following acute single dose
administration and during the course of long term maintenance therapy. The results
confirm that the therapeutic effect is a fall in blood pressure unaccompanied by a
clinically significant change in cardiac output, heart rate, renal blood flow and glomerular
filtration rate. There is no measurable negative chronotropic effect.
In clinical studies to date, prazosin hydrochloride has not increased plasma renin
activity.
In man, blood pressure is lowered in both the supine and standing positions. This effect
is most pronounced on the diastolic blood pressure.
Following oral administration, human plasma concentrations reach a peak at about
three hours with a plasma half-life of two to three hours. The drug is highly bound to
plasma protein. Bioavailability studies have demonstrated that the total absorption
relative to the drug in a 20% alcoholic solution is 90%, resulting in peak levels
approximately 65% of that of the drug in solution. Animal studies indicate that prazosin
hydrochloride is extensively metabolized, primarily by demethylation and conjugation,
and excreted mainly via bile and feces. Less extensive human studies suggest similar
metabolism and excretion in man.
In clinical studies in which lipid profiles were followed, there were generally no adverse
changes noted between pre- and post-treatment lipid levels.
INDICATIONS AND USAGE
MINIPRESS is indicated in the treatment of hypertension. It can be used alone or in
combination with other antihypertensive drugs such as diuretics or beta-adrenergic
blocking agents.
CONTRAINDICATIONS
MINIPRESS is contraindicated in patients with known sensitivity to quinazolines,
prazosin, or any of the inert ingredients.
WARNINGS
As with all alpha-blockers, MINIPRESS may cause syncope with sudden loss of
consciousness. In most cases, this is believed to be due to an excessive postural
hypotensive effect, although occasionally the syncopal episode has been
preceded by a bout of severe tachycardia with heart rates of 120–160 beats per
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
minute. Syncopal episodes have usually occurred within 30 to 90 minutes of the
initial dose of the drug; occasionally, they have been reported in association with
rapid dosage increases or the introduction of another antihypertensive drug into
the regimen of a patient taking high doses of MINIPRESS. The incidence of
syncopal episodes is approximately 1% in patients given an initial dose of 2 mg
or greater. Clinical trials conducted during the investigational phase of this drug
suggest that syncopal episodes can be minimized by limiting the initial dose of
the drug to 1 mg, by subsequently increasing the dosage slowly, and by
introducing any additional antihypertensive drugs into the patient’s regimen with
caution (see DOSAGE AND ADMINISTRATION). Hypotension may develop in
patients given MINIPRESS who are also receiving a beta-blocker such as
propranolol.
If syncope occurs, the patient should be placed in the recumbent position and treated
supportively as necessary. This adverse effect is self-limiting and in most cases does
not recur after the initial period of therapy or during subsequent dose titration.
Patients should always be started on the 1 mg capsules of MINIPRESS. The 2 and
5 mg capsules are not indicated for initial therapy.
More common than loss of consciousness are the symptoms often associated with
lowering of the blood pressure, namely, dizziness and lightheadedness. The patient
should be cautioned about these possible adverse effects and advised what measures
to take should they develop. The patient should also be cautioned to avoid situations
where injury could result should syncope occur during the initiation of MINIPRESS
therapy.
PRECAUTIONS
General
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in
some patients treated with alpha-1 blockers. This variant of small pupil syndrome is
characterized by the combination of a flaccid iris that billows in response to
intraoperative irrigation currents, progressive intraoperative miosis despite preoperative
dilation with standard mydriatic drugs, and potential prolapse of the iris toward the
phacoemulsification incisions. The patient’s ophthalmologist should be prepared for
possible modifications to the surgical technique, such as the utilization of iris hooks, iris
dilator rings, or viscoelastic substances. There does not appear to be a benefit of
stopping alpha-1 blocker therapy prior to cataract surgery.
Information for Patients: Dizziness or drowsiness may occur after the first dose of this
medicine. Avoid driving or performing hazardous tasks for the first 24 hours after taking
this medicine or when the dose is increased. Dizziness, lightheadedness, or fainting
may occur, especially when rising from a lying or sitting position. Getting up slowly may
help lessen the problem. These effects may also occur if you drink alcohol, stand for
long periods of time, exercise, or if the weather is hot. While taking MINIPRESS, be
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
careful in the amount of alcohol you drink. Also, use extra care during exercise or hot
weather, or if standing for long periods. Check with your physician if you have any
questions.
Drug Interactions
MINIPRESS has been administered without any adverse drug interaction in limited
clinical experience to date with the following: (1) cardiac glycosides– digitalis and
digoxin; (2) hypoglycemics–insulin, chlorpropamide, phenformin, tolazamide, and
tolbutamide; (3) tranquilizers and sedatives–chlordiazepoxide, diazepam, and
phenobarbital; (4) antigout–allopurinol, colchicine, and probenecid; (5) antiarrhythmics–
procainamide, propranolol (see WARNINGS however), and quinidine; and (6)
analgesics, antipyretics and anti-inflammatories–propoxyphene, aspirin, indomethacin,
and phenylbutazone.
Addition of a diuretic or other antihypertensive agent to MINIPRESS has been shown to
cause an additive hypotensive effect. This effect can be minimized by reducing the
MINIPRESS dose to 1 to 2 mg three times a day, by introducing additional
antihypertensive drugs cautiously, and then by retitrating MINIPRESS based on clinical
response.
Concomitant administration of MINIPRESS with a phosphodiesterase-5 (PDE-5)
inhibitor can result in additive blood pressure lowering effects and symptomatic
hypotension (see DOSAGE AND ADMINISTRATION).
Drug/Laboratory Test Interactions
In a study on five patients given from 12 to 24 mg of prazosin per day for 10 to 14 days,
there was an average increase of 42% in the urinary metabolite of norepinephrine and
an average increase in urinary VMA of 17%. Therefore, false positive results may occur
in screening tests for pheochromocytoma in patients who are being treated with
prazosin. If an elevated VMA is found, prazosin should be discontinued and the patient
retested after a month.
Laboratory Tests
In clinical studies in which lipid profiles were followed, there were generally no adverse
changes noted between pre- and post-treatment lipid levels.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenic potential
was demonstrated in an 18 month study in rats with MINIPRESS at dose levels more
than 225 times the usual maximum recommended human dose of 20 mg per day.
MINIPRESS was not mutagenic in in vivo genetic toxicology studies. In a fertility and
general reproductive performance study in rats, both males and females, treated with
75 mg/kg (225 times the usual maximum recommended human dose), demonstrated
decreased fertility, while those treated with 25 mg/kg (75 times the usual maximum
recommended human dose) did not.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In chronic studies (one year or more) of MINIPRESS in rats and dogs, testicular
changes consisting of atrophy and necrosis occurred at 25 mg/kg/day (75 times the
usual maximum recommended human dose). No testicular changes were seen in rats
or dogs at 10 mg/kg/day (30 times the usual maximum recommended human dose). In
view of the testicular changes observed in animals, 105 patients on long term
MINIPRESS therapy were monitored for 17-ketosteroid excretion and no changes
indicating a drug effect were observed. In addition, 27 males on MINIPRESS for up to
51 months did not have changes in sperm morphology suggestive of drug effect.
Usage in Pregnancy: Pregnancy Category C. MINIPRESS has been shown to be
associated with decreased litter size at birth, 1, 4, and 21 days of age in rats when given
doses more than 225 times the usual maximum recommended human dose. No
evidence of drug-related external, visceral, or skeletal fetal abnormalities were
observed. No drug-related external, visceral, or skeletal abnormalities were observed in
fetuses of pregnant rabbits and pregnant monkeys at doses more than 225 times and
12 times the usual maximum recommended human dose, respectively.
The use of prazosin and a beta-blocker for the control of severe hypertension in
44 pregnant women revealed no drug-related fetal abnormalities or adverse effects.
Therapy with prazosin was continued for as long as 14 weeks.1
Prazosin has also been used alone or in combination with other hypotensive agents in
severe hypertension of pregnancy by other investigators. No fetal or neonatal
abnormalities have been reported with the use of prazosin.2
There are no adequate and well controlled studies which establish the safety of
MINIPRESS in pregnant women. MINIPRESS should be used during pregnancy only if
the potential benefit justifies the potential risk to the mother and fetus.
Nursing Mothers: MINIPRESS has been shown to be excreted in small amounts in
human milk. Caution should be exercised when MINIPRESS is administered to a
nursing woman.
Usage in Children: Safety and effectiveness in children have not been established.
ADVERSE REACTIONS
Clinical trials were conducted on more than 900 patients. During these trials and
subsequent marketing experience, the most frequent reactions associated with
MINIPRESS therapy are: dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of
energy 6.9%, weakness 6.5%, palpitations 5.3%, and nausea 4.9%. In most instances,
side effects have disappeared with continued therapy or have been tolerated with no
decrease in dose of drug.
Less frequent adverse reactions which are reported to occur in 1–4% of patients are:
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gastrointestinal: vomiting, diarrhea, constipation.
Cardiovascular: edema, orthostatic hypotension, dyspnea, syncope.
Central Nervous System: vertigo, depression, nervousness.
Dermatologic: rash.
Genitourinary: urinary frequency.
EENT: blurred vision, reddened sclera, epistaxis, dry mouth, nasal congestion.
In addition, fewer than 1% of patients have reported the following (in some instances,
exact causal relationships have not been established):
Gastrointestinal: abdominal discomfort and/or pain, liver function abnormalities,
pancreatitis.
Cardiovascular: tachycardia.
Central Nervous System: paresthesia, hallucinations.
Dermatologic: pruritus, alopecia, lichen planus.
Genitourinary: incontinence, impotence, priapism.
EENT: tinnitus.
Other: diaphoresis, fever, positive ANA titer, arthralgia.
Single reports of pigmentary mottling and serous retinopathy, and a few reports of
cataract development or disappearance have been reported. In these instances, the
exact causal relationship has not been established because the baseline observations
were frequently inadequate.
In more specific slit-lamp and funduscopic studies, which included adequate baseline
examinations, no drug-related abnormal ophthalmological findings have been reported.
Literature reports exist associating MINIPRESS therapy with a worsening of pre-existing
narcolepsy. A causal relationship is uncertain in these cases.
In post-marketing experience, the following adverse events have been reported:
Autonomic Nervous System: flushing.
Body As A Whole: allergic reaction, asthenia, malaise, pain.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cardiovascular, General: angina pectoris, hypotension.
Endocrine: gynecomastia.
Heart Rate/Rhythm: bradycardia.
Psychiatric: insomnia.
Skin/Appendages: urticaria.
Vascular (Extracardiac): vasculitis.
Vision: eye pain.
Special Senses: During cataract surgery, a variant of small pupil syndrome known as
Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha
1 blocker therapy (see PRECAUTIONS).
OVERDOSAGE
Accidental ingestion of at least 50 mg of MINIPRESS in a two year old child resulted in
profound drowsiness and depressed reflexes. No decrease in blood pressure was
noted. Recovery was uneventful.
Should overdosage lead to hypotension, support of the cardiovascular system is of first
importance. Restoration of blood pressure and normalization of heart rate may be
accomplished by keeping the patient in the supine position. If this measure is
inadequate, shock should first be treated with volume expanders. If necessary,
vasopressors should then be used. Renal function should be monitored and supported
as needed. Laboratory data indicate MINIPRESS is not dialysable because it is protein
bound.
DOSAGE AND ADMINISTRATION
The dose of MINIPRESS should be adjusted according to the patient’s individual blood
pressure response. The following is a guide to its administration:
Initial Dose
1 mg two or three times a day (see WARNINGS.)
Maintenance Dose
Dosage may be slowly increased to a total daily dose of 20 mg given in divided doses.
The therapeutic dosages most commonly employed have ranged from 6 mg to 15 mg
daily given in divided doses. Doses higher than 20 mg usually do not increase efficacy,
however a few patients may benefit from further increases up to a daily dose of 40 mg
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
given in divided doses. After initial titration some patients can be maintained adequately
on a twice daily dosage regimen.
Use With Other Drugs
When adding a diuretic or other antihypertensive agent, the dose of MINIPRESS should
be reduced to 1 mg or 2 mg three times a day and retitration then carried out.
Concomitant administration of MINIPRESS with a PDE-5 inhibitor can result in additive
blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5
inhibitor therapy should be initiated at the lowest dose in patients taking MINIPRESS.
HOW SUPPLIED
Capsule
Capsule
Package
Strength
Color
Code
NDC
Size
MINIPRESS® 1
mg
White
431
0069-4310-71
250’s
MINIPRESS® 2
mg
Pink and
White
437
0069-4370-71
250’s
MINIPRESS® 5
mg
Blue and
White
438
0069-4380-71
250’s
References
1. Lubbe, WF, and Hodge, JV: New Zealand Med J, 94 (691) 169–172, 1981.
2. Davey, DA, and Dommisse, J: S.A. Med J, Oct. 4, 1980 (551–556).
Rx only
Distributed by Company logo
Pfizer Labs
Division of Pfizer Inc, NY, NY 10017
LAB-0212-4.0
July 2009
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:11.213513
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017442s035lbl.pdf', 'application_number': 17442, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
10,990
|
Minipress®
Capsules
(prazosin hydrochloride)
For Oral Use
DESCRIPTION
MINIPRESS® (prazosin hydrochloride), a quinazoline derivative, is the first of a new chemical
class of antihypertensives. It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy
2-quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is:
struc
tural
f
or
mu
la
Molecular formula C19H21N5O4 HCl
It is a white, crystalline substance, slightly soluble in water and isotonic saline, and has a
molecular weight of 419.87. Each 1 mg capsule of MINIPRESS for oral use contains drug
equivalent to 1 mg free base.
Inert ingredients in the formulations are: hard gelatin capsules (which may contain Blue 1,
Red 3, Red 28, Red 40, and other inert ingredients); magnesium stearate; sodium lauryl sulfate;
starch; sucrose.
CLINICAL PHARMACOLOGY
The exact mechanism of the hypotensive action of prazosin is unknown. Prazosin causes a
decrease in total peripheral resistance and was originally thought to have a direct relaxant action
on vascular smooth muscle. Recent animal studies, however, have suggested that the vasodilator
effect of prazosin is also related to blockade of postsynaptic alpha-adrenoceptors. The results of
dog forelimb experiments demonstrate that the peripheral vasodilator effect of prazosin is
1
Reference ID: 3401095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
confined mainly to the level of the resistance vessels (arterioles). Unlike conventional
alpha-blockers, the antihypertensive action of prazosin is usually not accompanied by a reflex
tachycardia. Tolerance has not been observed to develop in long term therapy.
Hemodynamic studies have been carried out in man following acute single dose administration
and during the course of long term maintenance therapy. The results confirm that the therapeutic
effect is a fall in blood pressure unaccompanied by a clinically significant change in cardiac
output, heart rate, renal blood flow and glomerular filtration rate. There is no measurable
negative chronotropic effect.
In clinical studies to date, prazosin hydrochloride has not increased plasma renin activity.
In man, blood pressure is lowered in both the supine and standing positions. This effect is most
pronounced on the diastolic blood pressure.
Following oral administration, human plasma concentrations reach a peak at about three hours
with a plasma half-life of two to three hours. The drug is highly bound to plasma protein.
Bioavailability studies have demonstrated that the total absorption relative to the drug in a 20%
alcoholic solution is 90%, resulting in peak levels approximately 65% of that of the drug in
solution. Animal studies indicate that prazosin hydrochloride is extensively metabolized,
primarily by demethylation and conjugation, and excreted mainly via bile and feces. Less
extensive human studies suggest similar metabolism and excretion in man.
In clinical studies in which lipid profiles were followed, there were generally no adverse changes
noted between pre- and post-treatment lipid levels.
INDICATIONS AND USAGE
MINIPRESS is indicated for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive
drugs from a wide variety of pharmacologic classes, including this drug.
Control of high blood pressure should be part of comprehensive cardiovascular risk management,
including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking
cessation, exercise, and limited sodium intake. Many patients will require more than one drug to
achieve blood pressure goals. For specific advice on goals and management, see published
guidelines, such as those of the National High Blood Pressure Education Program’s Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
(JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
other pharmacologic property of the drugs, that is largely responsible for those benefits. The
largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of
2
Reference ID: 3401095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen
regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the absolute benefit is
greater in patients who are at higher risk independent of their hypertension (for example, patients
with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects (e.g.,
on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
therapy.
MINIPRESS can be used alone or in combination with other antihypertensive drugs such as
diuretics or beta-adrenergic blocking agents.
CONTRAINDICATIONS
MINIPRESS is contraindicated in patients with known sensitivity to quinazolines, prazosin, or
any of the inert ingredients.
WARNINGS
As with all alpha-blockers, MINIPRESS may cause syncope with sudden loss of
consciousness. In most cases, this is believed to be due to an excessive postural hypotensive
effect, although occasionally the syncopal episode has been preceded by a bout of severe
tachycardia with heart rates of 120–160 beats per minute. Syncopal episodes have usually
occurred within 30 to 90 minutes of the initial dose of the drug; occasionally, they have
been reported in association with rapid dosage increases or the introduction of another
antihypertensive drug into the regimen of a patient taking high doses of MINIPRESS. The
incidence of syncopal episodes is approximately 1% in patients given an initial dose of 2 mg
or greater. Clinical trials conducted during the investigational phase of this drug suggest
that syncopal episodes can be minimized by limiting the initial dose of the drug to 1 mg, by
subsequently increasing the dosage slowly, and by introducing any additional
antihypertensive drugs into the patient’s regimen with caution (see DOSAGE AND
ADMINISTRATION). Hypotension may develop in patients given MINIPRESS who are
also receiving a beta-blocker such as propranolol.
If syncope occurs, the patient should be placed in the recumbent position and treated
supportively as necessary. This adverse effect is self-limiting and in most cases does not recur
after the initial period of therapy or during subsequent dose titration.
3
Reference ID: 3401095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should always be started on the 1 mg capsules of MINIPRESS. The 2 and 5 mg capsules
are not indicated for initial therapy.
More common than loss of consciousness are the symptoms often associated with lowering of
the blood pressure, namely, dizziness and lightheadedness. The patient should be cautioned
about these possible adverse effects and advised what measures to take should they develop. The
patient should also be cautioned to avoid situations where injury could result should syncope
occur during the initiation of MINIPRESS therapy.
PRECAUTIONS
General
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some
patients treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by
the combination of a flaccid iris that billows in response to intraoperative irrigation currents,
progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs,
and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s
ophthalmologist should be prepared for possible modifications to the surgical technique, such as
the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to
be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.
Information for Patients:
Dizziness or drowsiness may occur after the first dose of this medicine. Avoid driving or
performing hazardous tasks for the first 24 hours after taking this medicine or when the dose is
increased. Dizziness, lightheadedness, or fainting may occur, especially when rising from a lying
or sitting position. Getting up slowly may help lessen the problem. These effects may also occur
if you drink alcohol, stand for long periods of time, exercise, or if the weather is hot. While
taking MINIPRESS, be careful in the amount of alcohol you drink. Also, use extra care during
exercise or hot weather, or if standing for long periods. Check with your physician if you have
any questions.
Drug Interactions
MINIPRESS has been administered without any adverse drug interaction in limited clinical
experience to date with the following: (1) cardiac glycosides– digitalis and digoxin; (2)
hypoglycemics–insulin, chlorpropamide, phenformin, tolazamide, and tolbutamide; (3)
tranquilizers and sedatives–chlordiazepoxide, diazepam, and phenobarbital; (4) antigout–
allopurinol, colchicine, and probenecid; (5) antiarrhythmics–procainamide, propranolol (see
WARNINGS however), and quinidine; and (6) analgesics, antipyretics and anti-inflammatories–
propoxyphene, aspirin, indomethacin, and phenylbutazone.
Addition of a diuretic or other antihypertensive agent to MINIPRESS has been shown to cause
an additive hypotensive effect. This effect can be minimized by reducing the MINIPRESS dose
to 1 to 2 mg three times a day, by introducing additional antihypertensive drugs cautiously, and
then by retitrating MINIPRESS based on clinical response.
4
Reference ID: 3401095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Concomitant administration of MINIPRESS with a phosphodiesterase-5 (PDE-5) inhibitor can
result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE
AND ADMINISTRATION).
Drug/Laboratory Test Interactions
In a study on five patients given from 12 to 24 mg of prazosin per day for 10 to 14 days, there
was an average increase of 42% in the urinary metabolite of norepinephrine and an average
increase in urinary VMA of 17%. Therefore, false positive results may occur in screening tests
for pheochromocytoma in patients who are being treated with prazosin. If an elevated VMA is
found, prazosin should be discontinued and the patient retested after a month.
Laboratory Tests
In clinical studies in which lipid profiles were followed, there were generally no adverse changes
noted between pre- and post-treatment lipid levels.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No carcinogenic potential was demonstrated in an 18 month study in rats with MINIPRESS at
dose levels more than 225 times the usual maximum recommended human dose of 20 mg per
day. MINIPRESS was not mutagenic in in vivo genetic toxicology studies. In a fertility and
general reproductive performance study in rats, both males and females, treated with 75 mg/kg
(225 times the usual maximum recommended human dose), demonstrated decreased fertility,
while those treated with 25 mg/kg (75 times the usual maximum recommended human dose) did
not.
In chronic studies (one year or more) of MINIPRESS in rats and dogs, testicular changes
consisting of atrophy and necrosis occurred at 25 mg/kg/day (75 times the usual maximum
recommended human dose). No testicular changes were seen in rats or dogs at 10 mg/kg/day
(30 times the usual maximum recommended human dose). In view of the testicular changes
observed in animals, 105 patients on long term MINIPRESS therapy were monitored for
17-ketosteroid excretion and no changes indicating a drug effect were observed. In addition,
27 males on MINIPRESS for up to 51 months did not have changes in sperm morphology
suggestive of drug effect.
Usage in Pregnancy:
Pregnancy Category C. MINIPRESS has been shown to be associated with decreased litter size
at birth, 1, 4, and 21 days of age in rats when given doses more than 225 times the usual
maximum recommended human dose. No evidence of drug-related external, visceral, or skeletal
fetal abnormalities were observed. No drug-related external, visceral, or skeletal abnormalities
were observed in fetuses of pregnant rabbits and pregnant monkeys at doses more than 225 times
and 12 times the usual maximum recommended human dose, respectively.
The use of prazosin and a beta-blocker for the control of severe hypertension in 44 pregnant
women revealed no drug-related fetal abnormalities or adverse effects. Therapy with prazosin
was continued for as long as 14 weeks.1
5
Reference ID: 3401095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Prazosin has also been used alone or in combination with other hypotensive agents in severe
hypertension of pregnancy by other investigators. No fetal or neonatal abnormalities have been
reported with the use of prazosin.2
There are no adequate and well controlled studies which establish the safety of MINIPRESS in
pregnant women. MINIPRESS should be used during pregnancy only if the potential benefit
justifies the potential risk to the mother and fetus.
Nursing Mothers:
MINIPRESS has been shown to be excreted in small amounts in human milk. Caution should be
exercised when MINIPRESS is administered to a nursing woman.
Usage in Children: Safety and effectiveness in children have not been established.
ADVERSE REACTIONS
Clinical trials were conducted on more than 900 patients. During these trials and subsequent
marketing experience, the most frequent reactions associated with MINIPRESS therapy are:
dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of energy 6.9%, weakness 6.5%,
palpitations 5.3%, and nausea 4.9%. In most instances, side effects have disappeared with
continued therapy or have been tolerated with no decrease in dose of drug.
Less frequent adverse reactions which are reported to occur in 1–4% of patients are:
Gastrointestinal: vomiting, diarrhea, constipation.
Cardiovascular: edema, orthostatic hypotension, dyspnea, syncope.
Central Nervous System: vertigo, depression, nervousness.
Dermatologic: rash.
Genitourinary: urinary frequency.
EENT: blurred vision, reddened sclera, epistaxis, dry mouth, nasal congestion.
In addition, fewer than 1% of patients have reported the following (in some instances, exact
causal relationships have not been established):
Gastrointestinal: abdominal discomfort and/or pain, liver function abnormalities, pancreatitis.
Cardiovascular: tachycardia.
Central Nervous System: paresthesia, hallucinations.
6
Reference ID: 3401095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dermatologic: pruritus, alopecia, lichen planus.
Genitourinary: incontinence, impotence, priapism.
EENT: tinnitus.
Other: diaphoresis, fever, positive ANA titer, arthralgia.
Single reports of pigmentary mottling and serous retinopathy, and a few reports of cataract
development or disappearance have been reported. In these instances, the exact causal
relationship has not been established because the baseline observations were frequently
inadequate.
In more specific slit-lamp and funduscopic studies, which included adequate baseline
examinations, no drug-related abnormal ophthalmological findings have been reported.
Literature reports exist associating MINIPRESS therapy with a worsening of pre-existing
narcolepsy. A causal relationship is uncertain in these cases.
In post-marketing experience, the following adverse events have been reported:
Autonomic Nervous System: flushing.
Body As A Whole: allergic reaction, asthenia, malaise, pain.
Cardiovascular, General: angina pectoris, hypotension.
Endocrine: gynecomastia.
Heart Rate/Rhythm: bradycardia.
Psychiatric: insomnia.
Skin/Appendages: urticaria.
Vascular (Extracardiac): vasculitis.
Vision: eye pain.
7
Reference ID: 3401095
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Special Senses: During cataract surgery, a variant of small pupil syndrome known as
Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha-1 blocker
therapy (see PRECAUTIONS).
OVERDOSAGE
Accidental ingestion of at least 50 mg of MINIPRESS in a two year old child resulted in
profound drowsiness and depressed reflexes. No decrease in blood pressure was noted. Recovery
was uneventful.
Should overdosage lead to hypotension, support of the cardiovascular system is of first
importance. Restoration of blood pressure and normalization of heart rate may be accomplished
by keeping the patient in the supine position. If this measure is inadequate, shock should first be
treated with volume expanders. If necessary, vasopressors should then be used. Renal function
should be monitored and supported as needed. Laboratory data indicate MINIPRESS is not
dialysable because it is protein bound.
DOSAGE AND ADMINISTRATION
The dose of MINIPRESS should be adjusted according to the patient’s individual blood pressure
response. The following is a guide to its administration:
Initial Dose
1 mg two or three times a day (see WARNINGS.)
Maintenance Dose
Dosage may be slowly increased to a total daily dose of 20 mg given in divided doses. The
therapeutic dosages most commonly employed have ranged from 6 mg to 15 mg daily given in
divided doses. Doses higher than 20 mg usually do not increase efficacy, however a few patients
may benefit from further increases up to a daily dose of 40 mg given in divided doses. After
initial titration some patients can be maintained adequately on a twice daily dosage regimen.
Use With Other Drugs
When adding a diuretic or other antihypertensive agent, the dose of MINIPRESS should be
reduced to 1 mg or 2 mg three times a day and retitration then carried out.
Concomitant administration of MINIPRESS with a PDE-5 inhibitor can result in additive blood
pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy
should be initiated at the lowest dose in patients taking MINIPRESS.
8
Reference ID: 3401095
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Capsule
Capsule
Package
Strength
Color
Code
NDC
Size
MINIPRESS® 1 mg
White
431
0069-4310-71
250’s
MINIPRESS® 2 mg
Pink and
White
437
0069-4370-71
250’s
MINIPRESS® 5 mg
Blue and
White
438
0069-4380-71
250’s
References
1. Lubbe, WF, and Hodge, JV: New Zealand Med J, 94 (691) 169–172, 1981.
2. Davey, DA, and Dommisse, J: S.A. Med J, Oct. 4, 1980 (551–556).
Rx only
Distributed by Pfizer
Pfizer Labs
Division of Pfizer Inc, NY, NY 10017
LAB-0212-4.x
November 2013
9
Reference ID: 3401095
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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/2013/017442s041lbl.pdf', 'application_number': 17442, 'submission_type': 'SUPPL ', 'submission_number': 41}
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Dantrium (dantrolene sodium) capsules
Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used
in conditions other than those recommended. Symptomatic hepatitis (fatal and non
fatal) has been reported at various dose levels of the drug. The incidence reported in
patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or
more per day. Even sporadic short courses of these higher dose levels within a
treatment regimen markedly increased the risk of serious hepatic injury. Liver
dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme
elevations) has been observed in patients exposed to Dantrium for varying periods of
time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has
been most frequently observed between the third and twelfth month of therapy. The risk
of hepatic injury appears to be greater in females, in patients over 35 years of age, and
in patients taking other medication(s) in addition to Dantrium (dantrolene sodium).
Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in
elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (see Geriatric Use subsection). Dantrium should be
used only in conjunction with appropriate monitoring of hepatic function including
frequent determination of SGOT or SGPT. If no observable benefit is derived from the
administration of Dantrium after a total of 45 days, therapy should be discontinued. The
lowest possible effective dose for the individual patient should be prescribed.
DESCRIPTION
The chemical formula of Dantrium (dantrolene sodium) is hydrated 1-[[[5-(4-nitrophenyl)-2
furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt. It is an orange powder, slightly
soluble in water, but due to its slightly acidic nature the solubility increases somewhat in alkaline
solution. The anhydrous salt has a molecular weight of 336. The hydrated salt contains
approximately 15% water (3-1/2 moles) and has a molecular weight of 399. The structural
formula for the hydrated salt is:
stru
ctu
ra
l
fo
rmula
Dantrium is supplied in capsules of 25 mg, 50 mg, and 100 mg.
Inactive Ingredients: Each capsule contains edible black ink, FD&C Yellow No.6, gelatin,
lactose, magnesium stearate, starch, synthetic iron oxide red, synthetic iron oxide yellow, talc
and titanium dioxide.,
CLINICAL PHARMACOLOGY
In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by
affecting the contractile response of the skeletal muscle at a site beyond the myoneural junction,
directly on the muscle itself. In skeletal muscle, Dantrium dissociates the excitation-contraction
coupling, probably by interfering with the release of Ca++ from the sarcoplasmic reticulum. This
effect appears to be more pronounced in fast muscle fibers as compared to slow ones, but
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 8
generally affects both. A central nervous system effect occurs, with drowsiness, dizziness, and
generalized weakness occasionally present. Although Dantrium does not appear to directly
affect the CNS, the extent of its indirect effect is unknown. The absorption of Dantrium after
oral administration in humans is incomplete and slow but consistent, and dose-related blood
levels are obtained. The duration and intensity of skeletal muscle relaxation is related to the
dosage and blood levels. The mean biologic half-life of Dantrium in adults is 8.7 hours after a
100-mg dose. Specific metabolic pathways in the degradation and elimination of Dantrium in
human subjects have been established. Metabolic patterns are similar in adults and pediatric
patients. In addition to the parent compound, dantrolene, which is found in measurable
amounts in blood and urine, the major metabolites noted in body fluids are the 5-hydroxy analog
and the acetamido analog. Since Dantrium is probably metabolized by hepatic microsomal
enzymes, enhancement of its metabolism by other drugs is possible. However, neither
phenobarbital nor diazepam appears to affect Dantrium metabolism.
Clinical experience in the management of fulminant human malignant hyperthermia, as well as
experiments conducted in malignant hyperthermia susceptible swine, have revealed that the
administration of intravenous dantrolene, combined with indicated supportive measures, is
effective in reversing the hypermetabolic process of malignant hyperthermia. Known
differences between human and swine malignant hyperthermia are minor. The prophylactic
administration of oral or intravenous dantrolene to malignant hyperthermia susceptible swine will
attenuate or prevent the development of signs of malignant hyperthermia in a manner
dependent upon the dosage of dantrolene administered and the intensity of the malignant
hyperthermia triggering stimulus. Limited clinical experience with the administration of oral
dantrolene to patients judged malignant hyperthermia susceptible, when combined with clinical
experience in the use of intravenous dantrolene for the treatment of malignant hyperthermia and
data derived from the above cited animal model experiments, suggests that oral dantrolene will
also attenuate or prevent the development of signs of human malignant hyperthermia, provided
that currently accepted practices in the management of such patients are adhered to (see
INDICATIONS AND USAGE); intravenous dantrolene should also be available for use should
the signs of malignant hyperthermia appear.
INDICATIONS AND USAGE
In Chronic Spasticity: Dantrium is indicated in controlling the manifestations of clinical
spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral
palsy, or multiple sclerosis). It is of particular benefit to the patient whose functional
rehabilitation has been retarded by the sequelae of spasticity. Such patients must have
presumably reversible spasticity where relief of spasticity will aid in restoring residual function.
Dantrium is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic
disorders.
If improvement occurs, it will ordinarily occur within the dosage titration (see DOSAGE AND
ADMINISTRATION), and will be manifested by a decrease in the severity of spasticity and the
ability to resume a daily function not quite attainable without Dantrium.
Occasionally, subtle but meaningful improvement in spasticity may occur with Dantrium
therapy. In such instances, information regarding improvement should be solicited from the
patient and those who are in constant daily contact and attendance with him. Brief withdrawal
of Dantrium for a period of 2 to 4 days will frequently demonstrate exacerbation of the
manifestations of spasticity and may serve to confirm a clinical impression.
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 9
A decision to continue the administration of Dantrium on a long-term basis is justified if
introduction of the drug into the patient's regimen:
produces a significant reduction in painful and/or disabling spasticity such as clonus, or
permits a significant reduction in the intensity and/or degree of nursing care
required, or rids the patient of any annoying manifestation of spasticity considered
important by the patient himself.
In Malignant Hyperthermia: Oral Dantrium is also indicated preoperatively to prevent or
attenuate the development of signs of malignant hyperthermia in known, or strongly suspect,
malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Currently
accepted clinical practices in the management of such patients must still be adhered to (careful
monitoring for early signs of malignant hyperthermia, minimizing exposure to triggering
mechanisms and prompt use of intravenous dantrolene sodium and indicated supportive
measures should signs of malignant hyperthermia appear); see also the package insert for
Dantrium® (dantrolene sodium) Intravenous.
Oral Dantrium should be administered following a malignant hyperthermic crisis to prevent
recurrence of the signs of malignant hyperthermia.
CONTRAINDICATIONS
Active hepatic disease, such as hepatitis and cirrhosis, is a contraindication for use of
Dantrium. Dantrium is contraindicated where spasticity is utilized to sustain upright posture
and balance in locomotion or whenever spasticity is utilized to obtain or maintain increased
function.
WARNINGS
It is important to recognize that fatal and non-fatal liver disorders of an idiosyncratic or
hypersensitivity type may occur with Dantrium therapy.
At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT, SGPT,
alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing
liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility
that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility
has not yet been established.
Liver function studies (e.g., SGOT or SGPT) should be performed at appropriate intervals during
Dantrium therapy. If such studies reveal abnormal values, therapy should generally be
discontinued. Only where benefits of the drug have been of major importance to the patient,
should reinitiation or continuation of therapy be considered. Some patients have revealed a
return to normal laboratory values in the face of continued therapy while others have not.
If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or
jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early,
the abnormalities in liver function characteristically have reverted to normal when the drug was
discontinued.
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 10
Dantrium therapy has been reinstituted in a few patients who have developed clinical and/or
laboratory evidence of hepatocellular injury. If such reinstitution of therapy is done, it should be
attempted only in patients who clearly need Dantrium and only after previous symptoms and
laboratory abnormalities have cleared. The patient should be hospitalized and the drug should
be restarted in very small and gradually increasing doses. Laboratory monitoring should be
frequent and the drug should be withdrawn immediately if there is any indication of recurrent
liver involvement. Some patients have reacted with unmistakable signs of liver abnormality
upon administration of a challenge dose, while others have not.
Dantrium should be used with particular caution in females and in patients over 35 years of age
in view of apparent greater likelihood of drug-induced, potentially fatal, hepatocellular disease in
these groups. Spontaneous reports suggest a higher proportion of hepatic events with fatal
outcome in elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (see Geriatric Use subsection).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term safety of Dantrium in
humans has not been established. Chronic studies in rats, dogs, and monkeys at dosages
greater than 30 mg/kg/day showed growth or weight depression and signs of hepatopathy and
possible occlusion nephropathy, all of which were reversible upon cessation of treatment.
Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30,
and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumors
compared with concurrent controls.At the highest dose level, there was an increase in the
incidence of benign lymphatic neoplasms. In a 30-month study at the same dose levels also in
Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary
neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic
lymphangiomas and hepatic angiosarcomas.
The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related
reduction in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR
mice revealed no evidence of carcinogenic activity.
Carcinogenicity in humans cannot be fully excluded, so that this possible risk of chronic
administration must be weighed against the benefits of the drug (i.e., after a brief trial) for the
individual patient.
Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial
mutagenesis assay in the presence and absence of a liver activating system.
Pregnancy: Pregnancy Category C: Pregnancy Category C: Adequate animal reproduction
studies have not been conducted with Dantrium. It is also not known whether Dantrium can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Dantrium should be given to a pregnant woman only if clearly needed.
Labor and Delivery: In one non-randomized open-label study, 21 term pregnant patients
received prophylactic oral Dantrium 100 mg per day for 2 to 10 days prior to delivery.
Dantrolene readily crossed the placenta with maternal and fetal whole blood levels
approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days
before declining sharply. No neonatal respiratory and neuromuscular side effects were detected
Reference ID: 3100954
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NDA 17443/S-/S-043/S-046/S-048/S-049
Page 11
at low dose. More data, at higher doses, are needed before more definitive conclusions can be
made.
Nursing Mothers: Dantrium should not be used in nursing mothers.
Usage in Pediatric Patients: The long-term safety of Dantrium in pediatric patients under the
age of 5 years has not been established. Because of the possibility that adverse effects of the
drug could become apparent only after many years, a benefit-risk consideration of the long-term
use of Dantrium is particularly important in pediatric patients.
Geriatric Use: Clinical studies of Dantrium 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 the literature 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. As with all patients receiving Dantrium, it is
recommended that elderly patients receive the lowest dose compatible with the optimal
response. Spontaneous reports suggest a higher proportion of hepatic events with fatal
outcome in elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (for hepatotoxicity details and its management see Black
Box and Warnings Sections).
Drug Interactions: Drowsiness may occur with Dantrium therapy, and the concomitant
administration of CNS depressants such as sedatives and tranquilizing agents may result in
further drowsiness.
While a definite drug interaction with estrogen therapy has not yet been established, caution
should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred
more often in women over 35 years of age receiving concomitant estrogen therapy.
Cardiovascular collapse in patients treated simultaneously with verapamil and dantrolene
sodium is rare. The combination of therapeutic doses of intravenous dantrolene sodium and
verapamil in halothane/-chloralose anesthetized swine has resulted in ventricular fibrillation
and cardiovascular collapse in association with marked hyperkalemia. Until the relevance of
these findings to humans is established, the combination of dantrolene sodium and calcium
channel blockers is not recommended during the management of malignant hyperthermia.
Administration of Dantrium may potentiate vecuronium-induced neuromuscular block.
PRECAUTIONS
Dantrium should be used with caution in patients with impaired pulmonary function, particularly
those with obstructive pulmonary disease, and in patients with severely impaired cardiac
function due to myocardial disease. Dantrium is associated with pleural effusion with associated
eosinophilia. It should be used with caution in patients with a history of previous liver disease or
dysfunction (see WARNINGS).
Reference ID: 3100954
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Page 12
Information for Patients: Patients should be cautioned against driving a motor vehicle or
participating in hazardous occupations while taking Dantrium. Caution should be exercised in
the concomitant administration of tranquilizing agents.
Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about
exposure to sunlight while taking it.
ADVERSE REACTIONS
The most frequently occurring side effects of Dantrium have been drowsiness, dizziness,
weakness, general malaise, fatigue, and diarrhea. These are generally transient, occurring
early in treatment, and can often be obviated by beginning with a low dose and increasing
dosage gradually until an optimal regimen is established. Diarrhea may be severe and may
necessitate temporary withdrawal of Dantrium therapy. If diarrhea recurs upon readministration
of Dantrium, therapy should probably be withdrawn permanently.
Other less frequent side effects, listed according to system, are:
Gastrointestinal: Constipation, rarely progressing to signs of intestinal obstruction, GI
bleeding, anorexia, swallowing difficulty, gastric irritation, abdominal cramps, nausea and/or
vomiting.
Hepatobiliary: Hepatitis (see WARNINGS).
Neurologic: Speech disturbance, seizure, headache, light-headedness, visual disturbance,
diplopia, alteration of taste, insomnia, drooling.
Cardiovascular: Tachycardia, erratic blood pressure, phlebitis, heart failure.
Hematologic: Aplastic anemia, anemia, leukopenia, lymphocytic lymphoma,
thrombocytopenia.
Psychiatric: Mental depression, mental confusion, increased nervousness.
Urogenital: Increased urinary frequency, crystalluria, hematuria, difficult erection, urinary
incontinence and/or nocturia, difficult urination and/or urinary retention.
Integumentary: Abnormal hair growth, acne-like rash, pruritus, urticaria, eczematoid eruption,
sweating.
Musculoskeletal: Myalgia, backache.
Respiratory: Feeling of suffocation, respiratory depression.
Special Senses: Excessive tearing.
Hypersensitivity: Pleural effusion with pericarditis, pleural effusion with associated
eosinophilia, anaphylaxis.
Other: Chills and fever.
Reference ID: 3100954
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The published literature has included some reports of Dantrium use in patients with Neuroleptic
Malignant Syndrome (NMS). Dantrium capsules are not indicated for the treatment of NMS
and patients may expire despite treatment with Dantrium capsules.
For medical advice about adverse reactions contact your medical professional. To report
SUSPECTED ADVERSE REACTIONS, contact JHP at 1-866-923-2547 or MEDWATCH at 1
800-FDA-1088 (1-800-332-1088) or http://www.fda.gov/medwatch/.
DRUG ABUSE AND DEPENDENCE
Drug abuse and dependency potential has not been evaluated in human or animal studies.
OVERDOSAGE
Symptoms which may occur in case of overdose include, but are not limited to, muscular
weakness and alterations in the state of consciousness (e.g. lethargy, coma), vomiting,
diarrhea, and crystalluria. For acute overdose, general supportive measures should be
employed along with immediate gastric lavage.
Intravenous fluids should be administered in fairly large quantities to avert the possibility of
crystalluria. An adequate airway should be maintained and artificial resuscitation equipment
should be at hand. Electrocardiographic monitoring should be instituted, and the patient
carefully observed. To date, no experience has been reported with dialysis and its value in
Dantrium overdose is not known.
DOSAGE AND ADMINISTRATION
For Use in Chronic Spasticity: Prior to the administration of Dantrium, consideration should
be given to the potential response to treatment. A decrease in spasticity sufficient to allow a
daily function not otherwise attainable should be the therapeutic goal of treatment with
Dantrium. Refer to INDICATIONS AND USAGE section for description of response to be
anticipated.
It is important to establish a therapeutic goal (regain and maintain a specific function such as
therapeutic exercise program, utilization of braces, transfer maneuvers, etc.) before beginning
Dantrium therapy. Dosage should be increased until the maximum performance compatible
with the dysfunction due to underlying disease is achieved. No further increase in dosage is
then indicated.
Usual Dosage: It is important that the dosage be titrated and individualized for maximum
effect. The lowest dose compatible with optimal response is recommended.
In view of the potential for liver damage in long-term Dantrium use, therapy should be stopped
if benefits are not evident within 45 days.
Adults:
The following gradual titration schedule is suggested. Some patients will not respond until
higher daily dosage is achieved. Each dosage level should be maintained for seven days to
determine the patient’s response. If no further benefit is observed at the next higher dose,
dosage should be decreased to the previous lower dose.
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 14
25 mg once daily for seven days, then
25 mg t.i.d. for seven days
50 mg t.i.d. for seven days
100 mg t.i.d.
Therapy with a dose four times daily may be necessary for some individuals. Doses higher than
100 mg four times daily should not be used. (See Box Warning.)
Pediatric Patients: The following gradual titration schedule is suggested. Some patients will
not respond until higher daily dosage is achieved. Each dosage level should be maintained for
seven days to determine the patient’s response. If no further benefit is observed at the next
higher dose, dosage should be decreased to the previous lower dose.
0.5 mg/kg once daily for seven days, then
0.5 mg/kg t.i.d. for seven days
1 mg/kg t.i.d. for seven days
2 mg/kg t.i.d.
Therapy with a dose four times daily may be necessary for some individuals. Doses higher than
100 mg four times daily should not be used. (See Box Warning.)
For Malignant Hyperthermia:
Preoperatively: Administer 4 to 8 mg/kg/day of oral Dantrium in 3 or 4 divided doses for one
or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before
scheduled surgery with a minimum of water.
This dosage will usually be associated with skeletal muscle weakness and sedation (sleepiness
or drowsiness); adjustment can usually be made within the recommended dosage range to
avoid incapacitation or excessive gastrointestinal irritation (including nausea and/or vomiting).
Post Crisis Follow-up: Oral Dantrium should also be administered following a malignant
hyperthermia crisis, in doses of 4 to 8 mg/kg per day in four divided doses, for a one to three
day period to prevent recurrence of the manifestations of malignant hyperthermia.
HOW SUPPLIED: Dantrium (dantrolene sodium) is available in:
25-mg opaque, orange and tan capsules imprinted with DANTRIUM 25 mg on the cap and 0149
0030 with a single bar on the body.
NDC 42023-124-01 bottle of 100
50-mg opaque, orange and tan capsules imprinted with DANTRIUM 50 mg on the cap and 0149
0031 with a double bar on the body.
NDC 42023-125-01 bottle of 100
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 15
100-mg opaque, orange and tan capsules imprinted with DANTRIUM 100 mg on the cap and
0149 0033 with a triple bar on the body.
NDC 42023-126-01 bottle of 100
Avoid excessive heat (over 104°F or 40°C).
Rx Only.
Prescribing information as of October 2011.
Distributed by:
JHP Pharmaceuticals, LLC.
Rochester, MI, 48307
3003041B
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
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Reference ID: 3100954
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/2012/017443s043s046s048s049lbl.pdf', 'application_number': 17443, 'submission_type': 'SUPPL ', 'submission_number': 43}
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Minipress®
Capsules
(prazosin hydrochloride)
For Oral Use
DESCRIPTION
MINIPRESS® (prazosin hydrochloride), a quinazoline derivative, is the first of a new chemical
class of antihypertensives. It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy
2-quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is:
s
tr
uc
tura
l
form
ula
Molecular formula C19H21N5O4HCl
It is a white, crystalline substance, slightly soluble in water and isotonic saline, and has a
molecular weight of 419.87. Each 1 mg capsule of MINIPRESS for oral use contains drug
equivalent to 1 mg free base.
Inert ingredients in the formulations are: hard gelatin capsules (which may contain Blue 1, Red 3,
Red 28, Red 40, and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch;
sucrose.
CLINICAL PHARMACOLOGY
The exact mechanism of the hypotensive action of prazosin is unknown. Prazosin causes a
decrease in total peripheral resistance and was originally thought to have a direct relaxant action
on vascular smooth muscle. Recent animal studies, however, have suggested that the vasodilator
effect of prazosin is also related to blockade of postsynaptic alpha-adrenoceptors. The results of
dog forelimb experiments demonstrate that the peripheral vasodilator effect of prazosin is
1
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confined mainly to the level of the resistance vessels (arterioles). Unlike conventional
alpha-blockers, the antihypertensive action of prazosin is usually not accompanied by a reflex
tachycardia. Tolerance has not been observed to develop in long term therapy.
Hemodynamic studies have been carried out in man following acute single dose administration
and during the course of long term maintenance therapy. The results confirm that the therapeutic
effect is a fall in blood pressure unaccompanied by a clinically significant change in cardiac
output, heart rate, renal blood flow and glomerular filtration rate. There is no measurable
negative chronotropic effect.
In clinical studies to date, prazosin hydrochloride has not increased plasma renin activity.
In man, blood pressure is lowered in both the supine and standing positions. This effect is most
pronounced on the diastolic blood pressure.
Following oral administration, human plasma concentrations reach a peak at about three hours
with a plasma half-life of two to three hours. The drug is highly bound to plasma protein.
Bioavailability studies have demonstrated that the total absorption relative to the drug in a 20%
alcoholic solution is 90%, resulting in peak levels approximately 65% of that of the drug in
solution. Animal studies indicate that prazosin hydrochloride is extensively metabolized,
primarily by demethylation and conjugation, and excreted mainly via bile and feces. Less
extensive human studies suggest similar metabolism and excretion in man.
In clinical studies in which lipid profiles were followed, there were generally no adverse changes
noted between pre- and post-treatment lipid levels.
INDICATIONS AND USAGE
MINIPRESS is indicated for the treatment of hypertension, to lower blood pressure. Lowering
blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive
drugs from a wide variety of pharmacologic classes, including this drug.
Control of high blood pressure should be part of comprehensive cardiovascular risk management,
including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking
cessation, exercise, and limited sodium intake. Many patients will require more than one drug to
achieve blood pressure goals. For specific advice on goals and management, see published
guidelines, such as those of the National High Blood Pressure Education Program’s Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
other pharmacologic property of the drugs, that is largely responsible for those benefits. The
2
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largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of
stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen
regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure
reduction is similar across populations with varying absolute risk, so the absolute benefit is
greater in patients who are at higher risk independent of their hypertension (for example, patients
with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects (e.g.,
on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
therapy.
MINIPRESS can be used alone or in combination with other antihypertensive drugs such as
diuretics or beta-adrenergic blocking agents.
CONTRAINDICATIONS
MINIPRESS is contraindicated in patients with known sensitivity to quinazolines, prazosin, or
any of the inert ingredients.
WARNINGS
As with all alpha-blockers, MINIPRESS may cause syncope with sudden loss of
consciousness. In most cases, this is believed to be due to an excessive postural hypotensive
effect, although occasionally the syncopal episode has been preceded by a bout of severe
tachycardia with heart rates of 120–160 beats per minute. Syncopal episodes have usually
occurred within 30 to 90 minutes of the initial dose of the drug; occasionally, they have
been reported in association with rapid dosage increases or the introduction of another
antihypertensive drug into the regimen of a patient taking high doses of MINIPRESS. The
incidence of syncopal episodes is approximately 1% in patients given an initial dose of 2 mg
or greater. Clinical trials conducted during the investigational phase of this drug suggest
that syncopal episodes can be minimized by limiting the initial dose of the drug to 1 mg, by
subsequently increasing the dosage slowly, and by introducing any additional
antihypertensive drugs into the patient’s regimen with caution (see DOSAGE AND
ADMINISTRATION). Hypotension may develop in patients given MINIPRESS who are
also receiving a beta-blocker such as propranolol.
If syncope occurs, the patient should be placed in the recumbent position and treated supportively
as necessary. This adverse effect is self-limiting and in most cases does not recur after the initial
period of therapy or during subsequent dose titration.
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Patients should always be started on the 1 mg capsules of MINIPRESS. The 2 and 5 mg capsules
are not indicated for initial therapy.
More common than loss of consciousness are the symptoms often associated with lowering of the
blood pressure, namely, dizziness and lightheadedness. The patient should be cautioned about
these possible adverse effects and advised what measures to take should they develop. The
patient should also be cautioned to avoid situations where injury could result should syncope
occur during the initiation of MINIPRESS therapy.
Priapism
Prolonged erections and priapism have been reported with alpha-1 blockers including prazosin in
post marketing experience. In the event of an erection that persists longer than 4 hours, seek
immediate medical assistance. If priapism is not treated immediately, penile tissue damage and
permanent loss of potency could result.
PRECAUTIONS
General
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some
patients treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by
the combination of a flaccid iris that billows in response to intraoperative irrigation currents,
progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and
potential prolapse of the iris toward the phacoemulsification incisions. The patient’s
ophthalmologist should be prepared for possible modifications to the surgical technique, such as
the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to
be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.
Information for Patients:
Dizziness or drowsiness may occur after the first dose of this medicine. Avoid driving or
performing hazardous tasks for the first 24 hours after taking this medicine or when the dose is
increased. Dizziness, lightheadedness, or fainting may occur, especially when rising from a lying
or sitting position. Getting up slowly may help lessen the problem. These effects may also occur
if you drink alcohol, stand for long periods of time, exercise, or if the weather is hot. While
taking MINIPRESS, be careful in the amount of alcohol you drink. Also, use extra care during
exercise or hot weather, or if standing for long periods. Check with your physician if you have
any questions.
Drug Interactions
MINIPRESS has been administered without any adverse drug interaction in limited clinical
experience to date with the following: (1) cardiac glycosides– digitalis and digoxin; (2)
hypoglycemics–insulin, chlorpropamide, phenformin, tolazamide, and tolbutamide; (3)
tranquilizers and sedatives–chlordiazepoxide, diazepam, and phenobarbital; (4) antigout–
allopurinol, colchicine, and probenecid; (5) antiarrhythmics–procainamide, propranolol (see
WARNINGS however), and quinidine; and (6) analgesics, antipyretics and anti-inflammatories–
propoxyphene, aspirin, indomethacin, and phenylbutazone.
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Addition of a diuretic or other antihypertensive agent to MINIPRESS has been shown to cause an
additive hypotensive effect. This effect can be minimized by reducing the MINIPRESS dose to 1
to 2 mg three times a day, by introducing additional antihypertensive drugs cautiously, and then
by retitrating MINIPRESS based on clinical response.
Concomitant administration of MINIPRESS with a phosphodiesterase-5 (PDE-5) inhibitor can
result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE
AND ADMINISTRATION).
Drug/Laboratory Test Interactions
In a study on five patients given from 12 to 24 mg of prazosin per day for 10 to 14 days, there
was an average increase of 42% in the urinary metabolite of norepinephrine and an average
increase in urinary VMA of 17%. Therefore, false positive results may occur in screening tests
for pheochromocytoma in patients who are being treated with prazosin. If an elevated VMA is
found, prazosin should be discontinued and the patient retested after a month.
Laboratory Tests
In clinical studies in which lipid profiles were followed, there were generally no adverse changes
noted between pre- and post-treatment lipid levels.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
No carcinogenic potential was demonstrated in an 18 month study in rats with MINIPRESS at
dose levels more than 225 times the usual maximum recommended human dose of 20 mg per
day. MINIPRESS was not mutagenic in in vivo genetic toxicology studies. In a fertility and
general reproductive performance study in rats, both males and females, treated with 75 mg/kg
(225 times the usual maximum recommended human dose), demonstrated decreased fertility,
while those treated with 25 mg/kg (75 times the usual maximum recommended human dose) did
not.
In chronic studies (one year or more) of MINIPRESS in rats and dogs, testicular changes
consisting of atrophy and necrosis occurred at 25 mg/kg/day (75 times the usual maximum
recommended human dose). No testicular changes were seen in rats or dogs at 10 mg/kg/day
(30 times the usual maximum recommended human dose). In view of the testicular changes
observed in animals, 105 patients on long term MINIPRESS therapy were monitored for
17-ketosteroid excretion and no changes indicating a drug effect were observed. In addition,
27 males on MINIPRESS for up to 51 months did not have changes in sperm morphology
suggestive of drug effect.
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Usage in Pregnancy:
Pregnancy Category C. MINIPRESS has been shown to be associated with decreased litter size at
birth, 1, 4, and 21 days of age in rats when given doses more than 225 times the usual maximum
recommended human dose. No evidence of drug-related external, visceral, or skeletal fetal
abnormalities were observed. No drug-related external, visceral, or skeletal abnormalities were
observed in fetuses of pregnant rabbits and pregnant monkeys at doses more than 225 times and
12 times the usual maximum recommended human dose, respectively.
The use of prazosin and a beta-blocker for the control of severe hypertension in 44 pregnant
women revealed no drug-related fetal abnormalities or adverse effects. Therapy with prazosin
was continued for as long as 14 weeks.1
Prazosin has also been used alone or in combination with other hypotensive agents in severe
hypertension of pregnancy by other investigators. No fetal or neonatal abnormalities have been
reported with the use of prazosin.2
There are no adequate and well controlled studies which establish the safety of MINIPRESS in
pregnant women. MINIPRESS should be used during pregnancy only if the potential benefit
justifies the potential risk to the mother and fetus.
Nursing Mothers:
MINIPRESS has been shown to be excreted in small amounts in human milk. Caution should be
exercised when MINIPRESS is administered to a nursing woman.
Usage in Children: Safety and effectiveness in children have not been established.
ADVERSE REACTIONS
Clinical trials were conducted on more than 900 patients. During these trials and subsequent
marketing experience, the most frequent reactions associated with MINIPRESS therapy are:
dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of energy 6.9%, weakness 6.5%,
palpitations 5.3%, and nausea 4.9%. In most instances, side effects have disappeared with
continued therapy or have been tolerated with no decrease in dose of drug.
Less frequent adverse reactions which are reported to occur in 1–4% of patients are:
Gastrointestinal: vomiting, diarrhea, constipation.
Cardiovascular: edema, orthostatic hypotension, dyspnea, syncope.
Central Nervous System: vertigo, depression, nervousness.
Dermatologic: rash.
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Genitourinary: urinary frequency.
EENT: blurred vision, reddened sclera, epistaxis, dry mouth, nasal congestion.
In addition, fewer than 1% of patients have reported the following (in some instances, exact
causal relationships have not been established):
Gastrointestinal: abdominal discomfort and/or pain, liver function abnormalities, pancreatitis.
Cardiovascular: tachycardia.
Central Nervous System: paresthesia, hallucinations.
Dermatologic: pruritus, alopecia, lichen planus.
Genitourinary: incontinence, impotence, priapism.
EENT: tinnitus.
Other: diaphoresis, fever, positive ANA titer, arthralgia.
Single reports of pigmentary mottling and serous retinopathy, and a few reports of cataract
development or disappearance have been reported. In these instances, the exact causal
relationship has not been established because the baseline observations were frequently
inadequate.
In more specific slit-lamp and funduscopic studies, which included adequate baseline
examinations, no drug-related abnormal ophthalmological findings have been reported.
Literature reports exist associating MINIPRESS therapy with a worsening of pre-existing
narcolepsy. A causal relationship is uncertain in these cases.
In post-marketing experience, the following adverse events have been reported:
Autonomic Nervous System: flushing.
Body As A Whole: allergic reaction, asthenia, malaise, pain.
Cardiovascular, General: angina pectoris, hypotension.
Endocrine: gynecomastia.
Heart Rate/Rhythm: bradycardia.
Psychiatric: insomnia.
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Reference ID: 3708942
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Skin/Appendages: urticaria.
Vascular (Extracardiac): vasculitis.
Vision: eye pain.
Special Senses: During cataract surgery, a variant of small pupil syndrome known as
Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha-1 blocker
therapy (see PRECAUTIONS).
OVERDOSAGE
Accidental ingestion of at least 50 mg of MINIPRESS in a two year old child resulted in
profound drowsiness and depressed reflexes. No decrease in blood pressure was noted. Recovery
was uneventful.
Should overdosage lead to hypotension, support of the cardiovascular system is of first
importance. Restoration of blood pressure and normalization of heart rate may be accomplished
by keeping the patient in the supine position. If this measure is inadequate, shock should first be
treated with volume expanders. If necessary, vasopressors should then be used. Renal function
should be monitored and supported as needed. Laboratory data indicate MINIPRESS is not
dialysable because it is protein bound.
DOSAGE AND ADMINISTRATION
The dose of MINIPRESS should be adjusted according to the patient’s individual blood pressure
response. The following is a guide to its administration:
Initial Dose
1 mg two or three times a day (see WARNINGS.)
Maintenance Dose
Dosage may be slowly increased to a total daily dose of 20 mg given in divided doses. The
therapeutic dosages most commonly employed have ranged from 6 mg to 15 mg daily given in
divided doses. Doses higher than 20 mg usually do not increase efficacy, however a few patients
may benefit from further increases up to a daily dose of 40 mg given in divided doses. After
initial titration some patients can be maintained adequately on a twice daily dosage regimen.
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Reference ID: 3708942
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Use With Other Drugs
When adding a diuretic or other antihypertensive agent, the dose of MINIPRESS should be
reduced to 1 mg or 2 mg three times a day and retitration then carried out.
Concomitant administration of MINIPRESS with a PDE-5 inhibitor can result in additive blood
pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy
should be initiated at the lowest dose in patients taking MINIPRESS.
HOW SUPPLIED
Capsule
Capsule
Package
Strength
Color
Code
NDC
Size
MINIPRESS® 1 mg
White
431
0069-4310-71
250’s
MINIPRESS® 2 mg
Pink and
White
437
0069-4370-71
250’s
MINIPRESS® 5 mg
Blue and
White
438
0069-4380-71
250’s
References
1. Lubbe, WF, and Hodge, JV: New Zealand Med J, 94 (691) 169–172, 1981.
2. Davey, DA, and Dommisse, J: S.A. Med J, Oct. 4, 1980 (551–556). company logo
LAB-0212-6.0
February 2015
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017442 s043lbl.pdf', 'application_number': 17442, 'submission_type': 'SUPPL ', 'submission_number': 43}
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Dantrium (dantrolene sodium) capsules
Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used
in conditions other than those recommended. Symptomatic hepatitis (fatal and non
fatal) has been reported at various dose levels of the drug. The incidence reported in
patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or
more per day. Even sporadic short courses of these higher dose levels within a
treatment regimen markedly increased the risk of serious hepatic injury. Liver
dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme
elevations) has been observed in patients exposed to Dantrium for varying periods of
time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has
been most frequently observed between the third and twelfth month of therapy. The risk
of hepatic injury appears to be greater in females, in patients over 35 years of age, and
in patients taking other medication(s) in addition to Dantrium (dantrolene sodium).
Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in
elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (see Geriatric Use subsection). Dantrium should be
used only in conjunction with appropriate monitoring of hepatic function including
frequent determination of SGOT or SGPT. If no observable benefit is derived from the
administration of Dantrium after a total of 45 days, therapy should be discontinued. The
lowest possible effective dose for the individual patient should be prescribed.
DESCRIPTION
The chemical formula of Dantrium (dantrolene sodium) is hydrated 1-[[[5-(4-nitrophenyl)-2
furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt. It is an orange powder, slightly
soluble in water, but due to its slightly acidic nature the solubility increases somewhat in alkaline
solution. The anhydrous salt has a molecular weight of 336. The hydrated salt contains
approximately 15% water (3-1/2 moles) and has a molecular weight of 399. The structural
formula for the hydrated salt is:
stru
ctu
ra
l
fo
rmula
Dantrium is supplied in capsules of 25 mg, 50 mg, and 100 mg.
Inactive Ingredients: Each capsule contains edible black ink, FD&C Yellow No.6, gelatin,
lactose, magnesium stearate, starch, synthetic iron oxide red, synthetic iron oxide yellow, talc
and titanium dioxide.,
CLINICAL PHARMACOLOGY
In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by
affecting the contractile response of the skeletal muscle at a site beyond the myoneural junction,
directly on the muscle itself. In skeletal muscle, Dantrium dissociates the excitation-contraction
coupling, probably by interfering with the release of Ca++ from the sarcoplasmic reticulum. This
effect appears to be more pronounced in fast muscle fibers as compared to slow ones, but
Reference ID: 3100954
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generally affects both. A central nervous system effect occurs, with drowsiness, dizziness, and
generalized weakness occasionally present. Although Dantrium does not appear to directly
affect the CNS, the extent of its indirect effect is unknown. The absorption of Dantrium after
oral administration in humans is incomplete and slow but consistent, and dose-related blood
levels are obtained. The duration and intensity of skeletal muscle relaxation is related to the
dosage and blood levels. The mean biologic half-life of Dantrium in adults is 8.7 hours after a
100-mg dose. Specific metabolic pathways in the degradation and elimination of Dantrium in
human subjects have been established. Metabolic patterns are similar in adults and pediatric
patients. In addition to the parent compound, dantrolene, which is found in measurable
amounts in blood and urine, the major metabolites noted in body fluids are the 5-hydroxy analog
and the acetamido analog. Since Dantrium is probably metabolized by hepatic microsomal
enzymes, enhancement of its metabolism by other drugs is possible. However, neither
phenobarbital nor diazepam appears to affect Dantrium metabolism.
Clinical experience in the management of fulminant human malignant hyperthermia, as well as
experiments conducted in malignant hyperthermia susceptible swine, have revealed that the
administration of intravenous dantrolene, combined with indicated supportive measures, is
effective in reversing the hypermetabolic process of malignant hyperthermia. Known
differences between human and swine malignant hyperthermia are minor. The prophylactic
administration of oral or intravenous dantrolene to malignant hyperthermia susceptible swine will
attenuate or prevent the development of signs of malignant hyperthermia in a manner
dependent upon the dosage of dantrolene administered and the intensity of the malignant
hyperthermia triggering stimulus. Limited clinical experience with the administration of oral
dantrolene to patients judged malignant hyperthermia susceptible, when combined with clinical
experience in the use of intravenous dantrolene for the treatment of malignant hyperthermia and
data derived from the above cited animal model experiments, suggests that oral dantrolene will
also attenuate or prevent the development of signs of human malignant hyperthermia, provided
that currently accepted practices in the management of such patients are adhered to (see
INDICATIONS AND USAGE); intravenous dantrolene should also be available for use should
the signs of malignant hyperthermia appear.
INDICATIONS AND USAGE
In Chronic Spasticity: Dantrium is indicated in controlling the manifestations of clinical
spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral
palsy, or multiple sclerosis). It is of particular benefit to the patient whose functional
rehabilitation has been retarded by the sequelae of spasticity. Such patients must have
presumably reversible spasticity where relief of spasticity will aid in restoring residual function.
Dantrium is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic
disorders.
If improvement occurs, it will ordinarily occur within the dosage titration (see DOSAGE AND
ADMINISTRATION), and will be manifested by a decrease in the severity of spasticity and the
ability to resume a daily function not quite attainable without Dantrium.
Occasionally, subtle but meaningful improvement in spasticity may occur with Dantrium
therapy. In such instances, information regarding improvement should be solicited from the
patient and those who are in constant daily contact and attendance with him. Brief withdrawal
of Dantrium for a period of 2 to 4 days will frequently demonstrate exacerbation of the
manifestations of spasticity and may serve to confirm a clinical impression.
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A decision to continue the administration of Dantrium on a long-term basis is justified if
introduction of the drug into the patient's regimen:
produces a significant reduction in painful and/or disabling spasticity such as clonus, or
permits a significant reduction in the intensity and/or degree of nursing care
required, or rids the patient of any annoying manifestation of spasticity considered
important by the patient himself.
In Malignant Hyperthermia: Oral Dantrium is also indicated preoperatively to prevent or
attenuate the development of signs of malignant hyperthermia in known, or strongly suspect,
malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Currently
accepted clinical practices in the management of such patients must still be adhered to (careful
monitoring for early signs of malignant hyperthermia, minimizing exposure to triggering
mechanisms and prompt use of intravenous dantrolene sodium and indicated supportive
measures should signs of malignant hyperthermia appear); see also the package insert for
Dantrium® (dantrolene sodium) Intravenous.
Oral Dantrium should be administered following a malignant hyperthermic crisis to prevent
recurrence of the signs of malignant hyperthermia.
CONTRAINDICATIONS
Active hepatic disease, such as hepatitis and cirrhosis, is a contraindication for use of
Dantrium. Dantrium is contraindicated where spasticity is utilized to sustain upright posture
and balance in locomotion or whenever spasticity is utilized to obtain or maintain increased
function.
WARNINGS
It is important to recognize that fatal and non-fatal liver disorders of an idiosyncratic or
hypersensitivity type may occur with Dantrium therapy.
At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT, SGPT,
alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing
liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility
that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility
has not yet been established.
Liver function studies (e.g., SGOT or SGPT) should be performed at appropriate intervals during
Dantrium therapy. If such studies reveal abnormal values, therapy should generally be
discontinued. Only where benefits of the drug have been of major importance to the patient,
should reinitiation or continuation of therapy be considered. Some patients have revealed a
return to normal laboratory values in the face of continued therapy while others have not.
If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or
jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early,
the abnormalities in liver function characteristically have reverted to normal when the drug was
discontinued.
Reference ID: 3100954
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Page 10
Dantrium therapy has been reinstituted in a few patients who have developed clinical and/or
laboratory evidence of hepatocellular injury. If such reinstitution of therapy is done, it should be
attempted only in patients who clearly need Dantrium and only after previous symptoms and
laboratory abnormalities have cleared. The patient should be hospitalized and the drug should
be restarted in very small and gradually increasing doses. Laboratory monitoring should be
frequent and the drug should be withdrawn immediately if there is any indication of recurrent
liver involvement. Some patients have reacted with unmistakable signs of liver abnormality
upon administration of a challenge dose, while others have not.
Dantrium should be used with particular caution in females and in patients over 35 years of age
in view of apparent greater likelihood of drug-induced, potentially fatal, hepatocellular disease in
these groups. Spontaneous reports suggest a higher proportion of hepatic events with fatal
outcome in elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (see Geriatric Use subsection).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term safety of Dantrium in
humans has not been established. Chronic studies in rats, dogs, and monkeys at dosages
greater than 30 mg/kg/day showed growth or weight depression and signs of hepatopathy and
possible occlusion nephropathy, all of which were reversible upon cessation of treatment.
Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30,
and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumors
compared with concurrent controls.At the highest dose level, there was an increase in the
incidence of benign lymphatic neoplasms. In a 30-month study at the same dose levels also in
Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary
neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic
lymphangiomas and hepatic angiosarcomas.
The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related
reduction in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR
mice revealed no evidence of carcinogenic activity.
Carcinogenicity in humans cannot be fully excluded, so that this possible risk of chronic
administration must be weighed against the benefits of the drug (i.e., after a brief trial) for the
individual patient.
Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial
mutagenesis assay in the presence and absence of a liver activating system.
Pregnancy: Pregnancy Category C: Pregnancy Category C: Adequate animal reproduction
studies have not been conducted with Dantrium. It is also not known whether Dantrium can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Dantrium should be given to a pregnant woman only if clearly needed.
Labor and Delivery: In one non-randomized open-label study, 21 term pregnant patients
received prophylactic oral Dantrium 100 mg per day for 2 to 10 days prior to delivery.
Dantrolene readily crossed the placenta with maternal and fetal whole blood levels
approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days
before declining sharply. No neonatal respiratory and neuromuscular side effects were detected
Reference ID: 3100954
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NDA 17443/S-/S-043/S-046/S-048/S-049
Page 11
at low dose. More data, at higher doses, are needed before more definitive conclusions can be
made.
Nursing Mothers: Dantrium should not be used in nursing mothers.
Usage in Pediatric Patients: The long-term safety of Dantrium in pediatric patients under the
age of 5 years has not been established. Because of the possibility that adverse effects of the
drug could become apparent only after many years, a benefit-risk consideration of the long-term
use of Dantrium is particularly important in pediatric patients.
Geriatric Use: Clinical studies of Dantrium 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 the literature 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. As with all patients receiving Dantrium, it is
recommended that elderly patients receive the lowest dose compatible with the optimal
response. Spontaneous reports suggest a higher proportion of hepatic events with fatal
outcome in elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (for hepatotoxicity details and its management see Black
Box and Warnings Sections).
Drug Interactions: Drowsiness may occur with Dantrium therapy, and the concomitant
administration of CNS depressants such as sedatives and tranquilizing agents may result in
further drowsiness.
While a definite drug interaction with estrogen therapy has not yet been established, caution
should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred
more often in women over 35 years of age receiving concomitant estrogen therapy.
Cardiovascular collapse in patients treated simultaneously with verapamil and dantrolene
sodium is rare. The combination of therapeutic doses of intravenous dantrolene sodium and
verapamil in halothane/-chloralose anesthetized swine has resulted in ventricular fibrillation
and cardiovascular collapse in association with marked hyperkalemia. Until the relevance of
these findings to humans is established, the combination of dantrolene sodium and calcium
channel blockers is not recommended during the management of malignant hyperthermia.
Administration of Dantrium may potentiate vecuronium-induced neuromuscular block.
PRECAUTIONS
Dantrium should be used with caution in patients with impaired pulmonary function, particularly
those with obstructive pulmonary disease, and in patients with severely impaired cardiac
function due to myocardial disease. Dantrium is associated with pleural effusion with associated
eosinophilia. It should be used with caution in patients with a history of previous liver disease or
dysfunction (see WARNINGS).
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 12
Information for Patients: Patients should be cautioned against driving a motor vehicle or
participating in hazardous occupations while taking Dantrium. Caution should be exercised in
the concomitant administration of tranquilizing agents.
Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about
exposure to sunlight while taking it.
ADVERSE REACTIONS
The most frequently occurring side effects of Dantrium have been drowsiness, dizziness,
weakness, general malaise, fatigue, and diarrhea. These are generally transient, occurring
early in treatment, and can often be obviated by beginning with a low dose and increasing
dosage gradually until an optimal regimen is established. Diarrhea may be severe and may
necessitate temporary withdrawal of Dantrium therapy. If diarrhea recurs upon readministration
of Dantrium, therapy should probably be withdrawn permanently.
Other less frequent side effects, listed according to system, are:
Gastrointestinal: Constipation, rarely progressing to signs of intestinal obstruction, GI
bleeding, anorexia, swallowing difficulty, gastric irritation, abdominal cramps, nausea and/or
vomiting.
Hepatobiliary: Hepatitis (see WARNINGS).
Neurologic: Speech disturbance, seizure, headache, light-headedness, visual disturbance,
diplopia, alteration of taste, insomnia, drooling.
Cardiovascular: Tachycardia, erratic blood pressure, phlebitis, heart failure.
Hematologic: Aplastic anemia, anemia, leukopenia, lymphocytic lymphoma,
thrombocytopenia.
Psychiatric: Mental depression, mental confusion, increased nervousness.
Urogenital: Increased urinary frequency, crystalluria, hematuria, difficult erection, urinary
incontinence and/or nocturia, difficult urination and/or urinary retention.
Integumentary: Abnormal hair growth, acne-like rash, pruritus, urticaria, eczematoid eruption,
sweating.
Musculoskeletal: Myalgia, backache.
Respiratory: Feeling of suffocation, respiratory depression.
Special Senses: Excessive tearing.
Hypersensitivity: Pleural effusion with pericarditis, pleural effusion with associated
eosinophilia, anaphylaxis.
Other: Chills and fever.
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 13
The published literature has included some reports of Dantrium use in patients with Neuroleptic
Malignant Syndrome (NMS). Dantrium capsules are not indicated for the treatment of NMS
and patients may expire despite treatment with Dantrium capsules.
For medical advice about adverse reactions contact your medical professional. To report
SUSPECTED ADVERSE REACTIONS, contact JHP at 1-866-923-2547 or MEDWATCH at 1
800-FDA-1088 (1-800-332-1088) or http://www.fda.gov/medwatch/.
DRUG ABUSE AND DEPENDENCE
Drug abuse and dependency potential has not been evaluated in human or animal studies.
OVERDOSAGE
Symptoms which may occur in case of overdose include, but are not limited to, muscular
weakness and alterations in the state of consciousness (e.g. lethargy, coma), vomiting,
diarrhea, and crystalluria. For acute overdose, general supportive measures should be
employed along with immediate gastric lavage.
Intravenous fluids should be administered in fairly large quantities to avert the possibility of
crystalluria. An adequate airway should be maintained and artificial resuscitation equipment
should be at hand. Electrocardiographic monitoring should be instituted, and the patient
carefully observed. To date, no experience has been reported with dialysis and its value in
Dantrium overdose is not known.
DOSAGE AND ADMINISTRATION
For Use in Chronic Spasticity: Prior to the administration of Dantrium, consideration should
be given to the potential response to treatment. A decrease in spasticity sufficient to allow a
daily function not otherwise attainable should be the therapeutic goal of treatment with
Dantrium. Refer to INDICATIONS AND USAGE section for description of response to be
anticipated.
It is important to establish a therapeutic goal (regain and maintain a specific function such as
therapeutic exercise program, utilization of braces, transfer maneuvers, etc.) before beginning
Dantrium therapy. Dosage should be increased until the maximum performance compatible
with the dysfunction due to underlying disease is achieved. No further increase in dosage is
then indicated.
Usual Dosage: It is important that the dosage be titrated and individualized for maximum
effect. The lowest dose compatible with optimal response is recommended.
In view of the potential for liver damage in long-term Dantrium use, therapy should be stopped
if benefits are not evident within 45 days.
Adults:
The following gradual titration schedule is suggested. Some patients will not respond until
higher daily dosage is achieved. Each dosage level should be maintained for seven days to
determine the patient’s response. If no further benefit is observed at the next higher dose,
dosage should be decreased to the previous lower dose.
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 14
25 mg once daily for seven days, then
25 mg t.i.d. for seven days
50 mg t.i.d. for seven days
100 mg t.i.d.
Therapy with a dose four times daily may be necessary for some individuals. Doses higher than
100 mg four times daily should not be used. (See Box Warning.)
Pediatric Patients: The following gradual titration schedule is suggested. Some patients will
not respond until higher daily dosage is achieved. Each dosage level should be maintained for
seven days to determine the patient’s response. If no further benefit is observed at the next
higher dose, dosage should be decreased to the previous lower dose.
0.5 mg/kg once daily for seven days, then
0.5 mg/kg t.i.d. for seven days
1 mg/kg t.i.d. for seven days
2 mg/kg t.i.d.
Therapy with a dose four times daily may be necessary for some individuals. Doses higher than
100 mg four times daily should not be used. (See Box Warning.)
For Malignant Hyperthermia:
Preoperatively: Administer 4 to 8 mg/kg/day of oral Dantrium in 3 or 4 divided doses for one
or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before
scheduled surgery with a minimum of water.
This dosage will usually be associated with skeletal muscle weakness and sedation (sleepiness
or drowsiness); adjustment can usually be made within the recommended dosage range to
avoid incapacitation or excessive gastrointestinal irritation (including nausea and/or vomiting).
Post Crisis Follow-up: Oral Dantrium should also be administered following a malignant
hyperthermia crisis, in doses of 4 to 8 mg/kg per day in four divided doses, for a one to three
day period to prevent recurrence of the manifestations of malignant hyperthermia.
HOW SUPPLIED: Dantrium (dantrolene sodium) is available in:
25-mg opaque, orange and tan capsules imprinted with DANTRIUM 25 mg on the cap and 0149
0030 with a single bar on the body.
NDC 42023-124-01 bottle of 100
50-mg opaque, orange and tan capsules imprinted with DANTRIUM 50 mg on the cap and 0149
0031 with a double bar on the body.
NDC 42023-125-01 bottle of 100
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 15
100-mg opaque, orange and tan capsules imprinted with DANTRIUM 100 mg on the cap and
0149 0033 with a triple bar on the body.
NDC 42023-126-01 bottle of 100
Avoid excessive heat (over 104°F or 40°C).
Rx Only.
Prescribing information as of October 2011.
Distributed by:
JHP Pharmaceuticals, LLC.
Rochester, MI, 48307
3003041B
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 16
Reference ID: 3100954
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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2025-02-12T13:44:11.530021
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf', 'application_number': 17443, 'submission_type': 'SUPPL ', 'submission_number': 48}
|
10,993
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NDA 17443/S-/S-043/S-046/S-048/S-049
Page 7
Dantrium (dantrolene sodium) capsules
Dantrium (dantrolene sodium) has a potential for hepatotoxicity, and should not be used
in conditions other than those recommended. Symptomatic hepatitis (fatal and non
fatal) has been reported at various dose levels of the drug. The incidence reported in
patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or
more per day. Even sporadic short courses of these higher dose levels within a
treatment regimen markedly increased the risk of serious hepatic injury. Liver
dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme
elevations) has been observed in patients exposed to Dantrium for varying periods of
time. Overt hepatitis has occurred at varying intervals after initiation of therapy, but has
been most frequently observed between the third and twelfth month of therapy. The risk
of hepatic injury appears to be greater in females, in patients over 35 years of age, and
in patients taking other medication(s) in addition to Dantrium (dantrolene sodium).
Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in
elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (see Geriatric Use subsection). Dantrium should be
used only in conjunction with appropriate monitoring of hepatic function including
frequent determination of SGOT or SGPT. If no observable benefit is derived from the
administration of Dantrium after a total of 45 days, therapy should be discontinued. The
lowest possible effective dose for the individual patient should be prescribed.
DESCRIPTION
The chemical formula of Dantrium (dantrolene sodium) is hydrated 1-[[[5-(4-nitrophenyl)-2
furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt. It is an orange powder, slightly
soluble in water, but due to its slightly acidic nature the solubility increases somewhat in alkaline
solution. The anhydrous salt has a molecular weight of 336. The hydrated salt contains
approximately 15% water (3-1/2 moles) and has a molecular weight of 399. The structural
formula for the hydrated salt is:
stru
ctu
ra
l
fo
rmula
Dantrium is supplied in capsules of 25 mg, 50 mg, and 100 mg.
Inactive Ingredients: Each capsule contains edible black ink, FD&C Yellow No.6, gelatin,
lactose, magnesium stearate, starch, synthetic iron oxide red, synthetic iron oxide yellow, talc
and titanium dioxide.,
CLINICAL PHARMACOLOGY
In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by
affecting the contractile response of the skeletal muscle at a site beyond the myoneural junction,
directly on the muscle itself. In skeletal muscle, Dantrium dissociates the excitation-contraction
coupling, probably by interfering with the release of Ca++ from the sarcoplasmic reticulum. This
effect appears to be more pronounced in fast muscle fibers as compared to slow ones, but
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 8
generally affects both. A central nervous system effect occurs, with drowsiness, dizziness, and
generalized weakness occasionally present. Although Dantrium does not appear to directly
affect the CNS, the extent of its indirect effect is unknown. The absorption of Dantrium after
oral administration in humans is incomplete and slow but consistent, and dose-related blood
levels are obtained. The duration and intensity of skeletal muscle relaxation is related to the
dosage and blood levels. The mean biologic half-life of Dantrium in adults is 8.7 hours after a
100-mg dose. Specific metabolic pathways in the degradation and elimination of Dantrium in
human subjects have been established. Metabolic patterns are similar in adults and pediatric
patients. In addition to the parent compound, dantrolene, which is found in measurable
amounts in blood and urine, the major metabolites noted in body fluids are the 5-hydroxy analog
and the acetamido analog. Since Dantrium is probably metabolized by hepatic microsomal
enzymes, enhancement of its metabolism by other drugs is possible. However, neither
phenobarbital nor diazepam appears to affect Dantrium metabolism.
Clinical experience in the management of fulminant human malignant hyperthermia, as well as
experiments conducted in malignant hyperthermia susceptible swine, have revealed that the
administration of intravenous dantrolene, combined with indicated supportive measures, is
effective in reversing the hypermetabolic process of malignant hyperthermia. Known
differences between human and swine malignant hyperthermia are minor. The prophylactic
administration of oral or intravenous dantrolene to malignant hyperthermia susceptible swine will
attenuate or prevent the development of signs of malignant hyperthermia in a manner
dependent upon the dosage of dantrolene administered and the intensity of the malignant
hyperthermia triggering stimulus. Limited clinical experience with the administration of oral
dantrolene to patients judged malignant hyperthermia susceptible, when combined with clinical
experience in the use of intravenous dantrolene for the treatment of malignant hyperthermia and
data derived from the above cited animal model experiments, suggests that oral dantrolene will
also attenuate or prevent the development of signs of human malignant hyperthermia, provided
that currently accepted practices in the management of such patients are adhered to (see
INDICATIONS AND USAGE); intravenous dantrolene should also be available for use should
the signs of malignant hyperthermia appear.
INDICATIONS AND USAGE
In Chronic Spasticity: Dantrium is indicated in controlling the manifestations of clinical
spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral
palsy, or multiple sclerosis). It is of particular benefit to the patient whose functional
rehabilitation has been retarded by the sequelae of spasticity. Such patients must have
presumably reversible spasticity where relief of spasticity will aid in restoring residual function.
Dantrium is not indicated in the treatment of skeletal muscle spasm resulting from rheumatic
disorders.
If improvement occurs, it will ordinarily occur within the dosage titration (see DOSAGE AND
ADMINISTRATION), and will be manifested by a decrease in the severity of spasticity and the
ability to resume a daily function not quite attainable without Dantrium.
Occasionally, subtle but meaningful improvement in spasticity may occur with Dantrium
therapy. In such instances, information regarding improvement should be solicited from the
patient and those who are in constant daily contact and attendance with him. Brief withdrawal
of Dantrium for a period of 2 to 4 days will frequently demonstrate exacerbation of the
manifestations of spasticity and may serve to confirm a clinical impression.
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 9
A decision to continue the administration of Dantrium on a long-term basis is justified if
introduction of the drug into the patient's regimen:
produces a significant reduction in painful and/or disabling spasticity such as clonus, or
permits a significant reduction in the intensity and/or degree of nursing care
required, or rids the patient of any annoying manifestation of spasticity considered
important by the patient himself.
In Malignant Hyperthermia: Oral Dantrium is also indicated preoperatively to prevent or
attenuate the development of signs of malignant hyperthermia in known, or strongly suspect,
malignant hyperthermia susceptible patients who require anesthesia and/or surgery. Currently
accepted clinical practices in the management of such patients must still be adhered to (careful
monitoring for early signs of malignant hyperthermia, minimizing exposure to triggering
mechanisms and prompt use of intravenous dantrolene sodium and indicated supportive
measures should signs of malignant hyperthermia appear); see also the package insert for
Dantrium® (dantrolene sodium) Intravenous.
Oral Dantrium should be administered following a malignant hyperthermic crisis to prevent
recurrence of the signs of malignant hyperthermia.
CONTRAINDICATIONS
Active hepatic disease, such as hepatitis and cirrhosis, is a contraindication for use of
Dantrium. Dantrium is contraindicated where spasticity is utilized to sustain upright posture
and balance in locomotion or whenever spasticity is utilized to obtain or maintain increased
function.
WARNINGS
It is important to recognize that fatal and non-fatal liver disorders of an idiosyncratic or
hypersensitivity type may occur with Dantrium therapy.
At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT, SGPT,
alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing
liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility
that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility
has not yet been established.
Liver function studies (e.g., SGOT or SGPT) should be performed at appropriate intervals during
Dantrium therapy. If such studies reveal abnormal values, therapy should generally be
discontinued. Only where benefits of the drug have been of major importance to the patient,
should reinitiation or continuation of therapy be considered. Some patients have revealed a
return to normal laboratory values in the face of continued therapy while others have not.
If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or
jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early,
the abnormalities in liver function characteristically have reverted to normal when the drug was
discontinued.
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 10
Dantrium therapy has been reinstituted in a few patients who have developed clinical and/or
laboratory evidence of hepatocellular injury. If such reinstitution of therapy is done, it should be
attempted only in patients who clearly need Dantrium and only after previous symptoms and
laboratory abnormalities have cleared. The patient should be hospitalized and the drug should
be restarted in very small and gradually increasing doses. Laboratory monitoring should be
frequent and the drug should be withdrawn immediately if there is any indication of recurrent
liver involvement. Some patients have reacted with unmistakable signs of liver abnormality
upon administration of a challenge dose, while others have not.
Dantrium should be used with particular caution in females and in patients over 35 years of age
in view of apparent greater likelihood of drug-induced, potentially fatal, hepatocellular disease in
these groups. Spontaneous reports suggest a higher proportion of hepatic events with fatal
outcome in elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (see Geriatric Use subsection).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term safety of Dantrium in
humans has not been established. Chronic studies in rats, dogs, and monkeys at dosages
greater than 30 mg/kg/day showed growth or weight depression and signs of hepatopathy and
possible occlusion nephropathy, all of which were reversible upon cessation of treatment.
Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30,
and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumors
compared with concurrent controls.At the highest dose level, there was an increase in the
incidence of benign lymphatic neoplasms. In a 30-month study at the same dose levels also in
Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary
neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic
lymphangiomas and hepatic angiosarcomas.
The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related
reduction in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR
mice revealed no evidence of carcinogenic activity.
Carcinogenicity in humans cannot be fully excluded, so that this possible risk of chronic
administration must be weighed against the benefits of the drug (i.e., after a brief trial) for the
individual patient.
Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial
mutagenesis assay in the presence and absence of a liver activating system.
Pregnancy: Pregnancy Category C: Pregnancy Category C: Adequate animal reproduction
studies have not been conducted with Dantrium. It is also not known whether Dantrium can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
Dantrium should be given to a pregnant woman only if clearly needed.
Labor and Delivery: In one non-randomized open-label study, 21 term pregnant patients
received prophylactic oral Dantrium 100 mg per day for 2 to 10 days prior to delivery.
Dantrolene readily crossed the placenta with maternal and fetal whole blood levels
approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days
before declining sharply. No neonatal respiratory and neuromuscular side effects were detected
Reference ID: 3100954
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 11
at low dose. More data, at higher doses, are needed before more definitive conclusions can be
made.
Nursing Mothers: Dantrium should not be used in nursing mothers.
Usage in Pediatric Patients: The long-term safety of Dantrium in pediatric patients under the
age of 5 years has not been established. Because of the possibility that adverse effects of the
drug could become apparent only after many years, a benefit-risk consideration of the long-term
use of Dantrium is particularly important in pediatric patients.
Geriatric Use: Clinical studies of Dantrium 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 the literature 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. As with all patients receiving Dantrium, it is
recommended that elderly patients receive the lowest dose compatible with the optimal
response. Spontaneous reports suggest a higher proportion of hepatic events with fatal
outcome in elderly patients receiving Dantrium. However, the majority of these cases were
complicated with confounding factors such as intercurrent illnesses and/or concomitant
potentially hepatotoxic medications (for hepatotoxicity details and its management see Black
Box and Warnings Sections).
Drug Interactions: Drowsiness may occur with Dantrium therapy, and the concomitant
administration of CNS depressants such as sedatives and tranquilizing agents may result in
further drowsiness.
While a definite drug interaction with estrogen therapy has not yet been established, caution
should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred
more often in women over 35 years of age receiving concomitant estrogen therapy.
Cardiovascular collapse in patients treated simultaneously with verapamil and dantrolene
sodium is rare. The combination of therapeutic doses of intravenous dantrolene sodium and
verapamil in halothane/-chloralose anesthetized swine has resulted in ventricular fibrillation
and cardiovascular collapse in association with marked hyperkalemia. Until the relevance of
these findings to humans is established, the combination of dantrolene sodium and calcium
channel blockers is not recommended during the management of malignant hyperthermia.
Administration of Dantrium may potentiate vecuronium-induced neuromuscular block.
PRECAUTIONS
Dantrium should be used with caution in patients with impaired pulmonary function, particularly
those with obstructive pulmonary disease, and in patients with severely impaired cardiac
function due to myocardial disease. Dantrium is associated with pleural effusion with associated
eosinophilia. It should be used with caution in patients with a history of previous liver disease or
dysfunction (see WARNINGS).
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 12
Information for Patients: Patients should be cautioned against driving a motor vehicle or
participating in hazardous occupations while taking Dantrium. Caution should be exercised in
the concomitant administration of tranquilizing agents.
Dantrium might possibly evoke a photosensitivity reaction; patients should be cautioned about
exposure to sunlight while taking it.
ADVERSE REACTIONS
The most frequently occurring side effects of Dantrium have been drowsiness, dizziness,
weakness, general malaise, fatigue, and diarrhea. These are generally transient, occurring
early in treatment, and can often be obviated by beginning with a low dose and increasing
dosage gradually until an optimal regimen is established. Diarrhea may be severe and may
necessitate temporary withdrawal of Dantrium therapy. If diarrhea recurs upon readministration
of Dantrium, therapy should probably be withdrawn permanently.
Other less frequent side effects, listed according to system, are:
Gastrointestinal: Constipation, rarely progressing to signs of intestinal obstruction, GI
bleeding, anorexia, swallowing difficulty, gastric irritation, abdominal cramps, nausea and/or
vomiting.
Hepatobiliary: Hepatitis (see WARNINGS).
Neurologic: Speech disturbance, seizure, headache, light-headedness, visual disturbance,
diplopia, alteration of taste, insomnia, drooling.
Cardiovascular: Tachycardia, erratic blood pressure, phlebitis, heart failure.
Hematologic: Aplastic anemia, anemia, leukopenia, lymphocytic lymphoma,
thrombocytopenia.
Psychiatric: Mental depression, mental confusion, increased nervousness.
Urogenital: Increased urinary frequency, crystalluria, hematuria, difficult erection, urinary
incontinence and/or nocturia, difficult urination and/or urinary retention.
Integumentary: Abnormal hair growth, acne-like rash, pruritus, urticaria, eczematoid eruption,
sweating.
Musculoskeletal: Myalgia, backache.
Respiratory: Feeling of suffocation, respiratory depression.
Special Senses: Excessive tearing.
Hypersensitivity: Pleural effusion with pericarditis, pleural effusion with associated
eosinophilia, anaphylaxis.
Other: Chills and fever.
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 13
The published literature has included some reports of Dantrium use in patients with Neuroleptic
Malignant Syndrome (NMS). Dantrium capsules are not indicated for the treatment of NMS
and patients may expire despite treatment with Dantrium capsules.
For medical advice about adverse reactions contact your medical professional. To report
SUSPECTED ADVERSE REACTIONS, contact JHP at 1-866-923-2547 or MEDWATCH at 1
800-FDA-1088 (1-800-332-1088) or http://www.fda.gov/medwatch/.
DRUG ABUSE AND DEPENDENCE
Drug abuse and dependency potential has not been evaluated in human or animal studies.
OVERDOSAGE
Symptoms which may occur in case of overdose include, but are not limited to, muscular
weakness and alterations in the state of consciousness (e.g. lethargy, coma), vomiting,
diarrhea, and crystalluria. For acute overdose, general supportive measures should be
employed along with immediate gastric lavage.
Intravenous fluids should be administered in fairly large quantities to avert the possibility of
crystalluria. An adequate airway should be maintained and artificial resuscitation equipment
should be at hand. Electrocardiographic monitoring should be instituted, and the patient
carefully observed. To date, no experience has been reported with dialysis and its value in
Dantrium overdose is not known.
DOSAGE AND ADMINISTRATION
For Use in Chronic Spasticity: Prior to the administration of Dantrium, consideration should
be given to the potential response to treatment. A decrease in spasticity sufficient to allow a
daily function not otherwise attainable should be the therapeutic goal of treatment with
Dantrium. Refer to INDICATIONS AND USAGE section for description of response to be
anticipated.
It is important to establish a therapeutic goal (regain and maintain a specific function such as
therapeutic exercise program, utilization of braces, transfer maneuvers, etc.) before beginning
Dantrium therapy. Dosage should be increased until the maximum performance compatible
with the dysfunction due to underlying disease is achieved. No further increase in dosage is
then indicated.
Usual Dosage: It is important that the dosage be titrated and individualized for maximum
effect. The lowest dose compatible with optimal response is recommended.
In view of the potential for liver damage in long-term Dantrium use, therapy should be stopped
if benefits are not evident within 45 days.
Adults:
The following gradual titration schedule is suggested. Some patients will not respond until
higher daily dosage is achieved. Each dosage level should be maintained for seven days to
determine the patient’s response. If no further benefit is observed at the next higher dose,
dosage should be decreased to the previous lower dose.
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 14
25 mg once daily for seven days, then
25 mg t.i.d. for seven days
50 mg t.i.d. for seven days
100 mg t.i.d.
Therapy with a dose four times daily may be necessary for some individuals. Doses higher than
100 mg four times daily should not be used. (See Box Warning.)
Pediatric Patients: The following gradual titration schedule is suggested. Some patients will
not respond until higher daily dosage is achieved. Each dosage level should be maintained for
seven days to determine the patient’s response. If no further benefit is observed at the next
higher dose, dosage should be decreased to the previous lower dose.
0.5 mg/kg once daily for seven days, then
0.5 mg/kg t.i.d. for seven days
1 mg/kg t.i.d. for seven days
2 mg/kg t.i.d.
Therapy with a dose four times daily may be necessary for some individuals. Doses higher than
100 mg four times daily should not be used. (See Box Warning.)
For Malignant Hyperthermia:
Preoperatively: Administer 4 to 8 mg/kg/day of oral Dantrium in 3 or 4 divided doses for one
or two days prior to surgery, with the last dose being given approximately 3 to 4 hours before
scheduled surgery with a minimum of water.
This dosage will usually be associated with skeletal muscle weakness and sedation (sleepiness
or drowsiness); adjustment can usually be made within the recommended dosage range to
avoid incapacitation or excessive gastrointestinal irritation (including nausea and/or vomiting).
Post Crisis Follow-up: Oral Dantrium should also be administered following a malignant
hyperthermia crisis, in doses of 4 to 8 mg/kg per day in four divided doses, for a one to three
day period to prevent recurrence of the manifestations of malignant hyperthermia.
HOW SUPPLIED: Dantrium (dantrolene sodium) is available in:
25-mg opaque, orange and tan capsules imprinted with DANTRIUM 25 mg on the cap and 0149
0030 with a single bar on the body.
NDC 42023-124-01 bottle of 100
50-mg opaque, orange and tan capsules imprinted with DANTRIUM 50 mg on the cap and 0149
0031 with a double bar on the body.
NDC 42023-125-01 bottle of 100
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 15
100-mg opaque, orange and tan capsules imprinted with DANTRIUM 100 mg on the cap and
0149 0033 with a triple bar on the body.
NDC 42023-126-01 bottle of 100
Avoid excessive heat (over 104°F or 40°C).
Rx Only.
Prescribing information as of October 2011.
Distributed by:
JHP Pharmaceuticals, LLC.
Rochester, MI, 48307
3003041B
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17443/S-/S-043/S-046/S-048/S-049
Page 16
Reference ID: 3100954
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:11.564029
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf', 'application_number': 17443, 'submission_type': 'SUPPL ', 'submission_number': 46}
|
10,996
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NDA 17-463/S-104
Page 3
Motrin®
Ibuprofen Tablets, USP
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
myocardial infarction, and stroke, which can be fatal. This risk may increase with
duration of use. Patients with cardiovascular disease or risk factors for
cardiovascular disease may be at greater risk (See WARNINGS).
• MOTRIN tablets are contraindicated for treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which
can be fatal. These events can occur at any time during use and without warning
symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
(See WARNINGS).
DESCRIPTION
MOTRIN tablets contain the active ingredient ibuprofen, which is (±) - 2 - (p - isobutylphenyl)
propionic acid. Ibuprofen is a white powder with a melting point of 74-77° C and is very slightly
soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone.
The structural formula is represented below:
MOTRIN tablets, a nonsteroidal anti-inflammatory drug (NSAID), is available in 400 mg, 600 mg,
and 800 mg tablets for oral administration. Inactive ingredients: carnauba wax, colloidal silicon
dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose,
propylene glycol, titanium dioxide.
CLINICAL PHARMACOLOGY
MOTRIN tablets contain ibuprofen which possesses analgesic and antipyretic activities. Its mode of
action, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin
synthetase inhibition.
In clinical studies in patients with rheumatoid arthritis and osteoarthritis, MOTRIN tablets have been
shown to be comparable to aspirin in controlling pain and inflammation and to be associated with a
statistically significant reduction in the milder gastrointestinal side effects (see ADVERSE
REACTIONS). MOTRIN tablets may be well tolerated in some patients who have had gastrointestinal
side effects with aspirin, but these patients when treated with MOTRIN tablets should be carefully
followed for signs and symptoms of gastrointestinal ulceration and bleeding. Although it is not
definitely known whether MOTRIN tablets causes less peptic ulceration than aspirin, in one study
involving 885 patients with rheumatoid arthritis treated for up to one year, there were no reports of
NDA 17-463/S-104
Page 4
gastric ulceration with MOTRIN tablets whereas frank ulceration was reported in 13 patients in the
aspirin group (statistically significant p<.001).
Gastroscopic studies at varying doses show an increased tendency toward gastric irritation at higher
doses. However, at comparable doses, gastric irritation is approximately half that seen with aspirin.
Studies using 51Cr-tagged red cells indicate that fecal blood loss associated with MOTRIN tablets in
doses up to 2400 mg daily did not exceed the normal range, and was significantly less than that seen in
aspirin-treated patients.
In clinical studies in patients with rheumatoid arthritis, MOTRIN tablets have been shown to be
comparable to indomethacin in controlling the signs and symptoms of disease activity and to be associated
with a statistically significant reduction of the milder gastrointestinal (see ADVERSE REACTIONS) and
CNS side effects.
MOTRIN tablets may be used in combination with gold salts and/or corticosteroids.
Controlled studies have demonstrated that MOTRIN tablets are a more effective analgesic than
propoxyphene for the relief of episiotomy pain, pain following dental extraction procedures, and for the
relief of the symptoms of primary dysmenorrhea.
In patients with primary dysmenorrhea, MOTRIN tablets have been shown to reduce elevated levels of
prostaglandin activity in the menstrual fluid and to reduce resting and active intrauterine pressure, as well
as the frequency of uterine contractions. The probable mechanism of action is to inhibit prostaglandin
synthesis rather than simply to provide analgesia.
The ibuprofen in MOTRIN tablets is rapidly absorbed. Peak serum ibuprofen levels are generally attained
one to two hours after administration. With single doses up to 800 mg, a linear relationship exists between
amount of drug administered and the integrated area under the serum drug concentration vs time curve.
Above 800 mg, however, the area under the curve increases less than proportional to increases in dose.
There is no evidence of drug accumulation or enzyme induction.
The administration of MOTRIN tablets either under fasting conditions or immediately before meals
yields quite similar serum ibuprofen concentration-time profiles. When MOTRIN tablets are administered
immediately after a meal, there is a reduction in the rate of absorption but no appreciable decrease in the
extent of absorption. The bioavailability of the drug is minimally altered by the presence of food.
A bioavailability study has shown that there was no interference with the absorption of ibuprofen when
MOTRIN tablets were given in conjunction with an antacid containing both aluminum hydroxide and
magnesium hydroxide.
Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually
complete 24 hours after the last dose. The serum half-life is 1.8 to 2.0 hours.
Studies have shown that following ingestion of the drug, 45% to 79% of the dose was recovered in the
urine within 24 hours as metabolite A (25%), (+)-2-[p-(2hydroxymethyl-propyl) phenyl] propionic acid
and metabolite B (37%), (+)-2-[p-(2carboxypropyl)phenyl] propionic acid; the percentages of free and
conjugated ibuprofen were approximately 1% and 14%, respectively.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of MOTRIN tablets and other treatment options
before deciding to use MOTRIN. Use the lowest effective dose for the shortest duration consistent
with individual patient treatment goals (see WARNINGS).
MOTRIN tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis and
osteoarthritis.
MOTRIN tablets are indicated for relief of mild to moderate pain.
MOTRIN tablets are also indicated for the treatment of primary dysmenorrhea.
NDA 17-463/S-104
Page 5
Controlled clinical trials to establish the safety and effectiveness of MOTRIN tablets in children have not
been conducted.
CONTRAINDICATIONS
MOTRIN tablets are contraindicated in patients with known hypersensitivity to Ibuprofen.
MOTRIN tablets should not be given to patients who have experienced asthma, urticaria, or allergic-
type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions, and
PRECAUTIONS, Preexisting Asthma).
MOTRIN tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
Hypertension
NSAIDs including MOTRIN tablets, can lead to onset of new hypertension or worsening of pre-
existing hypertension, either of which may contribute to the increased incidence of CV events. Patients
taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including MOTRIN tablets, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout
the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. MOTRIN tablets
should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including MOTRIN tablets, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
NDA 17-463/S-104
Page 6
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of
patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those
with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic
ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased
risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other
factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use
of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol,
older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients,
alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-
dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired
renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the
elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of MOTRIN tablets in
patients with advanced renal disease. Therefore, treatment with MOTRIN tablets is not recommended
in these patients with advanced renal disease. If MOTRIN tablet therapy must be initiated, close
monitoring of the patients renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure
to MOTRIN tablets. MOTRIN tablets should not be given to patients with the aspirin triad. This
symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal
polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including MOTRIN tablets, can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be
fatal. These serious events may occur without warning. Patients should be informed about the signs
NDA 17-463/S-104
Page 7
and symptoms of serious skin manifestations and use of the drug should be discontinued at the first
appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, MOTRIN tablets should be avoided because it may cause
premature closure of the ductus arteriosus.
PRECAUTIONS
General
MOTRIN tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to
discontinue corticosteroids.
The pharmacological activity of MOTRIN tablets in reducing fever and inflammation may diminish
the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hepatic effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs,
including MOTRIN tablets. These laboratory abnormalities may progress, may remain unchanged, or
may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or
more times the upper limit of normal) have been reported in approximately 1% of patients in clinical
trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant
hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values,
should be evaluated for evidence of the development of a more severe hepatic reaction while on
therapy with MOTRIN tablets. If clinical signs and symptoms consistent with liver disease develop, or
if systemic manifestations occur (e.g., eosinophilia, rash, etc.), MOTRIN tablets should be dis-
continued.
Hematological effects
Anemia is sometimes seen in patients receiving NSAIDs, including MOTRIN tablets. This may be
due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon
erythropoiesis. Patients on long-term treatment with NSAIDs, including MOTRIN tablets, should have
their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
In two postmarketing clinical studies the incidence of a decreased hemoglobin level was greater than
previously reported. Decrease in hemoglobin of 1 gram or more was observed in17.1% of 193 patients
on 1600 mg ibuprofen daily (osteoarthritis), and in 22.8% of 189 patients taking 2400 mg of ibuprofen
daily (rheumatoid arthritis). Positive stool occult blood tests and elevated serum creatinine levels were
also observed in these studies.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
NDA 17-463/S-104
Page 8
Patients receiving MOTRIN tablets who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants should be carefully
monitored.
Preexisting asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and NSAIDs has been reported in such aspirin-
sensitive patients, MOTRIN tablets should not be administered to patients with this form of aspirin
sensitivity and should be used with caution in patients with preexisting asthma.
Ophthalmological effects
Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a
patient develops such complaints while receiving MOTRIN tablets, the drug should be discontinued, and
the patient should have an ophthalmologic examination which includes central visual fields and color
vision testing.
Aseptic Meningitis
Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen
therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus
and related connective tissue diseases, it has been reported in patients who do not have an underlying
chronic disease. If signs or symptoms of meningitis develop in a patient on MOTRIN tablets, the
possibility of its being related to MOTRIN tablets should be considered.
Information for Patients
Patients should be informed of the following information before initiating therapy with an NSAID and
periodically during the course of ongoing therapy. Patients should also be encouraged to read the
NSAID Medication Guide that accompanies each prescription dispensed.
• MOTRIN tablets like other NSAIDs, may cause serious CV side effects, such as MI or stroke,
which may result in hospitalization and even death. Although serious CV events can occur
without warning symptoms, patients should be alert for the signs and symptoms of chest pain,
shortness of breath, weakness, slurring of speech, and should ask for medical advice when
observing any indicative sign or symptoms. Patients should be apprised of the importance of
this follow-up (see WARNINGS, Cardiovascular Effects).
• MOTRIN tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side
effects, such as ulcers and bleeding, which may result in hospitalization and even death.
Although serious GI tract ulcerations and bleeding can occur without warning symptoms,
patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask
for medical advice when observing any indicative signs or symptoms including epigastric pain,
dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this
follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding and
Perforation).
• MOTRIN tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious
skin reactions may occur without warning, patients should be alert for the signs and symptoms
NDA 17-463/S-104
Page 9
of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask
for medical advice when observing any indicative sign or symptoms. Patients should be advised
to stop the drug immediately if they develop any type of rash and contact their physicians as
soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to
their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and seek immediate medical
therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, MOTRIN tablets should be avoided because it may
cause premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash
etc.), or abnormal liver tests persist or worsen, MOTRIN tablets should be discontinued.
Drug Interactions
ACE-inhibitors:
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This
interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-
inhibitors.
Aspirin
When MOTRIN tablets are administered with aspirin, its protein binding is reduced, although the
clearance of free MOTRIN tablets is not altered. The clinical significance of this interaction is not
known; however, as with other NSAIDs, concomitant administration of ibuprofen and aspirin is not
generally recommended because of the potential for increased adverse effects.
Diuretics
Clinical studies, as well as post marketing observations, have shown that MORTIN tablets can reduce
the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to
inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient
should be observed closely for signs of renal failure (see PRECAUTIONS, Renal Effects), as well as
to assure diuretic efficacy.
NDA 17-463/S-104
Page 10
Lithium
Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in
a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the
renal clearance of lithium was decreased by 19% during this period of concomitant drug
administration.
This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when
ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of
lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.)
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney
slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used
when NSAIDs are administered concomitantly with methotrexate.
Warfarin-type anticoagulants
Several short-term controlled studies failed to show that MOTRIN tablets significantly affected
prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-
type anticoagulants. However, because bleeding has been reported when MOTRIN tablets and other
NSAIDs have been administered to patients on coumarin-type anticoagulants, the physician should be
cautious when administering MOTRIN tablets to patients on anticoagulants. The effects of warfarin
and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of
serious GI bleeding higher than users of either drug alone.
H-2 Antagonists
In studies with human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had
no substantive effect on ibuprofen serum concentrations.
Pregnancy
Teratogenic effects: Pregnancy Category C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental
abnormalities. However, animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies in pregnant women. Motrin should be used in
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic effects
Because of the known effects of NSAIDs on the fetal cardiovascular system (closure of ductus
arteriosus), use during late pregnancy should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an
increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects
of MOTRIN tablets on labor and delivery in pregnant women are unknown.
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
NDA 17-463/S-104
Page 11
MOTRIN tablets, a decision should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of MOTRIN tablets in pediatric patients have not been established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
ADVERSE REACTIONS
The most frequent type of adverse reaction occurring with MOTRIN tablets is gastrointestinal. In
controlled clinical trials the percentage of patients reporting one or more gastrointestinal complaints
ranged from 4% to 16%.
In controlled studies when MOTRIN tablets were compared to aspirin and indomethacin in equally
effective doses, the overall incidence of gastrointestinal complaints was about half that seen in either
the aspirin- or indomethacin-treated patients.
Adverse reactions observed during controlled clinical trials at an incidence greater than 1% are listed
in the table. Those reactions listed in Column one encompass observations in approximately 3,000
patients. More than 500 of these patients were treated for periods of at least 54 weeks.
Still other reactions occurring less frequently than 1 in 100 were reported in controlled clinical trials
and from marketing experience. These reactions have been divided into two categories: Column two of
the table lists reactions with therapy with MOTRIN tablets where the probability of a causal
relationship exists: for the reactions in Column three, a causal relationship with MOTRIN tablets has
not been established.
Reported side effects were higher at doses of 3200 mg/day than at doses of 2400 mg or less per day
in clinical trials of patients with rheumatoid arthritis. The increases in incidence were slight and still
within the ranges reported in the table.
NDA 17-463/S-104
Page 12
Incidence Greater than 1%
(but less than 3%)
Probable Causal Relationship
Precise Incidence Unknown
(but less than 1%)
Probable Causal Relationship**
Precise Incidence Unknown
(but less than 1%)
Causal Relationship
Unknown**
GASTROINTESTINAL
Nausea*, epigastric pain*, heartburn*, diarrhea, Gastric or duodenal ulcer with bleeding and/or perfo-
abdominal distress, nausea and vomiting,
ration, gastrointestinal hemorrhage, melena, gastritis,
indigestion, constipation, abdominal cramps or hepatitis, jaundice, abnormal liver function tests; pan-
Pain, fullness of GI tract (bloating and
Creatitis
flatulence)
CENTRAL NERVOUS SYSTEM
Dizziness*, headache, nervousness
Depression, insomnia, confusion, emotional liability, Paresthesias, hallucinations,
somnolence, aseptic meningitis with fever and coma dream abnormalities, pseudo-
(see PRECAUTIONS)
tumor cerebri
DERMATOLOGIC
Rash* (including maculopapular type), pruritus Vesiculobullous eruptions, urticaria, erythema multi- Toxic epidermal necrolysis, pho-
forme, Stevens-Johnson syndrome, alopecia
toallergic skin reactions
SPECIAL SENSES
Tinnitus
Hearing loss, amblyopia (blurred and/or diminished
Conjunctivitis, diplopia, optic
vision, scotomata and/or changes in color vision) (see neuritis, cataracts
PRECAUTIONS)
HEMATOLOGIC
Neutropenia, agranulocytosis, aplastic anemia,
Bleeding episodes (eg epistaxis,
hemolytic anemia (sometimes Coombs positive),
menorrhagia)
thrombocytopenia with or without purpura,
eosinophilia, decreases in hemoglobin and hematocrit
(see PRECAUTIONS)
METABOLIC/ENDOCRINE
Decreased appetite
Gynecomastia, hypoglycemic
reaction, acidosis
CARDIOVASCULAR
Edema, fluid retention (generally responds
Congestive heart failure in patients with marginal car- Arrhythmias (sinus tachycardia,
promptly to drug discontinuation) (see PRE-
diac function, elevated blood pressure, palpitations
sinus bradycardia)
CAUTIONS)
ALLERGIC
Syndrome of abdominal pain, fever, chills, nausea
Serum sickness, lupus erythe-
and vomiting; anaphylaxis; bronchospasm (see CON- matosus syndrome. Henoch-
TRAINDICATIONS)
Schonlein vasculitis, angioedema
RENAL
Acute renal failure (see PRECAUTIONS), decreased Renal papillary necrosis
creatinine clearance, polyuria, azotemia, cystitis,
Hematuria
MISCELLANEOUS
Dry eyes and mouth, gingival ulcer, rhinitis
* Reactions occurring in 3% to 9% of patients treated with MOTRIN. (Those reactions occurring in less than 3% of the patients are
unmarked.)
** Reactions are classified under "Probable Causal Relationship (PCR)" if there has been one positive rechallenge or if three or more
cases occur which might be causally related. Reactions are classified under "Causal Relationship Unknown" if seven or more events
have been reported but the criteria for PCR have not been met.
NDA 17-463/S-104
Page 13
OVERDOSAGE
Approximately 1½ hours after the reported ingestion of from 7 to 10 MOTRIN tablets (400 mg), a
19-month old child weighing 12 kg was seen in the hospital emergency room, apneic and cyanotic,
responding only to painful stimuli. This type of stimulus, however, was sufficient to induce respiration.
Oxygen and parenteral fluids were given; a greenish-yellow fluid was aspirated from the stomach with
no evidence to indicate the presence of ibuprofen. Two hours after ingestion the child’s condition
seemed stable; she still responded only to painful stimuli and continued to have periods of apnea
lasting from 5 to 10 seconds. She was admitted to intensive care and sodium bicarbonate was
administered as well as infusions of dextrose and normal saline. By four hours post-ingestion she could
be aroused easily, sit by herself and respond to spoken commands. Blood level of ibuprofen was 102.9
µg/mL approximately 8½ hours after accidental ingestion. At 12 hours she appeared to be completely
recovered.
In two other reported cases where children (each weighing approximately 10 kg) accidentally, acutely
ingested approximately 120 mg/kg, there were no signs of acute intoxication or late sequelae. Blood
level in one child 90 minutes after ingestion was 700 µg/mL — about 10 times the peak levels seen in
absorption-excretion studies.
A 19-year old male who had taken 8,000 mg of ibuprofen over a period of a few hours complained of
dizziness, and nystagmus was noted. After hospitalization, parenteral hydration and three days bed
rest, he recovered with no reported sequelae.
In cases of acute overdosage, the stomach should be emptied by vomiting or lavage, though little drug
will likely be recovered if more than an hour has elapsed since ingestion. Because the drug is
acidic and is excreted in the urine, it is theoretically beneficial to administer alkali and
induce diuresis. In addition to supportive measures, the use of oral activated charcoal may
help to reduce the absorption and reabsorption of MOTRIN tablets.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of MOTRIN tablets and other treatment options
before deciding to use MOTRIN tablets. Use the lowest effective dose for the shortest duration
consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with MOTRIN tablets, the dose and frequency should
be adjusted to suit an individual patient’s needs.
Do not exceed 3200 mg total daily dose. If gastrointestinal complaints occur, administer MOTRIN
tablets with meals or milk.
Rheumatoid arthritis and osteoarthritis, including flare-ups of chronic disease:
Suggested Dosage: 1200 mg-3200 mg daily (300 mg qid; 400 mg, 600 mg or 800 mg tid or qid).
Individual patients may show a better response to 3200 mg daily, as compared with 2400 mg, although
in well-controlled clinical trials patients on 3200 mg did not show a better mean response in terms of
efficacy. Therefore, when treating patients with 3200 mg/day, the physician should observe sufficient
increased clinical benefits to offset potential increased risk.
The dose should be tailored to each patient, and may be lowered or raised depending on the severity
of symptoms either at time of initiating drug therapy or as the patient responds or fails to respond.
In general, patients with rheumatoid arthritis seem to require higher doses of MOTRIN tablets than do
patients with osteoarthritis.
NDA 17-463/S-104
Page 14
The smallest dose of MOTRIN tablets that yields acceptable control should be employed. A linear
blood level dose-response relationship exists with single doses up to 800 mg (See CLINICAL
PHARMACOLOGY for effects of food on rate of absorption).
The availability of four tablet strengths facilitates dosage adjustment.
In chronic conditions, a therapeutic response to therapy with MOTRIN tablets is sometimes seen in a
few days to a week but most often is observed by two weeks. After a satisfactory response has been
achieved, the patient’s dose should be reviewed and adjusted as required.
Mild to moderate pain: 400 mg every 4 to 6 hours as necessary for relief of pain.
In controlled analgesic clinical trials, doses of MOTRIN tablets greater than 400 mg were no more
effective than the 400 mg dose.
Dysmenorrhea: For the treatment of dysmenorrhea, beginning with the earliest onset of
such pain, MOTRIN tablets should be given in a dose of 400 mg every 4 hours as necessary for the
relief of pain.
HOW SUPPLIED
MOTRIN tablets are available in the following strengths, colors and sizes:
400 mg (white, round, imprinted with MOTRIN 400)
Bottles of 100
NDC 0009-7385-01
Bottles of 500
NDC 0009-7385-02
Unit dose blister of 100
NDC 0009-7385-04
600 mg (white, elliptical, imprinted with MOTRIN 600)
Bottles of 90
NDC 0009-7386-05
Bottles of 100
NDC 0009-7386-01
Bottles of 270
NDC 0009-7386-09
Bottles of 500
NDC 0009-7386-02
Unit dose blister of 100
NDC 0009-7386-04
800 mg (white, elliptical, imprinted with MOTRIN 800)
Bottles of 100
NDC 0009-7387-01
Bottles of 270
NDC 0009-7387-08
Bottles of 500
NDC 0009-7387-02
Unit dose blister of 100
NDC 0009-7387-04
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Distributed by:
Pharmacia & Upjohn Company
Division of Pfizer Inc, NY, NY 10017
NDA 17-463/S-104
Page 15
Revised January 2006
LAB-0128-2.1
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
NDA 17-463/S-104
Page 16
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
NDA 17-463/S-104
Page 17
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017463s104lbl.pdf', 'application_number': 17463, 'submission_type': 'SUPPL ', 'submission_number': 104}
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NDA 17-468/S-019
NDA 17-469/S-031
Page 3
Packaging Insert
1/8% Econopred
1 % Econopred
Plus
(prednisolone acetate ophthalmic suspension)
DESCRIPTION: ECONOPRED and ECONOPRED Plus (Prednisolone Acetate ophthalmic
suspension) are adrenocortical steroid products prepared as sterile ophthalmic suspensions. The active
ingredient is represented by the chemical structure:
[Structure]
Established name: Prednisolone Acetate
Chemical name: Pregna-1,4-diene-3,20-dione,21-(acetyloxy)-11,17-dihydroxy-,(11β)-.
Each mL contains: Active: prednisolone acetate 1.0% or 0.125%. Preservative: benzalkonium
chloride 0.01 %. Vehicle: hydroxypropyl methylcellulose. Inactive: dibasic sodium phosphate,
polysorbate 80, edetate disodium, glycerin, citric acid and/or sodium hydroxide (to adjust pH), purified
water.
CLINICAL PHARMACOLOGY: Corticosteroids inhibit the inflammatory response to a variety of
inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary
dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen,
and scar formation associated with inflammation.
There is no generally accepted explanation for the mechanism of action of ocular corticosteroids.
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.
Corticosteroids are capable of producing a rise in intraocular pressure.
INDICATIONS AND USAGE: Steroid responsive inflammatory conditions of the palpebral and
bulbar conjunctiva, cornea, and anterior segment of the globe such as allergic conjunctivitis, acne
rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective
conjunctivitides, when the inherent hazard of steroid use is accepted to obtain an advisable diminution
in edema and inflammation; corneal injury from chemical, radiation, or thermal burns, or penetration
of foreign bodies.
CONTRAINDICATIONS: ECONOPRED and ECONOPRED Plus (prednisolone acetate ophthalmic
suspension) are contraindicated in most viral diseases of the cornea and conjunctiva including
epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in
mycobacterial infection of the eye and fungal diseases of ocular structures. ECONOPRED and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-468/S-019
NDA 17-469/S-031
Page 4
ECONOPRED Plus (prednisolone acetate ophthalmic suspension) are also contraindicated in
individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and
to other corticosteroids.
WARNINGS: FOR TOPICAL OPHTHALMIC USE ONLY. Prolonged use of corticosteroids may
result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in
posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response
and thus increase the hazard of secondary ocular infections.
Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal
and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may
lead to perforation.
Acute purulent infections of the eye may be masked or activity enhanced by the presence of
corticosteroid medication.
If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even
though it may be difficult in children and uncooperative patients. Steroids should be used with caution
in the presence of glaucoma. Intraocular pressure should be checked frequently.
The use of steroids after cataract surgery may delay healing and increase the incidence of bleb
formation.
Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections
of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of
patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is
recommended.
Corticosteroids are not effective in mustard gas keratitis and Sjögren's keratoconjunctivitis.
PRECAUTIONS: General: The initial prescription and renewal of the medication order should be
made by a physician only after examination of the patient with the aid of magnification, such as slit
lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to
improve after two days, the patient should be re-evaluated.
As fungal infections of the cornea are particularly prone to develop coincidentally with long-term local
corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration
where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate.
If this product is used for 10 days or longer, intraocular pressure should be monitored (SEE
WARNINGS).
Information for Patients: If inflammation or pain persists longer than 48 hours or becomes
aggravated, the patient should be advised to discontinue use of the medication and consult a physician.
This product is sterile when packaged. To prevent contamination, care should be taken to avoid
touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person
may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been conducted in animals
or in humans to evaluate the potential of these effects.
Pregnancy: Teratogenic effects. Pregnancy Category C. Prednisolone has been shown to be
teratogenic in mice when given in doses 1-10 times the human dose. Dexamethasone, hydrocortisone
and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on days 10
through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-468/S-019
NDA 17-469/S-031
Page 5
fetuses of the treated mice. There are no adequate and well controlled studies in pregnant women.
ECONOPRED and ECONOPRED Plus (prednisolone acetate ophthalmic suspension) should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether topical administration of corticosteroids could result in
sufficient systemic absorption to produce detectable quantities in human milk. Systemically
administered corticosteroids appear in human milk and could suppress growth, interfere with
endogenous corticosteroid production, or cause other untoward effects. Because of the potential for
serious adverse reactions in nursing infants from prednisolone acetate, 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 pediatric patients have not been established.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly
and younger patients.
ADVERSE REACTIONS: Adverse reactions include, in decreasing order of frequency, elevation of
intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage,
posterior subcapsular cataract formation, and delayed wound healing.
Although systemic effects are extremely uncommon, there have been rare occurrences of systemic
hypercorticoidism after use of topical steroids.
Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and
perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia,
loss of accommodation and ptosis have occasionally been reported following local use of
corticosteroids.
The development of secondary ocular infection (bacterial, fungal and viral) has occurred. Fungal and
viral infections of the cornea are particularly prone to develop coincidentally with long-term
applications of steroid. The possibility of fungal invasion should be considered in any persistent
corneal ulceration where steroid treatment has been used (SEE WARNINGS).
DOSAGE AND ADMINISTRATION: SHAKE WELL BEFORE USING. Two drops topically in
the eye(s) four times daily. In cases of bacterial infections, concomitant use of anti-infective agents is
mandatory. Care should be taken not to discontinue therapy prematurely.
If signs and symptoms fail to improve after two days, the patient should be re-evaluated (SEE
PRECAUTIONS).
The dosing of ECONOPRED and ECONOPRED Plus may be reduced, but care should be taken not to
discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out
by gradually decreasing the frequency of applications.
HOW SUPPLIED: 5mL and 10mL in plastic DROP-TAINER® dispensers.
1/8% ECONOPRED:
1% ECONOPRED Plus:
5 mL NDC 0998-0635-05
5 mL NDC 0998-0637-05
10 mL NDC 0998-0635-10
10 mL NDC 0998-0637-10
STORAGE: STORE at 8° - 24°C (46° - 75°F) in an UPRIGHT position.
Rx Only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-468/S-019
NDA 17-469/S-031
Page 6
Revised: August 2002
Alcon
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
Printed in USA
2002 Alcon Laboraties, Inc.
ECOGER-0802
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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2025-02-12T13:44:11.912727
|
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NDA 17-469/S-040
Page 3
Omnipred™ (prednisolone acetate ophthalmic suspension)
DESCRIPTION: Omnipred™ (prednisolone acetate ophthalmic suspension) is an adrenocortical
steroid product prepared as sterile ophthalmic suspension. The active ingredient is represented by the
chemical structure:
--- CHEMICAL STRUCTURE ---
Established name: Prednisolone Acetate
Chemical name: Pregna-1,4-diene-3,20-dione,21-(acetyloxy)-11,17-dihydroxy-,(11β)-.
Each mL contains: Active: prednisolone acetate 1.0%. Preservative: benzalkonium chloride 0.01%.
Vehicle: hypromellose. Inactives: dibasic sodium phosphate, polysorbate 80, edetate disodium,
glycerin, citric acid and/or sodium hydroxide (to adjust pH), purified water.
CLINICAL PHARMACOLOGY: Corticosteroids inhibit the inflammatory response to a variety of
inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary
dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen,
and scar formation associated with inflammation. There is no generally accepted explanation for the
mechanism of action of ocular corticosteroids. 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.
Corticosteroids are capable of producing a rise in intraocular pressure.
INDICATIONS AND USAGE: Steroid responsive inflammatory conditions of the palpebral and
bulbar conjunctiva, cornea, and anterior segment of the globe such as allergic conjunctivitis, acne
rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective
conjunctivitides, when the inherent hazard of steroid use is accepted to obtain an advisable diminution
in edema and inflammation; corneal injury from chemical, radiation, or thermal burns, or penetration
of foreign bodies.
CONTRAINDICATIONS: Omnipred™ (prednisolone acetate ophthalmic suspension) is
contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex
keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and
fungal diseases of ocular structures. Omnipred™ (prednisolone acetate ophthalmic suspension) is also
contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-469/S-040
Page 4
this preparation and to other corticosteroids.
WARNINGS: FOR TOPICAL OPHTHALMIC USE ONLY. Prolonged use of corticosteroids may
result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in
posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response
and thus increase the hazard of secondary ocular infections. Various ocular diseases and long-term use
of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical
corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation. Acute purulent
infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication.
If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even
though it may be difficult in children and uncooperative patients. Steroids should be used with caution
in the presence of glaucoma.
Intraocular pressure should be checked frequently.
The use of steroids after cataract surgery may delay healing and increase the incidence of bleb
formation.
Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections
of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of
patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is
recommended.
Corticosteroids are not effective in mustard gas keratitis and Sjögren’s keratoconjunctivitis.
PRECAUTIONS: General: The initial prescription and renewal of the medication order should be
made by a physician only after examination of the patient with the aid of magnification, such as slit
lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to
improve after two days, the patient should be re-evaluated.
As fungal infections of the cornea are particularly prone to develop coincidentally with long-term local
corticosteroid applications, fungal invasion should be suspected in any persistent corneal ulceration
where a corticosteroid has been used or is in use. Fungal cultures should be taken when appropriate.
If this product is used for 10 days or longer, intraocular pressure should be monitored (SEE
WARNINGS).
Information for Patients: If inflammation or pain persists longer than 48 hours or becomes
aggravated, the patient should be advised to discontinue use of the medication and consult a physician.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-469/S-040
Page 5
This product is sterile when packaged. To prevent contamination, care should be taken to avoid
touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person
may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been conducted in animals
or in humans to evaluate the potential of these effects.
Pregnancy: Teratogenic effects. Pregnancy Category C. Prednisolone has been shown to be
teratogenic in mice when given in doses 1-10 times the human dose.
Dexamethasone, hydrocortisone and prednisolone were ocularly applied to both eyes of pregnant mice
five times per day on days 10 through 13 of gestation. A significant increase in the incidence of cleft
palate was observed in the fetuses of the treated mice. There are no adequate and well controlled
studies in pregnant women. Omnipred™ (prednisolone acetate ophthalmic suspension) should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether topical administration of corticosteroids could result in
sufficient systemic absorption to produce detectable quantities in human milk. Systemically
administered corticosteroids appear in human milk and could suppress growth, interfere with
endogenous corticosteroid production, or cause other untoward effects. Because of the potential for
serious adverse reactions in nursing infants from prednisolone acetate, 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 pediatric patients have not been established.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly
and younger patients.
ADVERSE REACTIONS: Adverse reactions include, in decreasing order of frequency, elevation of
intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage,
posterior subcapsular cataract formation, and delayed wound healing.
Although systemic effects are extremely uncommon, there have been rare occurrences of systemic
hypercorticoidism after use of topical steroids.
Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and
perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-469/S-040
Page 6
loss of accommodation and ptosis have occasionally been reported following local use of
corticosteroids.
The development of secondary ocular infection (bacterial, fungal and viral) has occurred. Fungal and
viral infections of the cornea are particularly prone to develop coincidentally with long-term
applications of steroid. The possibility of fungal invasion should be considered in any persistent
corneal ulceration where steroid treatment has been used (SEE WARNINGS).
DOSAGE AND ADMINISTRATION: SHAKE WELL BEFORE USING. Two drops topically in
the eye(s) four times daily. In cases of bacterial infections, concomitant use of anti-infective agents is
mandatory. Care should be taken not to discontinue therapy prematurely. If signs and symptoms fail to
improve after two days, the patient should be re-evaluated (SEE PRECAUTIONS).
The dosing of Omnipred™ suspension may be reduced, but care should be taken not to discontinue
therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually
decreasing the frequency of applications.
HOW SUPPLIED: Omnipred™ (prednisolone acetate ophthalmic suspension) is supplied in a white,
round low density polyethylene DROP-TAINER® dispenser with a natural low density polyethylene
dispensing plug and pink polypropylene cap. Tamper evidence is provided with a shrink band around
the closure and neck area of the package.
Omnipred™s suspension:
5 mL NDC 0065-06378-27
10 mL NDC 0065-06378-25
STORAGE: STORE at 8° - 24°C (46° - 75°F) in an UPRIGHT position.
Rx Only
ALCON LABORATORIES, INC.
Fort Worth, Texas 76134 USA
Printed in USA
©2006 Alcon, Inc.
Revised: June 2006
9001774-0706
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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2025-02-12T13:44:11.987445
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017469s040lbl.pdf', 'application_number': 17469, 'submission_type': 'SUPPL ', 'submission_number': 40}
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1
XXXXXX
ORAP® (Pimozide)
Tablets
GATE
151
187
DESCRIPTION
ORAP
® (pimozide) is an orally active antipsychotic agent of the diphenyl-butylpiperidine
series.
The structural formula of pimozide, 1-[1-[4,4-bis(4-fluorophenyl) butyl]-4
piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one is: structural formula
The solubility of pimozide in water is less than 0.01 mg/mL; it is slightly soluble in most
organic solvents.
Each white ORAP tablet contains either 1 mg or 2 mg of pimozide and the following
inactive ingredients: calcium stearate, microcrystalline cellulose, lactose anhydrous and
corn starch.
CLINICAL PHARMACOLOGY
Pharmacodynamic Actions
ORAP (pimozide) is an orally active antipsychotic drug product which shares with other
antipsychotics the ability to blockade dopaminergic receptors on neurons in the central
nervous system. Although its exact mode of action has not been established, the ability
of pimozide to suppress motor and phonic tics in Tourette’s Disorder is thought to be a
function of its dopaminergic blocking activity. However, receptor blockade is often
accompanied by a series of secondary alterations in central dopamine metabolism and
function which may contribute to both pimozide’s therapeutic and untoward effects. In
addition, pimozide, in common with other antipsychotic drugs, has various effects on
other central nervous system receptor systems which are not fully characterized.
Metabolism and Pharmacokinetics
More than 50% of a dose of pimozide is absorbed after oral administration. Based on the
pharmacokinetic and metabolic profile, pimozide appears to undergo significant first pass
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2
metabolism. Peak serum levels occur generally six to eight hours (range 4-12 hours)
after dosing.
Pimozide is extensively metabolized, primarily by N-dealkylation in the liver. This
metabolism is catalyzed mainly by the cytochrome P450 3A4 (CYP 3A4) enzymatic
system and to a lesser extent, by cytochrome P450 1A2 (CYP 1A2). Two major
metabolites have been identified, 1-(4-piperidyl)-2-benzimidazolinone and 4,4-bis(4
fluorophenyl) butyric acid.
The antipsychotic activity of these metabolites is
undetermined. The major route of elimination of pimozide and its metabolites is through
the kidney.
The mean serum elimination half-life of pimozide in schizophrenic patients was
approximately 55 hours. There was a 13-fold interindividual difference in the area under
the serum pimozide level-time curve and an equivalent degree of variation in peak serum
levels among patients studied. The significance of this is unclear since there are few
correlations between plasma levels and clinical findings.
Effects of food and disease upon the absorption, distribution, metabolism and elimination
of pimozide are not known. Effects of concomitant medication on pimozide metabolism
are described in the CONTRAINDICATIONS section.
INDICATIONS AND USAGE
ORAP (pimozide) is indicated for the suppression of motor and phonic tics in patients
with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment.
ORAP is not intended as a treatment of first choice nor is it intended for the treatment of
tics that are merely annoying or cosmetically troublesome. ORAP should be reserved for
use in Tourette’s Disorder patients whose development and/or daily life function is
severely compromised by the presence of motor and phonic tics.
Evidence supporting approval of pimozide for use in Tourette’s Disorder was obtained in
two controlled clinical investigations which enrolled patients between the ages of 8 and
53 years. Most subjects in the two trials were 12 or older.
CONTRAINDICATIONS
1. ORAP (pimozide) is contraindicated in the treatment of simple tics or tics other than
those associated with Tourette’s Disorder.
2. ORAP should not be used in patients taking drugs that may, themselves, cause motor
and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until such patients
have been withdrawn from these drugs to determine whether or not the drugs, rather than
Tourette’s Disorder, are responsible for the tics.
3. Because ORAP prolongs the QT interval of the electrocardiogram it is contraindicated
in patients with congenital long QT syndrome, patients with a history of cardiac
arrhythmias, patients taking other drugs which prolong the QT interval of the
electrocardiogram or patients with known hypokalemia or hypomagnesemia (see also
PRECAUTIONS - Drug Interactions).
Reference ID: 2870808
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3
4.
ORAP is contraindicated in patients with severe toxic central nervous system
depression or comatose states from any cause.
5. ORAP is contraindicated in patients with hypersensitivity to it. As it is not known
whether cross-sensitivity exists among the antipsychotics, pimozide should be used with
appropriate caution in patients who have demonstrated hypersensitivity to other
antipsychotic drugs.
6.
Ventricular arrhythmias have been rarely associated with the use of macrolide
antibiotics in patients with prolonged QT intervals, as might be produced by ORAP.
Specifically, two sudden deaths have been reported when clarithromycin was added to
ongoing pimozide therapy. Furthermore, some evidence suggests that pimozide is
metabolized partly by the enzyme system cytochrome P450 3A4 (CYP 3A4). Macrolide
antibiotics are inhibitors of CYP 3A4, and thus could potentially impede pimozide
metabolism. For these reasons, ORAP is contraindicated in patients receiving the
macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and
troleandomycin.
7.
Concomitant use in patients taking Celexa or Lexapro is contraindicated (see
Precautions - Drug Interactions - Pimozide and Celexa).
Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus
may likewise impair pimozide metabolism, ORAP is contraindicated in patients receiving
the azole antifungal agents itraconazole and ketoconazole.
Similarly, protease inhibitor drugs are also inhibitors of CYP 3A4, and thus ORAP is
contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir,
indinavir, and nelfinavir. (See PRECAUTIONS - Drug Interactions.)
Nefazodone is a potent inhibitor of CYP 3A4, and its concomitant use with ORAP is also
contraindicated.
Other drugs that are relatively less potent inhibitors of CYP 3A4 should also be avoided,
in view of the risks: e.g. zileuton, fluvoxamine.
Concomitant use of pimozide in patients taking sertraline is contraindicated (See
PRECAUTIONS - Drug Interactions).
WARNINGS
The use of ORAP (pimozide) in the treatment of Tourette’s Disorder involves different
risk/benefit considerations than when antipsychotic drugs are used to treat other
conditions. Consequently, a decision to use ORAP should take into consideration the
following (see also PRECAUTIONS - Information for Patients).
Tardive Dyskinesia
Reference ID: 2870808
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4
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements
may develop in patients treated with antipsychotic drugs. Although the prevalence of the
syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic
treatment, which patients are likely to develop the syndrome. Whether antipsychotic
drug products differ in their potential to cause tardive dyskinesia is unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total cumulative
dose of antipsychotic drugs administered to the patient increase. However, the syndrome
can develop, although much less commonly, after relatively brief treatment periods at
low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs
and symptoms of the syndrome and thereby may possibly mask the underlying process.
The effect that symptomatic suppression has upon the long-term course of the syndrome
is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that is
most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness that,
1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally
effective, but potentially less harmful treatments are not available or appropriate. In
patients who do require chronic treatment, the smallest dose and the shortest duration of
treatment producing a satisfactory clinical response should be sought. The need for
continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug
discontinuation should be considered. However, some patients may require treatment
despite the presence of the syndrome.
(For further information about the description of tardive dyskinesia and its clinical
detection, please refer to ADVERSE REACTIONS and PRECAUTIONS -
Information for Patients.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including
catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure,
tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include
elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal
failure.
Reference ID: 2870808
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5
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases where the clinical presentation includes both
serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or
inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of antipsychotic
drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic
treatment and medical monitoring, and 3) treatment of any concomitant serious medical
problems for which specific treatments are available. There is no general agreement
about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be
carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia, not associated with the above symptom complex, has been reported with
other antipsychotic drugs.
Other
Sudden, unexpected deaths have occurred in experimental studies of conditions other
than Tourette’s Disorder. These deaths occurred while patients were receiving dosages
in the range of 1 mg per kg. One possible mechanism for such deaths is prolongation of
the QT interval predisposing patients to ventricular arrhythmia. An electrocardiogram
should be performed before ORAP treatment is initiated and periodically thereafter,
especially during the period of dose adjustment.
ORAP may have a tumorigenic potential. Based on studies conducted in mice, it is
known that pimozide can produce a dose-related increase in pituitary tumors. The full
significance of this finding is not known, but should be taken into consideration in the
physician’s and patient’s decisions to use this drug product. This finding should be given
special consideration when the patient is young and chronic use of pimozide is
anticipated
(see
PRECAUTIONS
-
Carcinogenesis,
Mutagenesis,
Impairment of Fertility).
PRECAUTIONS
Leukopenia, Neutropenia and Agranulocytosis
Class Effect:
In clinical trial and/or postmarketing experience, events of
leukopenia/neutropenia and agranulocytosis have been reported temporally related to
antipsychotic agents.
Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell
count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a
history of a clinically significant low WBC or drug induced leukopenia/neutropenia
should have their complete blood count (CBC) monitored frequently during the first few
Reference ID: 2870808
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6
months of therapy and discontinuation of ORAP should be considered at the first sign of
a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or
other symptoms or signs of infection and treated promptly if such symptoms or signs
occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should
discontinue ORAP and have their WBC followed until recovery.
General
ORAP (pimozide) may impair the mental and/or physical abilities required for the
performance of potentially hazardous tasks, such as driving a car or operating machinery,
especially during the first few days of therapy.
ORAP produces anticholinergic side effects and should be used with caution in
individuals whose conditions may be aggravated by anticholinergic activity.
ORAP should be administered cautiously to patients with impairment of liver or kidney
function, because it is metabolized by the liver and excreted by the kidneys.
Antipsychotics should be administered with caution to patients receiving anticonvulsant
medication, with a history of seizures, or with EEG abnormalities, because they may
lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be
maintained concomitantly.
Information for Patients
Treatment with ORAP exposes the patient to serious risks. A decision to use ORAP
chronically in Tourette’s Disorder is one that deserves full consideration by the patient
(or patient’s family) as well as by the treating physician. Because the goal of treatment is
symptomatic improvement, the patient’s view of the need for treatment and assessment of
response are critical in evaluating the impact of therapy and weighing its benefits against
the risks. Since the physician is the primary source of information about the use of a
drug in any disease, it is recommended that the following information be discussed with
patients and/or their families.
ORAP is intended only for use in patients with Tourette’s Disorder whose symptoms are
severe and who cannot tolerate, or who do not respond to HALDOL® (haloperidol).
Given the likelihood that a proportion of patients exposed chronically to antipsychotics
will develop tardive dyskinesia, it is advised that all patients in whom chronic use is
contemplated be given, if possible, full information about this risk. The decision to
inform patients and/or their guardians must obviously take into account the clinical
circumstances and the competency of the patient to understand the information provided.
There is limited information available on the use of ORAP in children under 12 years of
age.
Reference ID: 2870808
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7
The information available on ORAP from foreign marketing experience and from U.S.
clinical trials indicates that ORAP has a side effect profile similar to that of other
antipsychotic drugs. Patients should be informed that all types of side effects associated
with the use of antipsychotics may be associated with the use of ORAP.
In addition, sudden, unexpected deaths have occurred in patients taking high doses of
ORAP for conditions other than Tourette’s Disorder. These deaths may have been the
result of an effect of ORAP upon the heart. Therefore, patients should be instructed not
to exceed the prescribed dose of ORAP and they should realize the need for the initial
ECG and for follow-up ECGs during treatment.
Also, pimozide, at a dose about 15 times that given humans, caused an increase in the
number of benign tumors of the pituitary gland in female mice. It is not possible to say
how important this is. Similar tumors were not seen in rats given pimozide, nor at lower
doses in mice, which is reassuring. However, any such finding must be considered to
suggest a possible risk of long term use of the drug.
Because substances in grapefruit juice may inhibit the metabolism of pimozide by CYP
3A4, patients should be advised to avoid grapefruit juice.
Laboratory Tests
An ECG should be done at baseline and periodically thereafter throughout the period of
dose adjustment. Any indication of prolongation of QTc interval beyond an absolute
limit of 0.47 seconds (children) or 0.52 seconds (adults), or more than 25% above the
patient’s original baseline should be considered a basis for stopping further dose increase
(see CONTRAINDICATIONS) and considering a lower dose.
Since hypokalemia has been associated with ventricular arrhythmias, potassium
insufficiency, secondary to diuretics, diarrhea, or other cause, should be corrected before
ORAP therapy is initiated and normal potassium maintained during therapy.
Drug Interactions
Because ORAP prolongs the QT interval of the electrocardiogram, an additive effect on
QT interval would be anticipated if administered with other drugs, such as
phenothiazines, tricyclic antidepressants or antiarrhythmic agents, which prolong the QT
interval. Accordingly, pimozide should not be given with dofetilide, sotalol, quinidine,
other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine,
droperidol,
sparfloxacin,
gatifloxacin,
moxifloxacin,
halofantrine,
mefloquine,
pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol,
tacrolimus, ziprasidone, or other drugs that have demonstrated QT prolongation as one of
their pharmacodynamic effects. Also, the use of macrolide antibiotics in patients with
prolonged QT intervals has been rarely associated with ventricular arrhythmias. Such
concomitant administration should not be undertaken (see CONTRAINDICATIONS).
Pimozide and Celexa – In a controlled study, a single dose of pimozide 2 mg co
administered with racemic citalopram 40 mg given once daily for 11 days was associated
with a mean increase in QTc values of approximately 10 msec compared to pimozide
Reference ID: 2870808
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8
given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The
mechanism of this pharmacodynamic interaction is not known.
Since ORAP is partly metabolized via CYP 3A4, it should not be administered
concomitantly with inhibitors of this metabolic system, such as azole antifungal agents
and protease inhibitor drugs (see CONTRAINDICATIONS).
As CYP 1A2 may also contribute to the metabolism of ORAP, prescribers should be
aware of the theoretical potential for drug interactions with inhibitors of this enzymatic
system.
ORAP may be capable of potentiating CNS depressants, including analgesics, sedatives,
anxiolytics, and alcohol.
Rare case reports have suggested possible additive effects of pimozide and fluoxetine
leading to bradycardia.
Concomitant administration of pimozide and sertraline should be contraindicated (See
CONTRAINDICATIONS).
Interaction with Food
Patients should avoid grapefruit juice because it may inhibit the metabolism of pimozide
by CYP 3A4.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in mice and rats. In mice, pimozide causes a
dose-related increase in pituitary and mammary tumors.
When mice were treated for up to 18 months with pimozide, pituitary gland changes
developed in females only. These changes were characterized as hyperplasia at doses
approximating the human dose and adenoma at doses about fifteen times the maximum
recommended human dose on a mg per kg basis. The mechanism for the induction of
pituitary tumors in mice is not known.
Mammary gland tumors in female mice were also increased, but these tumors are
expected in rodents treated with antipsychotic drugs which elevate prolactin levels.
Chronic administration of an antipsychotic also causes elevated prolactin levels in
humans. Tissue culture experiments indicate that approximately one-third of human
breast cancers are prolactin-dependent in vitro, a factor of potential importance if the
prescription of these drugs is contemplated in a patient with a previously detected breast
cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported with antipsychotic drugs, the clinical significance of
elevated serum prolactin levels is unknown for most patients. Neither clinical studies nor
epidemiologic studies conducted to date have shown an association between chronic
administration of these drugs and mammary tumorigenesis. The available evidence,
however, is considered too limited to be conclusive at this time.
Reference ID: 2870808
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9
In a 24-month carcinogenicity study in rats, animals received up to 50 times the
maximum recommended human dose. No increased incidence of overall tumors or
tumors at any site was observed in either sex. Because of the limited number of animals
surviving this study, the meaning of these results is unclear.
Pimozide did not have mutagenic activity in the Ames test with four bacterial test strains,
in the mouse dominant lethal test or in the micronucleus test in rats.
Reproduction studies in animals were not adequate to assess all aspects of fertility.
Nevertheless, female rats administered pimozide had prolonged estrus cycles, an effect
also produced by other antipsychotic drugs.
Pregnancy
Category C. Reproduction studies performed in rats and rabbits at oral doses up to 8
times the maximum human dose did not reveal evidence of teratogenicity. In the rat,
however, this multiple of the human dose resulted in decreased pregnancies and in the
retarded development of fetuses. These effects are thought to be due to an inhibition or
delay in implantation which is also observed in rodents administered other antipsychotic
drugs.
In the rabbit, maternal toxicity, mortality, decreased weight gain, and
embryotoxicity including increased resorptions were dose-related. Because animal
reproduction studies are not always predictive of human response, pimozide should be
given to a pregnant woman only if the potential benefits of treatment clearly outweigh the
potential risks.
Nonteratogenic effects. Neonates exposed to antipsychotic drugs, during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms
following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor,
somnolence, respiratory distress and feeding disorder in these neonates. These
complications have varied in severity; while in some cases symptoms have been self-
limited, in other cases neonates have required intensive care unit support and prolonged
hospitalization.
ORAP should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Labor and Delivery
This drug has no recognized use in labor or delivery.
Nursing Mothers
It is not known whether pimozide is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for tumorigenicity and unknown
cardiovascular effects in the infant, 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
Reference ID: 2870808
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Although Tourette's Disorder most often has its onset between the ages of 2 and 15 years,
information on the use and efficacy of ORAP in patients less than 12 years of age is
limited. A 24-week open label study in 36 children between the ages of 2 and 12
demonstrated that pimozide has a similar safety profile in this age group as in older
patients and there were no safety findings that would preclude its use in this age group.
Because its use and safety have not been evaluated in other childhood disorders, ORAP is
not recommended for use in any condition other than Tourette’s Disorder.
ADVERSE REACTIONS
General
Extrapyramidal Reactions: Neuromuscular (extrapyramidal) reactions during the
administration of ORAP
® (pimozide) have been reported frequently, often during the first
few days of treatment. In most patients, these reactions involved Parkinson-like
symptoms which, when first observed, were usually mild to moderately severe and
usually reversible.
Other types of neuromuscular reactions (motor restlessness, dystonia, akathisia,
hyperreflexia, opisthotonos, oculogyric crises) have been reported far less frequently.
Severe extrapyramidal reactions have been reported to occur at relatively low doses.
Generally the occurrence and severity of most extrapyramidal symptoms are dose-related
since they occur at relatively high doses and have been shown to disappear or become
less severe when the dose is reduced. Administration of antiparkinson drugs such as
benztropine mesylate or trihexyphenidyl hydrochloride may be required for control of
such reactions. It should be noted that persistent extrapyramidal reactions have been
reported and that the drug may have to be discontinued in such cases.
Withdrawal Emergent Neurological Signs: Generally, patients receiving short term
therapy experience no problems with abrupt discontinuation of antipsychotic drugs.
However, some patients on maintenance treatment experience transient dyskinetic signs
after abrupt withdrawal.
In certain of these cases the dyskinetic movements are
indistinguishable from the syndrome described below under “Tardive Dyskinesia” except
for duration. It is not known whether gradual withdrawal of antipsychotic drugs will
reduce the rate of occurrence of withdrawal emergent neurological signs, but until further
evidence becomes available, it seems reasonable to gradually withdraw use of ORAP.
Tardive Dyskinesia: ORAP may be associated with persistent dyskinesias. Tardive
dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic
movements, may appear in some patients on long-term therapy or may occur after drug
therapy has been discontinued. The risk appears to be greater in elderly patients on high-
dose therapy, especially females. The symptoms are persistent and in some patients
appear irreversible.
The syndrome is characterized by rhythmical involuntary
movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks,
puckering of mouth, chewing movements). Sometimes these may be accompanied by
involuntary movements of extremities and the trunk.
Reference ID: 2870808
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11
There is no known effective treatment for tardive dyskinesia; antiparkinson agents
usually do not alleviate the symptoms of this syndrome. It is suggested that all
antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to
reinstitute treatment, or increase the dosage of the agent, or switch to a different
antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early sign of
tardive dyskinesia and if the medication is stopped at that time the syndrome may not
develop.
Electrocardiographic Changes: Electrocardiographic changes have been observed in
clinical trials of ORAP in Tourette’s Disorder and schizophrenia. These have included
prolongation of the QT interval, flattening, notching and inversion of the T wave and the
appearance of U waves. Sudden, unexpected deaths and grand mal seizure have occurred
at doses above 20 mg/day.
Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome (NMS) has been
reported with ORAP. (See WARNINGS for further information concerning NMS.)
Hyperpyrexia: Hyperpyrexia has been reported with other antipsychotic drugs.
Clinical Trials
The following adverse reaction tabulation was derived from 20 patients in a 6-week long
placebo-controlled clinical trial of ORAP in Tourette’s Disorder.
Body System/
Adverse Reaction
Pimozide
(N = 20)
Placebo
(N = 20)
Body as a Whole
Headache
1
2
Gastrointestinal
Dry Mouth
Diarrhea
Nausea
Vomiting
Constipation
Eructations
Thirsty
Appetite increase
5
1
0
0
4
0
1
1
1
0
2
1
2
1
0
0
Endocrine
Menstrual disorder
Breast secretions
0
0
1
1
Reference ID: 2870808
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12
Musculoskeletal
Muscle cramps
0
1
Muscle tightness
3
0
Stooped posture
2
0
CNS
Drowsiness
7
3
Sedation
14
5
Insomnia
2
2
Dizziness
0
1
Akathisia
8
0
Rigidity
2
0
Speech disorder
2
0
Handwriting change
1
0
Akinesia
8
0
Psychiatric
Depression
2
3
Excitement
0
1
Nervous
1
0
Adverse behavior effect
5
0
Special Senses
Visual disturbance
4
0
Taste change
1
0
Sensitivity of eyes to light
1
0
Decrease accommodation
4
1
Spots before eyes
0
1
Urogenital
Impotence
3
0
The following adverse event tabulation was derived from 36 children (age 2 to 12) in a
24-week open trial of ORAP in Tourette’s Disorder.
Body System/
Adverse Reaction
Number of Patients
Experiencing Each Event (%)
All Events
(N=36)
Drug-Related
Events
(N=36)
Body as a Whole
Asthenia
9 (25.0)
5 (13.8)
Reference ID: 2870808
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13
Headache
8 (22.2)
1 (2.7)
Gastrointestinal
Dysphagia
Increased Salivation
1 (2.7)
5 (13.8)
1 (2.7)
2 (5.5)
Musculoskeletal
Myalgia
1 (2.7)
1 (2.7)
Central Nervous System
Dreaming Abnormal
Hyperkinesia
Somnolence
Torticollis
Tremor, Limbs
1 (2.7)
2 (5.5)
10 (27.7)
1 (2.7)
1 (2.7)
1 (2.7)
1 (2.7)
9 (25.0)
1 (2.7)
1 (2.7)
Psychiatric
Adverse Behavior Effect
Nervous
10 (27.7)
3 (8.3)
8 (22.2)
2 (5.5)
Skin
Rash
3 (8.3)
1 (2.7)
Special Senses
Visual Disturbance
2 (5.5)
1 (2.7)
Cardiovascular
ECG Abnormal
1 (2.7)
1 (2.7)
Because clinical investigational experience with ORAP in Tourette’s Disorder is limited,
uncommon adverse reactions may not have been detected. The physician should consider
that other adverse reactions associated with antipsychotics may occur.
Other Adverse Reactions
In addition to the adverse reactions listed above, those listed below have been reported in
U.S. clinical trials of ORAP in conditions other than Tourette’s Disorder.
Body as a Whole: Asthenia, chest pain, periorbital edema
Reference ID: 2870808
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14
Cardiovascular/Respiratory:
Postural
hypotension,
hypotension,
hypertension,
tachycardia, palpitations
Gastrointestinal: Increased salivation, nausea, vomiting, anorexia, GI distress
Endocrine: Loss of libido
Metabolic/Nutritional: Weight gain, weight loss
Central Nervous System: Dizziness, tremor, parkinsonism, fainting, dyskinesia
Psychiatric: Excitement
Skin: Rash, sweating, skin irritation
Special Senses: Blurred vision, cataracts
Urogenital: Nocturia, urinary frequency
Postmarketing Reports
The following experiences were described in spontaneous postmarketing reports. These
reports do not provide sufficient information to establish a clear causal relationship with
the use of ORAP.
Gastrointestinal: Gingival hyperplasia in one patient
Hematologic: Hemolytic anemia
Metabolic/Nutritional: Hyponatremia
Other: Seizure
OVERDOSAGE
In general, the signs and symptoms of overdosage with ORAP (pimozide) would be an
exaggeration of known pharmacologic effects and adverse reactions, the most prominent
of which would be: 1) electrocardiographic abnormalities, 2) severe extrapyramidal
reactions, 3) hypotension, 4) a comatose state with respiratory depression.
In the event of overdosage, gastric lavage, establishment of a patent airway and, if
necessary,
mechanically-assisted
respiration
are
advised.
Electrocardiographic
monitoring should commence immediately and continue until the ECG parameters are
within the normal range. Hypotension and circulatory collapse may be counteracted by
use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such
as metaraminol, phenylephrine and norepinephrine.
Epinephrine should not be used.
In case of severe extrapyramidal reactions,
antiparkinson medication should be administered. Because of the long half-life of
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15
pimozide, patients who take an overdose should be observed for at least 4 days. As with
all drugs, the physician should consider contacting a poison control center for additional
information on the treatment of overdose.
DOSAGE AND ADMINISTRATION
General
The suppression of tics by ORAP requires a slow and gradual introduction of the drug.
The patient’s dose should be carefully adjusted to a point where the suppression of tics
and the relief afforded is balanced against the untoward side effects of the drug.
An ECG should be done at baseline and periodically thereafter, especially during the
period of dose adjustment (see WARNINGS and PRECAUTIONS - Laboratory
Tests). Periodic attempts should be made to reduce the dosage of ORAP to see
whether or not tics persist at the level and extent first identified. In attempts to reduce
the dosage of ORAP, consideration should be given to the possibility that increases of tic
intensity and frequency may represent a transient, withdrawal-related phenomenon rather
than a return of disease symptoms. Specifically, one to two weeks should be allowed to
elapse before one concludes that an increase in tic manifestations is a function of the
underlying disease syndrome rather than a response to drug withdrawal. A gradual
withdrawal is recommended in any case.
Children
Reliable dose response data for the effects of ORAP (pimozide) on tic manifestation in
Tourette’s Disorder patients below the age of twelve are not available.
Treatment should be initiated at a dose of 0.05 mg/kg preferably taken once at bedtime.
The dose may be increased every third day to a maximum of 0.2 mg/kg not to exceed 10
mg/day.
Adults
In general, treatment with ORAP should be initiated with a dose of 1 to 2 mg a day in
divided doses. The dose may be increased thereafter every other day. Most patients are
maintained at less than 0.2 mg/kg per day, or 10 mg/day, whichever is less. Doses
greater than 0.2 mg/kg/day or 10 mg/day are not recommended.
ANIMAL PHARMACOLOGY
A chronic study in dogs indicated that pimozide caused gingival hyperplasia when
administered for several months at about 5 times the maximum recommended human
dose. This condition was reversible after withdrawal.
HOW SUPPLIED
ORAP® (pimozide) 1 mg tablets are white, oval, scored tablets, debossed “ORAP 1”.
They are available in bottles of 100 (NDC 57844-151-01).
ORAP® (pimozide) 2 mg tablets are white, oval, scored tablets, debossed “LEMMON”
on one side and “ORAP 2” on the other. They are available in bottles of 100 (NDC
57844-187-01).
Reference ID: 2870808
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16
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled
Room Temperature].
Dispense in a tight, light-resistant container as defined in the official compendium.
Pharmacist: Dispense in child-resistant container.
Manufactured for:
GATE PHARMACEUTICALS
Div. of Teva Pharmaceuticals USA
Sellersville, PA 18960
Manufactured by:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. Q 08/2010
Reference ID: 2870808
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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.
/s/
THOMAS P LAUGHREN
12/01/2010
Reference ID: 2870808
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|
custom-source
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2025-02-12T13:44:12.402493
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017473s045lbl.pdf', 'application_number': 17473, 'submission_type': 'SUPPL ', 'submission_number': 45}
|
11,001
|
Reference ID: 3032878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3032878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3032878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3032878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3032878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3032878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:12.413576
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017478s014lbl.pdf', 'application_number': 17478, 'submission_type': 'SUPPL ', 'submission_number': 14}
|
11,000
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1
XXXXXX
ORAP® (Pimozide)
Tablets
GATE
151
187
DESCRIPTION
ORAP
® (pimozide) is an orally active antipsychotic agent of the diphenyl-butylpiperidine
series.
The structural formula of pimozide, 1-[1-[4,4-bis(4-fluorophenyl) butyl]-4
piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one is: structural formula
The solubility of pimozide in water is less than 0.01 mg/mL; it is slightly soluble in most
organic solvents.
Each white ORAP tablet contains either 1 mg or 2 mg of pimozide and the following
inactive ingredients: calcium stearate, microcrystalline cellulose, lactose anhydrous and
corn starch.
CLINICAL PHARMACOLOGY
Pharmacodynamic Actions
ORAP (pimozide) is an orally active antipsychotic drug product which shares with other
antipsychotics the ability to blockade dopaminergic receptors on neurons in the central
nervous system. Although its exact mode of action has not been established, the ability
of pimozide to suppress motor and phonic tics in Tourette’s Disorder is thought to be a
function of its dopaminergic blocking activity. However, receptor blockade is often
accompanied by a series of secondary alterations in central dopamine metabolism and
function which may contribute to both pimozide’s therapeutic and untoward effects. In
addition, pimozide, in common with other antipsychotic drugs, has various effects on
other central nervous system receptor systems which are not fully characterized.
Metabolism and Pharmacokinetics
More than 50% of a dose of pimozide is absorbed after oral administration. Based on the
pharmacokinetic and metabolic profile, pimozide appears to undergo significant first pass
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2
metabolism. Peak serum levels occur generally six to eight hours (range 4-12 hours)
after dosing.
Pimozide is extensively metabolized, primarily by N-dealkylation in the liver. This
metabolism is catalyzed mainly by the cytochrome P450 3A4 (CYP 3A4) enzymatic
system and to a lesser extent, by cytochrome P450 1A2 (CYP 1A2) and cytochrome P450
2D6 (CYP 2D6).
Two major metabolites have been identified, 1-(4-piperidyl)-2
benzimidazolinone and 4,4-bis(4-fluorophenyl) butyric acid. The antipsychotic activity
of these metabolites is undetermined. The major route of elimination of pimozide and its
metabolites is through the kidney.
The mean serum elimination half-life of pimozide in schizophrenic patients was
approximately 55 hours. There was a 13-fold interindividual difference in the area under
the serum pimozide level-time curve and an equivalent degree of variation in peak serum
levels among patients studied. The significance of this is unclear since there are few
correlations between plasma levels and clinical findings.
Effects of food and disease upon the absorption, distribution, metabolism and elimination
of pimozide are not known. Effects of concomitant medication and genetic variations on
pimozide
metabolism
are
described
in
the
CONTRAINDICATIONS
and
PRECAUTIONS sections.
INDICATIONS AND USAGE
ORAP (pimozide) is indicated for the suppression of motor and phonic tics in patients
with Tourette’s Disorder who have failed to respond satisfactorily to standard treatment.
ORAP is not intended as a treatment of first choice nor is it intended for the treatment of
tics that are merely annoying or cosmetically troublesome. ORAP should be reserved for
use in Tourette’s Disorder patients whose development and/or daily life function is
severely compromised by the presence of motor and phonic tics.
Evidence supporting approval of pimozide for use in Tourette’s Disorder was obtained in
two controlled clinical investigations which enrolled patients between the ages of 8 and
53 years. Most subjects in the two trials were 12 or older.
CONTRAINDICATIONS
1. ORAP (pimozide) is contraindicated in the treatment of simple tics or tics other than
those associated with Tourette’s Disorder.
2. ORAP should not be used in patients taking drugs that may, themselves, cause motor
and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until such patients
have been withdrawn from these drugs to determine whether or not the drugs, rather than
Tourette’s Disorder, are responsible for the tics.
3. Because ORAP prolongs the QT interval of the electrocardiogram it is contraindicated
in patients with congenital long QT syndrome, patients with a history of cardiac
arrhythmias, patients taking other drugs which prolong the QT interval of the
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3
electrocardiogram or patients with known hypokalemia or hypomagnesemia (see also
PRECAUTIONS - Drug Interactions).
4.
ORAP is contraindicated in patients with severe toxic central nervous system
depression or comatose states from any cause.
5. ORAP is contraindicated in patients with hypersensitivity to it. As it is not known
whether cross-sensitivity exists among the antipsychotics, pimozide should be used with
appropriate caution in patients who have demonstrated hypersensitivity to other
antipsychotic drugs.
6.
Ventricular arrhythmias have been rarely associated with the use of macrolide
antibiotics in patients with prolonged QT intervals, as might be produced by ORAP.
Specifically, two sudden deaths have been reported when clarithromycin was added to
ongoing pimozide therapy. Furthermore, some evidence suggests that pimozide is
metabolized partly by the enzyme system cytochrome P450 3A4 (CYP 3A4). Macrolide
antibiotics are inhibitors of CYP 3A4, and thus could potentially impede pimozide
metabolism. For these reasons, ORAP is contraindicated in patients receiving the
macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and
troleandomycin.
7.
Concomitant use in patients taking Celexa or Lexapro is contraindicated (see
Precautions - Drug Interactions - Pimozide and Celexa).
8. Clinical drug interaction studies have demonstrated that pimozide is also metabolized
by CYP 2D6. Concomitant use of ORAP with paroxetine and other strong CYP 2D6
inhibitors is contraindicated (See PRECAUTIONS – Drug Interactions).
9. Concomitant use of pimozide in patients taking sertraline is contraindicated (See
PRECAUTIONS – Drug Interactions).
Because azole antifungal agents are also inhibitors of the CYP 3A4 enzymes and thus
may likewise impair pimozide metabolism, ORAP is contraindicated in patients receiving
the azole antifungal agents itraconazole and ketoconazole.
Similarly, protease inhibitor drugs are also inhibitors of CYP 3A4, and thus ORAP is
contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir,
indinavir, and nelfinavir. (See PRECAUTIONS - Drug Interactions.)
Nefazodone is a potent inhibitor of CYP 3A4, and its concomitant use with ORAP is also
contraindicated.
Other drugs that are relatively less potent inhibitors of CYP 3A4 should also be avoided,
in view of the risks: e.g. zileuton, fluvoxamine.
WARNINGS
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The use of ORAP (pimozide) in the treatment of Tourette’s Disorder involves different
risk/benefit considerations than when antipsychotic drugs are used to treat other
conditions. Consequently, a decision to use ORAP should take into consideration the
following (see also PRECAUTIONS - Information for Patients).
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements
may develop in patients treated with antipsychotic drugs. Although the prevalence of the
syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic
treatment, which patients are likely to develop the syndrome. Whether antipsychotic
drug products differ in their potential to cause tardive dyskinesia is unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total cumulative
dose of antipsychotic drugs administered to the patient increase. However, the syndrome
can develop, although much less commonly, after relatively brief treatment periods at
low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs
and symptoms of the syndrome and thereby may possibly mask the underlying process.
The effect that symptomatic suppression has upon the long-term course of the syndrome
is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that is
most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness that,
1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally
effective, but potentially less harmful treatments are not available or appropriate. In
patients who do require chronic treatment, the smallest dose and the shortest duration of
treatment producing a satisfactory clinical response should be sought. The need for
continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug
discontinuation should be considered. However, some patients may require treatment
despite the presence of the syndrome.
(For further information about the description of tardive dyskinesia and its clinical
detection, please refer to ADVERSE REACTIONS and PRECAUTIONS -
Information for Patients.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including
Reference ID: 3020950
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5
catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure,
tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include
elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal
failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases where the clinical presentation includes both
serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or
inadequately treated extrapyramidal signs and symptoms (EPS).
Other important
considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of antipsychotic
drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic
treatment and medical monitoring, and 3) treatment of any concomitant serious medical
problems for which specific treatments are available. There is no general agreement
about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be
carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia, not associated with the above symptom complex, has been reported with
other antipsychotic drugs.
Other
Sudden, unexpected deaths have occurred in experimental studies of conditions other
than Tourette’s Disorder. These deaths occurred while patients were receiving dosages
in the range of 1 mg per kg. One possible mechanism for such deaths is prolongation of
the QT interval predisposing patients to ventricular arrhythmia. An electrocardiogram
should be performed before ORAP treatment is initiated and periodically thereafter,
especially during the period of dose adjustment.
ORAP may have a tumorigenic potential. Based on studies conducted in mice, it is
known that pimozide can produce a dose-related increase in pituitary tumors. The full
significance of this finding is not known, but should be taken into consideration in the
physician’s and patient’s decisions to use this drug product. This finding should be given
special consideration when the patient is young and chronic use of pimozide is
anticipated
(see
PRECAUTIONS
-
Carcinogenesis,
Mutagenesis,
Impairment of Fertility).
PRECAUTIONS
Leukopenia, Neutropenia and Agranulocytosis
Class Effect:
In clinical trial and/or postmarketing experience, events of
leukopenia/neutropenia and agranulocytosis have been reported temporally related to
antipsychotic agents.
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Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell
count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a
history of a clinically significant low WBC or drug induced leukopenia/neutropenia
should have their complete blood count (CBC) monitored frequently during the first few
months of therapy and discontinuation of ORAP should be considered at the first sign of
a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or
other symptoms or signs of infection and treated promptly if such symptoms or signs
occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should
discontinue ORAP and have their WBC followed until recovery.
General
ORAP (pimozide) may impair the mental and/or physical abilities required for the
performance of potentially hazardous tasks, such as driving a car or operating machinery,
especially during the first few days of therapy.
ORAP produces anticholinergic side effects and should be used with caution in
individuals whose conditions may be aggravated by anticholinergic activity.
ORAP should be administered cautiously to patients with impairment of liver or kidney
function, because it is metabolized by the liver and excreted by the kidneys.
Antipsychotics should be administered with caution to patients receiving anticonvulsant
medication, with a history of seizures, or with EEG abnormalities, because they may
lower the convulsive threshold. If indicated, adequate anticonvulsant therapy should be
maintained concomitantly.
Information for Patients
Treatment with ORAP exposes the patient to serious risks. A decision to use ORAP
chronically in Tourette’s Disorder is one that deserves full consideration by the patient
(or patient’s family) as well as by the treating physician. Because the goal of treatment is
symptomatic improvement, the patient’s view of the need for treatment and assessment of
response are critical in evaluating the impact of therapy and weighing its benefits against
the risks. Since the physician is the primary source of information about the use of a
drug in any disease, it is recommended that the following information be discussed with
patients and/or their families.
ORAP is intended only for use in patients with Tourette’s Disorder whose symptoms are
severe and who cannot tolerate, or who do not respond to HALDOL® (haloperidol).
Given the likelihood that a proportion of patients exposed chronically to antipsychotics
will develop tardive dyskinesia, it is advised that all patients in whom chronic use is
contemplated be given, if possible, full information about this risk. The decision to
inform patients and/or their guardians must obviously take into account the clinical
circumstances and the competency of the patient to understand the information provided.
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There is limited information available on the use of ORAP in children under 12 years of
age.
The information available on ORAP from foreign marketing experience and from U.S.
clinical trials indicates that ORAP has a side effect profile similar to that of other
antipsychotic drugs. Patients should be informed that all types of side effects associated
with the use of antipsychotics may be associated with the use of ORAP.
In addition, sudden, unexpected deaths have occurred in patients taking high doses of
ORAP for conditions other than Tourette’s Disorder. These deaths may have been the
result of an effect of ORAP upon the heart. Therefore, patients should be instructed not
to exceed the prescribed dose of ORAP and they should realize the need for the initial
ECG and for follow-up ECGs during treatment.
Also, pimozide, at a dose about 15 times that given humans, caused an increase in the
number of benign tumors of the pituitary gland in female mice. It is not possible to say
how important this is. Similar tumors were not seen in rats given pimozide, nor at lower
doses in mice, which is reassuring. However, any such finding must be considered to
suggest a possible risk of long term use of the drug.
Because substances in grapefruit juice may inhibit the metabolism of pimozide by CYP
3A4, patients should be advised to avoid grapefruit juice.
Laboratory Tests
An ECG should be done at baseline and periodically thereafter throughout the period of
dose adjustment. Any indication of prolongation of QTc interval beyond an absolute
limit of 0.47 seconds (children) or 0.52 seconds (adults), or more than 25% above the
patient’s original baseline should be considered a basis for stopping further dose increase
(see CONTRAINDICATIONS) and considering a lower dose.
Since hypokalemia has been associated with ventricular arrhythmias, potassium
insufficiency, secondary to diuretics, diarrhea, or other cause, should be corrected before
ORAP therapy is initiated and normal potassium maintained during therapy.
Drug Interactions
Because ORAP prolongs the QT interval of the electrocardiogram, an additive effect on
QT interval would be anticipated if administered with other drugs, such as
phenothiazines, tricyclic antidepressants or antiarrhythmic agents, which prolong the QT
interval. Accordingly, pimozide should not be given with dofetilide, sotalol, quinidine,
other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine,
droperidol,
sparfloxacin,
gatifloxacin,
moxifloxacin,
halofantrine,
mefloquine,
pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol,
tacrolimus, ziprasidone, or other drugs that have demonstrated QT prolongation as one of
their pharmacodynamic effects. Also, the use of macrolide antibiotics in patients with
prolonged QT intervals has been rarely associated with ventricular arrhythmias. Such
concomitant administration should not be undertaken (see CONTRAINDICATIONS).
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Since ORAP is partly metabolized via CYP 3A4, it should not be administered
concomitantly with inhibitors of this metabolic system, such as azole antifungal agents
and protease inhibitor drugs (see CONTRAINDICATIONS).
Pimozide and Celexa: In a controlled study, a single dose of pimozide 2 mg co
administered with racemic citalopram 40 mg given once daily for 11 days was associated
with a mean increase in QTc values of approximately 10 msec compared to pimozide
given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The
mechanism of this pharmacodynamic interaction is not known. Concomitant use of
pimozide and Celexa or Lexapro is contraindicated (See CONTRAINDICATIONS).
CYP 2D6 inhibitors: In healthy subjects, co-administration of pimozide 2 mg (single
dose) and paroxetine 60 mg resulted in a 151% increase in pimozide AUC and a 62%
increase in pimozide Cmax compared to pimozide administered alone. The increase in
pimozide AUC and Cmax is related to the CYP 2D6 inhibitory properties of paroxetine.
Concomitant use of pimozide and paroxetine or other strong CYP 2D6 inhibitors are
contraindicated (see CONTRAINDICATIONS).
As CYP 1A2 may also contribute to the metabolism of ORAP, prescribers should be
aware of the theoretical potential for drug interactions with inhibitors of this enzymatic
system.
ORAP may be capable of potentiating CNS depressants, including analgesics, sedatives,
anxiolytics, and alcohol.
Rare case reports have suggested possible additive effects of pimozide and fluoxetine
leading to bradycardia.
Concomitant administration of pimozide and sertraline should be contraindicated (See
CONTRAINDICATIONS).
PharmacogenomicsIndividuals with genetic variations resulting in poor CYP 2D6
metabolism (approximately 5 to 10% of the population) exhibit higher pimozide
concentrations than extensive CYP 2D6 metabolizers. The concentrations observed in
poor CYP 2D6 metabolizers are similar to those seen with strong CYP 2D6 inhibitors
such as paroxetine. The time to achieve steady state pimozide concentrations is expected
to be longer (approximately 2 weeks) in poor CYP 2D6 metabolizers because of the
prolonged half-life. Alternative dosing strategies are recommended in patients who are
genetically poor CYP 2D6 metabolizers (see DOSAGE and ADMINISTRATION).
Interaction with Food
Patients should avoid grapefruit juice because it may inhibit the metabolism of pimozide
by CYP 3A4.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in mice and rats. In mice, pimozide causes a
dose-related increase in pituitary and mammary tumors.
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9
When mice were treated for up to 18 months with pimozide, pituitary gland changes
developed in females only. These changes were characterized as hyperplasia at doses
approximating the human dose and adenoma at doses about fifteen times the maximum
recommended human dose on a mg per kg basis. The mechanism for the induction of
pituitary tumors in mice is not known.
Mammary gland tumors in female mice were also increased, but these tumors are
expected in rodents treated with antipsychotic drugs which elevate prolactin levels.
Chronic administration of an antipsychotic also causes elevated prolactin levels in
humans. Tissue culture experiments indicate that approximately one-third of human
breast cancers are prolactin-dependent in vitro, a factor of potential importance if the
prescription of these drugs is contemplated in a patient with a previously detected breast
cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and
impotence have been reported with antipsychotic drugs, the clinical significance of
elevated serum prolactin levels is unknown for most patients. Neither clinical studies nor
epidemiologic studies conducted to date have shown an association between chronic
administration of these drugs and mammary tumorigenesis. The available evidence,
however, is considered too limited to be conclusive at this time.
In a 24-month carcinogenicity study in rats, animals received up to 50 times the
maximum recommended human dose. No increased incidence of overall tumors or
tumors at any site was observed in either sex. Because of the limited number of animals
surviving this study, the meaning of these results is unclear.
Pimozide did not have mutagenic activity in the Ames test with four bacterial test strains,
in the mouse dominant lethal test or in the micronucleus test in rats.
Reproduction studies in animals were not adequate to assess all aspects of fertility.
Nevertheless, female rats administered pimozide had prolonged estrus cycles, an effect
also produced by other antipsychotic drugs.
Pregnancy
Category C. Reproduction studies performed in rats and rabbits at oral doses up to 8
times the maximum human dose did not reveal evidence of teratogenicity. In the rat,
however, this multiple of the human dose resulted in decreased pregnancies and in the
retarded development of fetuses. These effects are thought to be due to an inhibition or
delay in implantation which is also observed in rodents administered other antipsychotic
drugs.
In the rabbit, maternal toxicity, mortality, decreased weight gain, and
embryotoxicity including increased resorptions were dose-related. Because animal
reproduction studies are not always predictive of human response, pimozide should be
given to a pregnant woman only if the potential benefits of treatment clearly outweigh the
potential risks.
Nonteratogenic effects. Neonates exposed to antipsychotic drugs, during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms
following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor,
somnolence, respiratory distress and feeding disorder in these neonates. These
Reference ID: 3020950
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10
complications have varied in severity; while in some cases symptoms have been self-
limited, in other cases neonates have required intensive care unit support and prolonged
hospitalization.
ORAP should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Labor and Delivery
This drug has no recognized use in labor or delivery.
Nursing Mothers
It is not known whether pimozide is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for tumorigenicity and unknown
cardiovascular effects in the infant, 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
Although Tourette's Disorder most often has its onset between the ages of 2 and 15 years,
information on the use and efficacy of ORAP in patients less than 12 years of age is
limited. A 24-week open label study in 36 children between the ages of 2 and 12
demonstrated that pimozide has a similar safety profile in this age group as in older
patients and there were no safety findings that would preclude its use in this age group.
Because its use and safety have not been evaluated in other childhood disorders, ORAP is
not recommended for use in any condition other than Tourette’s Disorder.
ADVERSE REACTIONS
General
Extrapyramidal Reactions: Neuromuscular (extrapyramidal) reactions during the
administration of ORAP
® (pimozide) have been reported frequently, often during the first
few days of treatment. In most patients, these reactions involved Parkinson-like
symptoms which, when first observed, were usually mild to moderately severe and
usually reversible.
Other types of neuromuscular reactions (motor restlessness, dystonia, akathisia,
hyperreflexia, opisthotonos, oculogyric crises) have been reported far less frequently.
Severe extrapyramidal reactions have been reported to occur at relatively low doses.
Generally the occurrence and severity of most extrapyramidal symptoms are dose-related
since they occur at relatively high doses and have been shown to disappear or become
less severe when the dose is reduced. Administration of antiparkinson drugs such as
benztropine mesylate or trihexyphenidyl hydrochloride may be required for control of
such reactions. It should be noted that persistent extrapyramidal reactions have been
reported and that the drug may have to be discontinued in such cases.
Withdrawal Emergent Neurological Signs: Generally, patients receiving short term
therapy experience no problems with abrupt discontinuation of antipsychotic drugs.
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11
However, some patients on maintenance treatment experience transient dyskinetic signs
after abrupt withdrawal.
In certain of these cases the dyskinetic movements are
indistinguishable from the syndrome described below under “Tardive Dyskinesia” except
for duration. It is not known whether gradual withdrawal of antipsychotic drugs will
reduce the rate of occurrence of withdrawal emergent neurological signs, but until further
evidence becomes available, it seems reasonable to gradually withdraw use of ORAP.
Tardive Dyskinesia: ORAP may be associated with persistent dyskinesias. Tardive
dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic
movements, may appear in some patients on long-term therapy or may occur after drug
therapy has been discontinued. The risk appears to be greater in elderly patients on high-
dose therapy, especially females. The symptoms are persistent and in some patients
appear irreversible.
The syndrome is characterized by rhythmical involuntary
movements of tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks,
puckering of mouth, chewing movements). Sometimes these may be accompanied by
involuntary movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents
usually do not alleviate the symptoms of this syndrome. It is suggested that all
antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to
reinstitute treatment, or increase the dosage of the agent, or switch to a different
antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early sign of
tardive dyskinesia and if the medication is stopped at that time the syndrome may not
develop.
Electrocardiographic Changes: Electrocardiographic changes have been observed in
clinical trials of ORAP in Tourette’s Disorder and schizophrenia. These have included
prolongation of the QT interval, flattening, notching and inversion of the T wave and the
appearance of U waves. Sudden, unexpected deaths and grand mal seizure have occurred
at doses above 20 mg/day.
Neuroleptic Malignant Syndrome: Neuroleptic malignant syndrome (NMS) has been
reported with ORAP. (See WARNINGS for further information concerning NMS.)
Hyperpyrexia: Hyperpyrexia has been reported with other antipsychotic drugs.
Clinical Trials
The following adverse reaction tabulation was derived from 20 patients in a 6-week long
placebo-controlled clinical trial of ORAP in Tourette’s Disorder.
Body System/
Pimozide
Placebo
Adverse Reaction
(N = 20)
(N = 20)
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12
Body as a Whole
Headache
1
2
Gastrointestinal
Dry Mouth
5
1
Diarrhea
1
0
Nausea
0
2
Vomiting
0
1
Constipation
4
2
Eructations
0
1
Thirsty
1
0
Appetite increase
1
0
Endocrine
Menstrual disorder
0
1
Breast secretions
0
1
Musculoskeletal
Muscle cramps
0
1
Muscle tightness
3
0
Stooped posture
2
0
CNS
Drowsiness
7
3
Sedation
14
5
Insomnia
2
2
Dizziness
0
1
Akathisia
8
0
Rigidity
2
0
Speech disorder
2
0
Handwriting change
1
0
Akinesia
8
0
Psychiatric
Depression
2
3
Excitement
0
1
Nervous
1
0
Adverse behavior effect
5
0
Special Senses
Visual disturbance
4
0
Taste change
1
0
Sensitivity of eyes to light
1
0
Decrease accommodation
4
1
Spots before eyes
0
1
Urogenital
Impotence
3
0
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13
The following adverse event tabulation was derived from 36 children (age 2 to 12) in a
24-week open trial of ORAP in Tourette’s Disorder.
Body System/
Number of Patients
Adverse Reaction
Experiencing Each Event (%)
All Events
Drug-Related
Events
(N=36)
(N=36)
Body as a Whole
Asthenia
9 (25.0)
5 (13.8)
Headache
8 (22.2)
1 (2.7)
Gastrointestinal
Dysphagia
1 (2.7)
1 (2.7)
Increased Salivation
5 (13.8)
2 (5.5)
Musculoskeletal
Myalgia
1 (2.7)
1 (2.7)
Central Nervous System
Dreaming Abnormal
1 (2.7)
1 (2.7)
Hyperkinesia
2 (5.5)
1 (2.7)
Somnolence
10 (27.7)
9 (25.0)
Torticollis
1 (2.7)
1 (2.7)
Tremor, Limbs
1 (2.7)
1 (2.7)
Psychiatric
Adverse Behavior Effect
10 (27.7)
8 (22.2)
Nervous
3 (8.3)
2 (5.5)
Skin
Rash
3 (8.3)
1 (2.7)
Special Senses
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14
Visual Disturbance
2 (5.5)
1 (2.7)
Cardiovascular
ECG Abnormal
1 (2.7)
1 (2.7)
Because clinical investigational experience with ORAP in Tourette’s Disorder is limited,
uncommon adverse reactions may not have been detected. The physician should consider
that other adverse reactions associated with antipsychotics may occur.
Other Adverse Reactions
In addition to the adverse reactions listed above, those listed below have been reported in
U.S. clinical trials of ORAP in conditions other than Tourette’s Disorder.
Body as a Whole: Asthenia, chest pain, periorbital edema
Cardiovascular/Respiratory:
Postural
hypotension,
hypotension,
hypertension,
tachycardia, palpitations
Gastrointestinal: Increased salivation, nausea, vomiting, anorexia, GI distress
Endocrine: Loss of libido
Metabolic/Nutritional: Weight gain, weight loss
Central Nervous System: Dizziness, tremor, parkinsonism, fainting, dyskinesia
Psychiatric: Excitement
Skin: Rash, sweating, skin irritation
Special Senses: Blurred vision, cataracts
Urogenital: Nocturia, urinary frequency
Postmarketing Reports
The following experiences were described in spontaneous postmarketing reports. These
reports do not provide sufficient information to establish a clear causal relationship with
the use of ORAP.
Gastrointestinal: Gingival hyperplasia in one patient
Hematologic: Hemolytic anemia
Metabolic/Nutritional: Hyponatremia
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15
Other: Seizure
OVERDOSAGE
In general, the signs and symptoms of overdosage with ORAP (pimozide) would be an
exaggeration of known pharmacologic effects and adverse reactions, the most prominent
of which would be: 1) electrocardiographic abnormalities, 2) severe extrapyramidal
reactions, 3) hypotension, 4) a comatose state with respiratory depression.
In the event of overdosage, gastric lavage, establishment of a patent airway and, if
necessary,
mechanically-assisted
respiration
are
advised.
Electrocardiographic
monitoring should commence immediately and continue until the ECG parameters are
within the normal range. Hypotension and circulatory collapse may be counteracted by
use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such
as metaraminol, phenylephrine and norepinephrine.
Epinephrine should not be used.
In case of severe extrapyramidal reactions,
antiparkinson medication should be administered. Because of the long half-life of
pimozide, patients who take an overdose should be observed for at least 4 days. As with
all drugs, the physician should consider contacting a poison control center for additional
information on the treatment of overdose.
DOSAGE AND ADMINISTRATION
General
The suppression of tics by ORAP requires a slow and gradual introduction of the drug.
The patient’s dose should be carefully adjusted to a point where the suppression of tics
and the relief afforded is balanced against the untoward side effects of the drug.
An ECG should be done at baseline and periodically thereafter, especially during the
period of dose adjustment (see WARNINGS and PRECAUTIONS - Laboratory
Tests). Periodic attempts should be made to reduce the dosage of ORAP to see
whether or not tics persist at the level and extent first identified. In attempts to reduce
the dosage of ORAP, consideration should be given to the possibility that increases of tic
intensity and frequency may represent a transient, withdrawal-related phenomenon rather
than a return of disease symptoms. Specifically, one to two weeks should be allowed to
elapse before one concludes that an increase in tic manifestations is a function of the
underlying disease syndrome rather than a response to drug withdrawal. A gradual
withdrawal is recommended in any case.
Children
Reliable dose response data for the effects of ORAP (pimozide) on tic manifestation in
Tourette’s Disorder patients below the age of twelve are not available.
Treatment should be initiated at a dose of 0.05 mg/kg preferably taken once at bedtime.
The dose may be increased every third day to a maximum of 0.2 mg/kg not to exceed 10
mg/day.
Reference ID: 3020950
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16
At doses above 0.05 mg/kg/day, CYP 2D6 genotyping should be performed. In poor CYP
2D6 metabolizers, ORAP doses should not exceed 0.05 mg/kg/day, and doses should not
be increased earlier than 14 days (see PRECAUTIONS – Pharmacogenomics).
Adults
In general, treatment with ORAP should be initiated with a dose of 1 to 2 mg a day in
divided doses. The dose may be increased thereafter every other day. Most patients are
maintained at less than 0.2 mg/kg/day, or 10 mg/day, whichever is less. Doses greater
than 0.2 mg/kg/day or 10 mg/day are not recommended.
At doses above 4 mg/day, CYP 2D6 genotyping should be performed. In poor CYP 2D6
metabolizers, ORAP doses should not exceed 4 mg/day, and doses should not be
increased earlier than 14 days (see PRECAUTIONS – Pharmacogenomics).
ANIMAL PHARMACOLOGY
A chronic study in dogs indicated that pimozide caused gingival hyperplasia when
administered for several months at about 5 times the maximum recommended human
dose. This condition was reversible after withdrawal.
HOW SUPPLIED
ORAP® (pimozide) 1 mg tablets are white, oval, scored tablets, debossed “ORAP 1”.
They are available in bottles of 100 (NDC 57844-151-01).
ORAP® (pimozide) 2 mg tablets are white, oval, scored tablets, debossed “LEMMON”
on one side and “ORAP 2” on the other. They are available in bottles of 100 (NDC
57844-187-01).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled
Room Temperature].
Dispense in a tight, light-resistant container as defined in the official compendium.
Pharmacist: Dispense in child-resistant container.
Manufactured for:
GATE PHARMACEUTICALS
Div. of Teva Pharmaceuticals USA
Sellersville, PA 18960
Manufactured by:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. R 08/2011
Reference ID: 3020950
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:12.422184
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017473s046lbl.pdf', 'application_number': 17473, 'submission_type': 'SUPPL ', 'submission_number': 46}
|
11,003
|
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3296493
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:12.878019
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017512s113,020163s020,020183s019lbl.pdf', 'application_number': 17512, 'submission_type': 'SUPPL ', 'submission_number': 113}
|
11,002
|
DIANEAL PD-2 Peritoneal Dialysis Solution
AMBU-FLEX Container For Peritoneal Dialysis
For intraperitoneal administration only
Description
DIANEAL PD-2 peritoneal dialysis solutions in AMBU-FLEX containers are
sterile, nonpyrogenic solutions for intraperitoneal administration only. They
contain no bacteriostatic or antimicrobial agents or added buffers.
Composition, calculated osmolarity, pH, and ionic concentrations are shown in
Table 1.
Potassium is omitted from DIANEAL solutions because dialysis may be
performed to correct hyperkalemia. In situations in which there is a normal serum
potassium level or hypokalemia, the addition of potassium chloride (up to a
concentration of 4 mEq/L) may be indicated to prevent severe hypokalemia.
Addition of potassium chloride should be made after careful evaluation of
serum and total body potassium and only under the direction of a
physician. Frequent monitoring of serum electrolytes is indicated.
Because average plasma magnesium levels in some chronic CAPD patients
have been observed to be elevated (Nolph et al. 1981), the magnesium
concentration of this formulation has been reduced to 0.5 mEq/L. Average
plasma magnesium levels have not been reported for chronic IPD and CCPD
patients. Serum magnesium levels should be monitored and if low, oral
magnesium supplements, oral magnesium containing phosphate binders, or
peritoneal dialysis solutions containing higher magnesium concentrations may be
used.
Because average serum bicarbonate levels in some chronic CAPD patients
(Nolph et al. 1981), some chronic IPD patients (La Greca et al. 1980), and some
chronic CCPD patients (Diaz-Buxo et al. 1983) have been observed to be
somewhat lower than normal values, the bicarbonate precursor (lactate)
concentration of this formulation has been raised to 40 mEq/L. Serum
bicarbonate levels should be monitored.
The osmolarities shown in Table 1 are calculated values. As an example,
measured osmolarity by freezing point depression determination of DIANEAL
PD-2 peritoneal dialysis solution with 1.5% dextrose is approximately
334 mOsmol/L, compared with measured values in normal human serum of 280
mOsmol/L.
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 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
tests for plastic containers as well as by tissue culture toxicity studies.
Clinical Pharmacology
Peritoneal dialysis is a procedure for removing toxic substances and metabolites
normally excreted by the kidneys, and for aiding in the regulation of fluid and
electrolyte balance.
The procedure is accomplished by instilling peritoneal dialysis fluid through a
conduit into the peritoneal cavity. With the exception of lactate, present as a
bicarbonate precursor, electrolyte concentrations in the fluid have been
formulated to attempt to normalize plasma electrolyte concentrations resulting
from osmosis and diffusion across the peritoneal membrane (between the
plasma of the patient and the dialysis fluid). Toxic substances and metabolites,
present in high concentrations in the blood, cross the peritoneal membrane into
the dialyzing fluid. Dextrose in the dialyzing fluid is used to produce a solution
hyperosmolar to the plasma, creating an osmotic gradient which facilitates fluid
removal from the patient’s plasma into the peritoneal cavity. After a period of time
(dwell time), the fluid is drained from the cavity.
Indications and Usage
Peritoneal dialysis is indicated for patients in acute or chronic renal failure when
nondialytic medical therapy is judged to be inadequate (Vaamonde and Perez
1977). It may also be indicated in the treatment of certain fluid and electrolyte
disturbances, and for patients intoxicated with certain poisons and drugs
(Knepshield et al. 1977). However, for many substances other methods of
detoxification have been reported to be more effective than peritoneal dialysis
(Vaamonde and Perez 1977; Chang 1977).
Contraindications
None known
Warnings
Peritoneal dialysis should be done with great care, if at all, in patients with a
number of abdominal conditions including disruption of the peritoneal membrane
or diaphragm by surgery or trauma, extensive adhesions, bowel distention,
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undiagnosed abdominal disease, abdominal wall infection, hernias or burns, fecal
fistula or colostomy, tense ascites, obesity, and large polycystic kidneys
(Vaamonde and Perez 1977). Other conditions include recent aortic graft
replacement and severe pulmonary disease. When assessing peritoneal dialysis
as the mode of therapy in such extreme situations, the benefits to the patient
must be weighed against the possible complications.
An accurate fluid balance record must be kept and the weight of the patient
carefully monitored to avoid over or under hydration with severe consequences
including congestive heart failure, volume depletion, and shock.
Excessive use of DIANEAL PD-2 peritoneal dialysis solution with 3.5% or 4.25%
dextrose during a peritoneal dialysis treatment can result in significant removal of
water from the patient.
In acute renal failure patients, plasma electrolyte concentrations should be
monitored periodically during the procedure. Stable patients undergoing
maintenance peritoneal dialysis should have routine periodic evaluation of blood
chemistries and hematologic factors, as well as other indicators of patient status.
Because average plasma magnesium levels in chronic CAPD patients have been
observed to be elevated (Nolph et al. 1981), the magnesium concentration of this
formulation has been reduced to 0.5 mEq/L. Average plasma magnesium levels
have not been reported for chronic IPD and CCPD patients. Serum magnesium
levels should be monitored and if low, oral magnesium supplements, oral
magnesium containing phosphate binders, or peritoneal dialysis solutions
containing higher magnesium concentrations may be used.
Because average serum bicarbonate levels in some chronic CAPD patients
(Nolph et al. 1981), some chronic IPD patients (La Greca et al. 1980), and some
chronic CCPD patients (Diaz-Buxo et al. 1983), have been observed to be
somewhat lower than normal values, the bicarbonate precursor (lactate)
concentration of this formulation has been raised to 40 mEq/L. Serum
bicarbonate levels should be monitored.
Not for use in the treatment of lactic acidosis.
Potassium is omitted from DIANEAL PD-2 solutions because dialysis may be
performed to correct hyperkalemia. Addition of potassium chloride should be
made after careful evaluation of serum and total body potassium and only
under the direction of a physician.
The use of 5 or 6 liters of dialysis solution is not indicated in a single exchange.
Refer to manufacturer’s directions accompanying drugs to obtain full information
on additives.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
If the resealable rubber plug on the medication port is missing or partially
removed, do not use product if medication is to be added.
After the pull ring has been removed, inspect connector of solution container for
fluid flow. A few drops of solution within the connector or pull ring may be present
due to condensation of water resulting from the sterilization process. If a
continuous stream of fluid is noted, discard solution because sterility may be
impaired.
After removing overwrap, check for minute leaks by squeezing container firmly. If
leaks are found, discard the solution because the sterility may be impaired.
Freezing of solution may occur at temperatures below 0°C (32°F). Do not flex or
manipulate container when frozen. Allow container to thaw naturally in ambient
conditions and thoroughly mix contents by shaking.
Precautions
Aseptic technique must be used throughout the procedure and at its termination
in order to reduce the possibility of infection. If peritonitis occurs, the choice and
dosage of antibiotics should be based upon the results of identification and
sensitivity studies of the isolated organism(s) when possible. Prior to
identification of the involved organism(s), broad-spectrum antibiotics may be
indicated.
Peritoneal dialysis solutions may be warmed in the overpouch to 37°C (98.6°F) to
enhance patient comfort. However, only dry heat (for example, heating pad)
should be used. Solutions should not be heated in water due to an increased risk
of infection. Microwave ovens should not be used to heat solutions because
there is a potential for damage to the solution container. Moreover, microwave
oven heating may potentially cause overheating and/or non-uniform heating of
the solution that may result in patient injury or discomfort.
Significant losses of protein, amino acids and water soluble vitamins may occur
during peritoneal dialysis. Replacement therapy should be provided as
necessary.
Pregnancy: Teratogenic Effects Pregnancy Category C. Animal reproduction
studies have not been conducted with DIANEAL peritoneal dialysis solutions. It is
also not known whether DIANEAL peritoneal dialysis solutions can cause fetal
harm when administered to a pregnant woman or can affect reproduction
capacity. DIANEAL peritoneal dialysis solutions should be given to a pregnant
woman only if clearly needed.
Do not administer unless solution is clear and seal is intact.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse Reactions
Adverse reactions to peritoneal dialysis include mechanical and solution related
problems as well as the results of contamination of equipment or improper
technique in catheter placement. Abdominal pain, bleeding, peritonitis,
subcutaneous infection around a chronic peritoneal catheter, catheter blockage,
difficulty in fluid removal, and ileus are among the complications of the
procedure. Solution related adverse reactions may include electrolyte and fluid
imbalances, hypovolemia, hypervolemia, hypertension, hypotension,
disequilibrium syndrome, and muscle cramping.
Dosage and Administration
DIANEAL PD-2 solutions are intended for intraperitoneal administration only.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
The mode of therapy (Intermittent Peritoneal Dialysis [IPD], Continuous
Ambulatory Peritoneal Dialysis [CAPD], or Continuous Cyclic Peritoneal Dialysis
[CCPD]), frequency of treatment, formulation, exchange volume, duration of
dwell, and length of dialysis should be selected by the physician responsible for
and supervising the treatment of the individual patient.
To avoid the risk of severe dehydration and hypovolemia and to minimize the
loss of protein, it is advisable to select the peritoneal dialysis solution with the
lowest level of osmolarity consistent with the fluid removal requirements for that
exchange.
Peritoneal dialysis solutions may be warmed in the overpouch to 37°C (98.6°F) to
enhance patient comfort. However, only dry heat (for example, heating pad)
should be used. (See Directions for Use)
The addition of heparin to the dialysis solution may be indicated to aid in
prevention of catheter blockage in patients with peritonitis, or when the solution
drainage contains fibrinous or proteinaceous material (Ribot et al. 1966). 1000 to
2000 USP units of heparin per liter of solution has been recommended for adults
(Furman et al. 1978). For children, 50 units of heparin per 100 mL of dialysis fluid
has been recommended (Irwin et al. 1981).
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Intermittent Peritoneal Dialysis (IPD)
For maintenance dialysis of chronic renal failure patients.
The cycle of instillation, dwell and removal of dialysis fluid is repeated
sequentially over a period of hours (8 to 36 hours) as many times per week as
indicated by the condition of the patient. For chronic renal failure patients,
maintenance dialysis is often accomplished by periodic dialysis (3 to 5 times
weekly) for shorter time periods (8 to 14 hours per session) (Mattocks and El-
Bassiouni 1971).
Continuous Ambulatory Peritoneal Dialysis (CAPD) and Continuous
Cyclic Peritoneal Dialysis (CCPD)
For maintenance dialysis of chronic renal failure patients.
In CAPD, 1.5 to 3.0 liters of dialysis solution (depending upon patient size) are
instilled into the peritoneal cavity of adults and the peritoneal access device is
then clamped (Kim et al. 1984; Twardowski and Janicka 1981; Twardowski and
Burrows 1984). For children, 30 to 50 mL/kg body weight with a maximum of 2
liters has been recommended (Potter et al. 1981; Irwin et al. 1981). The solution
remains in the cavity for dwell times of 4 to 8 hours during the day and 8 to 12
hours overnight. At the conclusion of each dwell period, the access device is
opened, the solution drained and fresh solution instilled. The procedure is
repeated 3 to 5 times per day, 6 to 7 days per week. Solution exchange volumes
and frequency of exchanges should be individualized for adequate biochemical
and fluid volume control (Moncrief et al. 1982; Twardowski et al. 1983). The
majority of exchanges will utilize 1.5% or 2.5% dextrose containing peritoneal
dialysis solutions, with 3.5% or 4.25% dextrose containing solutions being used
when extra fluid removal is required. Patient weight is used as the indicator of the
need for fluid removal (Popovich et al. 1978).
In CCPD, the patient receives 3 or 4 dialysis exchanges during the night which
range from 2-1/2 to 3 hours dwell duration. Typically 1.5 to 2.0 liters of dialysis
solution (depending upon patient size) are delivered each cycle by an automatic
peritoneal dialysis cycler machine. After the last outflow during the night, an
additional exchange is infused by the cycler machine into the peritoneum. The
equipment is then disconnected from the patient, and the dialysate remains in the
peritoneum for 14 to 15 hours during the day until the next nocturnal cycle (Diaz-
Buxo et al. 1981). Combinations of 1.5% or 2.5% dextrose containing peritoneal
dialysis solutions are usually used for the nighttime exchanges, while 3.5% or
4.25% dextrose is used when extra fluid removal is required such as during the
daytime exchange. Patient weight is used as the indicator of the need for fluid
removal (Popovich et al. 1978) so therapy should be individualized according to
the patient’s need for ultrafiltration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
It is recommended that adult patients being placed on chronic peritoneal dialysis
or, in the case of pediatric patients, the selected caretaker, (as well as the
patient, when suitable), should be appropriately trained in a program which is
under the supervision of a physician. Training materials are available from Baxter
Healthcare Corporation, Deerfield, IL 60015, USA to facilitate this training.
How Supplied
DIANEAL PD-2 peritoneal dialysis solutions in AMBU-FLEX II and AMBU-FLEX
lll containers are available in nominal size flexible containers with fill volumes and
dextrose concentrations as indicated in Table 1.
All DIANEAL PD-2 peritoneal dialysis solutions have overfills which are declared
on container labeling.
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
Use aseptic technique.
For complete system preparation, see directions accompanying ancillary
equipment.
Peritoneal dialysis solutions may be warmed in the overpouch to 37°C (98.6°F) to
enhance patient comfort. However, only dry heat (for example, heating pad)
should be used. Solutions should not be heated in water due to an increased risk
of infection. Microwave ovens should not be used to heat solutions because
there is a potential for damage to the solution container. Moreover, microwave
oven heating may potentially cause overheating and/or non-uniform heating of
the solution that may result in patient injury or discomfort.
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. If supplemental medication is desired, follow
directions below before preparing for administration. Check for minute leaks by
squeezing container firmly.
To Add Medication
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Additives may be incompatible.
If the resealable rubber plug on the medication port is missing or partially
removed, do not use product if medication is to be added.
1. Put on mask. Clean and/or disinfect hands.
2. Prepare medication site using aseptic technique.
3. Using a syringe with a 1 inch long 19 to 25 gauge needle, puncture resealable
medication port and inject medication.
4. Position container with ports up and evacuate the medication port by
squeezing and tapping it.
5. Mix solution and medication thoroughly.
Preparation for Administration
1. Put on mask. Clean and/or disinfect hands.
2. Place solution container on work surface.
3. Remove pull ring from connector of the solution container. If continuous fluid
flow from connector is observed, discard solution container.
4. Remove tip protector from tubing set and immediately attach to connector of
the solution container.
5. Continue with therapy set-up as instructed in user manual or directions
accompanying tubing sets.
6. Upon completion of therapy, discard unused portion.
References
Diaz-Buxo, J.A. et al. 1981. Continuous cyclic peritoneal dialysis: a preliminary
report. Int Soc Artif Organs 81:157-161.
Diaz-Buxo, J.A. et al. 1983. Observations on inadequate base buffer
concentrations in peritoneal dialysis solutions. ASAIO Abstracts 43.
Furman, K.l. et al. 1978. Activity of intraperitoneal heparin during peritoneal
dialysis. Clinical Nephrology 9:15-18.
Irwin, M.A. et al. 1981. Continuous ambulatory peritoneal dialysis in pediatrics.
AANNT J 8:11-13,44.
Kim, D. et al. 1984. Continuous ambulatory peritoneal dialysis with three-liter
exchanges: a prospective study. Peritoneal Dial Bull 4:82-85.
La Greca, G. et al. 1980. Acid base balance on peritoneal dialysis. Clinical
Nephrology 16(1):1- 6.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mattocks, A.M. and El-Bassiouni, E.A. 1971. Peritoneal dialysis: a review. J
Pharm Sci 60:1767-1782.
Moncrief, J.W. et al. 1982. CAPD: Are three exchanges per day adequate?
AANNT J 9:39-43.
Nolph, K.D. et al. 1981. Considerations for dialysis solution modifications. In
Peritoneal Dialysis, eds. Robert C. Atkins et al. Chapter 25. New York: Churchill
Livingston.
Popovich, R.P. et al. 1978. Continuous ambulatory peritoneal dialysis. Ann
Intern Med 8:449-456.
Potter, D.E. et al. 1981. Continuous ambulatory dialysis (CAPD) in children.
Trans Am Soc Artif Intern Organs 27:64-67.
Ribot, S. et al. 1966. Complications of peritoneal dialysis. Am J Med Sci
252:505-517.
Twardowski, Z.J. and Janicka, L. 1981. Three exchanges with a 2.5 liter volume
for continuous ambulatory peritoneal dialysis. Kidney Int 20:281-284.
Twardowski, Z.J. et al. 1983. High volume low frequency continuous ambulatory
peritoneal dialysis. Kidney Int 23:64-70.
Twardowski, Z.J. and Burrows, L. 1984. Two year experience with high volume,
low frequency continuous ambulatory peritoneal dialysis. Peritoneal Dial Bull
4:S67.
Vaamonde, C.A. and Perez, G.O. 1977. Peritoneal dialysis today. Kidney 10:31
36.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1.
Composition/
100 mL
Ionic Concentration
(mEq/L)
How Supplied
P
Fill
Container
Code
NDC
SP
P
P
S
Volume
Size
*Dextrose, Hydrous, U
Sodium Chloride, US
(NaCl)
Sodium Lactate
(C 3 H 5 NaO3 )
Calcium Chloride, US
(CaCl2 •2H2O)
Magnesium Chloride, U
(MgCl2 •6H2 O)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
Dianeal® PD-2
Peritoneal
Dialysis
Solution with
1.5% Dextrose
AMBU-FLEX
II
CONTAINER
1.5 g
538
mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
2500
3000
5000
6000
1000
3000
3000
3000
6000
6000
L5B5163
L5B5166
L5B5168
L5B5169
L5B5193
L5B9710
NDC 0941-0411-05
NDC 0941-0411-06
NDC 0941-0411-08
NDC 0941-0411-04
NDC 0941-0411-07
NDC 0941-0411-11
Dianeal® PD-2
Peritoneal
Dialysis
Solution with
1.5% Dextrose
AMBU-FLEX
III
CONTAINER
1.5 g
538
mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
250
500
750
1000
1500
2000
2500
500
1000
1000
1000
2000
2000
3000
5B5160
5B5161
5B5162
5B5163
5B5165
5B5166
5B5168
NDC 0941-0411-40
NDC 0941-0411-41
NDC 0941-0411-42
NDC 0941-0411-43
NDC 0941-0411-45
NDC 0941-0411-46
NDC 0941-0411-48
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3000
3000
5B5169
NDC 0941-0411-49
5000
5000
5B5193
NDC 0941-0411-25
6000
6000
5B9710
NDC 0941-0411-28
Dianeal® PD-2
Peritoneal
Dialysis
Solution with
2.5% Dextrose
AMBU-FLEX
II
CONTAINER
2.5 g
538
mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
2500
3000
5000
6000
1000
3000
3000
3000
6000
6000
L5B5173
L5B5177
L5B5178
L5B5179
L5B5194
L5B9711
NDC 0941-0413-05
NDC 0941-0413-06
NDC 0941-0413-08
NDC 0941-0413-04
NDC 0941-0413-07
NDC 0941-0413-01
Dianeal® PD-2
Peritoneal
Dialysis
Solution with
2.5% Dextrose
AMBU-FLEX
III
CONTAINER
2.5 g
538
mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
250
500
750
1000
1000
1500
2000
2500
3000
5000
6000
500
1000
1000
1000
2000
2000
3000
3000
3000
5000
6000
5B5170
5B5171
5B5172
5B5173
5B5174
5B5175
5B5177
5B5178
5B5179
5B5194
5B9711
NDC 0941-0413-40
NDC 0941-0413-41
NDC 0941-0413-42
NDC 0941-0413-43
NDC 0941-0413-44
NDC 0941-0413-45
NDC 0941-0413-47
NDC 0941-0413-48
NDC 0941-0413-49
NDC 0941-0413-25
NDC 0941-0413-28
Dianeal® PD-2
Peritoneal
Dialysis
Solution with
3.5% Dextrose
3.5 g
538
mg
448 mg
25.7 mg
5.08 mg
447
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
2500
3000
5B4804
NDC 0941-0423-48
Dianeal® PD-2
Peritoneal
Dialysis
Solution with
4.25
g
538
mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
2500
1000
3000
3000
L5B5183
L5B5187
L5B5188
NDC 0941-0415-05
NDC 0941-0415-06
NDC 0941-0415-08
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4.25% Dextrose
AMBU-FLEX
II
CONTAINER
3000
5000
6000
3000
6000
6000
L5B5189
L5B5195
L5B9712
NDC 0941-0415-04
NDC 0941-0415-07
NDC 0941-0415-01
Dianeal® PD-2
4.25
538
448 mg
25.7 mg
5.08 mg
485
5.2
132
3.5
0.5
96
40
250
500
5B5180
NDC 0941-0415-40
Peritoneal
g
mg
(4.0 to 6.5)
500
1000
5B5181
NDC 0941-0415-41
Dialysis
Solution with
750
1000
5B5182
NDC 0941-0415-42
4.25% Dextrose
1000
1000
5B5183
NDC 0941-0415-43
AMBU-FLEX
1000
2000
5B5184
NDC 0941-0415-44
III
1500
2000
5B5185
NDC 0941-0415-45
CONTAINER
2000
3000
5B5187
NDC 0941-0415-47
2500
3000
5B5188
NDC 0941-0415-48
3000
3000
5B5189
NDC 0941-0415-49
5000
5000
5B5195
NDC 0941-0415-25
6000
6000
5B9712
NDC 0941-0415-28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Chemcial Structure
Baxter, DIANEAL, AMBU-FLEX, and PL 146 are trademarks of Baxter
International Inc.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
©Copyright 1981, 1982, 1983, 1984, 1989 Baxter Healthcare Corporation. All
rights reserved.
07-19-59-178
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For current labeling information, please visit https://www.fda.gov/drugsatfda
DIANEAL Low Calcium Peritoneal Dialysis Solution
AMBU-FLEX Container For Peritoneal Dialysis
For intraperitoneal administration only
Description
DIANEAL Low Calcium peritoneal dialysis solutions in AMBU-FLEX containers
are sterile, nonpyrogenic solutions for intraperitoneal administration only. They
contain no bacteriostatic or antimicrobial agents or added buffers.
Composition, calculated osmolarity, pH and ionic concentrations are shown in
Table 1.
Potassium is omitted from peritoneal dialysis solutions because dialysis may be
performed to correct hyperkalemia. In situations in which there is a normal serum
potassium level or hypokalemia, the addition of potassium chloride (up to a
concentration of 4 mEq/L) may be indicated to prevent severe hypokalemia.
Addition of potassium chloride should be made after careful evaluation of
serum and total body potassium and only under the direction of a
physician. Frequent monitoring of serum electrolytes is indicated.
In some patients calcium carbonate is used as a phosphate binder. Because
serum calcium levels have been observed to be elevated in these patients
(Slatopolsky et al. 1986), the calcium concentration of DIANEAL Low Calcium
peritoneal dialysis solutions has been reduced to 2.5 mEq/L. Serum calcium
levels should be monitored and if low, the amount of oral calcium carbonate
phosphate binder may be increased or peritoneal dialysis solutions containing
higher calcium concentrations may be used. If serum calcium levels rise,
adjustments to the dosage of the calcium carbonate phosphate binder and/or
vitamin D analogs should be considered by the physician.
Because average plasma magnesium levels in some chronic CAPD patients
have been observed to be elevated (Nolph et al. 1981), the magnesium
concentration of this formulation has been reduced to 0.5 mEq/L. Average
plasma magnesium levels have not been reported for chronic IPD and CCPD
patients. Serum magnesium levels should be monitored and if low, oral
magnesium supplements, oral magnesium containing phosphate binders, or
peritoneal dialysis solutions containing higher magnesium concentrations may be
used.
Because average serum bicarbonate levels in some chronic CAPD patients
(Nolph et al. 1981), some chronic IPD patients (La Greca et al. 1980), and some
chronic CCPD patients (Diaz-Buxo et al. 1983), have been observed to be
somewhat lower than normal values, the bicarbonate precursor (lactate)
concentration of DIANEAL Low Calcium peritoneal dialysis solutions has been
raised to 40 mEq/L. Serum bicarbonate levels should be monitored.
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The osmolarities shown in Table 1 are calculated values. Calculated osmolarity
of DIANEAL Low Calcium peritoneal dialysis solution with 1.5% dextrose is 344
mOsmol/L, compared with measured values in normal human serum of 280
mOsmol/L.
The 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 overpouch 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 by tissue culture toxicity studies.
Clinical Pharmacology
Peritoneal dialysis is a procedure for removing toxic substances and metabolites
normally excreted by the kidneys, and for aiding in the regulation of fluid and
electrolyte balance.
The procedure is accomplished by instilling peritoneal dialysis fluid through a
conduit into the peritoneal cavity. With the exception of lactate, present as a
bicarbonate precursor, electrolyte concentrations in the fluid have been
formulated in an attempt to normalize plasma electrolyte concentrations resulting
from osmosis and diffusion across the peritoneal membrane (between the
patient’s plasma and the dialysis fluid). Toxic substances and metabolites,
present in high concentrations in the blood, cross the peritoneal membrane into
the dialyzing fluid. Dextrose in the dialyzing fluid is used to produce a solution
hyperosmolar to the plasma, creating an osmotic gradient which facilitates fluid
removal from the patient’s plasma into the peritoneal cavity.
After a period of time (dwell time), the fluid is drained from the cavity.
Indications and Usage
DIANEAL Low Calcium peritoneal dialysis solutions are indicated for use in
chronic renal failure patients being maintained on peritoneal dialysis.
Contraindications
None known.
Warnings
Peritoneal dialysis should be done with great care, if at all, in patients with a
number of abdominal conditions including disruption of the peritoneal membrane
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or diaphragm by surgery or trauma, extensive adhesions, bowel distention,
undiagnosed abdominal disease, abdominal wall infection, hernias or burns, fecal
fistula or colostomy, tense ascites, obesity, and large polycystic kidneys
(Vaamonde and Perez 1977). Other conditions include recent aortic graft
replacement and severe pulmonary disease. When assessing peritoneal dialysis
as the mode of therapy in such extreme situations, the benefits to the patient
must be weighed against the possible complications.
An accurate fluid balance record must be kept and the weight of the patient
carefully monitored to avoid over or under hydration with severe consequences
including congestive heart failure, volume depletion, and shock.
Excessive use of DIANEAL Low Calcium peritoneal dialysis solution with 3.5% or
4.25% dextrose during a peritoneal dialysis treatment can result in significant
removal of water from the patient.
Stable patients undergoing maintenance peritoneal dialysis should have routine
periodic evaluation of blood chemistries and hematologic factors, as well as other
indicators of patient status.
In some patients calcium carbonate is used as a phosphate binder. Because
serum calcium levels have been observed to be elevated in these patients
(Slatopolsky et al. 1986), the calcium concentration of DIANEAL Low
Calcium peritoneal dialysis solutions has been reduced to 2.5 mEq/L. Serum
calcium levels should be monitored and if low, the amount of oral calcium
carbonate phosphate binder may be increased or peritoneal dialysis solutions
containing higher calcium concentrations may be used. If serum calcium levels
rise, adjustments to the dosage of the calcium carbonate phosphate binder
and/or vitamin D analogs should be considered by the physician.
Because average plasma magnesium levels in some chronic CAPD patients
have been observed to be elevated (Nolph et al. 1981), the magnesium
concentration of this formulation has been reduced to 0.5 mEq/L. Average
plasma magnesium levels have not been reported for chronic IPD and CCPD
patients. Serum magnesium levels should be monitored and if low, oral
magnesium supplements, oral magnesium containing phosphate binders, or
peritoneal dialysis solutions containing higher magnesium concentrations may be
used.
Because average serum bicarbonate levels in some chronic CAPD patients
(Nolph et al. 1981), some chronic IPD patients (La Greca et al. 1980), and some
chronic CCPD patients (Diaz-Buxo et al. 1983), have been observed to be
somewhat lower than normal values, the bicarbonate precursor (lactate)
concentration of DIANEAL Low Calcium peritoneal dialysis solutions has been
raised to 40 mEq/L. Serum bicarbonate levels should be monitored.
This label may not be the latest approved by FDA.
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Not for use in the treatment of lactic acidosis.
Potassium is omitted from DIANEAL Low Calcium peritoneal dialysis solutions
because dialysis may be performed to correct hyperkalemia. Addition of
potassium chloride should be made after careful evaluation of serum and
total body potassium and only under the direction of a physician.
The use of 5 or 6 liters of dialysis solution is not indicated in a single exchange.
Refer to manufacturer’s directions accompanying drugs to obtain full information
on additives.
If the resealable rubber plug on the medication port is missing or partially
removed, do not use product if medication is to be added.
After the pull ring has been removed, inspect connector of solution container for
fluid flow. A few drops of solution within the connector or pull ring may be present
due to condensation of water resulting from the sterilization process. If a
continuous stream of fluid is noted, discard solution because sterility may be
impaired.
After removing overpouch, check for minute leaks by squeezing container firmly.
If leaks are found, discard the solution because the sterility may be impaired.
Freezing of solution may occur at temperatures below 0°C (32°F). Allow to thaw
naturally in ambient conditions and thoroughly mix contents by shaking.
Precautions
Aseptic technique must be used throughout the procedure and at its termination
in order to reduce the possibility of infection. If peritonitis occurs, the choice and
dosage of antibiotics should be based upon the results of identification and
sensitivity studies of the isolated organism(s) when possible. Prior to
identification of the involved organism(s), broad-spectrum antibiotics may be
indicated.
Peritoneal dialysis solutions may be warmed in the overpouch to 37°C (98.6°F) to
enhance patient comfort. However, only dry heat (for example, heating pad)
should be used. Solutions should not be heated in water due to an increased risk
of infection. Microwave ovens should not be used to heat solutions because
there is a potential for damage to the solution container. Moreover, microwave
oven heating may potentially cause overheating and/or non-uniform heating of
the solution that may result in patient injury or discomfort.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Significant losses of protein, amino acids and water soluble vitamins may occur
during peritoneal dialysis. Replacement therapy should be provided as
necessary.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted
with DIANEAL Low Calcium peritoneal dialysis solutions. It is also not known
whether DIANEAL Low Calcium peritoneal dialysis solutions can cause fetal
harm when administered to a pregnant woman or can affect reproduction
capacity. DIANEAL Low Calcium peritoneal dialysis solutions should be given to
a pregnant woman only if clearly needed.
Do not administer unless solution is clear and seal is intact.
Adverse Reactions
Adverse reactions to peritoneal dialysis include mechanical and solution related
problems as well as the results of contamination of equipment or improper
technique in catheter placement. Abdominal pain, bleeding,
peritonitis, subcutaneous infection around a chronic peritoneal catheter, catheter
blockage, difficulty in fluid removal, and ileus are among the complications of the
procedure. Solution related adverse reactions may include electrolyte and fluid
imbalances, hypovolemia, hypervolemia, hypertension, hypotension,
disequilibrium syndrome, and muscle cramping.
When prescribing the solution to be used for an individual patient, consideration
should be given to the potential interaction between the dialysis treatment and
therapy directed at other existing illnesses. For example, rapid potassium
removal may create arrhythmias in cardiac patients using digitalis or similar
drugs; digitalis toxicity may be masked by elevated potassium or magnesium, or
by hypocalcemia. Correction of electrolytes by dialysis may precipitate signs and
symptoms of digitalis excess. Conversely, toxicity may occur at suboptimal
dosages of digitalis if potassium is low or calcium high. Azotemic diabetics
require careful monitoring of insulin requirements during and following dialysis
with dextrose containing solutions.
Dosage and Administration
DIANEAL Low Calcium peritoneal dialysis solutions are intended for
intraperitoneal administration only.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit.
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The mode of therapy (Intermittent Peritoneal Dialysis [IPD], Continuous
Ambulatory Peritoneal Dialysis [CAPD], or Continuous Cyclic Peritoneal Dialysis
[CCPD]), frequency of treatment, formulation, exchange volume, duration of
dwell, and length of dialysis should be selected by the physician responsible for
and supervising the treatment of the individual patient.
To avoid the risk of severe dehydration and hypovolemia and to minimize the
loss of protein, it is advisable to select the peritoneal dialysis solution with the
lowest level of osmolarity consistent with the fluid removal requirements for that
exchange.
Peritoneal dialysis solutions may be warmed in the overpouch to 37°C (98.6°F) to
enhance patient comfort. However, only dry heat (for example, heating pad)
should be used. (See Directions for Use)
The addition of heparin to the dialysis solution may be indicated to aid in
prevention of catheter blockage in patients with peritonitis, or when the solution
drainage contains fibrinous or proteinaceous material (Ribot et al. 1966). 1000 to
2000 USP units of heparin per liter of solution has been recommended for adults
(Furman et al. 1978). For children, 50 units of heparin per 100 mL of dialysis fluid
has been recommended (Irwin et al. 1981).
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.
Intermittent Peritoneal Dialysis (IPD)
For maintenance dialysis of chronic renal failure patients.
The cycle of instillation, dwell and removal of dialysis fluid is repeated
sequentially over a period of hours (8 to 36 hours) as many times per week as
indicated by the condition of the patient. For chronic renal failure patients,
maintenance dialysis is often accomplished by periodic dialysis (3 to 5 times
weekly) for shorter time periods (8 to 14 hours per session) (Mattocks and El-
Bassiouni 1971).
Continuous Ambulatory Peritoneal Dialysis (CAPD) and Continuous Cyclic
Peritoneal Dialysis (CCPD)
For maintenance dialysis of chronic renal failure patients.
In CAPD, typically 1.5 to 3.0 liters of dialysis solution (depending upon patient
size) are instilled into the peritoneal cavity of adults and the peritoneal access
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device is then clamped (Kim et al. 1984; Twardowski and Janicka 1981;
Twardowski and Burrows 1984). For children, 30 to 50 mL/kg body weight with a
maximum of 2 liters has been recommended (Potter et al. 1981; Irwin et al.
1981). The solution remains in the cavity for dwell times of 4 to 8 hours during
the day and 8 to 12 hours overnight. At the conclusion of each dwell period, the
access device is opened, the solution drained and fresh solution instilled. The
procedure is repeated 3 to 5 times per day, 6 to 7 days per week. Solution
exchange volumes and frequency of exchanges should be individualized for
adequate biochemical and fluid volume control (Moncrief et al. 1982; Twardowski
et al. 1983). The majority of exchanges will utilize 1.5% or 2.5% dextrose
containing peritoneal dialysis solutions, with 3.5% or 4.25% dextrose containing
solutions being used when extra fluid removal is required. Patient weight is used
as the indicator of the need for fluid removal (Popovich et al. 1978).
In CCPD, the patient receives 3 or 4 dialysis exchanges during the night which
range from 2-1/2 to 3 hours dwell duration. Typically 1.5 to 2.0 liters of dialysis
solution (depending upon patient size) are delivered each cycle by an automatic
peritoneal dialysis cycler machine. After the last outflow during the night, an
additional exchange is infused by the cycler machine into the peritoneum. The
equipment is then disconnected from the patient, and the dialysate remains in the
peritoneum for 14 to 15 hours during the day until the next nocturnal cycle
(Diaz-Buxo et al. 1981). Combinations of 1.5% or 2.5% dextrose containing
peritoneal dialysis solutions are usually used for the nighttime exchanges, while
3.5% or 4.25% dextrose containing solution is used when extra fluid removal is
required such as during the daytime exchange. Patient weight is used as the
indicator of the need for fluid removal (Popovich et al. 1978) so therapy should
be individualized according to the patient’s need for ultrafiltration.
It is recommended that adult patients being placed on peritoneal dialysis or, in
the case of pediatric patients, the selected caretaker, (as well as the patient,
when suitable), should be appropriately trained in a program which is under the
supervision of a physician. Training materials are available from Baxter
Healthcare Corporation, Deerfield, IL 60015 USA to facilitate this training.
How Supplied
DIANEAL Low Calcium peritoneal dialysis solutions in AMBU-FLEX II and
AMBU-FLEX III containers are available in nominal size flexible containers with
fill volumes as indicated in Table 1.
All DIANEAL Low Calcium peritoneal dialysis solutions have overfills which are
declared on container labeling.
Exposure of pharmaceutical products to heat should be minimized. Avoid
excessive heat. It is recommended the product be stored at room temperature
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(25°C/77°F): brief exposure up to 40°C (104°F) does not adversely affect the
product.
Directions for Use
Use aseptic technique.
For complete system preparation, see directions accompanying ancillary
equipment.
Peritoneal dialysis solutions may be warmed in the overpouch to 37°C (98.6°F) to
enhance patient comfort. However, only dry heat (for example, heating pad)
should be used. Solutions should not be heated in water due to an increased risk
of infection. Microwave ovens should not be used to heat solutions because
there is a potential for damage to the solution container. Moreover, microwave
oven heating may potentially cause overheating and/or non-uniform heating of
the solution that may result in patient injury or discomfort.
To Open
Tear overpouch 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. If supplemental medication is desired, follow
directions below before preparing for administration. Check for minute leaks by
squeezing container firmly.
To Add Medication
Additives may be incompatible.
If the resealable rubber plug on the medication port is missing or partially
removed, do not use product if medication is to be added.
1. Put on mask. Clean and/or disinfect hands.
2. Prepare medication site using aseptic technique.
3. Using a syringe with a 1 inch long 19 to 25 gauge needle, puncture resealable
medication port and inject medication.
4. Position container with ports up and evacuate the medication port by
squeezing and tapping it.
5. Mix solution and medication thoroughly.
Preparation for Administration
1. Put on mask. Clean and/or disinfect hands.
2. Place solution container on work surface.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3. Remove pull ring from connector of the solution container. If continuous fluid
flow from connector is observed, discard solution container.
4. Remove tip protector from tubing set and immediately attach to connector of
the solution container.
5. Continue with therapy set-up as instructed in user manual or directions
accompanying tubing sets.
6. Upon completion of therapy, discard unused portion.
References
Diaz-Buxo, J.A. et al. 1981. Continuous cyclic peritoneal dialysis: a preliminary
report. Int Soc Artif Organs 81:157-161.
Diaz-Buxo, J.A. et al. 1983. Observations on inadequate base buffer
concentrations in peritoneal dialysis solutions. ASAIO Abstracts 43.
Furman, K.I. et al. 1978. Activity of intraperitoneal heparin during peritoneal
dialysis. Clinical Nephrology 9:15-18.
Irwin, M.A. et al. 1981. Continuous ambulatory peritoneal dialysis in pediatrics.
AANNT J 8:11-13, 44.
Kim, D. et al. 1984. Continuous ambulatory peritoneal dialysis with three-liter
exchanges: a prospective study. Peritoneal Dial Bull 4:82-85.
La Greca, G. et al. 1980. Acid base balance on peritoneal dialysis. Clinical
Nephrology 16(1):1-6.
Mattocks, A.M. and El-Bassiouni, E.A. 1971. Peritoneal dialysis: a review. J
Pharm Sci 60:1767-1782.
Moncrief, J.W. et al. 1982. CAPD: Are three exchanges per day adequate?
AANNT J 9:39-43.
Nolph, K.D. et al. 1981. Considerations for dialysis solution modifications. In
Peritoneal Dialysis, eds. Robert C. Atkins et al. Chapter 25. New York: Churchill
Livingston.
Popovich, R.P. et al. 1978. Continuous ambulatory peritoneal dialysis. Ann
Intern Med 8:449-456.
Potter, D.E. et al. 1981. Continuous ambulatory dialysis (CAPD) in children.
Trans Am Soc Artif Intern Organs 27:64-67.
Ribot, S. et al. 1966. Complications of peritoneal dialysis. Am J Med Sci
252:505-517.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Slatopolsky, E. et al. 1986. Calcium carbonate as a phosphate binder in patients
with chronic renal failure undergoing dialysis. NEJM 3:315, 157-160.
Twardowski, Z.J. and Janicka, L. 1981. Three exchanges with a 2.5 liter volume
for continuous ambulatory peritoneal dialysis. Kidney Int 20:281-284.
Twardowski, Z.J. et al. 1983. High volume low frequency continuous ambulatory
peritoneal dialysis. Kidney Int 23:64-70.
Twardowski, Z.J. and Burrows, L. 1984. Two year experience with high volume,
low frequency continuous ambulatory peritoneal dialysis. Peritoneal Dial Bull
4:S67.
Vaamonde, C.A. and Perez, G.O. 1977. Peritoneal dialysis today. Kidney 10:31
36.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1.
Composition/100mL
Ionic Concentration
(mEq/L)
How Supplied
Fill
Container
Code
NDC
P
SP
(mOsmol/L) (calc)
Y
Volume
Size
*Dextrose, Hydrous, US
Sodium Chloride, USP
(NaCl)
Sodium Lactate
(C 3 H 5 NaO3 )
Calcium Chloride, USP
(CaCl2 •2H2 O)
Magnesium Chloride, U
(MgCl2 •6H2 O)
OSMOLARIT
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
Dianeal® Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg
18.3 mg
5.08 mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
2500
3000
5000
6000
3000
3000
3000
6000
6000
L5B4825
L5B9718
L5B9901
L5B4826
L5B9770
NDC 0941-0409-06
NDC 0941-0409-08
NDC 0941-0409-05
NDC 0941-0409-07
NDC 0941-0409-01
Dianeal® Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX III
CONTAINER
1.5 g
538 mg
448 mg
18.3 mg
5.08 mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
5000
6000
2000
2000
3000
3000
5000
6000
5B9715
5B4825
5B9718
5B9901
5B4826
5B9770
NDC 0941-0409-45
NDC 0941-0409-36
NDC 0941-0409-48
NDC 0941-0409-49
NDC 0941-0409-27
NDC 0941-0409-28
Dianeal® Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
2.5 g
538 mg
448 mg
18.3 mg
5.08 mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
2500
3000
3000
L5B9727
L5B9728
NDC 0941-0457-08
NDC 0941-0457-07
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
3000
5000
6000
3000
6000
6000
L5B9902
L5B5202
L5B9771
NDC 0941-0457-02
NDC 0941-0457-05
NDC 0941-0457-01
Dianeal® Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX III
CONTAINER
2.5 g
538 mg
448 mg
18.3 mg
5.08 mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
5000
6000
2000
3000
3000
3000
5000
6000
5B9725
5B9727
5B9728
5B9902
5B5202
5B9771
NDC 0941-0457-45
NDC 0941-0457-47
NDC 0941-0457-48
NDC 0941-0457-49
NDC 0941-0457-25
NDC 0941-0457-28
Dianeal® Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 3.5%
Dextrose
3.5 g
538 mg
448 mg
18.3 mg
5.08 mg
445
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2500
3000
5B9738
NDC 0941-0463-48
Dianeal® Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg
18.3 mg
5.08 mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
2500
3000
5000
6000
3000
3000
3000
6000
6000
L5B9747
L5B9748
L5B9903
L5B5203
L5B9772
NDC 0941-0459-08
NDC 0941-0459-07
NDC 0941-0459-02
NDC 0941-0459-05
NDC 0941-0459-01
Dianeal® Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
AMBU-FLEX III
CONTAINER
4.25 g
538 mg
448 mg
18.3 mg
5.08 mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
5000
6000
2000
3000
3000
3000
5000
6000
5B9745
5B9747
5B9748
5B9903
5B5203
5B9772
NDC 0941-0459-45
NDC 0941-0459-47
NDC 0941-0459-48
NDC 0941-0459-49
NDC 0941-0459-25
NDC 0941-0459-28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Chemical Structure
Baxter, DIANEAL, AMBU-FLEX, and PL 146 are trademarks of Baxter
International Inc.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
©Copyright 1981, 1982, 1983, 1984, 1989 Baxter Healthcare Corporation. All
rights reserved.
071959179
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:13.207089
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017512s108lbl.pdf', 'application_number': 17512, 'submission_type': 'SUPPL ', 'submission_number': 108}
|
11,004
|
DIANEAL Peritoneal Dialysis Solution
For intraperitoneal administration only
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DESCRIPTION
DIANEAL Peritoneal Dialysis Solutions are sterile, nonpyrogenic solutions in flexible containers for
intraperitoneal administration only. The peritoneal dialysis solutions contain no bacteriostatic or
antimicrobial agents.
Composition, calculated osmolarity, pH, and ionic concentrations are shown in Tables 1-6.
DIANEAL is a hyperosmolar solution.
The plastic container is fabricated from 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 solution 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 by cell culture toxicity studies.
CLINICAL PHARMACOLOGY
Mechanism of Action
DIANEAL is a hypertonic peritoneal dialysis solution containing dextrose, a monosaccharide, as the
primary osmotic agent. An osmotic gradient must be created between the peritoneal membrane and
the dialysis solution in order for ultrafiltration to occur. The hypertonic concentration of glucose in
DIANEAL exerts an osmotic pressure across the peritoneal membrane resulting in transcapillary
ultrafiltration. Like other peritoneal dialysis solutions, DIANEAL contains electrolytes to facilitate the
correction of electrolyte abnormalities. DIANEAL contains a buffer, lactate, to help normalize acid-
base abnormalities.
Pharmacokinetics of DIANEAL
Glucose content in DIANEAL is expressed as dextrose monohydrate and is available in three
concentrations: 1.5%, 2.5% and 4.25%.
Reference ID: 3799174
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Glucose is rapidly absorbed from the peritoneal cavity by diffusion and appears quickly in the
circulation due to the high glucose concentration gradient between DIANEAL compared to blood
capillary glucose level. Absorption per unit time will be the highest at the start of an exchange and
decreases over time. The rate of glucose absorption will be dependent upon the transport
characteristics of the patient’s peritoneal membrane as determined by a peritoneal equilibration test
(PET). Glucose absorption will also depend upon the concentration of glucose used for the
exchange and the length of the dwell. Glucose is metabolized by normal cellular pathways (e.g.
glycolysis) and provides a source of calories and may elevate blood glucose levels.
Transport of other molecules across the peritoneal membrane, such as lactate, will occur by
diffusion. Metabolism of lactate occurs in the liver and results in the generation of the bicarbonate.
Transport of other molecules will be dependent upon the molecular size of the solute, the
concentration gradient, and the effective peritoneal surface area as determined by the PET.
INDICATIONS AND USAGE
DIANEAL peritoneal dialysis solutions are indicated for patients in acute or chronic renal failure
when nondialytic medical therapy is judged to be inadequate.
CONTRAINDICATIONS
DIANEAL is contraindicated in patients with pre-existing severe lactic acidosis.
WARNINGS
Encapsulating Peritoneal Sclerosis (EPS) is considered to be a known, rare complication of
peritoneal dialysis therapy. EPS has been reported in patients using peritoneal dialysis solutions
including DIANEAL. Infrequently, fatal outcomes of EPS have been reported with DIANEAL.
Because Dianeal is a dextrose-based solution, patients with allergy to corn or corn products are at
increased risk for allergic reaction, which may include anaphylactic/anaphylactoid reactions. Stop the
infusion immediately, drain the solution from the peritoneal cavity and treat appropriately if any signs
or symptoms of a suspected hypersensitivity reaction develop.
Patients with severe lactic acidosis should not be treated with lactate-based peritoneal dialysis
solutions (See Contraindications). Patients with conditions known to increase the risk of lactic
acidosis [e.g., severe hypotension or sepsis that can be associated with acute renal failure, hepatic
failure, inborn errors of metabolism, and treatment with drugs such as nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs)] must be monitored for the occurrence of lactic acidosis before the
start of treatment and during treatment with lactate-based peritoneal dialysis solutions.
When prescribing the solution to be used for an individual patient, consideration should be given to
the potential interaction between the dialysis treatment and therapy directed at other existing
illnesses. Serum potassium levels should be monitored carefully in patients treated with cardiac
glycosides. For example, rapid potassium removal may create arrhythmias in cardiac patients using
digitalis or similar drugs; digitalis toxicity may be masked by hyperkalemia, hypermagnesemia, or
hypocalcemia. Correction of electrolytes by dialysis may precipitate signs and symptoms of digitalis
excess. Conversely, toxicity may occur at suboptimal dosages of digitalis if potassium is low or
calcium is high.
Diabetics require careful monitoring of insulin requirements and other treatments for hyperglycemia
during and following dialysis with dextrose containing solutions.
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General
Peritoneal-Dialysis Related
DIANEAL is intended for intraperitoneal administration only. Not for intravenous administration.
The following conditions may predispose to adverse reactions to peritoneal dialysis procedures:
abdominal conditions, including uncorrectable mechanical defects that prevent effective peritoneal
dialysis or increase the risk of infection, disruption of the peritoneal membrane and diaphragm by
surgery, congenital anomalies or trauma prior to complete healing, abdominal tumors, abdominal
wall infections, hernias, fecal fistula, colostomies or ileostomies, frequent episodes of diverticulitis,
inflammatory or ischemic bowel disease, large polycystic kidneys, or other conditions that
compromise the integrity of the abdominal wall, abdominal surface, or intra-abdominal cavity, such
as documented loss of peritoneal function or extensive adhesions that compromise peritoneal
function. Conditions that preclude normal nutrition, impaired respiratory function, recent aortic graft
placement, and potassium deficiency may also predispose to complications of peritoneal dialysis.
Aseptic technique must be employed throughout the peritoneal dialysis procedure to reduce the
possibility of infection.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which
may indicate the presence of peritonitis.
If peritonitis occurs, the choice and dosage of antibiotics should be based upon the results of
identification and sensitivity studies of the isolated organism(s) when possible. Prior to identification
of the involved organism(s), broad-spectrum antibiotics may be indicated.
Overinfusion of peritoneal dialysis solution volume into the peritoneal cavity may be characterized by
abdominal distention, feeling of fullness and/or shortness of breath. Treatment of overinfusion is to
drain the peritoneal dialysis solution from the peritoneal cavity.
Need for Trained Physician
Treatment should be initiated and monitored under the supervision of a physician knowledgeable in
the management of patients with renal failure.
A patient’s volume status should be carefully monitored to avoid hyper- or hypovolemia and
potentially severe consequences including congestive heart failure, volume depletion and
hypovolemic shock. An accurate fluid balance record must be kept and the patient’s body weight
monitored. Excessive use of DIANEAL peritoneal dialysis solution with higher dextrose concentration
during a peritoneal dialysis treatment may result in significant removal of water from the patient (see
Dosage and Administration).
Significant losses of protein, amino acids, water-soluble vitamins and other medicines may occur
during peritoneal dialysis. The patient’s nutritional status should be monitored and replacement
therapy should be provided as necessary.
Information for Patients
Patients should be instructed not to use solutions if they are cloudy, discolored, contain visible
particulate matter, or if they show evidence of leaking containers (see Dosage and Administration).
Aseptic technique must be employed throughout the procedure.
An improper clamping sequence may result in infusion of air into the peritoneum (see Dosage and
Administration, Directions for Use).
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To reduce possible discomfort during administration, patients should be instructed that solutions may
be warmed to 37°C (98°F) prior to use. Only dry heat should be used. It is best to warm solutions
within the overwrap using a heating pad. To avoid contamination, solutions should not be immersed
in water for warming. Do not use a microwave oven to warm the solution (see Dosage and
Administration, Directions for Use).
Laboratory Tests
Serum Electrolytes
DIANEAL does not contain potassium. Evaluate serum potassium prior to administering potassium
chloride to the patient. In situations where there is a normal serum potassium level or hypokalemia,
addition of potassium chloride (up to a concentration of 4 mEq/L) to the solution may be necessary
to prevent severe hypokalemia. This should be made under careful evaluation of serum and total
body potassium, and only under the direction of a physician.
Fluid, hematology, blood chemistry, electrolyte concentrations, and bicarbonate should be monitored
periodically. If serum magnesium levels are low, magnesium supplements may be used.
Patients receiving DIANEAL solutions should have their calcium levels monitored for the
development of hypocalcemia or hypercalcemia. In these circumstances, adjustments to the dosage
of the phosphate binders, vitamin D analogs, and/or calcimimetics should be considered by the
physician. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis solution should be considered for
use in patients with hypercalcemia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies to evaluate the carcinogenic or mutagenic potential of this product, or its potential to affect
fertility adversely, have not been performed.
Drug Interactions
No clinical drug interaction studies were performed. As with other dialysis solutions, blood
concentrations of dialyzable drugs may be reduced by dialysis. Dosage adjustment of concomitant
medications may be necessary. In patients using cardiac glycosides (digoxin and others), plasma
levels of calcium, potassium and magnesium must be carefully monitored (see Warnings).
Use in Specific Population
Pregnancy
Pregnancy Category C. DIANEAL is a peritoneal dialysis solution of electrolytes, lactate and
dextrose and is pharmacologically inactive. Animal reproduction studies have not been conducted
with DIANEAL dialysis solution. While there are no adequate and well controlled studies in pregnant
women, appropriate administration of DIANEAL with monitoring of fluid, electrolyte, acid-base and
glucose balance, is not expected to cause fetal harm, or affect reproductive capacity. Maintenance
of normal acid-base balance is important for fetal well being. Physicians should carefully consider
the potential risks and benefits for each specific patient before prescribing DIANEAL.
Nursing Mothers
DIANEAL is a dialysis solution of electrolytes, lactate and dextrose and is pharmacologically
inactive. The components of DIANEAL are excreted in human milk. Appropriate administration of
DIANEAL with monitoring of fluid, electrolyte, acid-base and glucose balance, is not expected to
harm a nursing infant. Physicians should carefully consider the potential risks and benefits for each
specific patient before prescribing DIANEAL.
Pediatric Use
Safety and effectiveness have been established based on published clinical data. No adequate and
well-controlled studies have been conducted with DIANEAL solutions in pediatric patients.
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use
Safety and effectiveness have been established based on published clinical data.
ADVERSE REACTIONS
The following adverse reactions have been identified during post approval use of DIANEAL.
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 during drug exposure.
Adverse reactions are listed by MedDRA System Organ Class (SOC), then by Preferred Term in
order of severity.
INFECTIONS AND INFESTATIONS: Fungal peritonitis, Peritonitis bacterial, Catheter related
infection
METABOLISM AND NUTRITION DISORDERS: Hypovolemia, Hypervolemia, Fluid retention,
Hypokalemia, Hyponatremia, Dehydration, Hypochloremia
VASCULAR DISORDERS: Hypotension, Hypertension
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Dyspnea
GASTROINTESTINAL DISORDERS: Sclerosing encapsulating peritonitis, Peritonitis, Peritoneal
cloudy effluent, Vomiting, Diarrhea, Nausea, Constipation, Abdominal pain, Abdominal distension,
Abdominal discomfort
SKIN AND SUBCUTANEOUS DISORDERS: Stevens-Johnson syndrome, Urticaria, Rash, (including
pruritic, erythematous and generalized), Pruritus
MUSCULOSKELETAL, CONNECTIVE TISSUE DISORDERS: Myalgia, Muscle spasms,
Musculoskeletal pain
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Generalized edema,
Pyrexia, Malaise, Infusion site pain, Catheter related complication
DRUG ABUSE AND DEPENDENCE
There has been no observed potential of drug abuse or dependence with DIANEAL solution.
OVERDOSAGE
There is a potential for overdose resulting in hypervolemia, hypovolemia, electrolyte disturbances or
hyperglycemia. Excessive use of DIANEAL peritoneal dialysis solution with 4.25% dextrose during a
peritoneal dialysis treatment can result in significant removal of water from the patient.
DOSAGE AND ADMINISTRATION
DIANEAL peritoneal dialysis solutions are intended for intraperitoneal administration only.
The mode of therapy, frequency of treatment, formulation, exchange volume, duration of dwell, and
length of dialysis should be selected by the physician responsible for and supervising the treatment
of the individual patient. DIANEAL should be administered at a rate that is comfortable for the
patient, generally over a period of 10-20 minutes for a single exchange.
Patients on continuous ambulatory peritoneal dialysis (CAPD) typically perform 4 cycles per day (24
hours). Patients on automated peritoneal dialysis (APD) typically perform 4-5 cycles at night and up
Reference ID: 3799174
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For current labeling information, please visit https://www.fda.gov/drugsatfda
to 2 cycles during the day. The fill volume depends on body size, usually from 2.0 to 2.5 liters per
1.73m2 .
To avoid the risk of severe dehydration and hypovolemia and to minimize the loss of protein, it is
advisable to select the peritoneal dialysis solution with the lowest level of osmolarity consistent with
the fluid removal requirements for that exchange. As the patient’s body weight becomes closer to the
ideal dry weight, lowering the dextrose concentration of DIANEAL is recommended. DIANEAL
4.25% dextrose-containing solution has the highest osmolarity of the DIANEAL solutions and using it
for all exchanges may cause dehydration.
Solutions that are cloudy, discolored, contain visible particulate matter, or show evidence of leakage
should not be used.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness which
may indicate the presence of peritonitis.
For single use only. Discard unused portion.
It is recommended that patients being placed on peritoneal dialysis and/or their caretaker(s) should
be appropriately trained.
Addition of Potassium
Potassium is omitted from DIANEAL solutions because dialysis may be performed to correct
hyperkalemia. In situations where there is a normal serum potassium level or hypokalemia, the
addition of potassium chloride (up to a concentration of 4 mEq/L) may be indicated to prevent severe
hypokalemia. The decision to add potassium chloride should be made by the physician after careful
evaluation of serum potassium.
Addition of Insulin
Patients with insulin-dependent diabetes may require modification of insulin dosage following
initiation of treatment with DIANEAL. Appropriate monitoring of blood glucose should be performed
when initiating DIANEAL in diabetic patients and insulin dosage adjusted if needed (see Warnings).
Addition of Heparin
No human drug interaction studies with heparin were conducted. In vitro studies demonstrated no
evidence of incompatibility of heparin with DIANEAL.
Addition of Antibiotics
No formal clinical drug interaction studies have been performed. In vitro studies of the following
medications have demonstrated stability with DIANEAL: amphotericin B, ampicillin, cefazolin,
cefepime, cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, clindamycin, deferoxamine,
erythromycin, gentamicin, linezolid, mezlocillin, miconazole, moxifloxacin, nafcillin, ofloxacin,
penicillin G, piperacillin, sulfamethoxazole/trimethoprim, ticarcillin, tobramycin, and vancomycin.
However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.
Directions for Use
For complete CAPD and APD system preparation, see directions accompanying ancillary
equipment.
Aseptic technique must be used throughout the peritoneal dialysis procedure.
Warming
For patient comfort, DIANEAL can be warmed to 37°C (98°F). Only dry heat should be used. It is
best to warm solutions within the overwrap using a heating pad. Do not immerse DIANEAL in water
for warming. Do not use a microwave oven to warm DIANEAL.
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To Open
To open, tear the overwrap down at the slit and remove the solution container. Some opacity of the
plastic, due to moisture absorption during the sterilization process, may be observed. This does not
affect the solution quality or safety and may often leave a slight amount of moisture within the
overwrap. The opacity should diminish gradually.
Inspect for Container Integrity
Inspect the bag connector to ensure the tip protector (pull ring, blue pull tip, or blue twist-off tip) is
attached. Do not use if the tip protector is not attached to the connector. Inspect the DIANEAL
container for signs of leakage and check for minute leaks by squeezing the container firmly. If the
container has frangible(s), inspect that they are positioned correctly and are not broken. Do not use
DIANEAL if the frangible(s) are broken or leaks are suspected as sterility may be impaired.
For DIANEAL in UltraBag, inspect the tubing and drain container for presence of solution. Small
droplets are acceptable, but if solution flows past the frangible prior to use, do not use and discard
the units.
Adding Medications
Some drug additives may be incompatible with DIANEAL. See DOSAGE AND ADMINISTRATION
section for additional information. If the resealable rubber plug on the medication port is missing or
partly removed, do not use the product if medication is to be added.
1. Put on mask. Clean and/or disinfect hands.
2. Prepare medication port site using aseptic technique.
3. Using a syringe with a 1-inch long, 25- to 19-gauge needle, puncture the medication port and
inject additive.
4. Reposition container with container ports up and evacuate medication port by squeezing and
tapping it.
5. Mix solution and additive thoroughly.
Administration instructions for CAPD therapy using ULTRABAG containers
(Products listed in Tables 1-2)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
1) Uncoil tubing and drain bag, ensuring that the transfer set is closed.
2) Immediately attach the solution container to patient connector (transfer set) or appropriate
automated peritoneal dialysis set.
3) Break the connector (Y-set) frangible.
4) Remove the tip protector from the connector of solution container.
5) Clamp solution line and then break frangible near solution bag. Hang solution container and
place the drainage container below the level of the abdomen.
6) Open transfer set to drain the solution from abdomen. If drainage cannot be established,
contact your clinician. When drainage complete, close transfer set.
7) Remove clamp from solution line and flush new solution to flow into the drainage container
for 5 seconds to prime the line. Clamp drain line after flush complete.
8) Open transfer set to fill. When fill complete, close transfer set.
9) Disconnect UltraBag from transfer set and apply MiniCap.
10) Upon completion of therapy, discard any unused portion.
Administration instructions for APD therapy using containers with pull rings or blue pull tips
(Products listed in Tables 3-5)
Put on mask. Clean and/or disinfect hands. Using aseptic technique
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1) Remove the tip protector from connector of solution container. Do not reuse the solution or
container once the tip protector is removed.
2) Immediately attach the solution container to patient connector (transfer set) or appropriate
automated peritoneal dialysis set.
3) Continue therapy as instructed in user manual or accompanying tubing sets for automated
peritoneal dialysis. Upon completion of therapy, discard any unused portion.
Administration instructions for APD therapy using containers with blue twist-off tips
(Products listed in Tables 6)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
1) Place and fasten blue outlet port clamp on solution bag administration port, between the blue
connector and the solution container.
2) Twist off the blue twist-off tip from connector of solution container. Once the blue twist-off tip
has been removed do not reuse the solution or container.
3) Immediately insert the spike of the automated peritoneal dialysis set into the solution bag
port.
4) Continue with therapy as instructed in user manual or directions accompanying tubing sets
for automated peritoneal dialysis.
5) Upon completion of therapy, discard any unused portion.
HOW SUPPLIED
DIANEAL peritoneal dialysis solutions are available in nominal size flexible containers as shown in
Tables 1-6.
All DIANEAL peritoneal dialysis solutions have overfills which are declared on container labeling.
Freezing of solution may occur at temperatures below 0°C (32°F). Allow to thaw naturally in ambient
conditions and thoroughly mix contents by shaking.
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.
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. DIANEAL PD-2 Peritoneal Dialysis Solution (ULTRABAG CONTAINER for CAPD therapy )
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL PD-2
Peritoneal Dialysis
Solution with
1.5% Dextrose
1.5 g
538 mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9866
5B9868
5B9857
0941-0426-52
0941-0426-53
0941-0426-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
2.5% Dextrose
2.5 g
538 mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9876
5B9878
5B9858
0941-0427-52
0941-0427-53
0941-0427-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
4.25 g
538 mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9896
5B9898
5B9859
0941-0429-52
0941-0429-53
0941-0429-55
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (ULTRABAG CONTAINER for CAPD therapy)
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg 448 mg
18.3
mg
5.08
mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9765
5B9766
5B9768
5B9757
0941-0424-51
0941-0424-52
0941-0424-53
0941-0424-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg 448 mg
18.3
mg
5.08
mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9775
5B9776
5B9778
5B9758
0941-0430-51
0941-0430-52
0941-0430-53
0941-0430-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
4.25 g 538 mg 448 mg
18.3
mg
5.08
mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9795
5B9796
5B9798
5B9759
0941-0433-51
0941-0433-52
0941-0433-53
0941-0433-55
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. DIANEAL PD-2 Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER with pull ring for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
2 •6H2 O)
Fill
Container
SP
, U
SP
SP
USP (MgCl
e,
Volume
Size
Code
NDC
*Dextrose, Hydrous
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL PD-2
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5163
L5B5166
L5B5169
L5B5193
L5B9710
0941-0411-05
0941-0411-06
0941-0411-04
0941-0411-07
0941-0411-11
DIANEAL PD-2
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5173
L5B5177
L5B5179
L5B5194
L5B9711
0941-0413-05
0941-0413-06
0941-0413-04
0941-0413-07
0941-0413-01
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5183
L5B5187
L5B5189
L5B5195
L5B9712
0941-0415-05
0941-0415-06
0941-0415-04
0941-0415-07
0941-0415-01
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER with pull ring for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
SP (MgCl
Fill
Container
SP
U
SP
SP
e, U
Volume
Size
Code
NDC
*Dextrose, Hydrous,
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg 18.3 mg 5.08 mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B4825
L5B9901
L5B4826
L5B9770
0941-0409-06
0941-0409-05
0941-0409-07
0941-0409-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg
448 mg 18.3 mg 5.08 mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9727
L5B9902
L5B5202
L5B9771
0941-0457-08
0941-0457-02
0941-0457-05
0941-0457-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg 18.3 mg 5.08 mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9747
L5B9903
L5B5203
L5B9772
0941-0459-08
0941-0459-02
0941-0459-05
0941-0459-01
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution Made in Ireland (Plastic container with blue pull tip for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
)
3 )
H 5 NaO
2 •2H2 O)
gCl
Fill
Container
aCl
l
aC
(M
Volume
Size
Code
NDC
*Dextrose, Hydrous
Sodium Chloride (N
Sodium Lactate (C3
Calcium Chloride (C
Magnesium Chloride
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg
448 mg 18.4 mg 5.08 mg
344
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5245R 0941-0484-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg
448 mg 18.4 mg 5.08 mg
395
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5255R 0941-0487-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
4.25 g
538 mg
448 mg 18.4 mg 5.08 mg
483
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5265R 0941-0490-01
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution Made in Mexico (Plastic container with blue twist-off tip for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3)
5NaO
2 •2H2 O)
SP (MgCl
Fill
Container
SP
U
P
SP (CaCl
, U
Volume
Size
Code
NDC
*Dextrose, Hydrous,
Sodium Chloride, US
Sodium Lactate (C3 H
Calcium Chloride, U
Magnesium Chloride
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg
448 mg 18.3 mg 5.08 mg
344
5.0 to 5.6
132
2.5
0.5
95
40
6000
6000
VBB4928US 0941-0472-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg
448 mg 18.3 mg 5.08 mg
395
5.0 to 5.6
132
2.5
0.5
95
40
6000
6000
VBB4931US 0941-0475-01
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
Baxter, Dianeal, Ambu-Flex, UltraBag, and PL 146 are trademarks of Baxter International, Inc.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Reference ID: 3799174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:13.237753
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017512s120s121lbl.pdf', 'application_number': 17512, 'submission_type': 'SUPPL ', 'submission_number': 120}
|
10,995
|
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 4
Baxter
OSMITROL Injection (Mannitol Injection, USP)
in AVIVA Plastic Container
For Therapeutic Use Only
Description
Osmitrol Injection (Mannitol Injection, USP) is a sterile, nonpyrogenic solution of Mannitol, USP in a
single dose container for intravenous administration. It contains no antimicrobial agents. Mannitol**
is a six carbon sugar alcohol prepared commercially by the reduction of dextrose. Although virtually
inert metabolically in humans, it occurs naturally in fruits and vegetables. Mannitol is an obligatory
osmotic diuretic. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.
Composition, osmolarity, and pH are shown in Table 1.
Composition
Table 1
Size
(mL)
**Mannitol,
USP (g/L)
*Osmolarity
(mOsmol/L)
(calc)
pH
5%
OSMITROL
Injection (5%
Mannitol
Injection, USP)
1000
50
274
5.5
(4.5 TO 7.0)
500
10%
OSMITROL
Injection (10%
Mannitol
Injection, USP)
1000
100
549
5.5
(4.5 TO 7.0)
15%
OSMITROL
Injection (15%
Mannitol
Injection, USP)
500
150
823
5.5
(4.5 TO 7.0)
250
20%
OSMITROL
Injection (20%
Mannitol
Injection, USP)
500
200
1098
5.5
(4.5 TO 7.0)
*Normal physiologic osmolarity range is approximately 280 to 310 m0smol/L.
Administration of substantially hypertonic solutions (≥ 600 m0smol/L) may cause vein damage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 5
Mannitol
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.
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 the 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
Osmitrol Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic
diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not
secreted by the tubule, and is pharmacologically inert.
Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small
molecular size being largely confined to the extracellular space. Only relatively small amounts of the
dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney
over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a
100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even
at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted
by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 6
and chloride by elevating the osmolarity of the glomerular filtrate.
This increase in extracellular osmolarity effected by the intravenous administration of mannitol will
induce the movement of intracellular water to the extracellular and vascular spaces. This action
underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated
intraocular pressure.
Indications and Usage
Osmitrol Injection (Mannitol Injection, USP) is indicated for:
The promotion of diuresis, in the prevention and/or treatment of the oliguric phase of acute renal
failure before irreversible renal failure becomes established;
The reduction of intracranial pressure and treatment of cerebral edema by reducing brain mass;
The reduction of elevated intraocular pressure when the pressure cannot be lowered by other means,
and promoting the urinary excretion of toxic substances.
Contraindications
Osmitrol Injection (Mannitol Injection, USP) is contraindicated in patients with:
Well established anuria due to severe renal disease, severe pulmonary congestion or frank pulmonary
edema, active intracranial bleeding except during craniotomy, severe dehydration,Progressive renal
damage or dysfunction after institution of mannitol therapy, including increasing oliguria and
azotemia, and progressive heart failure or pulmonary congestion after institution of mannitol therapy.
Warnings
In patients with severe impairment of renal function, a test dose should be utilized (see Dosage and
Administration). A second test dose may be tried if there is an inadequate response, but no more than
two test doses should be attempted.
The obligatory diuretic response following rapid infusion of 15% or 20% mannitol injection may
further aggravate preexisting hemoconcentration. Excessive loss of water and electrolytes may lead to
serious imbalances. Serum sodium and potassium should be carefully monitored during mannitol
administration.
If urine output continues to decline during mannitol infusion, the patient’s clinical status should be
closely reviewed and mannitol infusion suspended if necessary. Accumulation of mannitol may result
in overexpansion of the extracellular fluid which may intensify existing or latent congestive heart
failure.
Excessive loss of water and electrolytes may lead to serious imbalances. With continued
administration of mannitol, loss of water in excess of electrolytes can cause hypernatremia. Electrolyte
measurements, including sodium and potassium, are therefore, of vital importance in monitoring the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 7
infusion of mannitol.
Osmotic nephrosis, a reversible vacuolization of the tubules of unknown clinical significance, may
proceed to severe irreversible nephrosis, so that the renal function must be closely monitored during
mannitol infusion.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
The cardiovascular status of the patient should be carefully evaluated before rapidly administrating
mannitol since sudden expansion of the extracellular fluid may lead to fulminating congestive heart
failure.
Shift of sodium free intracellular fluid into the extracellular compartment following mannitol infusion
may lower serum sodium concentration and aggravate preexisting hyponatremia.
By sustaining diuresis, mannitol administration may obscure and intensify inadequate hydration or
hypovolemia.
Electrolyte free mannitol should not be given conjointly with blood. If it is essential that blood be
given simultaneously, at least 20 mEq of sodium chloride should be added to each liter of mannitol
solution to avoid pseudoagglutination.
When exposed to low temperatures, solutions of mannitol may crystallize. Concentrations greater than
15% have a greater tendency to crystallization. Inspect for crystals prior to administration. If crystals
are visible, redissolve by warming the solution up to 70°C, with agitation. Allow the solution to cool
to room temperature before reinspection for crystals. Administer intravenously using sterile, filter-
type administration set.
Laboratory Tests
Although blood levels of mannitol can be measured, there is little if any clinical virtue in doing so.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 8
The appropriate monitoring of blood levels of sodium and potassium; degree of hemoconcentration or
hemodilution, if any; indices of renal, cardiac and pulmonary function are paramount in avoiding
excessive fluid and electrolyte shifts. The routine features of physical examination and clinical
chemistries suffice in achieving an adequate degree of appropriate patient monitoring.
Drug Interaction
Studies have not been conducted to evaluate drug/drug or drug/food interactions with Osmitrol
Injection (Mannitol Injection, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Osmitrol Injection (Mannitol Injection, USP) have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with mannitol. It is also
not known whether mannitol can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. Mannitol should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Osmitrol Injection (Mannitol Injection,
USP) on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
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 mannitol is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children below the age of 12 have not been established.
Usage in Children
Dosage requirements for patients 12 years of age and under have not been established.
Geriatric Use
Clinical studies of Osmitrol Injection (Mannitol 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 the responses between 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 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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 9
to have decreased renal function, care should be taken in dose selection, and it may be useful to
monitor renal function.
Adverse Reactions
Extensive use of mannitol over the last several decades has produced recorded adverse events, in a
variety of clinical settings, that are isolated or idiosyncratic in nature. None of these adverse reactions
have occurred with any great frequency nor with any security in attributing them to mannitol.
The inability to clearly exclude the drug related nature of such events in these isolated reports prompts
the necessity to list the reactions that have been observed in patients during or following mannitol
infusion. In this fashion, patients have exhibited nausea, vomiting, rhinitis, local pain, skin necrosis
and thrombophlebitis at the site of infection, chills, dizziness, urticaria, hypotension, hypertension,
tachycardia, fever and angina-like chest pains.
Of far greater clinical significance is a variety of events that are related to inappropriate recognition
and monitoring of fluid shifts. These are not intrinsic adverse reactions to the drug but the
consequence of manipulating osmolarity by any agency in a therapeutically inappropriate manner.
Failure to recognize severe impairment of renal function with the high likelihood of nondiuretic
response can lead to aggravated dehydration of tissues and increased vascular fluid load. Induced
diuresis in the presence of preexisting hemoconcentration and preexisting deficiency of water and
electrolytes can lead to serious imbalances. Expansion of the extracellular space can aggravate cardiac
decompensation or induce it in the presence of latent heart failure. Pulmonary congestion or edema
can be seriously aggravated with the expansion of the extracellular and therefore intravascular fluid
load. Hemodilution and dilution of the extracellular fluid space by osmotic shift of water can induce or
aggravate preexisting hyponatremia.
If unrecognized, such fluid and/or electrolyte shift can produce the reported adverse reactions of
pulmonary congestion, acidosis, electrolyte loss, dryness of mouth, thirst, edema, headache, blurred
vision, convulsions and congestive cardiac failure.
These are not truly adverse reactions to the drug and can be appropriately prevented by evaluation of
degree of renal failure with a test dose response to mannitol when indicated; evaluation of
hypervolemia and hypovolemia; sodium and potassium levels; hemodilution or hemoconcentration;
and evaluation of renal, cardiac and pulmonary function at the onset of therapy.
Dosage and Administration
Osmitrol Injection (Mannitol Injection, USP) should be administered only by intravenous infusion.
The total dosage, concentration, and rate of administration should be governed by the nature and
severity of the condition being treated, fluid requirement, and urinary output. The usual adult dosage
ranges from 20 to 100 g in a 24 hour period, but in most instances an adequate response will be
achieved at a dosage of approximately 50 to 100 g in a 24 hour period. The rate of administration is
usually adjusted to maintain a urine flow of at least 30 to 50 mL/hour. This outline of administration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 10
and dosage is only a general guide to therapy.
Parenteral dug 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.
Test Dose: A test dose of mannitol should be given prior to instituting Osmitrol Injection (Mannitol
Injection, USP) therapy for patients with marked oliguria, or those believed to have inadequate renal
function. Such a test dose may be approximately 0.2 g/kg body weight (about 75 mL of a 20%
solution or 100 mL of a 15% solution) infused in a period of three to five minutes to produce a urine
flow of at least 30 to 50 mL/hour. If urine flow does not increase, a second test dose may be given; if
there is an inadequate response, the patient should be reevaluated.
Prevention of Acute Renal Failure (Oliguria): When used during cardiovascular and other types of
surgery, 50 to 100 g of mannitol as a 5, 10, or 15% solution may be given. The concentration will
depend upon the fluid requirements of the patient.
Treatment of Oliguria: The usual dose for treatment of oliguria is 100 g administered as a 15 or 20%
solution.
Reduction of Intraocular Pressure: A dose of 1.5 to 2.0 g/kg as a 20% solution (7.5 to 10 mL/kg) or as
a 15% solution (10 to 13 mL/kg) may be given over a period as short as 30 minutes in order to obtain a
prompt and maximal effect. When used preoperatively the dose should be given one to one and one-
half hours before surgery to achieve maximal reduction of intraocular pressure before operation.
Reduction of Intracranial Pressure: Usually a maximum reduction in intracranial pressure in adults can
be achieved with a dose of 0.25 g/kg given not more frequently than every six to eight hours. An
osmotic gradient between the blood and cerebrospinal fluid of approximately 10 m0smols will yield a
satisfactory reduction in intracranial pressure.
Adjunctive Therapy for Intoxications: As an agent to promote diuresis in intoxications, 5%, 10%, 15%
or 20% mannitol is indicated. The concentration will depend upon the fluid requirement and urinary
output of the patient.
Measurement of glomerular filtration rate by creatinine clearance may be useful for determination of
dosage.
All injections in AVIVA containers are intended for intravenous administration using sterile
equipment.
The use of supplemental additive medication is not recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 11
How Supplied
Osmitrol Injection (Mannitol Injection, USP) in AVIVA plastic containers is available as follows:
Code
Size (mL)
NDC
Product Name
6E5604
1000
0338-6300-04
5% Osmitrol Injection
(5% Mannitol Injection, USP)
6E5613
6E5614
500
1000
0338-6301-03
0338-6301-04
10% Osmitrol Injection
(10% Mannitol Injection, USP)
6E5623
500
0338-6302-03
15% Osmitrol Injection
(15% Mannitol Injection, USP)
6E5632
6E5633
250
500
0338-6303-02
0338-6303-03
20% Osmitrol Injection
(20% Osmitrol Injection)
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
* Bar Code Position Only
XXXXXXXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 12
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, OSMITROL, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 13
Baxter
Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below.
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an
osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an
osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride.
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.
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
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 14
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis
procedures.
Contraindications
None known.
Warnings
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
In patients with diminished renal function, administration of Sodium Chloride Injection, USP may
result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 15
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride
Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 Sodium Chloride Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in
the pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Chloride 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 the responses between 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 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
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 16
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. 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.
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
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride Injection,
USP
6E1314
1000
0338-6333-04
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride Injection,
USP
6E1323
500
0338-6304-03
6E1324
1000
0338-6304-04
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
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 17
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
For Product Information
1-800-833-0303
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 18
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 19
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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 and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 20
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional 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 and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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 and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 21
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
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 Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride 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 the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 22
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or 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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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 and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 23
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 24
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 25
Baxter
Lactated Ringer’s and 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
Each 100 mL contains 5 g Dextrose Hydrous, USP*; 600 mg Sodium Chloride, USP (NaCl); 310 mg
Sodium Lactate (C3H5NaO3); 30 mg of Potassium Chloride, USP (KCl); and 20 mg Calcium Chloride,
USP (CaCl2•2H20). It contains no antimicrobial agents. Approximate pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
Lactated Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of
water, electrolytes, and calories. One liter has an ionic concentration of 130 mEq sodium, 4 mEq
potassium, 2.7 mEq calcium, 109 mEq chloride and 28 mEq lactate. The osmolarity is 525 mOsmol/L
(calc). Normal physiologic range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions may cause vein damage. The caloric content is 180 kcal/L.
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 26
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
Lactated Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Lactated Ringer’s and 5% Dextrose Injection, USP produces a metabolic alkalinizing effect. Lactate
ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of
hydrogen cations.
Indications and Usage
Lactated Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and
calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care. If at all, in patients
with congestive heart failure, severe renal insufficiency, and in clinical states in which there exists
edema with sodium retention.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients
with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great care in patients with
metabolic or respiratory alkalosis. The administration of lactate ions should be done with great care in
those conditions in which there is an increased level or an impaired utilization of these ions, such as
severe hepatic insufficiency.
Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with
blood through the same administration set because of the likelihood of coagulation.
The intravenous administration of Lactated Ringer’s and 5% Dextrose Injection, USP can cause fluid
and/or solute overloading resulting is dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 27
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Lactated Ringer’s and 5% Dextrose
Injection, USP may result in sodium or potassium retention.
Lactated Ringer’s and 5% Dextrose Injection, USP is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt
or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Lactated Ringer's and 5% Dextrose Injection, USP
to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Lactated Ringer's and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Lactated Ringer’s and 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 28
Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s
and 5% Dextrose Injection, USP. It is also not known whether Lactated Ringer’s and 5% Dextrose
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Lactated Ringer’s and 5% Dextrose Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Lactated Ringer's and 5% Dextrose
Injection, USP on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
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 Lactated Ringer’s and 5% Dextrose Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Lactated Ringer’s and 5% Dextrose Injection, USP in pediatric patients
have not been established by adequate and well controlled trials, however, the use of lactated ringer’s
and dextrose solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum amorality and possible hemorrhage.
Geriatric Use
Clinical studies of Lactated Ringer’s and 5% 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 the responses between
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 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
Allergic reactions or anaphylactic symptoms such as localized or generalized urinary and purities; per
orbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have been
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 29
reported during administration of Lactated Ringer’s and 5% Dextrose Injection, USP. The reporting
frequency of these signs and symptoms is higher in women during pregnancy.
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, extravasations, 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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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
Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown
below:
Code
Size
NDC
6E2073
500 mL
NDC 0338-6306-03
6E2074
1000 mL
NDC 0338-6306-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 30
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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 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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 31
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 32
Baxter
Lactated Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Lactated Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. Composition, osmolarity, pH, ionic concentration and caloric content are shown in Table 1.
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.
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.
Composition (g/L)
Ionic Concentration (mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP, (NaCl)
Sodium Lactate, (C3H5NaO3)
Potassium Chloride, USP, (KCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
Lactate
Caloric Content
(kcal/L)
250
500
Lactated
Ringer’s
Injection, USP
1000
6
3.1
0.3
0.2
273
6.5
(6.0 to 7.5)
130
4
2.7
109
28
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 33
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
Lactated Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Lactated Ringer’s Injection, USP produces a metabolic alkalinizing effect. Lactate ions are
metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen
cations.
Indications and Usage
Lactated Ringer’s Injection, USP is indicated as a source of water and electrolytes or as an alkalinizing
agent.
Contraindications
None known
Warnings
Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Lactated Ringer’s Injection, USP should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Lactated Ringer’s Injection, USP should be used with great care in patients with metabolic or
respiratory alkalosis. The administration of lactate ions should be done with great care in those
conditions in which there is an increased level or an impaired utilization of these ions, such as severe
hepatic insufficiency.
Lactated Ringer’s Injection, USP should not be administered simultaneously with blood through the
same administration set because of the likelihood of coagulation.
The intravenous administration of Lactated Ringer’s Injection, USP can cause fluid and/or solute
overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states,
or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte
concentration 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.
In patients with diminished renal function, administration of Lactated Ringer’s Injection, USP may
result in sodium or potassium retention. Lactated Ringer’s injection, USP is not for use in the
treatment of lactic acidosis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 34
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Lactated Ringer’s Injections, USP must be used with caution. Excess administration may result in
metabolic alkalosis.
Laboratory Test
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.
Drug Interactions
Caution must be exercised in the administration of Lactated Ringer's Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Lactated Ringer's Injection, USP.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
STUDIES WITH LACTATED RINGER'S INJECTION, USP HAVE NOT BEEN PERFORMED TO EVALUATE
CARCINOGENIC POTENTIAL, MUTAGENIC POTENTIAL, OR EFFECTS ON FERTILITY.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Lactated Ringer’s
Injection, USP. It is also not known whether Lactated Ringer’s Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Lactated Ringer’s
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Lactated Ringer's Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 35
Nursing Mothers
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 Lactated Ringer's Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Lactated Ringer’s Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of electrolyte solutions in the
pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Lactated Ringer’s 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 concomitant disease or 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
Allergic reactions or anaphylactoid symptoms such as localized or generalized urticaria and pruritis;
periorbital, facial, and/or laryngeal edema; coughing, sneezing, and/or difficulty with breathing have
been reported during administration of Lactated Ringer’s Injection, USP. The reporting frequency of
these signs and symptoms is higher in women during pregnancy.
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
infection, 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 36
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.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
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
Lactated Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2322
250
0338-6307-02
6E2323
500
0338-6307-03
6E2324
1000
0338-6307-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40° C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 37
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 38
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 39
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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 and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 40
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional 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 and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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 and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 41
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
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 Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride 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 the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 42
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or 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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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 and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 43
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 44
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 45
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 46
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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 and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 47
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional 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 and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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 and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 48
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
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 Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride 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 the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 49
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or 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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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 and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 50
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 51
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 52
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 53
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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 and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 54
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional 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 and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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 and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 55
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
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 Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride 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 the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 56
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or 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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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 and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 57
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 58
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 59
Baxter
Sodium Lactate Injection, USP (M/6 Sodium Lactate)
in AVIVA Plastic Container
Description
Sodium Lactate Injection, USP (M/6 Sodium Lactate) is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
It contains no antimicrobial agents. The pH may have been adjusted with lactic acid. Composition,
osmolarity, pH, ionic concentration and caloric content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
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.
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
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
Size
(mL)
Sodium Lactate
(C3H5NaO3)
*Osmolarity
(mOsmol/L)
(calc)
pH
Sodium
Lactate
Caloric Content
(kcal/L)
500
Sodium
Lactate
Injection, USP
(M/6 Sodium
Lactate)
1000
18.7
334
6.5
(6.0 to 7.3)
167
167
54
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 60
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Sodium Lactate Injection, USP has value as a source of water, electrolytes, and calories. It is capable
of inducing diuresis depending on the clinical condition of the patient.
Sodium Lactate Injection, USP produces a metabolic alkalinizing effect. Lactate ions are metabolized
ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
Sodium Lactate Injection, USP is indicated as a source of water, electrolytes, and calories or as an
alkalinizing agent.
Contraindications
None known
Warnings
Sodium Lactate Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Sodium Lactate Injection, USP should be used with great care in patients with metabolic or respiratory
alkalosis. The administration of lactate ions should be done with great care in those conditions in
which there is an increased level or an impaired utilization of these ions, such as severe hepatic
insufficiency.
The intravenous administration of these injections can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
Excessive administration of Sodium Lactate Injection, USP may result in significant hypokalemia.
In patients with diminished renal function, administration of Sodium Lactate Injection, USP may result
in sodium retention.
Sodium Lactate Injection, USP is not for use in the treatment of lactic acidosis.
Precautions
General
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 61
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Sodium Lactate Injection, USP (M/6 Sodium
Lactate) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Lactate Injection, USP (M/6 Sodium Lactate).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Lactate Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Lactate
Injection, USP. It is also not known whether Sodium Lactate Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Lactate
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Lactate Injection, USP (M/6
Sodium Lactate) on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
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 Sodium Lactate Injection, USP is administered to a
nursing mother.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 62
Pediatric Use
Safety and effectiveness of Sodium Lactate Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of sodium lactate solutions in the
pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Lactate 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 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
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
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 63
How Supplied
Sodium Lactate Injection, USP (M/6 Sodium Lactate) in AVIVA plastic container is available as
follows:
Code
Size (mL)
NDC
6E1803
500
0338-6311-03
6E1804
1000
0338-6311-04
EXPOSURE OF PHARMACEUTICAL PRODUCTS TO HEAT SHOULD BE MINIMIZED. AVOID EXCESSIVE
HEAT. IT IS RECOMMENDED THE PRODUCT BE STORED AT ROOM TEMPERATURE (25°C); BRIEF
EXPOSURE UP TO 40°C DOES NOT ADVERSELY AFFECT THE PRODUCT.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 64
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 65
Baxter
Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in
single dose containers for intravenous administration. It contains no antimicrobial agents. The pH
may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration
are shown in Table 1.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP (NaCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Potassium Chloride, USP (KCl)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
500
Ringer’s
Injection,
USP
1000
8.6
0.33
0.3
309
5.5
(5.0 to 7.5)
147.5
4
4.5
156
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 66
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.
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
Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing
diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart
failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe
renal failure, and in conditions in which potassium retention is present.
Ringer’s Injection, USP should not be administered simultaneously with blood through the same
administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading
resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 67
edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the
injection. The risk of solute overload causing congested states with peripheral and pulmonary edema
is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s Injection, USP may result in
sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving
corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer’s Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential,
mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection,
USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a
pregnant woman 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 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 68
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and
delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 Ringer’s Injection, USP is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by
adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Ringer’s 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 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
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
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. Do not administer unless solution is clear and
seal is intact.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 69
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
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
Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2303
500
NDC 0338-6312-03
6E2304
1000
NDC 0338-6312-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 70
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 71
Baxter
Ringer’s Injection, USP
in AVIVA Plastic Container
Description
Ringer’s Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment in
single dose containers for intravenous administration. It contains no antimicrobial agents. The pH
may have been adjusted with sodium hydroxide. Composition, osmolarity, pH and ionic concentration
are shown in Table 1.
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.
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.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium Chloride, USP (NaCl)
Calcium Chloride, USP
(CaCl2·2H2O)
Potassium Chloride, USP (KCl)
Osmolarity
(mOsmol/L) (calc)
pH
Sodium
Potassium
Calcium
Chloride
500
Ringer’s
Injection,
USP
1000
8.6
0.33
0.3
309
5.5
(5.0 to 7.5)
147.5
4
4.5
156
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 72
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
Ringer’s Injection, USP has value as a source of water and electrolytes. It is capable of inducing
diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
Ringer’s Injection, USP should be used with great care, if at all, in patients with congestive heart
failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
Ringer’s Injection, USP should be used with great care, if at all, in patients with hyperkalemia, severe
renal failure, and in conditions in which potassium retention is present.
Ringer’s Injection, USP should not be administered simultaneously with blood through the same
administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s Injection, USP can cause fluid and/or solute overloading
resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary
edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the
injection. The risk of solute overload causing congested states with peripheral and pulmonary edema
is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s Injection, USP may result in
sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 73
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.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Ringer’s Injection, USP to patients receiving
corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer’s Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer’s Injection, USP have not been performed to evaluate carcinogenic potential,
mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer’s Injection,
USP. It is also not known whether Ringer’s Injection, USP can cause fetal harm when administered to
a pregnant woman or can affect reproduction capacity. Ringer’s Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer’s Injection, USP on labor and
delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 Ringer’s Injection, USP is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of Ringer’s Injection, USP in pediatric patients have not been established by
adequate and well controlled trials, however, the use of electrolyte solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 74
Geriatric Use
Clinical studies of Ringer’s 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 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
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
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. 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.
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
Ringer’s Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
6E2303
500
NDC 0338-6312-03
6E2304
1000
NDC 0338-6312-04
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 75
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure to up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 76
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 77
Baxter
Ringer’s and 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Ringer’s and 5% Dextrose Injection, USP is sterile, nonpyrogenic solution for fluid and electrolyte
replenishment and caloric supply in a single dose container for intravenous administration. Each 100
mL contains 5 g Dextrose Hydrous, USP*; 860 mg of Sodium Chloride, USP (NaCl); 33 mg of
Calcium Chloride, USP (CaCl2•2H2O); and 30 mg of Potassium Chloride, USP (KCl). It contains no
antimicrobial agents. The pH is 4.0 (3.5 to 6.5).
c
*
D-Glucopyranose monohydrate
Ringer’s and 5% Dextrose Injection, USP administered intravenously has value as a source of water,
electrolytes, and calories. One liter has an ionic concentration of 147.5 mEq sodium, 4.5 mEq calcium,
4 mEq potassium, and 156 mEq chloride. The osmolarity is 561 mOsmol/L (calc). Normal
physiologic range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions may cause vein damage. The caloric content is 170 kcal/L.
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 78
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
Ringer’s and 5% Dextrose Injection, USP has value as a source of water, electrolytes, and calories. It
is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Ringer’s and 5% Dextrose Injection, USP is indicated as a source of water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Ringer’s and 5% Dextrose Injection, USP should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Ringer’s and 5% Dextrose Injection, USP should not be administered simultaneously with blood
through the same administration set because of the likelihood of coagulation.
The intravenous administration of Ringer’s and 5% Dextrose Injection, USP can cause fluid and/or
solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested
states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte
concentrations of the injection. The risk of solute overload causing congested states with peripheral
and pulmonary edema is directly proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of Ringer’s and 5% Dextrose Injection, USP
may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one container
before administration of the fluid from a secondary container is completed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 79
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.
Ringer’s and 5% Dextrose Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Ringer's and 5% Dextrose Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Ringer's and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Ringer's and 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Ringer's and 5%
Dextrose Injection, USP. It is also not known whether Ringer's and 5% Dextrose Injection, USP can
cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ringer's
and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Ringer's and 5% Dextrose Injection, USP on
labor and delivery. Caution should be exercised when administering this drug during labor and
delivery.
Nursing Mothers
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 Ringer's and 5% Dextrose Injection, USP is
administered to a nursing woman.
Pediatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 80
Safety and effectiveness of Ringer's and 5% Dextrose Injection, USP in pediatric patients have not
been established by adequate and well controlled trials, however, the use of ringer's and dextrose
solutions in the pediatric population is referenced in the medical literature. The warnings, precautions
and adverse reactions identified in the label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Ringer's and 5% 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 the responses between 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 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
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
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. 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.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 81
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
Ringer's and 5% Dextrose Injection, USP in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2064
1000
NDC 0338-6313-04
6E2063
500
NDC 0338-6313-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C): brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 82
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter Healthcare International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 83
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 84
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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 and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 85
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional 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 and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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 and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 86
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
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 Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride 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 the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 87
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or 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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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 and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 88
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 89
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 90
Baxter
Dextrose and Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in single dose containers for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (> 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic
Concentration
(mEq/L)
Table 1
Size (mL)
** Dextrose
Hydrous, USP
Sodium
Chloride, USP
(NaCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Sodium
Chloride
Caloric Content
(kcal/L)
2.5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
500
1000
25
4.5
280
4.5
(3.2 to 6.5)
77
77
85
5% Dextrose and 0.2%
Sodium Chloride
Injection, USP
250
500
1000
50
2
321
4.0
(3.2 to 6.5)
34
34
170
5% Dextrose and 0.33%
Sodium Chloride
Injection, USP
250
500
1000
50
3.3
365
4.0
(3.2 to 6.5)
56
56
170
5% Dextrose and 0.45%
Sodium Chloride
Injection, USP
250
500
1000
50
4.5
406
4.0
(3.2 to 6.5)
77
77
170
5% Dextrose and 0.9%
Sodium Chloride
Injection, USP
250
500
1000
50
9
560
4.0
(3.2 to 6.5)
154
154
170
10% Dextrose and 0.9%
Sodium Chloride
Injection, USP
500
1000
100
9
813
4.0
(3.2 to 6.5)
154
154
340
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 91
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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 and Sodium Chloride Injection, USP has value as a source of water, electrolytes, and
calories. It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Dextrose and Sodium Chloride Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 92
Dextrose and Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
Dextrose injections with low electrolyte concentrations should not be administered simultaneously
with blood through the same administration set because of the possibility of pseudoagglutination or
hemolysis. The container label for these injections bears the statement: Do not administer
simultaneously with blood.
The intravenous administration of Dextrose and Sodium Chloride Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional 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 and Sodium Chloride Injection, USP may result in significant
hypokalemia.
In patients with diminished renal function, administration of Dextrose and Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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 and Sodium Chloride Injection, USP should be used with caution in patients with overt or
subclinical diabetes mellitus.
Laboratory Tests
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 93
Drug Interactions
Caution must be exercised in the administration of Dextrose and Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Dextrose and Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Dextrose and
Sodium Chloride Injection, USP. It is also know known whether Dextrose and Sodium Chloride
Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Dextrose and Sodium Chloride Injection, USP should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Dextrose and Sodium Chloride Injection,
USP on labor and delivery. Caution should be exercised when administering this drug during labor
and delivery.
Nursing Mothers
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 Dextrose and Sodium Chloride Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Dextrose and Sodium Chloride Injection, USP in pediatric patients have
not been established by adequate and well controlled trials, however, the use of dextrose and sodium
chloride solutions in the pediatric population is referenced in the medical literature. The warnings,
precautions and adverse reactions identified in the label copy should be observed in the pediatric
population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of Dextrose and Sodium Chloride 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 the responses between elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually starting
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 94
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function and of concomitant disease or 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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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 and Sodium Chloride Injection, USP in AVIVA plastic container is supplied as follows:
Code
Size (mL)
NDC
Product Name
6E1023
6E1024
500
1000
0338-6315-03
0338-6315-04
2.5% Dextrose and 0.45% Sodium Chloride
Injection, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 95
6E1092
6E1093
6E1094
250
500
1000
0338-6310-02
0338-6310-03
0338-6310-04
5% Dextrose and 0.2% Sodium Chloride
Injection, USP
6E1082
6E1083
6E1084
250
500
1000
0338-6309-02
0338-6309-03
0338-6309-04
5% Dextrose and 0.33% Sodium Chloride
Injection, USP
6E1072
6E1073
6E1074
250
500
1000
0338-6308-02
0338-6308-03
0338-6308-04
5% Dextrose and 0.45% Sodium Chloride
Injection, USP
6E1062
6E1063
6E1064
250
500
1000
0338-6305-02
0338-6305-03
0338-6305-04
5% Dextrose and 0.9% Sodium Chloride
Injection, USP
6E1163
6E1164
500
1000
0338-6314-03
0338-6314-04
10% Dextrose and 0.9% Sodium Chloride
Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA plastic container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 96
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 97
Baxter
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1,
USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile,
nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL
contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl);
and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH
is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0).
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq
acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions may cause vein damage. The caloric content is 21 kcal/L.
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 98
Clinical Pharmacology
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic
alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide and water,
which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source
of water and electrolytes or as an alkalinizing agent.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) is compatible with
blood or blood components. It may be administered prior to or following the infusion of blood through
the same administration set (i.e., as a priming solution), added to or infused concurrently with blood
components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE 148
Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood
components.
Contraindications
None known
Warnings
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical
states in which there exists edema with sodium retention.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which
potassium retention is present.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
great care in patients with metabolic or respiratory alkalosis. The administration of acetate or
gluconate ions should be done with great care in those conditions in which there is an increased level
or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection,
Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 99
In patients with diminished renal function, administration of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
148 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-
LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 148 Injection
(Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman 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 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 100
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 Injection (Multiple
Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
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 PLASMA-LYTE 148 Injection (Multiple Electrolytes
Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, 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 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
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
As directed by a physician. Dosage is dependent upon the age, weight and clinical condition of the
patient as well as laboratory determinations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 101
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.
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
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
PLASMA-LYTE 148 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2534
1000
NDC 0338-6316-04
6E2533
500
NDC 0338-6316-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 102
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
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 103
Baxter
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection,
Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is a sterile,
nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL
contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl);
and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH
is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0).
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a sousrce of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq chloride, 27 mEq
acetate, and 23 mEq gluconate. The osmolarity is 294 mOsmol/L (calc). Normal physiologic
osmolarity range is 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions may
cause vein damage. The caloric content is 21 lcal/L.
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 104
Clinical Pharmacology
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) has value as a
source of water and electrolytes. It is capable of inducing diuresis depending on the clinical condition
of the patient.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) produces a
metabolic alkalinizing effect. Acetate and gluconate ions are metabolized ultimately to carbon dioxide
and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is indicated as a
source of water and electrolytes or as an alkalinizing agent.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) is compatible with
blood or blood components. It may be administered prior to or following the infusion of blood through
the same administration set (i.e., as a priming solution), added to or infused concurrently with blood
components, or used as a diluent in the transfusion of packed erythrocytes. PLASMA-LYTE A
Injection and 0.9% Sodium Chloride Injection, USP are equally compatible with blood or blood
components.
Contraindications
None known
Warnings
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in
clinical states in which there exists edema with sodium retention.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which
potassium retention is present.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with great care in patients with metabolic or respiratory alkalosis. The administration of acetate or
gluconate ions should be done with great care in those conditions in which there is an increased level
or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes
Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional
states is inversely proportional to the electrolyte concentrations of the injection. The risk of solute
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 105
overload causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE A Injection pH 7.4
(Multiple Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be used
with caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE A Injection pH 7.4 (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) have
not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) can cause fetal
harm when administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 106
A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant
woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE A Injection pH 7.4
(Multiple Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised
when administering this drug during labor and delivery.
Nursing Mothers
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 PLASMA-LYTE A Injection pH 7.4 (Multiple
Electrolytes Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type
1, USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, 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 elkerly 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 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
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 107
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. 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.
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
PLASMA-LYTE A Injection pH 7.4 (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2544
1000
NDC 0338-6317-04
6E2543
500
NDC 0338-6317-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 108
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 109
Baxter
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 234 mg Sodium Chloride, USP (NaCl); 128 mg Potassium Acetate, USP (C2H3KO2); and 32 mg
Magnesium Acetate, Tetrahydrate (C4H6MgO4•4H2O). It contains no antimicrobial agents. pH 5.0
(4.0 to 6.5). The pH is adjusted with hydrochloric acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq
chloride, and 16 mEq acetate. The osmolarity is 363 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic
solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 170 kcal/L.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 110
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
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) produces a metabolic alkalinizing effect. Acetate ions are metabolized ultimately to carbon
dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of acetate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 111
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
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 PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 56 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 56 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 112
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also
not known whether PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 PLASMA-LYTE 56 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, 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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 113
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 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
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
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.
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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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
PLASMA-LYTE 56 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 114
6E2573
500
NDC 0338-6318-03
6E2574
1000
NDC 0338-6318-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 115
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 116
Baxter
PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 161 mg Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 138 mg Sodium Lactate
(C3H5NaO3), 119 mg Potassium Chloride, USP (KCl), 94 mg Sodium Chloride, USP (NaCl), 37 mg
Calcium Chloride, USP (CaCl2•2H2O), and 30 mg Magnesium Chloride, USP (MgCl2•6H2O). It
contains no antimicrobial agents. The pH is 5.0 (4.0 to 6.5). The pH is adjusted with hydrochloric
acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 16 mEq potassium, 5 mEq calcium, 3 mEq magnesium,
40 mEq chloride, 12 mEq acetate, and 12 mEq lactate. The osmolarity is 377 mOsmol/L (calc).
Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is
180 kcal/L.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 117
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
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) produces a metabolic alkalinizing effect. Acetate and lactate ions are metabolized ultimately to
carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 118
administration of lactate or acetate ions should be done with great care in those conditions in which
there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should not be administered simultaneously with blood through the same administration set
because of the likelihood of coagulation.
The intravenous administration of PLASMA-LYTE M and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 2, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE M and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) containing sodium or potassium
ions may result in sodium or potassium retention.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 119
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 2, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP). It is also
not known whether PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 2, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 2, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE M and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 2, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 PLASMA-LYTE M and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 2, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 2, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 120
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 2, 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
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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 121
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
PLASMA-LYTE M and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 2,
USP) in AVIVA plastic containers is available as shown below:
Size (mL)
Code
NDC
1000
6E2564
NDC 0338-6319-04
500
6E2563
NDC 0338-6319-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 122
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
* Bar Code Position Only
XXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 123
Baxter
PLASMA-LYTE R INJECTION (Multiple Electrolytes Injection, Type
2, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is a sterile, nonpyrogenic
isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 640
mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 496 mg of Sodium Chloride, USP (NaCl);
89.6 mg of Sodium Lactate (C3H5NaO3); 74.6 mg of Potassium Chloride, USP (KCl); 36.8 mg of
Calcium Chloride, USP (CaCl2•2H2O); and 30.5 mg of Magnesium Chloride, USP (MgCl2•6H2O). It
contains no antimicrobial agents. The pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to
8.0).
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) administered
intravenously has value as a source of water, electrolytes, and calories. One liter has an ionic
concentration of 140 mEq sodium, 10 mEq potassium, 5 mEq calcium, 3 mEq magnesium, 103 mEq
chloride, 47 mEq acetate, and 8 mEq lactate. The osmolarity is 312 mOsmol/L (calc). Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially
hypertonic solutions may cause vein damage. The caloric content is 11 kcal/L.
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.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 124
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) produces a metabolic
alkalinizing effect. Acetate and lactate ions are metabolized ultimately to carbon dioxide and water,
which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) is indicated as a source of
water and electrolytes or as an alkalinizing agent.
Contraindications
None known
Warnings
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states
in which there exists edema with sodium retention.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium
retention is present.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with great
care in patients with metabolic or respiratory alkalosis. The administration of lactate or acetate ions
should be done with great care in those conditions in which there is an increased level or an impaired
utilization of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should not be
administered simultaneously with blood through the same administration set because of the likelihood
of coagulation.
The intravenous administration of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type
2, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE R Injection (Multiple
Electrolytes Injection, Type 2, USP) may result in sodium or potassium retention. PLASMA-LYTE R
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 125
Injection (Multiple Electrolytes Injection, Type 2, USP) is not for use in the treatment of lactic
acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE R Injection (Multiple Electrolytes
Injection, Type 2, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
R Injection (Multiple Electrolytes Injection, Type 2, USP). It is also not known whether PLASMA-
LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE R Injection
(Multiple Electrolytes Injection, Type 2, USP) should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 126
Studies have not been conducted to evaluate the effects of PLASMA-LYTE R Injection (Multiple
Electrolytes Injection, Type 2, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
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 PLASMA-LYTE R Injection (Multiple Electrolytes
Injection, Type 2, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, 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 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
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
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 127
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.
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
PLASMA-LYTE R Injection (Multiple Electrolytes Injection, Type 2, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2504
1000
NDC 0338-6320-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 128
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
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 129
Baxter
PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in
a single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 526 mg Sodium Chloride, USP (NaCl); 502 mg Sodium Gluconate (C6H11NaO7); 368 mg
Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O), 37 mg Potassium Chloride, USP (KCl); and 30
mg Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is 5.0 (4.0
to 6.5). The pH is adjusted with hydrochloric acid.
c
*
D-Glucopyranose monohydrate
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 140 mEq sodium, 5 mEq potassium, 3 mEq magnesium, 98 mEq
chloride, 27 mEq acetate and 23 mEq gluconate. The osmolarity is 547 mOsmol/L (calc). Normal
physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially
hypertonic solutions (>600 mOsmol/L) may cause vein damage. The caloric content is 190 kcal/L.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 130
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
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) has value as a source of water, electrolytes, and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) produces a metabolic alkalinizing effect. Acetate and gluconate ions are metabolized
ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) is indicated as a source of water, electrolytes, and calories, or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency and in clinical states in which there exists edema with sodium retention.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure and
in conditions in which potassium retention is present.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of acetate or gluconate ions should be done with great care in those conditions in which
there is an increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 131
The intravenous administration of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting
in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injection.
The risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 148 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with caution. Excess administration may result in metabolic alkalosis.
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 132
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also
not known whether PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 148 and 5% Dextrose
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 PLASMA-LYTE 148 and 5% Dextrose Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and
well controlled trials, however, the use of plasmalyte and dextrose solutions in the pediatric population
is referenced in the medical literature. The warnings, precautions and adverse reactions identified in
the label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, 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 drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 133
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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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
PLASMA-LYTE 148 and 5% Dextrose Injection (Multiple Electrolytes and Dextrose Injection, Type
1, USP) in AVIVA plastic containers is available as shown below:
Size (mL)
Code
NDC
1000
6E2584
NDC 0338-6321-04
500
6E2583
NDC 0338-6321-03
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 134
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
* Bar Code Position Only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 135
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE, and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 136
Baxter
5% Dextrose and Electrolyte No. 48 Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP)
in AVIVA Plastic Container
Description
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 260 mg Sodium Lactate (C3H5NaO3), 141 mg Potassium Chloride, USP (KCl), 31 mg
Magnesium Chloride, USP (MgCl2•6H20), 20 mg Monobasic Potassium Phosphate, NF (KH2PO4), and
12 mg Sodium Chloride, USP (NaCl). It contains no antimicrobial agents. pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 25 mEq sodium, 20 mEq potassium, 3 mEq magnesium, 24 mEq
chloride, 23 mEq lactate and 3 mEq phosphate as HPO4
=. The osmolarity is 348 mOsmol/L (calc).
Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of
substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is
180 kcal/L.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 137
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
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon
dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is indicated as a source of water, electrolytes, and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of lactate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 138
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
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 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes
and Dextrose Injection, Type 1, USP) can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of
solute overload causing congested states with peripheral and pulmonary edema is directly proportional
to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 48
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium or
potassium retention.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Do not administer simultaneously with blood.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 139
Drug Interactions
Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 48 Injection
(Multiple Electrolytes and Dextrose Injection, Type 1, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5%
Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and
Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP). It is also not
known whether 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, USP) can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 48
Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 5% Dextrose and Electrolyte No. 48 Injection (Multiple
Electrolytes and Dextrose Injection, Type 1, USP) is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and
Dextrose Injection, Type 1, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of dextrose and electrolytes solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemmorhage.
Geriatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 140
Clinical studies of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose
Injection, Type 1, 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 the responses between 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
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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 141
How Supplied
5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2102
250
NDC 0338-6322-02
6E2103
500
NDC 0338-6322-03
6E2104
1000
NDC 0338-6322-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 142
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 143
Baxter
Potassium Chloride in 5% Dextrose Injection, USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic solution for fluid and
electrolyte replenishment and caloric supply in a single dose container for intravenous administration.
It contains no antimicrobial agents. Composition, osmolarity, pH, ionic concentration and caloric
content are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
Composition
(g/L)
Ionic
Concentration
(mEq/L)
Table 1
Potassium Chloride in 5%
Dextrose Injection, USP
mEq Potassium
Size (mL)
**Dextrose Hydrous, USP
Potassium Chloride, USP (KCl)
*Osmolarity (mOsmol/L)
(calc.)
pH
Potassium
Chloride
Caloric Content (kcal/L)
10 mEq
1000
50
0.75
272
4.5
(3.5 to 6.5)
10
10
170
20 mEq
1000
50
1.5
293
4.5
(3.5 to 6.5)
20
20
170
30 mEq
1000
50
2.24
312
4.5
(3.5 to 6.5)
30
30
170
40 mEq
1000
20 mEq
500
50
3
333
4.5
(3.5 to 6.5)
40
40
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 144
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.
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 overwarp is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in 5% Dextrose Injection, USP is a source of water, electrolytes and calories. It is
capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose Injection, USP is indicated as a source of water, electrolytes, and
calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
Potassium Chloride in 5% Dextrose Injection, USP should be used with great care, if at all, in patients
with hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The bag label for these injections bears the statement: Do not
administer simultaneously with blood.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 145
The intravenous administration of Potassium Chloride in 5% Dextrose Injection, USP can cause fluid
and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose
Injection, USP may result in potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Potassium Chloride in 5% Dextrose Injection, USP should be used with caution in patients with overt
or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Studies have not been conducted to evaluate drug/drug or drug/food interactions with Potassium
Chloride in 5% Dextrose Injection, USP.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 146
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose Injection, USP. It is also not known whether Potassium Chloride in 5%
Dextrose Injection, USP can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Potassium Chloride in 5% Dextrose Injection, USP should be given to a
pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose
Injection, USP on labor and delivery. Caution should be exercised when administering this drug labor
and delivery.
Nursing Mothers
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 Potassium Chloride in 5% Dextrose Injection, USP is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose Injection in pediatric patients have not
been established by adequate and well-controlled studies. However, the use of potassium chloride
injection in pediatric patients to treat potassium deficiency states when oral replacement therapy is not
feasible is referenced in the medical literature.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indication and
Usage). As reported in the literature, 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.
Geriatric Use
Clinical studies of Potassium Chloride in 5% 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 the responses between
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 drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 147
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
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
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.
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
Potassium Chloride in 5% Dextrose Injection, USP in AVIVA plastic container is available as follows:
Code
Size (mL)
NDC
Product Name
6E1124
1000
0338-6323-04
10 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1134
1000
0338-6324-04
20 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 148
6E1174
1000
0338-6325-04
30 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1264
1000
0338-6326-04
40 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
6E1263
500
0338-6326-03
20 mEq Potassium
Chloride in 5%
Dextrose Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 149
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
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 150
Baxter
Potassium Chloride in Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Potassium Chloride in Sodium Chloride Injection, USP is a sterile, nonpyrogenic, solution for fluid
and electrolyte replenishment in a single dose container for intravenous administration. It contains no
antimicrobial agents. Composition, osmolarity, pH and ionic concentration are shown in Table 1.
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
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.
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
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
Sodium
Chloride, USP
(NaCl)
Potassium
Chloride, USP
(KCl)
*Osmolarity (mOsmol/L)
(Calc.)
pH
Sodium
Potassium
Chloride
20 mEq/L Potassium Chloride in
0.9% Sodium Chloride Injection,
USP
1000
9
1.5
348
5.5
(3.5 to 6.5)
154
20
174
40 mEq/L Potassium Chloride in
0.9% Sodium Chloride Injection,
USP
1000
9
3
388
5.5
(3.5 to 6.5)
154
40
194
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 151
(See Directions for Use). The primary function of the overwrap is to protect the container from the
physical environment.
Clinical Pharmacology
Potassium Chloride in Sodium Chloride Injection, USP has value as a source of water and electrolytes.
It is capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Potassium Chloride in Sodium Chloride Injection, USP is indicated as a source of water and
electrolytes.
Contraindications
None known
Warnings
Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in
patients with congestive heart failure, severe renal insufficiency and in clinical states in which there
exists edema with sodium retention.
Potassium Chloride in Sodium Chloride Injection, USP should be used with great care, if at all, in
patients with hyperkalemia, severe renal failure and in conditions in which potassium retention is
present.
The intravenous administration of Potassium Chloride in Sodium Chloride Injection, USP can cause
fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration,
congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injection. The risk of solute overload causing congested states with
peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of the
injection.
In patients with diminished renal function, administration of Potassium Chloride in Sodium Chloride
Injection, USP may result in sodium or potassium retention.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 152
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.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in Sodium Chloride Injection,
USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in Sodium Chloride Injection, USP have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in Sodium Chloride Injection, USP. It is also not known whether Potassium Chloride in
Sodium Chloride Injection, USP can cause fetal harm when administered to a pregnant woman or can
affect reproduction capacity. Potassium Chloride in Sodium Chloride Injection, USP should be given
to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in Sodium Chloride
Injection, USP on labor and delivery. Caution should be exercised when administering this drug
during labor and delivery.
Nursing Mothers
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 Potassium Chloride in Sodium Chloride Injection, USP
is administered to a nursing mother.
Pediatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 153
Safety and effectiveness of Potassium Chloride in Sodium Chloride Injection, USP in pediatric patients
have not been established by adequate and well-controlled studies. However, the use of potassium
chloride injection in pediatric patients to treat potassium deficiency states when oral replacement
therapy is not feasible is referenced in the medical literature.
Geriatric Use
Clinical studies of Potassium Chloride in Sodium Chloride 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 the responses between
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 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
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
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 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.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 154
Potassium Chloride in Sodium Chloride Injection, USP in AVIVA Plastic Container is available as
follows:
Code
Size (mL)
NDC
Product Name
6E1764
1000
0338-6327-04
20 mEq/L
Potassium Chloride
in 0.9% Sodium
Chloride Injection,
USP
6E1984
1000
0338-6328-04
40 mEq/L
Potassium Chloride
in 0.9% Sodium
Chloride Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25º C/77° F); brief exposure up to 40º C
(104º F) does not adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 155
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 156
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 157
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 158
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 159
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 160
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
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 Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 161
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, 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.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride 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 the
responses between 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 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
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
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 162
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 163
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 164
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 165
Baxter
Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
Sodium Chloride Injection, USP is a sterile, nonpyrogenic solution for fluid and electrolyte
replenishment in single dose containers for intravenous administration. It contains no antimicrobial
agents. The pH is 5.5 (4.5 to 7.0). Composition, osmolarity, and ionic concentration are shown below.
0.45% Sodium Chloride Injection, USP contains 4.5 g/L Sodium Chloride, USP (NaCl) with an
osmolarity of 154 mOsmol/L (calc). It contains 77 mEq/L sodium and 77 mEq/L chloride.
0.9% Sodium Chloride Injection, USP contains 9 g/L Sodium Chloride USP (NaCl) with an
osmolarity of 308 mOsmol/L (calc). It contains 154 mEq/L sodium and 154 mEq/L chloride.
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.
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
Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is capable of
inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 166
0.9% Sodium Chloride Injection, USP is also indicated for use as a priming solution in hemodialysis
procedures.
Contraindications
None known.
Warnings
Sodium Chloride Injection, USP should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there exists edema with sodium
retention.
In patients with diminished renal function, administration of Sodium Chloride Injection, USP may
result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Sodium Chloride Injection, USP to patients
receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Sodium Chloride Injection, USP have not been performed to evaluate carcinogenic
potential, mutagenic potential, or effects on fertility.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 167
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Chloride
Injection, USP. It is also know known whether Sodium Chloride Injection, USP can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. Sodium Chloride
Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Sodium Chloride Injection, USP on labor
and delivery. Caution should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 Sodium Chloride Injection, USP is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness of Sodium Chloride Injection, USP in pediatric patients have not been
established by adequate and well controlled trials, however, the use of Sodium Chloride solutions in
the pediatric population is referenced in the medical literature. The warnings, precautions and adverse
reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of Sodium Chloride 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 the responses between 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 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
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 168
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. 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.
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
The available sizes of each injection in AVIVA plastic containers are shown below:
Code
Size (mL)
NDC
Product Name
6E1313
500
0338-6333-03
0.45% Sodium Chloride Injection,
USP
6E1314
1000
0338-6333-04
6E1356
250
0338-6333-02
6E1322
250
0338-6304-02
0.9% Sodium Chloride Injection,
USP
6E1323
500
0338-6304-03
6E1324
1000
0338-6304-04
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
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 169
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
*Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
For Product Information
1-800-833-0303
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 170
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 171
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 172
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 173
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 174
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
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 Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 175
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, 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.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride 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 the
responses between 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 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
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
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 176
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 177
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 178
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 179
Baxter
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown in Table 1.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 180
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
Composition (g/L)
Ionic Concentration
(mEq/L)
Table 1
Size (mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Potassium Chloride, USP
(KCl)
*Osmolarity (mOsmol/L) (calc.)
pH
Sodium
Potassium
Chloride
Caloric Content (kcal/L)
Potassium Chloride in 5%
Dextrose and 0.2% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
2
0.75
341
4.5
(3.5 to 6.5)
34
10
44
170
20 mEq
10 mEq
1000
500
50
2
1.5
361
4.5
(3.5 to 6.5)
34
20
54
170
30 mEq
1000
50
2
2.24
381
4.5
(3.5 to 6.5)
34
30
64
170
40 mEq
1000
50
2
3
401
4.5
(3.5 to 6.5)
34
40
74
170
Potassium Chloride in 5%
Dextrose and 0.33% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
10 mEq
1000
500
50
3.3
1.5
405
4.5
(3.5 to 6.5)
56
20
76
170
30 mEq
1000
50
3.3
2.24
425
4.5
(3.5 to 6.5)
56
30
86
170
40 mEq
1000
50
3.3
3
446
4.5
(3.5 to 6.5)
56
40
96
170
Potassium Chloride in 5%
Dextrose and 0.45% Sodium
Chloride Injection, USP
mEq Potassium
10 mEq
1000
50
4.5
0.75
426
4.5
(3.5 to 6.5)
77
10
87
170
20 mEq
10 mEq
1000
500
50
4.5
1.5
447
4.5
(3.5 to 6.5)
77
20
97
170
30 mEq
1000
50
4.5
2.24
466
4.5
(3.5 to 6.5)
77
30
107
170
40 mEq
1000
50
4.5
3
487
4.5
(3.5 to 6.5)
77
40
117
170
Potassium Chloride in 5%
Dextrose and 0.9% Sodium
Chloride Injection, USP
mEq Potassium
20 mEq
1000
50
9
1.5
601
4.5
(3.5 to 6.5)
154
20
174
170
40 mEq
1000
50
9
3
641
4.5
(3.5 to 6.5)
154
40
194
170
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 181
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of
water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Indications and Usage
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP is indicated as a source of
water, electrolytes and calories.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 182
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Injections containing carbohydrates with low electrolyte concentration should not be administered
simultaneously with blood through the same administration set because of the possibility of
pseudoagglutination or hemolysis. The container label for these injections bears the statement: Do not
administer simultaneously with blood.
The intravenous administration of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP may result in sodium or potassium retention.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
For patients receiving potassium supplement of greater then maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 183
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP. It is also not known whether Potassium
Chloride in 5% Dextrose and Sodium Chloride Injection, USP can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in 5% Dextrose and
Sodium Chloride Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
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 Potassium Chloride in 5% Dextrose and Sodium
Chloride Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 184
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, 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.
Geriatric Use
Clinical studies of Potassium Chloride in 5% Dextrose and Sodium Chloride 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 the
responses between 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 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
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
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 185
How Supplied
Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP in AVIVA plastic container
is available as follows:
Code
Size (mL)
NDC
Product Name
6E1604
1000
0338-6334-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1614
6E1613
1000
500
0338-6335-04
0338-6335-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1624
1000
0338-6336-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1634
1000
0338-6337-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.2% Sodium Chloride Injection, USP
6E1474
6E1473
1000
500
0338-6348-04
0338-6348-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1484
1000
0338-6349-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1494
1000
0338-6350-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.33% Sodium Chloride Injection, USP
6E1644
1000
0338-6329-04
10 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1654
6E1653
1000
500
0338-6330-04
0338-6330-03
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1664
1000
0338-6331-04
30 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E1674
1000
0338-6332-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.45% Sodium Chloride Injection, USP
6E2434
1000
0338-6342-04
20 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
6E2454
1000
0338-6343-04
40 mEq/L Potassium Chloride in 5% Dextrose
and 0.9% Sodium Chloride Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 186
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 187
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 188
Baxter
5% Dextrose and Electrolyte No. 75 Injection
(Multiple Electrolytes and Dextrose Injection, Type 3, USP)
in AVIVA Plastic Container
Description
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment and caloric supply in a
single dose container for intravenous administration. Each 100 mL contains 5 g Dextrose Hydrous,
USP*, 220 mg Sodium Lactate (C3H5Na03), 205 mg Potassium Chloride, USP (KCl), 120 mg Sodium
Chloride, USP (NaCl), and 100 mg Monobasic Potassium Phosphate, NF (KH2PO4). It contains no
antimicrobial agents. pH 5.0 (4.0 to 6.5).
c
*
D-Glucopyranose monohydrate
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) administered intravenously has value as a source of water, electrolytes, and calories. One liter
has an ionic concentration of 40 mEq sodium, 35 mEq potassium, 48 mEq chloride, 20 mEq lactate,
and 15 mEq phosphate as HPO4
=. The osmolarity is 402 mOsmol/L (calc). Normal physiologic
osmolarity range is approximately 280 to 310 mOmsol/L. Administration of substantially hypertonic
solutions (≥ 600 mOsmol/L) may cause vein damage. The caloric content is 180 kcal/L.
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 189
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
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) has value as a source of water, electrolytes and calories. It is capable of inducing diuresis
depending on the clinical condition of the patient.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) produces a metabolic alkalinizing effect. Lactate ions are metabolized in the liver to glycogen,
and ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations.
Indications and Usage
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is indicated as a source of water, electrolytes and calories or as an alkalinizing agent.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
products.
Warnings
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care, if at all, in patients with congestive heart failure, severe renal
insufficiency, and in clinical states in which there exists edema with sodium retention.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care, if at all, in patients with hyperkalemia, severe renal failure, and in
conditions in which potassium retention is present.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with great care in patients with metabolic or respiratory alkalosis. The
administration of lactate ions should be done with great care in those conditions in which there is an
increased level or an impaired utilization of these ions, such as severe hepatic insufficiency.
The intravenous administration of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes
and Dextrose Injection, Type 3, USP) can cause fluid and/or solute overloading resulting in dilution of
serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 190
dilutional states is inversely proportional to the electrolyte concentrations of the injection. The risk of
solute overloading causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentrations of the injection.
In patients with diminished renal function, administration of 5% Dextrose and Electrolyte No. 75
Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) may result in sodium or
potassium retention.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) is not for use in the treatment of lactic acidosis.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with caution. Excess administration may result in metabolic alkalosis.
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) should be used with caution in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of 5% Dextrose and Electrolyte No. 75 Injection
(Multiple Electrolytes and Dextrose Injection, Type 3, USP) to patients receiving corticosteroids or
corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 5%
Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 191
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) have not been performed to evaluate carcinogenic potential, mutagenic
potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose and
Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP). It is also not
known whether 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, USP) can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and
Dextrose Injection, Type 3, USP) should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 5% Dextrose and Electrolyte No. 75
Injection (Multiple Electrolytes and Dextrose Injection, Type 3, USP) on labor and delivery. Caution
should be exercised when administering this drug during labor and delivery.
Nursing Mothers
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 5% DEXTROSE AND ELECTROLYTE NO. 75 INJECTION
(MULTIPLE ELECTROLYTES AND DEXTROSE INJECTION, TYPE 3, USP) IS ADMINISTERED TO A NURSING
MOTHER.
Pediatric Use
Safety and effectiveness of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and
Dextrose Injection, Type 3, USP) in pediatric patients have not been established by adequate and well
controlled trials, however, the use of dextrose and electrolyte solutions in the pediatric population is
referenced in the medical literature. The warnings, precautions and adverse reactions identified in the
label copy should be observed in the pediatric population.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible hemorrhage.
Geriatric Use
Clinical studies of 5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose
Injection, Type 3, 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 the responses between 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
drug therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 192
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
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
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. 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.
As reported in the literature, the dosage and constant infusion rate of intravenous dextrose must be
selected with caution in pediatric patients, particularly neonates and low weight infants, because of the
increased risk of hyperglycemia/hypoglycemia.
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
5% Dextrose and Electrolyte No. 75 Injection (Multiple Electrolytes and Dextrose Injection, Type 3,
USP) in AVIVA plastic containers is available as shown below:
Code
Size (mL)
NDC
6E2112
250
NDC 0338-6338-02
6E2113
500
NDC 0338-6338-03
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 193
6E2114
1000
NDC 0338-6338-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 194
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 195
Baxter
3% and 5% Sodium Chloride Injection, USP
in AVIVA Plastic Container
Description
3% and 5% Sodium Chloride Injection, USP is a sterile, nonpyrogenic, hypertonic solution for fluid
and electrolyte replenishment in single dose containers for intravenous administration. The pH may
have been adjusted with hydrochloric acid. It contains no antimicrobial agents. Composition, ionic
concentration, osmolarity, and pH are shown in Table 1.
Composition
(g/L)
Ionic Concentration
(mEq/L)
Table 1
size
(mL)
Sodium Chloride
USP (NaCl)
Sodium
Chloride
*Osmolarity
(mOsmol/L)
(calc)
pH
3% Sodium
Chloride Injection,
USP
500
30
513
513
1027
5.5
(4.5 to 7.0)
5% Sodium
Chloride Injection,
USP
500
50
856
856
1711
5.5
(4.5 to 7.0)
*Normal physiological osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (> 600 mOsmol/L)
may cause vein damage.
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.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 196
Clinical Pharmacology
3% and 5% Sodium Chloride Injection, USP has value as a source of water and electrolytes. It is
capable of inducing diuresis depending on the clinical condition of the patient.
Indications and Usage
3% and 5% Sodium Chloride Injection, USP is indicated as a source of water and electrolytes.
Contraindications
None known
Warnings
3% and 5% Sodium Chloride Injection, USP is strongly hypertonic and may cause vein damage.
3% and 5% Sodium Chloride Injection, USP should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there exists edema
with sodium retention.
In patients with diminished renal function, administration of 3% and 5% Sodium Chloride Injection,
USP may result in sodium retention.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of 3% and 5% Sodium Chloride Injection, USP to
patients receiving corticosteroids or corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 197
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with 3%
and 5% Sodium Chloride Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with 3% and 5% Sodium Chloride Injection, USP have not been performed to evaluate
carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 3% and 5%
Sodium Chloride Injection, USP. It is also not known whether 3% and 5% Sodium Chloride Injection,
USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
3% and 5% Sodium Chloride Injection, USP should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of 3% and 5% Sodium Chloride Injection, USP
on labor and delivery. Caution should be exercised when administering this drug during labor and
delivery.
Nursing Mothers
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 3% and 5% Sodium Chloride Injection, USP is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness of 3% and 5% Sodium Chloride Injection, USP in pediatric patients have not
been established by adequate and well controlled trials, however, the use of sodium chloride solutions
in the pediatric population is referenced in the medical literature. The warnings, precautions and
adverse reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
Clinical studies of 3% and 5% Sodium Chloride 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 the responses between 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 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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 198
Adverse Reactions
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
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.
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
3% and 5% Sodium Chloride Injection, USP in AVIVA Plastic Container is available as follows:
Code
Size (mL)
NDC
Product Name
6E1353
500
0338-6339-03
3% Sodium
Chloride Injection,
USP
6E1373
500
0338-6340-03
5% Sodium
Chloride Injection,
USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 199
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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
* Bar Code Position Only
XXXXXXX
©Copyright XXXX Baxter Healthcare 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
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 200
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 201
Baxter
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1,
USP)
in AVIVA Plastic Container
Description
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is a sterile, nonpyrogenic,
hypotonic solution in a single dose container for intravenous administration. Each 100 mL contains
234 mg of Sodium Chloride, USP (NaCl); 128 mg of Potassium Acetate, USP (C2H3KO2); and 32 mg
of Magnesium Acetate Tetrahydrate (Mg(C2H3O2)2•4H2O). It contains no antimicrobial agents. The
pH is adjusted with hydrochloric acid. The pH is 5.5 (4.0 to 8.0).
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) administered
intravenously has value as a source of water and electrolytes. One liter has an ionic concentration of
40 mEq sodium, 13 mEq potassium, 3 mEq magnesium, 40 mEq chloride, and 16 mEq acetate. The
osmolarity is 111 mOsmol/L (calc). Normal physiologic osmolarity range is approximately 280 to 310
mOsmol/L. Administration of substantially hypertonic solutions may cause vein damage.
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.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 202
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) has value as a source of
water and electrolytes. It is capable of inducing diuresis depending on the clinical condition of the
patient.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) produces a metabolic
alkalinizing effect. Acetate ions are metabolized ultimately to carbon dioxide and water, which
requires the consumption of hydrogen cations.
Indications and Usage
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) is indicated as a source of
water and electrolytes or as an alkalinizing agent.
Contraindications
None known
Warnings
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states
in which there exists edema with sodium retention.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure and in conditions in which potassium
retention is present.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with great
care in patients with metabolic or respiratory alkalosis. The administration of acetate ions should be
done with great care in those conditions in which there is an increased level or an impaired utilization
of these ions, such as severe hepatic insufficiency.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should not be
administered simultaneously with blood through the same administration set because of the possibility
of hemolysis.
The intravenous administration of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type
1, USP) can cause fluid and/or solute overloading resulting in dilution of serum electrolyte
concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is
inversely proportional to the electrolyte concentrations of the injection. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentrations of the injection.
In patients with diminished renal function, administration of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) may result in sodium or potassium retention.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 203
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) should be used with
caution. Excess administration may result in metabolic alkalosis.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) to patients receiving corticosteroids or corticotropin.
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP).
Carcinogenesis, mutagenesis, impairment of fertility
Studies with PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) have not
been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with PLASMA-LYTE
56 Injection (Multiple Electrolytes Injection, Type 1, USP). It is also not known whether PLASMA-
LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. PLASMA-LYTE 56 Injection
(Multiple Electrolytes Injection, Type 1, USP) should be given to a pregnant woman only if clearly
needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of PLASMA-LYTE 56 Injection (Multiple
Electrolytes Injection, Type 1, USP) on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 204
Nursing Mothers
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 PLASMA-LYTE 56 Injection (Multiple Electrolytes
Injection, Type 1, USP) is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1,
USP) in pediatric patients have not been established by adequate and well controlled trials, however,
the use of electrolyte solutions in the pediatric population is referenced in the medical literature. The
warnings, precautions and adverse reactions identified in the label copy should be observed in the
pediatric population.
Geriatric Use
Clinical studies of PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, 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 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
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
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.
Do not administer unless solution is clear and seal is intact.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 205
All injections in AVIVA plastic containers are intended for intravenous administration using sterile
equipment.
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
PLASMA-LYTE 56 Injection (Multiple Electrolytes Injection, Type 1, USP) in AVIVA plastic
containers is available as shown below:
Code
Size (mL)
NDC
6E2524
1000
NDC 0338-6341-04
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25°C); brief exposure up to 40°C does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 206
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter, PLASMA-LYTE and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 207
Baxter
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection,
USP
in AVIVA Plastic Container
Description
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP is a sterile, nonpyrogenic
solution for fluid and electrolyte replenishment and caloric supply in a single dose container for
intravenous administration. It contains no antimicrobial agents. Composition, osmolarity, pH, ionic
concentration and caloric content are shown below:
Composition (g/L)
Potassium Chloride in
Lactated Ringer’s and
5% Dextrose Injection,
USP
mEq Potassium added
Size
(mL)
**Dextrose Hydrous, USP
Sodium Chloride, USP
(NaCl)
Sodium Lactate, (C3H5NaO3)
Potassium Chloride, USP
(KCl)
Calcium Chloride, USP
(CaCl2•2H2O)
*Osmolarity
(mOsmol/L) (calc.)
20 mEq
1000
50
6
3.1
1.79
0.2
565
40 mEq
1000
50
6
3.1
3.28
0.2
605
*Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may
cause vein damage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 208
HO
O
OH • H O
OH
OH
HO
2
**
D-Glucose monohydrate
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.
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.
Ionic Concentration
(mEq/L)
Potassium Chloride in
Lactated Ringer’s and
5% Dextrose
Injection, USP
mEq Potassium added
pH
Sodium
Potassium
Calcium
Chloride
Lactate
Caloric Content
(kcal/L)
20 mEq
5.0
(3.5 to 6.5)
130
24
3
129
28
170
40 mEq
5.0
(3.5 to 6.5)
130
44
3
149
28
170
** The chemical structure for Dextrose Hydrous, USP is shown below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 209
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
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have value as a source of
water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition
of the patient.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP produce a metabolic
alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which
requires the consumption of hydrogen cations.
Indications and Usage
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are indicated as a source of
water, electrolytes, and calories or as alkalinizing agents.
Contraindications
Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn
product.
Warnings
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with congestive heart failure, severe renal insufficiency, and in clinical states
in which there exists edema with sodium retention.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with hyperkalemia, severe renal failure, and in conditions in which potassium
retention is present.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with great
care, if at all, in patients with metabolic or respiratory alkalosis. The administration of lactate ions
should be done with great care in those conditions in which there is an increased level or an impaired
utilization of these ions, such as severe hepatic insufficiency.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should not be administered
with blood through the same administration set because of the likelihood of coagulation.
The intravenous administration of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection,
USP can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations,
overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely
proportional to the electrolyte concentrations of the injection. The risk of solute overload causing
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 210
congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injection.
In patients with diminished renal function, administration of Potassium Chloride in Lactated Ringer’s
and 5% Dextrose Injection, USP may result in sodium or potassium retention.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP are not for use in the
treatment of lactic acidosis.
In very low birth weight infants, excessive or rapid administration of dextrose injection may result in
increased serum osmolality and possible intracerebral hemorrhage.
Potassium salts should never be administered by IV push.
Precautions
General
Do not connect flexible plastic containers of intravenous solutions in series, i.e., do not piggyback
connections. Such use could result in air embolism due to residual air being drawn from one 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.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution.
Excess administration may result in metabolic alkalosis.
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP should be used with caution
in patients with overt or subclinical diabetes mellitus.
Laboratory Tests
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.
Drug Interactions
Caution must be exercised in the administration of Potassium Chloride in Lactated Ringer’s and 5%
Dextrose Injection, USP to patients receiving corticosteroids or corticotropin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 211
Studies have not been conducted to evaluate additional drug/drug or drug/food interactions with
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP.
Carcinogenesis, mutagenesis, impairment of fertility
Studies with Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP have not been
performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium
Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP. It is also not known whether
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Potassium Chloride in Lactated
Ringer’s and 5% Dextrose Injection, USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
Studies have not been conducted to evaluate the effects of Potassium Chloride in Lactated Ringer’s
and 5% Dextrose Injection, USP on labor and delivery. Caution should be exercised when
administering this drug during labor and delivery.
Nursing Mothers
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 Potassium Chloride in Lactated Ringer’s and 5%
Dextrose Injection, USP is administered to a nursing mother.
Pediatric Use
Safety and effectiveness of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP
in pediatric patients have not been established by adequate and well controlled studies. However, the
use of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, 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 in prescribed to pediatric patients, particularly
neonates and low birth weight infants.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Geriatric Use
Clinical studies of Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP did not
include sufficient numbers of subjects aged 65 and over to determine whether they respond differently
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 212
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 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
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
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 final filter is recommended during
administration of fall 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.
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
Potassium Chloride in Lactated Ringer’s and 5% Dextrose Injection, USP in AVIVA plastic containers
is available as shown below:
Code
Size (mL)
NDC
Product Name
6E2224
1000
NDC 0338-6344-04
20 mEq/L Potassium
Chloride in Lactated
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 213
Ringer’s and 5%
Dextrose Injection, USP
6E2244
1000
NDC 0338-6345-04
40 mEq/L Potassium
Chloride in Lactated
Ringer’s and 5%
Dextrose Injection, USP
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. It is
recommended the product be stored at room temperature (25ºC); brief exposure to up to 40ºC does not
adversely affect the product.
Directions for Use of AVIVA Plastic Container
To Open
Tear overwrap down side at slit and remove solution container. Moisture and 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 directions below.
Preparation for Administration
Caution: Do not use plastic containers in series connections.
Caution: Use only with a non-vented set or a vented set with the vent closed.
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 13-684/S-092, 16-677/S-139, 16-678/S-100, 16-679/S-099, 16-682/S-100,
16-683/S-096, 16-687/S-097, 16-689/S-100, 16-692/S-091, 16-693/S-091,
16-695/S-093, 16-696/S-094, 16-697/S-093, 17-378/S-063, 17-385/S-055,
17-390/S-060, 17-438/S-059, 17-451/S-058, 17-484/S-062, 17-634/S-065,
17-648/S-065, 18-008/S-065, 18-016/S-057, 18-037/S-065, 18-840/S-029,
19-022/S-022, 19-047/S-024, 19-308/S-022, 19-367/S-022
Page 214
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
* Bar Code Position Only
XXXXXXXXX
©Copyright XXXX Baxter Healthcare Corporation
All rights reserved.
X-XX-XX-XXX
Rev. August 2005
Baxter and AVIVA are trademarks of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:13.397018
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/013684s092,016677s139,et al_lbl.pdf', 'application_number': 17451, 'submission_type': 'SUPPL ', 'submission_number': 58}
|
11,005
|
DIANEAL Peritoneal Dialysis Solution
For intraperitoneal administration only
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
PD-2
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 1.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With 2.5%
Dextrose
DIANEAL
Low
Calcium
(2.5
mEq/L)
Peritoneal
Dialysis
Solution
With
4.25%
Dextrose
DESCRIPTION
DIANEAL Peritoneal Dialysis Solutions are sterile, nonpyrogenic solutions in flexible containers for
intraperitoneal administration only. The peritoneal dialysis solutions contain no bacteriostatic or
antimicrobial agents.
Composition, calculated osmolarity, pH, and ionic concentrations are shown in Tables 1-6.
DIANEAL is a hyperosmolar solution.
The plastic container is fabricated from 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 solution 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 by cell culture toxicity studies.
CLINICAL PHARMACOLOGY
Mechanism of Action
DIANEAL is a hypertonic peritoneal dialysis solution containing dextrose, a monosaccharide, as the
primary osmotic agent. An osmotic gradient must be created between the peritoneal membrane and
the dialysis solution in order for ultrafiltration to occur. The hypertonic concentration of glucose in
DIANEAL exerts an osmotic pressure across the peritoneal membrane resulting in transcapillary
ultrafiltration. Like other peritoneal dialysis solutions, DIANEAL contains electrolytes to facilitate the
correction of electrolyte abnormalities. DIANEAL contains a buffer, lactate, to help normalize acid-
base abnormalities.
Pharmacokinetics of DIANEAL
Glucose content in DIANEAL is expressed as dextrose monohydrate and is available in three
concentrations: 1.5%, 2.5% and 4.25%.
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Glucose is rapidly absorbed from the peritoneal cavity by diffusion and appears quickly in the
circulation due to the high glucose concentration gradient between DIANEAL compared to blood
capillary glucose level. Absorption per unit time will be the highest at the start of an exchange and
decreases over time. The rate of glucose absorption will be dependent upon the transport
characteristics of the patient’s peritoneal membrane as determined by a peritoneal equilibration test
(PET). Glucose absorption will also depend upon the concentration of glucose used for the
exchange and the length of the dwell. Glucose is metabolized by normal cellular pathways (e.g.
glycolysis) and provides a source of calories and may elevate blood glucose levels.
Transport of other molecules across the peritoneal membrane, such as lactate, will occur by
diffusion. Metabolism of lactate occurs in the liver and results in the generation of the bicarbonate.
Transport of other molecules will be dependent upon the molecular size of the solute, the
concentration gradient, and the effective peritoneal surface area as determined by the PET.
INDICATIONS AND USAGE
DIANEAL peritoneal dialysis solutions are indicated for patients in acute or chronic renal failure
when nondialytic medical therapy is judged to be inadequate.
CONTRAINDICATIONS
DIANEAL is contraindicated in patients with pre-existing severe lactic acidosis.
WARNINGS
Encapsulating Peritoneal Sclerosis (EPS) is considered to be a known, rare complication of
peritoneal dialysis therapy. EPS has been reported in patients using peritoneal dialysis solutions
including DIANEAL. Infrequently, fatal outcomes of EPS have been reported with DIANEAL.
Because Dianeal is a dextrose-based solution, patients with allergy to corn or corn products are at
increased risk for allergic reaction, which may include anaphylactic/anaphylactoid reactions. Stop the
infusion immediately, drain the solution from the peritoneal cavity and treat appropriately if any signs
or symptoms of a suspected hypersensitivity reaction develop.
Patients with severe lactic acidosis should not be treated with lactate-based peritoneal dialysis
solutions (See Contraindications). Patients with conditions known to increase the risk of lactic
acidosis [e.g., severe hypotension or sepsis that can be associated with acute renal failure, hepatic
failure, inborn errors of metabolism, and treatment with drugs such as nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs)] must be monitored for the occurrence of lactic acidosis before the
start of treatment and during treatment with lactate-based peritoneal dialysis solutions.
When prescribing the solution to be used for an individual patient, consideration should be given to
the potential interaction between the dialysis treatment and therapy directed at other existing
illnesses. Serum potassium levels should be monitored carefully in patients treated with cardiac
glycosides. For example, rapid potassium removal may create arrhythmias in cardiac patients using
digitalis or similar drugs; digitalis toxicity may be masked by hyperkalemia, hypermagnesemia, or
hypocalcemia. Correction of electrolytes by dialysis may precipitate signs and symptoms of digitalis
excess. Conversely, toxicity may occur at suboptimal dosages of digitalis if potassium is low or
calcium is high.
Diabetics require careful monitoring of insulin requirements and other treatments for hyperglycemia
during and following dialysis with dextrose containing solutions.
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General
Peritoneal-Dialysis Related
DIANEAL is intended for intraperitoneal administration only. Not for intravenous administration.
The following conditions may predispose to adverse reactions to peritoneal dialysis procedures:
abdominal conditions, including uncorrectable mechanical defects that prevent effective peritoneal
dialysis or increase the risk of infection, disruption of the peritoneal membrane and diaphragm by
surgery, congenital anomalies or trauma prior to complete healing, abdominal tumors, abdominal
wall infections, hernias, fecal fistula, colostomies or ileostomies, frequent episodes of diverticulitis,
inflammatory or ischemic bowel disease, large polycystic kidneys, or other conditions that
compromise the integrity of the abdominal wall, abdominal surface, or intra-abdominal cavity, such
as documented loss of peritoneal function or extensive adhesions that compromise peritoneal
function. Conditions that preclude normal nutrition, impaired respiratory function, recent aortic graft
placement, and potassium deficiency may also predispose to complications of peritoneal dialysis.
Aseptic technique must be employed throughout the peritoneal dialysis procedure to reduce the
possibility of infection.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness, which
may indicate the presence of peritonitis.
If peritonitis occurs, the choice and dosage of antibiotics should be based upon the results of
identification and sensitivity studies of the isolated organism(s) when possible. Prior to identification
of the involved organism(s), broad-spectrum antibiotics may be indicated.
Overinfusion of peritoneal dialysis solution volume into the peritoneal cavity may be characterized by
abdominal distention, feeling of fullness and/or shortness of breath. Treatment of overinfusion is to
drain the peritoneal dialysis solution from the peritoneal cavity.
Need for Trained Physician
Treatment should be initiated and monitored under the supervision of a physician knowledgeable in
the management of patients with renal failure.
A patient’s volume status should be carefully monitored to avoid hyper- or hypovolemia and
potentially severe consequences including congestive heart failure, volume depletion and
hypovolemic shock. An accurate fluid balance record must be kept and the patient’s body weight
monitored. Excessive use of DIANEAL peritoneal dialysis solution with higher dextrose concentration
during a peritoneal dialysis treatment may result in significant removal of water from the patient (see
Dosage and Administration).
Significant losses of protein, amino acids, water-soluble vitamins and other medicines may occur
during peritoneal dialysis. The patient’s nutritional status should be monitored and replacement
therapy should be provided as necessary.
Information for Patients
Patients should be instructed not to use solutions if they are cloudy, discolored, contain visible
particulate matter, or if they show evidence of leaking containers (see Dosage and Administration).
Aseptic technique must be employed throughout the procedure.
An improper clamping sequence may result in infusion of air into the peritoneum (see Dosage and
Administration, Directions for Use).
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To reduce possible discomfort during administration, patients should be instructed that solutions may
be warmed to 37°C (98°F) prior to use. Only dry heat should be used. It is best to warm solutions
within the overwrap using a heating pad. To avoid contamination, solutions should not be immersed
in water for warming. Do not use a microwave oven to warm the solution (see Dosage and
Administration, Directions for Use).
Laboratory Tests
Serum Electrolytes
DIANEAL does not contain potassium. Evaluate serum potassium prior to administering potassium
chloride to the patient. In situations where there is a normal serum potassium level or hypokalemia,
addition of potassium chloride (up to a concentration of 4 mEq/L) to the solution may be necessary
to prevent severe hypokalemia. This should be made under careful evaluation of serum and total
body potassium, and only under the direction of a physician.
Fluid, hematology, blood chemistry, electrolyte concentrations, and bicarbonate should be monitored
periodically. If serum magnesium levels are low, magnesium supplements may be used.
Patients receiving DIANEAL solutions should have their calcium levels monitored for the
development of hypocalcemia or hypercalcemia. In these circumstances, adjustments to the dosage
of the phosphate binders, vitamin D analogs, and/or calcimimetics should be considered by the
physician. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis solution should be considered for
use in patients with hypercalcemia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies to evaluate the carcinogenic or mutagenic potential of this product, or its potential to affect
fertility adversely, have not been performed.
Drug Interactions
No clinical drug interaction studies were performed. As with other dialysis solutions, blood
concentrations of dialyzable drugs may be reduced by dialysis. Dosage adjustment of concomitant
medications may be necessary. In patients using cardiac glycosides (digoxin and others), plasma
levels of calcium, potassium and magnesium must be carefully monitored (see Warnings).
Use in Specific Population
Pregnancy
Pregnancy Category C. DIANEAL is a peritoneal dialysis solution of electrolytes, lactate and
dextrose and is pharmacologically inactive. Animal reproduction studies have not been conducted
with DIANEAL dialysis solution. While there are no adequate and well controlled studies in pregnant
women, appropriate administration of DIANEAL with monitoring of fluid, electrolyte, acid-base and
glucose balance, is not expected to cause fetal harm, or affect reproductive capacity. Maintenance
of normal acid-base balance is important for fetal well being. Physicians should carefully consider
the potential risks and benefits for each specific patient before prescribing DIANEAL.
Nursing Mothers
DIANEAL is a dialysis solution of electrolytes, lactate and dextrose and is pharmacologically
inactive. The components of DIANEAL are excreted in human milk. Appropriate administration of
DIANEAL with monitoring of fluid, electrolyte, acid-base and glucose balance, is not expected to
harm a nursing infant. Physicians should carefully consider the potential risks and benefits for each
specific patient before prescribing DIANEAL.
Pediatric Use
Safety and effectiveness have been established based on published clinical data. No adequate and
well-controlled studies have been conducted with DIANEAL solutions in pediatric patients.
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use
Safety and effectiveness have been established based on published clinical data.
ADVERSE REACTIONS
The following adverse reactions have been identified during post approval use of DIANEAL.
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 during drug exposure.
Adverse reactions are listed by MedDRA System Organ Class (SOC), then by Preferred Term in
order of severity.
INFECTIONS AND INFESTATIONS: Fungal peritonitis, Peritonitis bacterial, Catheter related
infection
METABOLISM AND NUTRITION DISORDERS: Hypovolemia, Hypervolemia, Fluid retention,
Hypokalemia, Hyponatremia, Dehydration, Hypochloremia
VASCULAR DISORDERS: Hypotension, Hypertension
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Dyspnea
GASTROINTESTINAL DISORDERS: Sclerosing encapsulating peritonitis, Peritonitis, Peritoneal
cloudy effluent, Vomiting, Diarrhea, Nausea, Constipation, Abdominal pain, Abdominal distension,
Abdominal discomfort
SKIN AND SUBCUTANEOUS DISORDERS: Stevens-Johnson syndrome, Urticaria, Rash, (including
pruritic, erythematous and generalized), Pruritus
MUSCULOSKELETAL, CONNECTIVE TISSUE DISORDERS: Myalgia, Muscle spasms,
Musculoskeletal pain
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Generalized edema,
Pyrexia, Malaise, Infusion site pain, Catheter related complication
DRUG ABUSE AND DEPENDENCE
There has been no observed potential of drug abuse or dependence with DIANEAL solution.
OVERDOSAGE
There is a potential for overdose resulting in hypervolemia, hypovolemia, electrolyte disturbances or
hyperglycemia. Excessive use of DIANEAL peritoneal dialysis solution with 4.25% dextrose during a
peritoneal dialysis treatment can result in significant removal of water from the patient.
DOSAGE AND ADMINISTRATION
DIANEAL peritoneal dialysis solutions are intended for intraperitoneal administration only.
The mode of therapy, frequency of treatment, formulation, exchange volume, duration of dwell, and
length of dialysis should be selected by the physician responsible for and supervising the treatment
of the individual patient. DIANEAL should be administered at a rate that is comfortable for the
patient, generally over a period of 10-20 minutes for a single exchange.
Patients on continuous ambulatory peritoneal dialysis (CAPD) typically perform 4 cycles per day (24
hours). Patients on automated peritoneal dialysis (APD) typically perform 4-5 cycles at night and up
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
to 2 cycles during the day. The fill volume depends on body size, usually from 2.0 to 2.5 liters per
1.73m2 .
To avoid the risk of severe dehydration and hypovolemia and to minimize the loss of protein, it is
advisable to select the peritoneal dialysis solution with the lowest level of osmolarity consistent with
the fluid removal requirements for that exchange. As the patient’s body weight becomes closer to the
ideal dry weight, lowering the dextrose concentration of DIANEAL is recommended. DIANEAL
4.25% dextrose-containing solution has the highest osmolarity of the DIANEAL solutions and using it
for all exchanges may cause dehydration.
Solutions that are cloudy, discolored, contain visible particulate matter, or show evidence of leakage
should not be used.
Following use, the drained fluid should be inspected for the presence of fibrin or cloudiness which
may indicate the presence of peritonitis.
For single use only. Discard unused portion.
It is recommended that patients being placed on peritoneal dialysis and/or their caretaker(s) should
be appropriately trained.
Addition of Potassium
Potassium is omitted from DIANEAL solutions because dialysis may be performed to correct
hyperkalemia. In situations where there is a normal serum potassium level or hypokalemia, the
addition of potassium chloride (up to a concentration of 4 mEq/L) may be indicated to prevent severe
hypokalemia. The decision to add potassium chloride should be made by the physician after careful
evaluation of serum potassium.
Addition of Insulin
Patients with insulin-dependent diabetes may require modification of insulin dosage following
initiation of treatment with DIANEAL. Appropriate monitoring of blood glucose should be performed
when initiating DIANEAL in diabetic patients and insulin dosage adjusted if needed (see Warnings).
Addition of Heparin
No human drug interaction studies with heparin were conducted. In vitro studies demonstrated no
evidence of incompatibility of heparin with DIANEAL.
Addition of Antibiotics
No formal clinical drug interaction studies have been performed. In vitro studies of the following
medications have demonstrated stability with DIANEAL: amphotericin B, ampicillin, cefazolin,
cefepime, cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, clindamycin, deferoxamine,
erythromycin, gentamicin, linezolid, mezlocillin, miconazole, moxifloxacin, nafcillin, ofloxacin,
penicillin G, piperacillin, sulfamethoxazole/trimethoprim, ticarcillin, tobramycin, and vancomycin.
However, aminoglycosides should not be mixed with penicillins due to chemical incompatibility.
Directions for Use
For complete CAPD and APD system preparation, see directions accompanying ancillary
equipment.
Aseptic technique must be used throughout the peritoneal dialysis procedure.
Warming
For patient comfort, DIANEAL can be warmed to 37°C (98°F). Only dry heat should be used. It is
best to warm solutions within the overwrap using a heating pad. Do not immerse DIANEAL in water
for warming. Do not use a microwave oven to warm DIANEAL.
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To Open
To open, tear the overwrap down at the slit and remove the solution container. Some opacity of the
plastic, due to moisture absorption during the sterilization process, may be observed. This does not
affect the solution quality or safety and may often leave a slight amount of moisture within the
overwrap. The opacity should diminish gradually.
Inspect for Container Integrity
Inspect the bag connector to ensure the tip protector (pull ring, blue pull tip, or blue twist-off tip) is
attached. Do not use if the tip protector is not attached to the connector. Inspect the DIANEAL
container for signs of leakage and check for minute leaks by squeezing the container firmly. If the
container has frangible(s), inspect that they are positioned correctly and are not broken. Do not use
DIANEAL if the frangible(s) are broken or leaks are suspected as sterility may be impaired.
For DIANEAL in ULTRABAG, inspect the tubing and drain container for presence of solution. Small
droplets are acceptable, but if solution flows past the frangible prior to use, do not use and discard
the units.
Adding Medications
Some drug additives may be incompatible with DIANEAL. See DOSAGE AND ADMINISTRATION
section for additional information. If the resealable rubber plug on the medication port is missing or
partly removed, do not use the product if medication is to be added.
1. Put on mask. Clean and/or disinfect hands.
2. Prepare medication port site using aseptic technique.
3. Using a syringe with a 1-inch long, 25- to 19-gauge needle, puncture the medication port and
inject additive.
4. Reposition container with container ports up and evacuate medication port by squeezing and
tapping it.
5. Mix solution and additive thoroughly.
Administration instructions for CAPD therapy using ULTRABAG containers
(Products listed in Tables 1-2)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
1) Uncoil tubing and drain bag, ensuring that the transfer set is closed.
2) Immediately attach the solution container to patient connector (transfer set).
3) Break the connector (Y-set) frangible.
4) Remove the tip protector from connector of solution container. Do not reuse the solution or
container once the tip protector is removed.
5) Clamp solution line and then break frangible near solution bag. Hang solution container and
place the drainage container below the level of the abdomen.
6) Open transfer set to drain the solution from abdomen. If drainage cannot be established,
contact your clinician. When drainage complete, close transfer set.
7) Remove clamp from solution line and flush new solution to flow into the drainage container
for 5 seconds to prime the line. Clamp drain line after flush complete.
8) Open transfer set to fill. When fill complete, close transfer set.
9) Disconnect ULTRABAG from transfer set and apply MINICAP.
10) Upon completion of therapy, discard any unused portion.
Administration instructions for APD therapy using containers with pull rings or blue pull tips
(Products listed in Tables 3-5)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1) Remove the tip protector from connector of solution container. Do not reuse the solution or
container once the tip protector is removed.
2) Immediately attach the solution container to an appropriate automated peritoneal dialysis set.
3) Continue therapy as instructed in user manual or directions accompanying tubing sets for
automated peritoneal dialysis.
4) Upon completion of therapy, discard any unused portion.
Administration instructions for APD therapy using containers with blue twist-off tips
(Products listed in Table 6)
Put on mask. Clean and/or disinfect hands. Using aseptic technique;
1) Place and fasten blue outlet port clamp on solution bag administration port, between the blue
connector and the solution container.
2) Remove the blue twist-off tip from connector of solution container. Do not reuse the solution
or container once the blue twist-off tip is removed.
3) Immediately insert the spike of the automated peritoneal dialysis set into the solution bag
port.
4) Continue therapy as instructed in user manual or directions accompanying tubing sets for
automated peritoneal dialysis.
5) Upon completion of therapy, discard any unused portion.
HOW SUPPLIED
DIANEAL peritoneal dialysis solutions are available in nominal size flexible containers as shown in
Tables 1-6.
All DIANEAL peritoneal dialysis solutions have overfills which are declared on container labeling.
Freezing of solution may occur at temperatures below 0°C (32°F). Allow to thaw naturally in ambient
conditions and thoroughly mix contents by shaking.
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.
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. DIANEAL PD-2 Peritoneal Dialysis Solution (ULTRABAG CONTAINER for CAPD therapy)
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL PD-2
Peritoneal Dialysis
Solution with
1.5% Dextrose
1.5 g
538 mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9866
5B9868
5B9857
0941-0426-52
0941-0426-53
0941-0426-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
2.5% Dextrose
2.5 g
538 mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9876
5B9878
5B9858
0941-0427-52
0941-0427-53
0941-0427-55
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
4.25 g
538 mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to
6.5)
132
3.5
0.5
96
40
2000
2500
3000
2000
3000
5000
5B9896
5B9898
5B9859
0941-0429-52
0941-0429-53
0941-0429-55
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (ULTRABAG CONTAINER for CAPD therapy)
Composition/100 mL
OSMOLARITY
(mOsmol/L) (calc)
pH
Ionic Concentration
(mEq/L)
How Supplied
*Dextrose, Hydrous, USP
Sodium Chloride, USP (NaCl)
Sodium Lactate (C3 H5 NaO3 )
Calcium Chloride, USP (CaCl2 •2H2 O)
Magnesium Chloride, USP (MgCl2 •6H2 O)
Sodium
Calcium
Magnesium
Chloride
Lactate
Fill
Volume
(mL)
Container
Size (mL)
Code
NDC
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg 448 mg
18.3
mg
5.08
mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9765
5B9766
5B9768
5B9757
0941-0424-51
0941-0424-52
0941-0424-53
0941-0424-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg 448 mg
18.3
mg
5.08
mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9775
5B9776
5B9778
5B9758
0941-0430-51
0941-0430-52
0941-0430-53
0941-0430-55
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
4.25 g 538 mg 448 mg
18.3
mg
5.08
mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
1500
2000
2500
3000
2000
2000
3000
5000
5B9795
5B9796
5B9798
5B9759
0941-0433-51
0941-0433-52
0941-0433-53
0941-0433-55
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. DIANEAL PD-2 Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER with pull ring for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
2 •6H2 O)
Fill
Container
SP
, U
SP
SP
USP (MgCl
e,
Volume
Size
Code
NDC
*Dextrose, Hydrous
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL PD-2
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg
25.7 mg
5.08 mg
346
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5163
L5B5166
L5B5169
L5B5193
L5B9710
0941-0411-05
0941-0411-06
0941-0411-04
0941-0411-07
0941-0411-11
DIANEAL PD-2
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg
448 mg
25.7 mg
5.08 mg
396
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5173
L5B5177
L5B5179
L5B5194
L5B9711
0941-0413-05
0941-0413-06
0941-0413-04
0941-0413-07
0941-0413-01
DIANEAL PD-2
Peritoneal Dialysis
Solution with
4.25% Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg
25.7 mg
5.08 mg
485
5.2
(4.0 to 6.5)
132
3.5
0.5
96
40
1000
2000
3000
5000
6000
1000
3000
3000
6000
6000
L5B5183
L5B5187
L5B5189
L5B5195
L5B9712
0941-0415-05
0941-0415-06
0941-0415-04
0941-0415-07
0941-0415-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution (AMBU-FLEX CONTAINER with pull ring for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3 )
5 NaO
(CaCl
SP (MgCl
Fill
Container
SP
U
SP
SP
e, U
Volume
Size
Code
NDC
*Dextrose, Hydrous,
Sodium Chloride, U
Sodium Lactate (C3 H
Calcium Chloride, U
2 •2H2 O)
Magnesium Chlorid
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
AMBU-FLEX II
CONTAINER
1.5 g
538 mg
448 mg 18.3 mg 5.08 mg
344
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B4825
L5B9901
L5B4826
L5B9770
0941-0409-06
0941-0409-05
0941-0409-07
0941-0409-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
AMBU-FLEX II
CONTAINER
2.5 g
538 mg
448 mg 18.3 mg 5.08 mg
395
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9727
L5B9902
L5B5202
L5B9771
0941-0457-08
0941-0457-02
0941-0457-05
0941-0457-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
AMBU-FLEX II
CONTAINER
4.25 g
538 mg
448 mg 18.3 mg 5.08 mg
483
5.2
(4.0 to 6.5)
132
2.5
0.5
95
40
2000
3000
5000
6000
3000
3000
6000
6000
L5B9747
L5B9903
L5B5203
L5B9772
0941-0459-08
0941-0459-02
0941-0459-05
0941-0459-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution Made in Ireland (Plastic container with blue pull tip for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
)
3 )
H 5 NaO
2 •2H2 O)
gCl
Fill
Container
aCl
l
aC
(M
Volume
Size
Code
NDC
*Dextrose, Hydrous
Sodium Chloride (N
Sodium Lactate (C3
Calcium Chloride (C
Magnesium Chloride
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg
448 mg 18.4 mg 5.08 mg
344
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5245R 0941-0484-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg
448 mg 18.4 mg 5.08 mg
395
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5255R 0941-0487-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 4.25%
Dextrose
4.25 g
538 mg
448 mg 18.4 mg 5.08 mg
483
5.0 to 6.5
132
2.5
0.5
95
40
5000
5000
EZPB5265R 0941-0490-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 6. DIANEAL Low Calcium (2.5 mEq/L) Peritoneal Dialysis Solution Made in Mexico (Plastic container with blue twist-off tip for APD therapy)
Composition/100 mL
Ionic Concentration
(mEq/L)
How Supplied
(NaCl)
3)
5NaO
2 •2H2 O)
SP (MgCl
Fill
Container
SP
U
P
SP (CaCl
, U
Volume
Size
Code
NDC
*Dextrose, Hydrous,
Sodium Chloride, US
Sodium Lactate (C3 H
Calcium Chloride, U
Magnesium Chloride
2 •6H2 O)
OSMOLARITY
(mOsmol/L) (calc)
pH
Sodium
Calcium
Magnesium
Chloride
Lactate
(mL)
(mL)
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 1.5%
Dextrose
1.5 g
538 mg
448 mg 18.3 mg 5.08 mg
344
5.0 to 5.6
132
2.5
0.5
95
40
6000
6000
VBB4928US 0941-0472-01
DIANEAL Low
Calcium (2.5 mEq/L)
Peritoneal Dialysis
Solution with 2.5%
Dextrose
2.5 g
538 mg
448 mg 18.3 mg 5.08 mg
395
5.0 to 5.6
132
2.5
0.5
95
40
6000
6000
VBB4931US 0941-0475-01
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
BAXTER, DIANEAL, AMBU-FLEX, ULTRABAG, MINICAP, and PL 146 are trademarks of Baxter
International, Inc.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
08/2015
071975233
Reference ID: 3814105
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:13.774906
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017512s122,020163s027,020183s026lbl.pdf', 'application_number': 17512, 'submission_type': 'SUPPL ', 'submission_number': 122}
|
11,007
|
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
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.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
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 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
This label may not be the latest approved by FDA.
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
This label may not be the latest approved by FDA.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:14.035743
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/017521s068lbl.pdf', 'application_number': 17521, 'submission_type': 'SUPPL ', 'submission_number': 68}
|
11,008
|
RETIN-A®
Cream Gel Liquid
(tretinoin)
For Topical Use Only
Prescribing Information
Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne
vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or
0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert-
butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of
three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl
myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified
water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and
alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid
and has the following structure:
Leave space for structure.
Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests
that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation.
Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing
extrusion of the comedones.
Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety
and efficacy of the long-term use of this product in the treatment of other disorders have not been established.
Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is
noted.
Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out
of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication
should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN-
A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened
susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun
exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of
sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided.
Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.
RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous
membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of
local irritation warrants, patients should be directed to use the medication less frequently, discontinue use
temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin
and should be used with utmost caution in patients with this condition.
Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and
cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or
lime should be used with caution because of possible interaction with tretinoin. Particular caution should be
exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to
“rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun.
Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were
administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in
the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was
observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035%
formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human
systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear
because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because
they were within the background natural occurrence rate for these tumors in this strain of mice. There was no
evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times
the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the
animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1%
RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential
of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study
in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05%
tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to
sunlight or artificial ultraviolet irradiation sources.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay,
both of which were negative.
In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant)
decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose
adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of
nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for
total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been
performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of
neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does
adjusted for total body surface area).
Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats,
mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or
topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body
surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the
cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal
malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times
the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were
observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have
also been reported in pigtail macaques.
Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity
(shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal
incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times
the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head
and hydrocephaly, typical of retinoid-induced fetal malformations in this species.
In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but
not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum
human systemic does adjusted for total body surface area in both species).
With widespread use of any drug, a small number of birth defect reports associated temporally with the
administration of the drug would be expected by chance alone. Thirty human cases of temporally associated
congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite
pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe
the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the
forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.
Nonteratogenic effects:
Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting
in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the
maximum human systemic dose adjusted for total body surface area).
There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: 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 RETIN-A is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established.
Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of
RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered,
or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is
restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical
tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application
of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under
treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of
therapy (see Dosage and Administration Section).
Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked
redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those
associated with excessive oral intake of Vitamin A.
Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the
skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be
applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to
oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive
application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient.
Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to
temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of
application increased when the patients become able to tolerate the treatment.
Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of
the clinical therapeutic response and skin tolerance.
During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the
action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue
therapy.
Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required
before definite beneficial effects are seen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less
frequent applications, or other dosage forms.
Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be
cleansed thoroughly before the medication is applied. (See Precautions)
How Supplied:
RETIN-A (tretinoin) is supplied as:
RETIN-A Cream
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0165-01
0.025% Cream
20g
0062-0165-02
0.025% Cream
45g
0062-0175-12
0.05% Cream
20g
0062-0175-13
0.05% Cream
45g
0062-0275-23
0.1% Cream
20g
0062-0275-01
0.1% Cream
45g
RETIN-A Gel
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0575-44
0.01% Gel
15g
0062-0575-46
0.01% Gel
45g
0062-0475-42
0.025% Gel
15g
0062-0475-45
0.025% Gel
45g
RETIN-A Liquid
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0075-07
0.05% Liquid
28 mL
Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN-
A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETIN-A®
PATIENT INSTRUCTIONS Cream Gel Liquid
(tretinoin)
Acne Treatment
For Topical Use Only
IMPORTANT
Read Directions Carefully Before Using
THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED
BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S
INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO
OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS
PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY
QUESTIONS, BE SURE TO ASK YOUR DOCTOR.
WARNINGS
RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of
reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
PRECAUTIONS
The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a
sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and
even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care
taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn
and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized.
Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors.
These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated
with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice
treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was
reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either
laboratory animals or humans. However, investigations in this area are continuing.
Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An
effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an
SPF level which will provide you with the necessary high level of protection). For extended sun exposure,
protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you
do become sunburned, stop your therapy with RETIN-A until your skin has recovered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated
with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your
acne treatment under such conditions.
Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or
crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your
physician.
There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or
decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when
the skin was allowed to adjust to RETIN-A or therapy was discontinued.
Use other medication only on your physician’s advice. Only your physician knows which other medications
may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions
carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may
include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and
hair permanent solutions. Do not allow anyone else to use this medication.
Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you
have used in the past might cause unnecessary redness or peeling.
If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in
humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are
nursing a baby, consult your physician before using the medication.
AND WHILE YOU’RE ON RETIN-A THERAPY
Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no
matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times
actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be
sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician,
etc., may worsen your acne.
HOW TO USE RETIN-A (TRETINOIN)
To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given
for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be
patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN,
FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF
YOU HAVE QUESTIONS, ASK YOU DOCTOR.
To help you use the medication correctly, keep these simple instructions in mind.
(Insert picture)
•
Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise,
especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First,
wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING
MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation.
•
It is better not to use more than the amount suggested by your physician or to apply more frequently than
instructed. Too much may irritate the skin, waste medication and won’t give faster or better results.
•
Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from
these areas when applying.
•
RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be
enough for your whole face, after you have some experience with the medication you may find you need
slightly more or less to do the job. The medication should become invisible almost immediately. If it is still
visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first
dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth
gently into the skin.
•
RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough
for your whole face, after you have some experience with the medication you may find you need slightly more
or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry
flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with
RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over
the entire affected are. Smooth gently into the skin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear,
spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or
cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area
where treatment is not intended (such as corners of the mouth, eyes, and nose).
•
It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your
acne (noncomedogenic) every morning after you wash.
WHAT TO EXPECT WITH YOUR NEW TREATMENT
RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying
more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient.
There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their
skin begins to take on a blush.
These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually
subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully.
Should the effects become excessively troublesome, consult your doctor.
BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At
this stage it is important to continue using RETIN-A.
If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your
appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop
treatment at the first signs of improvement.
Once your acne is under control you should continue regular application of RETIN-A until your physician instructs
otherwise.
IF YOU HAVE QUESTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A
(tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday
through Friday.
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
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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/
---------------------
Markham Luke
6/10/02 11:40:52 AM
Acting for Dr. Jonathan Wilkin, Division Director, DDDDP
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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2025-02-12T13:44:14.256639
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 17522, 'submission_type': 'SUPPL ', 'submission_number': 23}
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11,006
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SINEQUAN®
(doxepin HCl)
CAPSULES
ORAL CONCENTRATE
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 Sinequan 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. Sinequan is not approved for use in pediatric
patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for
Patients, and Precautions: Pediatric Use)
DESCRIPTION
SINEQUAN® (doxepin hydrochloride) is one of a class of psychotherapeutic agents known as
dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO•HCl
having a molecular weight of 316. It is a white crystalline solid readily soluble in water, lower
alcohols and chloroform.
Inert ingredients for the capsule formulations are: hard gelatin capsules (which may contain Blue
1, Red 3, Red 40, Yellow 10, and other inert ingredients); magnesium stearate; sodium lauryl
sulfate; starch.
Inert ingredients for the oral concentrate formulation are: glycerin; methylparaben; peppermint
oil; propylparaben; water.
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CHEMISTRY
SINEQUAN (doxepin HCl) is a dibenzoxepin derivative and is the first of a family of tricyclic
psychotherapeutic agents. Specifically, it is an isomeric mixture of:
1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride. structural formula
ACTIONS
The mechanism of action of SINEQUAN (doxepin HCl) is not definitely known. It is not a
central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is
that the clinical effects are due, at least in part, to influences on the adrenergic activity at the
synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented.
Animal studies suggest that doxepin HCl does not appreciably antagonize the antihypertensive
action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects
on smooth muscle have been demonstrated. At higher than usual clinical doses, norepinephrine
response was potentiated in animals. This effect was not demonstrated in humans.
At clinical dosages up to 150 mg per day, SINEQUAN can be given to man concomitantly with
guanethidine and related compounds without blocking the antihypertensive effect. At dosages
above 150 mg per day blocking of the antihypertensive effect of these compounds has been
reported.
SINEQUAN is virtually devoid of euphoria as a side effect. Characteristic of this type of
compound, SINEQUAN has not been demonstrated to produce the physical tolerance or
psychological dependence associated with addictive compounds.
INDICATIONS
SINEQUAN is recommended for the treatment of:
1. Psychoneurotic patients with depression and/or anxiety.
2. Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with
alcohol).
3. Depression and/or anxiety associated with organic disease (the possibility of drug
interaction should be considered if the patient is receiving other drugs concomitantly).
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4. Psychotic depressive disorders with associated anxiety including involutional depression
and manic-depressive disorders.
The target symptoms of psychoneurosis that respond particularly well to SINEQUAN include
anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of
energy, fear, apprehension and worry.
Clinical experience has shown that SINEQUAN is safe and well tolerated even in the elderly
patient. Owing to lack of clinical experience in the pediatric population, SINEQUAN is not
recommended for use in children under 12 years of age.
CONTRAINDICATIONS
SINEQUAN is contraindicated in individuals who have shown hypersensitivity to the drug.
Possibility of cross sensitivity with other dibenzoxepines should be kept in mind.
SINEQUAN is contraindicated in patients with glaucoma or a tendency to urinary retention.
These disorders should be ruled out, particularly in older patients.
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 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
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.
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
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include daily observation by families and caregivers. Prescriptions for Sinequan 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 Sinequan is not approved for use in treating bipolar
depression.
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many
antidepressant drugs including Sinequan may trigger an angle closure attack in a patient with
anatomically narrow angles who does not have a patent iridectomy.
Usage in Geriatrics: The use of SINEQUAN on a once-a-day dosage regimen in geriatric
patients should be adjusted carefully based on the patient’s condition (see
PRECAUTIONS−Geriatric Use).
Usage in Pregnancy: Reproduction studies have been performed in rats, rabbits, monkeys and
dogs and there was no evidence of harm to the animal fetus. The relevance to humans is not
known. Since there is no experience in pregnant women who have received this drug, safety in
pregnancy has not been established. There has been a report of apnea and drowsiness occurring
in a nursing infant whose mother was taking SINEQUAN.
Usage in Children: The use of SINEQUAN in children under 12 years of age is not
recommended because safe conditions for its use have not been established.
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 Sinequan 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 Sinequan. 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
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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 Sinequan.
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.
Patients should be advised that taking Sinequan 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.
Pediatric Use-Safety and effectiveness in the pediatric population have not been established
(see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk).
Anyone considering the use of SINEQUAN in a child or adolescent must balance the potential
risks with the clinical need.
Drug 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 7–10% 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
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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., citalopram, escitalopram, fluoxetine,
sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. 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 tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6
may require lower doses than usually prescribed for either the tricyclic antidepressant or the other
drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an
increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma
levels whenever a TCA is going to be co-administered with another drug known to be an
inhibitor of P450 2D6.
Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways).
Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors
[SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly.
The extent of interaction depends on the variability of effect on CYP2D6. The clinical
significance of this interaction with doxepin has not been systematically evaluated.
MAO Inhibitors: Serious side effects and even death have been reported following the
concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be
discontinued at least two weeks prior to the cautious initiation of therapy with SINEQUAN. The
exact length of time may vary and is dependent upon the particular MAO inhibitor being used,
the length of time it has been administered, and the dosage involved.
Cimetidine: Cimetidine has been reported to produce clinically significant fluctuations in
steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic
symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with
elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated.
Additionally, higher than expected tricyclic antidepressant levels have been observed when they
are begun in patients already taking cimetidine. In patients who have been reported to be well
controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation
of cimetidine has been reported to decrease established steady-state serum tricyclic
antidepressant levels and compromise their therapeutic effects.
Alcohol: It should be borne in mind that alcohol ingestion may increase the danger inherent in
any intentional or unintentional SINEQUAN overdosage. This is especially important in patients
who may use alcohol excessively.
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Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient
maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).
Drowsiness: Since drowsiness may occur with the use of this drug, patients should be warned
of the possibility and cautioned against driving a car or operating dangerous machinery while
taking the drug. Patients should also be cautioned that their response to alcohol may be
potentiated.
Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally
should be started on low doses of SINEQUAN and observed closely. (See
PRECAUTIONS−Geriatric Use.)
Suicide: Since suicide is an inherent risk in any depressed patient and may remain so until
significant improvement has occurred, patients should be closely supervised during the early
course of therapy. Prescriptions should be written for the smallest feasible amount.
Psychosis: Should increased symptoms of psychosis or shift to manic symptomatology occur,
it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen.
Geriatric Use: A determination has not been made whether controlled clinical studies of
SINEQUAN included sufficient numbers of subjects aged 65 and over to define a difference in
response 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.
The extent of renal excretion of SINEQUAN has not been determined. Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selections.
Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally
should be started on low doses of SINEQUAN and observed closely. (See WARNINGS.)
ADVERSE REACTIONS
NOTE: Some of the adverse reactions noted below have not been specifically reported with
SINEQUAN use. However, due to the close pharmacological similarities among the tricyclics,
the reactions should be considered when prescribing SINEQUAN (doxepin HCl).
Anticholinergic Effects: Dry mouth, blurred vision, constipation, and urinary retention have been
reported. If they do not subside with continued therapy, or become severe, it may be necessary to
reduce the dosage.
Central Nervous System Effects: Drowsiness is the most commonly noticed side effect. This
tends to disappear as therapy is continued. Other infrequently reported CNS side effects are
confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal
symptoms, seizures, tardive dyskinesia, and tremor.
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Cardiovascular: Cardiovascular effects including hypotension, hypertension, and tachycardia
have been reported occasionally.
Allergic: Skin rash, edema, photosensitization, and pruritus have occasionally occurred.
Hematologic: Eosinophilia has been reported in a few patients. There have been occasional
reports of bone marrow depression manifesting as agranulocytosis, leukopenia,
thrombocytopenia, and purpura.
Gastrointestinal: Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia, and
aphthous stomatitis have been reported. (See Anticholinergic Effects.)
Endocrine: Raised or lowered libido, testicular swelling, gynecomastia in males, enlargement of
breasts and galactorrhea in the female, raising or lowering of blood sugar levels, and syndrome of
inappropriate antidiuretic hormone secretion have been reported with tricyclic administration.
Other: Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice,
alopecia, headache, exacerbation of asthma, angle closure glaucoma, mydriasis and hyperpyrexia
(in association with chlorpromazine) have been occasionally observed as adverse effects.
Withdrawal Symptoms: The possibility of development of withdrawal symptoms upon abrupt
cessation of treatment after prolonged SINEQUAN administration should be borne in mind.
These are not indicative of addiction and gradual withdrawal of medication should not cause
these symptoms.
DOSAGE AND ADMINISTRATION
For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is
recommended. Dosage may subsequently be increased or decreased at appropriate intervals and
according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day.
In more severely ill patients higher doses may be required with subsequent gradual increase to
300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a
dose of 300 mg/day.
In patients with very mild symptomatology or emotional symptoms accompanying organic
disease, lower doses may suffice. Some of these patients have been controlled on doses as low as
25–50 mg/day.
The total daily dosage of SINEQUAN may be given on a divided or once-a-day dosage schedule.
If the once-a-day schedule is employed, the maximum recommended dose is
150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for
maintenance therapy only and is not recommended for initiation of treatment.
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Anti-anxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect
may not be evident for two to three weeks.
OVERDOSAGE
Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including
alcohol) is common in deliberate tricyclic antidepressant 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
antidepressant overdose; therefore, hospital monitoring is required as soon as possible.
Manifestations: 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 antidepressant toxicity.
Other signs of overdose may include: confusion, disturbed concentration, transient visual
hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity,
vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE
REACTIONS.
Deaths have been reported involving overdoses of doxepin.
General Recommendations:
General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s
airway, establish an intravenous line and initiate gastric decontamination. A minimum of six
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 strongly
advised. If signs of toxicity occur at any time during this period, extended monitoring is
recommended. 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 antidepressant 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
mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate
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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
antidepressant 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.
HOW SUPPLIED
SINEQUAN is available as capsules containing doxepin HCl equivalent to:
10 mg– 100’s
(NDC 0049-5340-66)
25 mg– 100’s
(NDC 0049-5350-66)
50 mg– 100’s
(NDC 0049-5360-66)
75 mg– 100’s
(NDC 0049-5390-66)
100 mg– 100’s
(NDC 0049-5380-66)
150 mg– 50’s
(NDC 0049-5370-50)
SINEQUAN Oral Concentrate is available in 120 mL bottles (NDC 0049-5100-47) with an
accompanying dropper calibrated at 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. Each mL contains
doxepin HCl equivalent to 10 mg doxepin. Just prior to administration, SINEQUAN Oral
Concentrate should be diluted with approximately 120 mL of water, whole or skimmed milk, or
orange, grapefruit, tomato, prune or pineapple juice. SINEQUAN Oral Concentrate is not
physically compatible with a number of carbonated beverages. For those patients requiring
antidepressant therapy who are on methadone maintenance, SINEQUAN Oral Concentrate and
methadone syrup can be mixed together with Gatorade®, lemonade, orange juice, sugar water,
Tang®, or water; but not with grape juice. Preparation and storage of bulk dilutions is not
recommended.
Rx only
11
Reference ID: 3592606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Distributed by:
Roerig
Division of Pfizer Inc, NY, NY 10017
LAB-0072-10.0
June 2014
12
Reference ID: 3592606
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
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
•
an extreme increase in activity and
• attempts to commit suicide
talking (mania)other unusual changes
• new or worse depression
in behavior or mood
• new or worse anxiety
•
Visual problems
• feeling very agitated or restless
•
eye pain
• panic attacks
•
changes in vision
• trouble sleeping (insomnia)
•
swelling or redness in or
• new or worse irritability
around the eye
• acting aggressive, being angry, or
Only some people are at risk for
violent
these problems. You may want to
• acting on dangerous impulses
undergo an eye examination to
13
Reference ID: 3592606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
see if you are at risk and receive
preventative treatment if you are.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
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.
Revised June 2014
2
Reference ID: 3592606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:14.278037
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016798s056,017516s025lbl.pdf', 'application_number': 17516, 'submission_type': 'SUPPL ', 'submission_number': 25}
|
11,009
|
RETIN-A®
Cream Gel Liquid
(tretinoin)
For Topical Use Only
Prescribing Information
Description: RETIN-A Gel, Cream, and Liquid, containing tretinoin are used for the topical treatment of acne
vulgaris. RETIN-A Gel contains tretinoin (retinoic acid, vitamin A acid) in either of two strengths, 0.025% or
0.01% by weight, in a gel vehicle of butyl alcohol, hydroxypropyl cellulose and alcohol (denatured with tert-
butylated hydroxytoluene, and brucine sulfate) 90% w/w. RETIN-A (tretinoin) Cream contains tretinoin in either of
three strengths, 0.1%, 0.05%, or 0.025% by weight, in a hydrophilic cream vehicle of stearic acid, isopropyl
myristate, polyoxyl 40 stearate, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified
water. RETIN-A Liquid contains tretinoin 0.05% by weight, polyethylene glycol 400, butylated hydroxytoluene and
alcohol (denatured with tert-butyl alcohol and brucine sulfate) 55%. Chemically, tretinoin is all-trans-retinoic acid
and has the following structure:
Leave space for structure.
Clinical Pharmacology: Although the exact mode of action of tretinoin is unknown, current evidence suggests
that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation.
Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing
extrusion of the comedones.
Indications and Usage: RETIN-A is indicated for topical application in the treatment of acne vulgaris. The safety
and efficacy of the long-term use of this product in the treatment of other disorders have not been established.
Contraindications: Use of the product should be discontinued if hypersensitivity to any of the ingredients is
noted.
Warnings: GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out
of reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Precautions: General: If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication
should be discontinued. Exposure to sunlight, including sunlamps, should be minimized during the use of RETIN-
A, and patients with sunburn should be advised not to use the product until fully recovered because of heightened
susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun
exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of
sunscreen products and protective clothing over treated areas is recommended when exposure cannot be avoided.
Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin.
RETIN-A (tretinoin) acne treatment should be kept away from the eyes, the mouth, angles of the nose, and mucous
membranes. Topical use may induce severe local erythema and peeling at the site of application. If the degree of
local irritation warrants, patients should be directed to use the medication less frequently, discontinue use
temporarily, or discontinue use altogether. Tretinoin has been reported to cause severe irritation on eczematous skin
and should be used with utmost caution in patients with this condition.
Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and
cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or
lime should be used with caution because of possible interaction with tretinoin. Particular caution should be
exercised in using preparations containing sulfur, resorcinol, or salicylic acid with RETIN-A. It also is advisable to
“rest” a patient’s skin until the effects of such preparations subside before use of RETIN-A is begun.
Carcinogenesis, Mutagenesis, Impairment to Fertility: In a 91-week dermal study in which CD-1 mice were
administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in
the treatment area were observed in some female mice. A dose-related incidence of liver tumors in male mice was
observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035%
formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human
systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear
because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because
they were within the background natural occurrence rate for these tumors in this strain of mice. There was no
evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times
the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the
animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of 0.1%
RETIN-A applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential
of carcinogenic doses of UVB and UVA light form a solar simulator. This effect has been confirmed in a later study
in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05%
tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to
sunlight or artificial ultraviolet irradiation sources.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay,
both of which were negative.
In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant)
decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose
adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of
nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose adjusted for
total body surface area) and above were observed. A dermal Segment III study with RETIN-A has not been
performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of
neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (16 times the human topical does
adjusted for total body surface area).
Pregnancy: Teratogenic effects. Pregnancy Category C. Oral tretinoin has been shown to be teratogenic in rats,
mice, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or
topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose adjusted for total body
surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the
cynomolgus monkey, which metabolically is closer to humans for tretinoin than the other species examined, fetal
malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times
the maximum human systemic does adjusted for total body surface area), although increased skeletal variations were
observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have
also been reported in pigtail macaques.
Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity
(shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal
incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (3.3 times
the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head
and hydrocephaly, typical of retinoid-induced fetal malformations in this species.
In contrast, several well-controlled animals studies have shown that dermally applied tretinoin may be fetoxic, but
not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (8 times the maximum
human systemic does adjusted for total body surface area in both species).
With widespread use of any drug, a small number of birth defect reports associated temporally with the
administration of the drug would be expected by chance alone. Thirty human cases of temporally associated
congenital malformations have been reported during two decades of clinical use of RETIN-A. Although no definite
pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe
the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the
forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.
Nonteratogenic effects:
Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum
human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting
in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (20 times the
maximum human systemic dose adjusted for total body surface area).
There are, however, no adequate and well-controlled studies in pregnant women. Tretinoin should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: 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 RETIN-A is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 12 have not been established.
Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of
RETIN-A did not include sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse Reactions: The skin of certain sensitive individuals may become excessively red, edematous, blistered,
or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is
restored, or the medication should be adjusted to a level the patient can tolerate. True contact allergy to topical
tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application
of RETIN-A. Some individuals have been reported to have heightened susceptibility to sunlight while under
treatment with RETIN-A. To date, all adverse effects of RETIN-A have been reversible upon discontinuance of
therapy (see Dosage and Administration Section).
Overdosage: If medication is applied excessively, no more rapid or better results will be obtained and marked
redness, peeling, or discomfort may occur. Oral ingestion of the drug may lead to the same side effects as those
associated with excessive oral intake of Vitamin A.
Dosage and Administration: RETIN-A Gel, Cream or Liquid should be applied once a day, before retiring, to the
skin where acne lesions appear, using enough to cover the entire affected area lightly. Liquid: the liquid may be
applied using a fingertip, gauze pad, or cotton swab. If gauze or cotton is employed, care should be taken not to
oversaturate it, to the extent that the liquid would run into areas where treatment is not intended. Gel: Excessive
application results in “pilling” of the gel, which minimizes the likelihood of over application by the patient.
Application may cause a transitory feeling of warmth or slight stinging. In cases where it has been necessary to
temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or frequency of
application increased when the patients become able to tolerate the treatment.
Alteration of vehicle, drug concentration, or dose frequency should be closely monitored by careful observation of
the clinical therapeutic response and skin tolerance.
During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. This is due to the
action of the medication on deep, previously unseen lesions and should not be considered a reason to discontinue
therapy.
Therapeutic results should be noticed after two to three weeks but more than six weeks of therapy may be required
before definite beneficial effects are seen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Once the acne lesions have responded satisfactorily, it may be possible to maintain the improvement with less
frequent applications, or other dosage forms.
Patients treated with RETIN-A (tretinoin) acne treatment may use cosmetics, but the area to be treated should be
cleansed thoroughly before the medication is applied. (See Precautions)
How Supplied:
RETIN-A (tretinoin) is supplied as:
RETIN-A Cream
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0165-01
0.025% Cream
20g
0062-0165-02
0.025% Cream
45g
0062-0175-12
0.05% Cream
20g
0062-0175-13
0.05% Cream
45g
0062-0275-23
0.1% Cream
20g
0062-0275-01
0.1% Cream
45g
RETIN-A Gel
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0575-44
0.01% Gel
15g
0062-0575-46
0.01% Gel
45g
0062-0475-42
0.025% Gel
15g
0062-0475-45
0.025% Gel
45g
RETIN-A Liquid
NDC Code
RETIN-A
Strength/Form
RETIN-A
Qty.
0062-0075-07
0.05% Liquid
28 mL
Storage Conditions: RETIN-A Liquid, 0.05%, and RETIN-A Gel, 0.025% and 0.01%: store below 86°F. RETIN-
A Cream, 0.1%, 0.05%, and 0.025%: store below 80°F.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETIN-A®
PATIENT INSTRUCTIONS Cream Gel Liquid
(tretinoin)
Acne Treatment
For Topical Use Only
IMPORTANT
Read Directions Carefully Before Using
THIS LEAFLET TELLS YOU ABOUT RETIN-A (TRETINOIN) ACNE TREATMENT AS PRESCRIBED
BY YOUR PHYSICIAN. THIS PRODUCT IS TO BE USED ONLY ACCORDING TO YOUR DOCTOR’S
INSTRUCTIONS, AND IT SHOULD NOT BE APPLIED TO OTHER AREAS OF THE BODY OR TO
OTHER GROWTHS OR LESIONS. THE LONG-TERM SAFETY AND EFFECTIVENESS OF THIS
PRODUCT IN OTHER DISORDERS HAVE NOT BEEN EVALUATED. IF YOU HAVE ANY
QUESTIONS, BE SURE TO ASK YOUR DOCTOR.
WARNINGS
RETIN- A GELS ARE FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING USE. Keep out of
reach of children. Keep tube tightly closed. Do not expose to heat or store at temperatures above 120°F (49°C).
PRECAUTIONS
The effects of the sun on your skin. As you know, overexposure to natural sunlight or the artificial sunlight of a
sunlamp can cause sunburn. Overexposure to the sun over many years may cause premature aging of the skin and
even skin cancer. The chance of these effects occurring will vary depending on skin type, the climate and the care
taken to avoid overexposure to the sun. Therapy with RETIN-A may make your skin more susceptible to sunburn
and other adverse effects of the sun, so unprotected exposure to natural or artificial sunlight should be minimized.
Laboratory findings. When laboratory mice are exposed to artificial sunlight, they often develop skin tumors.
These sunlight-induced tumors may appear more quickly and in greater number if the mouse is also topically treated
with the active ingredient in RETIN-A, tretinoin. In some studies, under different conditions, however, when mice
treated with tretinoin were exposed to artificial sunlight, the incidence and rate of development of skin tumors was
reduced. There is no evidence to date that tretinoin alone will cause the development of skin tumors in either
laboratory animals or humans. However, investigations in this area are continuing.
Use caution in the sun. When outside, even on hazy days, areas treated with RETIN-A should be protected. An
effective sunscreen should be used any time you are outside (consult your physician for a recommendation of an
SPF level which will provide you with the necessary high level of protection). For extended sun exposure,
protective clothing, like a hat, should be worn. Do not use artificial sunlamps while you are using RETIN-A. If you
do become sunburned, stop your therapy with RETIN-A until your skin has recovered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoid excessive exposure to wind or cold. Extremes of climate tend to dry or burn normal skin. Skin treated
with RETIN-A may be more vulnerable to these extremes. Your physician can recommend ways to manage your
acne treatment under such conditions.
Possible problems. The skin of certain sensitive individuals may become excessively red, swollen, blistered or
crusted. If you are experiencing severe or persistent irritation, discontinues the use of RETIN-A and consult your
physician.
There have been reports that, in some patients, areas treated with RETIN-A developed a temporary increase or
decrease in the amount of skin pigment (color) present. The pigment in these areas returned to normal either when
the skin was allowed to adjust to RETIN-A or therapy was discontinued.
Use other medication only on your physician’s advice. Only your physician knows which other medications
may be helpful during treatment and will recommend them to you if necessary. Follow the physician’s instructions
carefully. In addition, you should avoid preparations that may dry or irritate your skin. These preparations may
include certain astringents, toiletries containing alcohol, spices or lime, or certain medicated soaps, shampoos and
hair permanent solutions. Do not allow anyone else to use this medication.
Do not use other medications with RETIN-A which are not recommended by your doctor. The medications you
have used in the past might cause unnecessary redness or peeling.
If you are pregnant, think you are pregnant or are nursing an infant: No studies have been conducted in
humans to establish the safety of RETIN-A in pregnant women. If you are pregnant, think you are pregnant, or are
nursing a baby, consult your physician before using the medication.
AND WHILE YOU’RE ON RETIN-A THERAPY
Use a mild, non-medicated soap. Avoid frequent washings and harsh scrubbing. Acne isn’t caused by dirt, so no
matter how hard you scrub, you can’t wash it away. Washing too frequently or scrubbing too roughly may at times
actually make your acne worse. Wash your skin gently with a mild bland soap. (Two or three times a day should be
sufficient). Pat skin dry with a towel. Let the face dry 20-30 minutes before applying RETIN-A. Remember,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
excessive irritation such as rubbing, too much washing, use of other medications not suggested by your physician,
etc., may worsen your acne.
HOW TO USE RETIN-A (TRETINOIN)
To get the best results with RETIN-A therapy, it is necessary to use it properly. Forget about the instructions given
for other products and the advice of friends. Just stick to the special plan your doctor has laid out for you and be
patient. Remember, when RETIN-A is used properly, many users see improvement by 12 weeks. AGAIN,
FOLLOW INSTRUCTIONS - BE PATIENT - DON’T START AND STOP THERAPY ON YOUR OWN - IF
YOU HAVE QUESTIONS, ASK YOU DOCTOR.
To help you use the medication correctly, keep these simple instructions in mind.
(Insert picture)
•
Apply RETIN-A once daily before bedtime, or as directed by your physician. Your physician may advise,
especially if your skin is sensitive, that you start your therapy by applying RETIN-A every other night. First,
wash with a mild soap and dry your skin gently. WAIT 20 TO 30 MINUTES BEFORE APPLYING
MEDICATION; it is important for skin to be completely dry in order to minimize possible irritation.
•
It is better not to use more than the amount suggested by your physician or to apply more frequently than
instructed. Too much may irritate the skin, waste medication and won’t give faster or better results.
•
Keep the medication away from the corners of the nose, mouth, eyes and open wounds. Spread away from
these areas when applying.
•
RETIN-A Cream: Squeeze about a half inch or less of medication onto the fingertip. While that should be
enough for your whole face, after you have some experience with the medication you may find you need
slightly more or less to do the job. The medication should become invisible almost immediately. If it is still
visible, you are using too much. Cover the affected area lightly with RETIN-A (tretinoin cream) Cream by first
dabbing it on your forehead, chin and both cheeks, then spreading it over the entire affected area. Smooth
gently into the skin.
•
RETIN-A Gel: Squeeze about a half inch or less of medication onto the fingertip. While that should be enough
for your whole face, after you have some experience with the medication you may find you need slightly more
or less to do the job. The medication should become invisible almost immediately. If it is still visible, or if dry
flaking occurs from the gel within a minute or so, you are using too much. Cover the affected area lightly with
RETIN-A (tretinoin gel) Gel by first dabbing it on your forehead, chin and both cheeks, then spreading it over
the entire affected are. Smooth gently into the skin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
RETIN-A Liquid. RETIN-A (tretinoin liquid) Liquid may be applied to the skin where acne lesions appear,
spreading the medication over the entire affected area, using a fingertip, gauze pad, or cotton swab. If gauze or
cotton is employed, care should be taken not to oversaturate it to the extent that the liquid would run into area
where treatment is not intended (such as corners of the mouth, eyes, and nose).
•
It is recommended that you apply a moisturizer or a moisturizer with sunscreen that will not aggravate your
acne (noncomedogenic) every morning after you wash.
WHAT TO EXPECT WITH YOUR NEW TREATMENT
RETIN-A works deep inside your skin and this takes time. You cannot make RETIN-A work any faster by applying
more than one dose each day, but an excess amount of RETIN-A may irritate your skin. Be patient.
There may be some discomfort or peeling during the early days of treatment. Some patients also notice that their
skin begins to take on a blush.
These reactions do not happen to everyone. If they do, it is just your skin adjusting to RETIN-A and this usually
subsides within two to four weeks. These reactions can usually be minimized by following instructions carefully.
Should the effects become excessively troublesome, consult your doctor.
BY THREE TO SIX WEEKS, some patients notice an appearance of new blemishes (papules and pustules). At
this stage it is important to continue using RETIN-A.
If RETIN-A is going to have a beneficial effect for you, you should notice a continued improvement in your
appearance after 6 to 12 weeks of therapy. Don’t be discouraged if you see no immediate improvement. Don’t stop
treatment at the first signs of improvement.
Once your acne is under control you should continue regular application of RETIN-A until your physician instructs
otherwise.
IF YOU HAVE QUESTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All questions of a medical nature should be taken up with your doctor. For more information about RETIN-A
(tretinoin), call our toll-free number: 800-426-7762. Call between 9:00 a.m. and 3:00 p.m. Eastern Time, Monday
through Friday.
Ortho Dermatological
(new logo)
Division of Ortho-McNeil Pharmaceutical, Inc.
Skillman, New Jersey 08558
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/
---------------------
Markham Luke
6/10/02 11:40:52 AM
Acting for Dr. Jonathan Wilkin, Division Director, DDDDP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:14.567065
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/16921s21s22s25lbl.pdf', 'application_number': 17522, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
11,011
|
Tigan®
(trimethobenzamide hydrochloride)
Capsules/Suppositories/Injectable
DESCRIPTION
Chemically, trimethobenzamide HCl is N-[p-[2-(dimethylamino)ethoxy]benzyl]-
3,4,5-trimethoxybenz- amide monohydrochloride. It has a molecular weight of
424.93 and the following structural formula:
(CH3)2N-CH2CH2O
CH2NHC
OCH3
OCH3
OCH3
O
• HCl
Capsules: Each 300-mg Tigan® capsule for oral use contains
trimethobenzamide hydrochloride equivalent to 300 mg. The capsule has an
opaque purple cap marked “Tigan” and an opaque purple body marked “M079”.
Inactive Ingredients: D&C Red No. 28, FD&C Blue No. 1, lactose, magnesium
stearate, starch and titanium dioxide.
Suppositories (200 mg): Each suppository contains 200 mg trimethobenzamide
hydrochloride and 2% benzocaine in a base compounded with polysorbate 80,
white beeswax and propylene glycol monostearate.
Suppositories, Pediatric (100 mg): Each suppository contains 100 mg
trimethobenzamide hydrochloride and 2% benzocaine in a base compounded
with polysorbate 80, white beeswax and propylene glycol monostearate.
Single-Dose Vials: Each 2-mL single-dose vial contains 200 mg
trimethobenzamide hydrochloride compounded with 1 mg sodium citrate and 0.4
mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium
hydroxide.
Multi-Dose Vials: Each mL contains 100 mg trimethobenzamide hydrochloride
compounded with 0.45% phenol as preservative, 0.5 mg sodium citrate and 0.2
mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium
hydroxide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Tigan® as determined in animals is obscure, but may
involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata
through which emetic impulses are conveyed to the vomiting center; direct
impulses to the vomiting center apparently are not similarly inhibited. In dogs
pretreated with trimethobenzamide HCl, the emetic response to apomorphine is
inhibited, while little or no protection is afforded against emesis induced by
intragastric copper sulfate.
Pharmacokinetics
The pharmacokinetics of trimethobenzamide have been studied in healthy adult
subjects. Following administration of 200 mg (100 mg/mL) Tigan I.M. injection,
the time to reach maximum plasma concentration (Tmax) was about half an hour,
about 15 minutes longer for Tigan 300 mg oral capsule than an I.M. injection. A
single dose of Tigan 300 mg oral capsule provided a plasma concentration profile
of trimethobenzamide similar to Tigan 200 mg I.M. The relative bioavailability of
the capsule formulation compared to the solution is 100%. The mean elimination
half-life of trimethobenzamide is 7 to 9 hours.
Special Populations
Gender
Systemic exposure to trimethobenzamide was similar between men (N=40) and
women (N=28).
Race
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African
Americans (N=12).
INDICATIONS
Tigan® is indicated for the treatment of postoperative nausea and vomiting and
for nausea associated with gastroenteritis.
CONTRAINDICATIONS
Use of the injectable form of Tigan® in children, the suppositories in premature or
newborn infants, and use of any dosage form in patients with known
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hypersensitivity to trimethobenzamide are contraindicated. Since the
suppositories contain benzocaine they should not be used in patients known to
be sensitive to this or similar local anesthetics.
WARNINGS
Caution should be exercised when administering Tigan® to children for the
treatment of vomiting. Antiemetics are not recommended for treatment of
uncomplicated vomiting in children and their use should be limited to prolonged
vomiting of known etiology. There are two principal reasons for caution:
1. The extrapyramidal symptoms which can occur secondary to Tigan® may be
confused with the central nervous system signs of an undiagnosed primary
disease responsible for the vomiting, e.g., Reye’s syndrome or other
encephalopathy.
2. It has been suspected that drugs with hepatotoxic potential, such as Tigan®,
may unfavorably alter the course of Reye’s syndrome. Such drugs should
therefore be avoided in children whose signs and symptoms (vomiting) could
represent Reye’s syndrome.
Tigan® may produce drowsiness. Patients should not operate motor vehicles or
other dangerous machinery until their individual responses have been
determined.
Usage in Pregnancy: Trimethobenzamide hydrochloride was studied in
reproduction experiments in rats and rabbits and no teratogenicity was
suggested. The only effects observed were an increased percentage of
embryonic resorptions or stillborn pups in rats administered 20 mg and 100
mg/kg and increased resorptions in rabbits receiving 100 mg/kg. In each study
these adverse effects were attributed to one or two dams. The relevance to
humans is not known. Since there is no adequate experience in pregnant or
lactating women who have received this drug, safety in pregnancy or in nursing
mothers has not been established.
Usage with Alcohol: Concomitant use of alcohol with Tigan® may result in an
adverse drug interaction.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
During the course of acute febrile illness, encephalitides, gastroenteritis,
dehydration and electrolyte imbalance, especially in children and the elderly or
debilitated, CNS reactions such as opisthotonos, convulsions, coma and
extrapyramidal symptoms have been reported with and without use of Tigan®
(trimethobenzamide hydrochloride) or other antiemetic agents. In such disorders
caution should be exercised in administering Tigan®, particularly to patients who
have recently received other CNS-acting agents (phenothiazines, barbiturates,
belladonna derivatives). Primary emphasis should be directed toward the
restoration of body fluids and electrolyte balance, the relief of fever and relief of
the causative disease process. Overhydration should be avoided since it may
result in cerebral edema.
The antiemetic effects of Tigan® may render diagnosis more difficult in such
conditions as appendicitis and obscure signs of toxicity due to overdosage of
other drugs.
ADVERSE REACTIONS
There have been reports of hypersensitivity reactions and Parkinson-like
symptoms. There have been instances of hypotension reported following
parenteral administration to surgical patients. There have been reports of blood
dyscrasias, blurring of vision, coma, convulsions, depression of mood, diarrhea,
disorientation, dizziness, drowsiness, headache, jaundice, muscle cramps and
opisthotonos. If these occur, the administration of the drug should be
discontinued. Allergic-type skin reactions have been observed; therefore, the
drug should be discontinued at the first sign of sensitization. While these
symptoms will usually disappear spontaneously, symptomatic treatment may be
indicated in some cases.
DOSAGE AND ADMINISTRATION
(See WARNINGS and PRECAUTIONS.)
Dosage should be adjusted according to the indication for therapy, severity of
symptoms and the response of the patient.
CAPSULES, 300 mg
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Usual Adult Dosage
One 300 mg capsule t.i.d. or q.i.d.
SUPPOSITORIES, 200 mg (not to be used in premature or newborn infants)
Usual Adult Dosage
One suppository (200 mg) t.i.d. or q.i.d.
Usual Children's Dosage
Under 30 lbs: One-half suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One-half to one suppository (100 to 200 mg) t.i.d. or
q.i.d.
SUPPOSITORIES, PEDIATRIC, 100 mg (not to be used in premature or
newborn infants)
Usual Children's Dosage
Under 30 lbs: One suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One to two suppositories (100 to 200 mg) t.i.d. or q.i.d.
INJECTABLE, 100 mg/mL (not for use in children)
Usual Adult Dosage
2 mL (200 mg) t.i.d. or q.i.d. intramuscularly.
NOTE: The injectable form is intended for intramuscular administration only; it is
not recommended for intravenous use.
Intramuscular administration may cause pain, stinging, burning, redness and
swelling at the site of injection. Such effects may be minimized by deep injection
into the upper outer quadrant of the gluteal region, and by avoiding the escape of
solution along the route.
Rx Only
STORAGE
Store at 25°C (77°F).
Excursions permitted to 15–30°C (59–86°F).
[See USP Controlled Room Temperature]
HOW SUPPLIED
Capsules, 300 mg trimethobenzamide hydrochloride each, bottles of 100 and
500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 61570-079-01 300 mg 100’s
NDC 61570-079-05 300 mg 500’s
Suppositories, Pediatric, 100 mg, boxes of 10
Suppositories, 200 mg, boxes of 10 and 50
NDC 61570-503-10 100 mg (box of 10)
NDC 61570-504-10 200 mg (box of 10)
NDC 61570-504-50 200 mg (box of 50)
Single-Dose Vials, 2 mL , trays of 25
NDC 61570-543-25 200 mg/mL in 2 mL Single-Dose Vials
Multi-Dose Vials, 20 mL
NDC 61570-541-20 100 mg/mL in 20 mL Multi-Dose Vials
Prescribing Information as of November 2004.
Distributed By: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Manufactured By: King Pharmaceuticals, Inc., Bristol, TN 37620
Rev. 11/04
3000437
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 61570-543-25
25 x 2 mL Single-Dose Vials
Injection
200 mg/2mL
Tigan Steri-Vial 2 mL
3-5/32"L x 3-5/32"W x 1-25/64"H
Tray, 25 pack
3000358
X
PMS
280 Blue
PMS
Black
Unvarnished
Area
Tigan®
(trimethobenzamide HCl)
NOT FOR USE IN CHILDREN.
FOR I.M. USE ONLY (preferably by deep IM Injection).
Each 2 mL of solution contains 200 mg trimethobenzamide hydrochloride com-
pounded with 1 mg sodium citrate and 0.4 mg citric acid as buffers, and sodium
hydroxide to adjust pH to approximately 5.0.
Dosage: See accompanying prescribing information.
Store at 25° C (77° F) (see insert).
Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Manufactured by: King Pharmaceuticals, Inc., Bristol, TN 37620
Lot and exp. date
3000358
998
FPO
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b)(4)
(b)(4)
Supplier to insert
live RSS bar code
(01)0036157054301.
NDC 61570-543-01
200 mg/2 mL
Tigan
®
(trimethobenzamide HCl)
Injection
For IM Use Only
Not for Use in Children
Dist. by: Monarch
Pharmaceuticals, Inc.
Bristol, TN 37620
(A wholly owned
subsidiary of King
Pharmaceuticals, Inc.)
Tigan Steri-Vial 2 mL
1-3/4" x 9/16"
Label
3000349
n/a
PMS
280 Blue
PMS
Black
Unvarnished
Area
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b)(4)
(b)(4)
|
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2025-02-12T13:44:14.928094
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017530s021,022,023lbl.pdf', 'application_number': 17530, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
11,013
|
NDA 17-530/S-024
Page 3
Tigan®
(trimethobenzamide hydrochloride)
Injectable
For Intramuscular Use Only
Not for Use in Pediatric Patients
DESCRIPTION
Chemically,
trimethobenzamide
HCl
is
N-[p-[2-(dimethylamino)ethoxy]benzyl]-3,4,5
trimethoxybenzamide monohydrochloride. It has a molecular weight of 424.93 and the
following structural formula: Chemical Structure
Single-Dose Vials: Each 2-mL single-dose vial contains 200 mg trimethobenzamide
hydrochloride compounded with 1 mg sodium citrate and 0.4 mg citric acid as buffers and pH
adjusted to approximately 5.0 with sodium hydroxide.
Multi-Dose Vials: Each mL contains 100 mg trimethobenzamide hydrochloride compounded
with 0.45% phenol as preservative, 0.5 mg sodium citrate and 0.2 mg citric acid as buffers and
pH adjusted to approximately 5.0 with sodium hydroxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Tigan
® as determined in animals is obscure, but may involve the
chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic
impulses are conveyed to the vomiting center; direct impulses to the vomiting center
apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide HCl, the
emetic response to apomorphine is inhibited, while little or no protection is afforded against
emesis induced by intragastric copper sulfate.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-530/S-024
Page 4
Pharmacokinetics
The pharmacokinetics of trimethobenzamide have been studied in healthy adult subjects.
Following administration of 200 mg (100 mg/mL) Tigan I.M. injection, the time to reach
maximum plasma concentration (Tmax) was about half an hour, about 15 minutes longer for
Tigan 300 mg oral capsule than an I.M. injection. A single dose of Tigan 300 mg oral capsule
provided a plasma concentration profile of trimethobenzamide similar to Tigan 200 mg I.M.
The relative bioavailability of the capsule formulation compared to the solution is 100%. The
mean elimination half-life of trimethobenzamide is 7 to 9 hours. Between 30 – 50% of a single
dose in humans is excreted unchanged in the urine within 48 – 72 hours. The metabolic
disposition of trimethobenzamide in humans is not known. Specifically, it is not known if
active metabolites are generated in humans.
Special Populations
Age
The clearance of trimethobenzamide is not known in patients with renal impairment.
However, it may be advisable to consider reduction in the dosing of trimethobenzamide in
elderly patients with renal impairment considering that a substantial amount of excretion and
elimination of trimethobenzamide occurs via the kidney and that elderly patients may have
various degrees of renal impairment. (See PRECAUTIONS: General and DOSAGE AND
ADMINISTRATION).
Gender
Systemic exposure to trimethobenzamide was similar between men (N=40) and women
(N=28).
Race
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans
(N=12).
Renal Impairment
The clearance of trimethobenzamide is not known in patients with renal impairment.
However, it may be advisable to consider reduction in the dosing of trimethobenzamide in
patients with renal impairment considering that a substantial amount of excretion and
elimination of trimethobenzamide occurs via the kidney. (See PRECAUTIONS: General and
DOSAGE AND ADMINISTRATION).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-530/S-024
Page 5
INDICATIONS
Tigan
® is indicated for the treatment of postoperative nausea and vomiting and for nausea
associated with gastroenteritis.
CONTRAINDICATIONS
The injectable form of Tigan
® is contraindicated in pediatric patients and in patients with
known hypersensitivity to trimethobenzamide.
WARNINGS
Tigan
® may produce drowsiness. Patients should not operate motor vehicles or other
dangerous machinery until their individual responses have been determined.
Usage in Pregnancy: Trimethobenzamide hydrochloride was studied in reproduction
experiments in rats and rabbits and no teratogenicity was suggested. The only effects
observed were an increased percentage of embryonic resorptions or stillborn pups in rats
administered 20 mg and 100 mg/kg and increased resorptions in rabbits receiving 100 mg/kg.
In each study these adverse effects were attributed to one or two dams. The relevance to
humans is not known. Since there is no adequate experience in pregnant or lactating women
who have received this drug, safety in pregnancy or in nursing mothers has not been
established.
Usage with Alcohol: Concomitant use of alcohol with Tigan
® may result in an adverse drug
interaction.
PRECAUTIONS
During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and
electrolyte imbalance, especially in children and the elderly or debilitated, CNS reactions
such as opisthotonos, convulsions, coma and extrapyramidal symptoms have been reported
with and without use of Tigan
® (trimethobenzamide hydrochloride) or other antiemetic agents.
In such disorders caution should be exercised in administering Tigan
®, particularly to patients
who have recently received other CNS-acting agents (phenothiazines, barbiturates,
belladonna derivatives). Primary emphasis should be directed toward the restoration of body
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-530/S-024
Page 6
fluids and electrolyte balance, the relief of fever and relief of the causative disease process.
Overhydration should be avoided since it may result in cerebral edema.
The antiemetic effects of Tigan
® may render diagnosis more difficult in such conditions as
appendicitis and obscure signs of toxicity due to overdosage of other drugs.
General
Adjustment of Dose in Renal Failure
A substantial route of elimination of unchanged trimethobenzamide is via the kidney. Dosage
adjustment should be considered in patients with reduced renal function including some
elderly
patients.
(See
CLINICAL
PHARMACOLOGY
and
DOSAGE
AND
ADMINISTRATION).
Geriatric Use
Clinical studies of trimethobenzamide hydrochloride did not include sufficient numbers of
patients aged 65 and over to determine whether they respond differently from younger
patients. Although there are studies reported in the literature that included elderly patients
>65 years old with younger patients, it is not known if there are differences in efficacy or
safety parameters for elderly and non-elderly patients treated with trimethobenzamide. 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. (See CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION).
ADVERSE REACTIONS
There have been reports of hypersensitivity reactions and Parkinson-like symptoms. There
have been instances of hypotension reported following parenteral administration to surgical
patients. There have been reports of blood dyscrasias, blurring of vision, coma, convulsions,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-530/S-024
Page 7
depression of mood, diarrhea, disorientation, dizziness, drowsiness, headache, jaundice,
muscle cramps and opisthotonos. If these occur, the administration of the drug should be
discontinued. Allergic-type skin reactions have been observed; therefore, the drug should be
discontinued at the first sign of sensitization. While these symptoms will usually disappear
spontaneously, symptomatic treatment may be indicated in some cases.
DOSAGE AND ADMINISTRATION
(See WARNINGS and PRECAUTIONS.)
Dosage should be adjusted according to the indication for therapy, severity of symptoms and
the response of the patient.
Geriatric Patients
Dose adjustment such as reducing the total dose administered at each dosing or increasing
the dosing interval should be considered in elderly patients with renal impairment (creatinine
clearance ≤ 70 mL/min/1.73m2). Final dose adjustment should be based upon integration of
clinical efficacy and safety considerations. (See CLINICAL PHARMACOLOGY and
PRECAUTIONS).
Patients with Renal Impairment
In subjects with renal impairment (creatinine clearance ≤ 70 mL/min/1.73m2), dose
adjustment such as reducing the total dose administered at each dosing or increasing the
dosing interval should be considered. (See CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION).
INJECTABLE, 100 mg/mL (Not for use in pediatric patients)
Usual Adult Dosage
2 mL (200 mg) t.i.d. or q.i.d. intramuscularly.
NOTE: The injectable form is intended for intramuscular administration only; it is not
recommended for intravenous use.
Intramuscular administration may cause pain, stinging, burning, redness and swelling at the
site of injection. Such effects may be minimized by deep injection into the upper outer
quadrant of the gluteal region, and by avoiding the escape of solution along the route.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-530/S-024
Page 8
STORAGE
Store at 25°C (77°F).
Excursions permitted to 15-30°C (59-86°F).
[See USP Controlled Room Temperature]
HOW SUPPLIED
Single-Dose Vials, 2 mL, trays of 25
NDC 42023-119-25 100 mg/mL in 2 mL Single-Dose Vials
Multi-Dose Vials, 20 mL
NDC 42023-118-01 100 mg/mL in 20 mL Multi-Dose Vials
Rx Only
Prescribing Information as of January 2008.
Manufactured and Distributed by:
JHP Pharmaceuticals, LLC
Rochester, MI 48307
3000358D
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:14.930791
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017530s024lbl.pdf', 'application_number': 17530, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
11,010
|
NDA 17-531/S-010
Tigan®
(trimethobenzamide hydrochloride)
Capsules/Suppositories/Injectable
DESCRIPTION
Chemically, trimethobenzamide HCl is N-[p-[2-(dimethylamino)ethoxy]benzyl]-3,4,5-trimethoxybenzamide
monohydrochloride. It has a molecular weight of 424.93 and the following structural formula:
(CH3)2N-CH2CH2O
CH2NHC
OCH3
OCH3
OCH3
O
• HCl
Capsules: Each 300-mg Tigan® capsule for oral use contains trimethobenzamide hydrochloride equivalent to 300 mg. The
capsule has an opaque purple cap marked “Tigan” and an opaque purple body marked “M079”.
Inactive Ingredients: D&C Red No. 28, FD&C Blue No. 1, lactose, magnesium stearate, starch and titanium dioxide.
Suppositories (200 mg): Each suppository contains 200 mg trimethobenzamide hydrochloride and 2% benzocaine in a base
compounded with polysorbate 80, white beeswax and propylene glycol monostearate.
Suppositories, Pediatric (100 mg): Each suppository contains 100 mg trimethobenzamide hydrochloride and 2%
benzocaine in a base compounded with polysorbate 80, white beeswax and propylene glycol monostearate.
Ampuls: Each 2-mL ampul contains 200 mg trimethobenzamide hydrochloride compounded with 0.2% parabens (methyl
and propyl) as preservatives, 1 mg sodium citrate and 0.4 mg citric acid as buffers and pH adjusted to approximately 5.0
with sodium hydroxide.
Multi-Dose Vials: Each mL contains 100 mg trimethobenzamide hydrochloride compounded with 0.45% phenol as
preservative, 0.5 mg sodium citrate and 0.2 mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium
hydroxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Tigan® as determined in animals is obscure, but may involve the
chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly
inhibited. In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is
inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate.
Pharmacokinetics
The pharmacokinetics of trimethobenzamide have been studied in healthy adult subjects. Following administration of 200
mg (100 mg/mL) Tigan I.M. injection, the time to reach maximum plasma concentration (Tmax) was about half an hour,
about 15 minutes longer for Tigan 300 mg oral capsule than an I.M. injection. A single dose of Tigan 300 mg oral capsule
provided a plasma concentration profile of trimethobenzamide similar to Tigan 200 mg I.M. The relative bioavailability of
the capsule formulation compared to the solution is 100%. The mean elimination half-life of trimethobenzamide is 7 to 9
hours.
Special Populations
Gender
Systemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28).
Race
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12).
INDICATIONS
Tigan® is indicated for the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis.
CONTRAINDICATIONS
Use of the injectable form of Tigan® in children, the suppositories in premature or newborn infants, and use of any dosage
form in patients with known hypersensitivity to trimethobenzamide are contraindicated. Since the suppositories contain
benzocaine they should not be used in patients known to be sensitive to this or similar local anesthetics.
WARNINGS
Caution should be exercised when administering Tigan® to children for the treatment of vomiting. Antiemetics are not
recommended for treatment of uncomplicated vomiting in children and their use should be limited to prolonged vomiting
of known etiology. There are three principal reasons for caution:
1. The extrapyramidal symptoms which can occur secondary to Tigan® may be confused with the central nervous
system signs of an undiagnosed primary disease responsible for the vomiting, e.g., Reye’s syndrome or other
encephalopathy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
2. It has been suspected that drugs with hepatotoxic potential, such as Tigan®, may unfavorably alter the course of
Reye’s syndrome. Such drugs should therefore be avoided in children whose signs and symptoms (vomiting)
could represent Reye’s syndrome.
Tigan® may produce drowsiness. Patients should not operate motor vehicles or other dangerous machinery until their
individual responses have been determined.
Usage in Pregnancy: Trimethobenzamide hydrochloride was studied in reproduction experiments in rats and rabbits and no
teratogenicity was suggested. The only effects observed were an increased percentage of embryonic resorptions or stillborn
pups in rats administered 20 mg and 100 mg/kg and increased resorptions in rabbits receiving 100 mg/kg. In each study
these adverse effects were attributed to one or two dams. The relevance to humans is not known. Since there is no adequate
experience in pregnant or lactating women who have received this drug, safety in pregnancy or in nursing mothers has not
been established.
Usage with Alcohol: Concomitant use of alcohol with Tigan® may result in an adverse drug interaction.
PRECAUTIONS
During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and electrolyte imbalance, especially in
children and the elderly or debilitated, CNS reactions such as opisthotonos, convulsions, coma and extrapyramidal
symptoms have been reported with and without use of Tigan® (trimethobenzamide hydrochloride) or other antiemetic
agents. In such disorders caution should be exercised in administering Tigan®, particularly to patients who have recently
received other CNS-acting agents (phenothiazines, barbiturates, belladonna derivatives). Primary emphasis should be
directed toward the restoration of body fluids and electrolyte balance, the relief of fever and relief of the causative disease
process. Overhydration should be avoided since it may result in cerebral edema.
The antiemetic effects of Tigan® may render diagnosis more difficult in such conditions as appendicitis and obscure signs of
toxicity due to overdosage of other drugs.
ADVERSE REACTIONS
There have been reports of hypersensitivity reactions and Parkinson-like symptoms. There have been instances of
hypotension reported following parenteral administration to surgical patients. There have been reports of blood dyscrasias,
blurring of vision, coma, convulsions, depression of mood, diarrhea, disorientation, dizziness, drowsiness, headache,
jaundice, muscle cramps and opisthotonos. If these occur, the administration of the drug should be discontinued. Allergic-
type skin reactions have been observed; therefore, the drug should be discontinued at the first sign of sensitization. While
these symptoms will usually disappear spontaneously, symptomatic treatment may be indicated in some cases.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
DOSAGE AND ADMINISTRATION
(See WARNINGS and PRECAUTIONS.)
Dosage should be adjusted according to the indication for therapy, severity of symptoms and the response of the patient.
CAPSULES, 300 mg
Usual Adult Dosage
One 300 mg capsule t.i.d. or q.i.d.
SUPPOSITORIES, 200 mg (not to be used in premature or newborn infants)
Usual Adult Dosage
One suppository (200 mg) t.i.d. or q.i.d.
Usual Children's Dosage
Under 30 lbs: One-half suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One-half to one suppository (100 to 200 mg) t.i.d. or q.i.d.
SUPPOSITORIES, PEDIATRIC, 100 mg (not to be used in premature or newborn infants)
Usual Children's Dosage
Under 30 lbs: One suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One to two suppositories (100 to 200 mg) t.i.d. or q.i.d.
INJECTABLE, 100 mg/mL (not for use in children)
Usual Adult Dosage
2 mL (200 mg) t.i.d. or q.i.d. intramuscularly.
NOTE: The injectable form is intended for intramuscular administration only; it is not recommended for intravenous use.
Intramuscular administration may cause pain, stinging, burning, redness and swelling at the site of injection. Such effects
may be minimized by deep injection into the upper outer quadrant of the gluteal region, and by avoiding the escape of
solution along the route.
Rx Only
STORAGE
Store 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
NDA 17-531/S-010
HOW SUPPLIED
Capsules, 300 mg trimethobenzamide hydrochloride each, bottles of 100 and 500
NDC 61570-079-01 300 mg 100’s
NDC 61570-079-05 300 mg 500’s
Suppositories, Pediatric, 100 mg, boxes of 10
Suppositories, 200 mg, boxes of 10 and 50
NDC 61570-503-10 100 mg (box of 10)
NDC 61570-504-10 200 mg (box of 10)
NDC 61570-504-50 200 mg (box of 50)
Ampuls, 2 mL, boxes of 10
NDC 61570-540-02 100 mg/mL in 2 mL ampul
Multi-Dose Vials, 20 mL
NDC 61570-541-20 100 mg/mL in 20 mL Multi-Dose Vials
Distributed By: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Manufactured By: King Pharmaceuticals, Inc., Bristol, TN 37620
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
Rev. 5/01
0934128
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:14.931407
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/17531s10lbl.pdf', 'application_number': 17530, 'submission_type': 'SUPPL ', 'submission_number': 18}
|
11,012
|
Tigan®
(trimethobenzamide hydrochloride)
Capsules/Suppositories/Injectable
DESCRIPTION
Chemically, trimethobenzamide HCl is N-[p-[2-(dimethylamino)ethoxy]benzyl]-
3,4,5-trimethoxybenz- amide monohydrochloride. It has a molecular weight of
424.93 and the following structural formula:
(CH3)2N-CH2CH2O
CH2NHC
OCH3
OCH3
OCH3
O
• HCl
Capsules: Each 300-mg Tigan® capsule for oral use contains
trimethobenzamide hydrochloride equivalent to 300 mg. The capsule has an
opaque purple cap marked “Tigan” and an opaque purple body marked “M079”.
Inactive Ingredients: D&C Red No. 28, FD&C Blue No. 1, lactose, magnesium
stearate, starch and titanium dioxide.
Suppositories (200 mg): Each suppository contains 200 mg trimethobenzamide
hydrochloride and 2% benzocaine in a base compounded with polysorbate 80,
white beeswax and propylene glycol monostearate.
Suppositories, Pediatric (100 mg): Each suppository contains 100 mg
trimethobenzamide hydrochloride and 2% benzocaine in a base compounded
with polysorbate 80, white beeswax and propylene glycol monostearate.
Single-Dose Vials: Each 2-mL single-dose vial contains 200 mg
trimethobenzamide hydrochloride compounded with 1 mg sodium citrate and 0.4
mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium
hydroxide.
Multi-Dose Vials: Each mL contains 100 mg trimethobenzamide hydrochloride
compounded with 0.45% phenol as preservative, 0.5 mg sodium citrate and 0.2
mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium
hydroxide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Tigan® as determined in animals is obscure, but may
involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata
through which emetic impulses are conveyed to the vomiting center; direct
impulses to the vomiting center apparently are not similarly inhibited. In dogs
pretreated with trimethobenzamide HCl, the emetic response to apomorphine is
inhibited, while little or no protection is afforded against emesis induced by
intragastric copper sulfate.
Pharmacokinetics
The pharmacokinetics of trimethobenzamide have been studied in healthy adult
subjects. Following administration of 200 mg (100 mg/mL) Tigan I.M. injection,
the time to reach maximum plasma concentration (Tmax) was about half an hour,
about 15 minutes longer for Tigan 300 mg oral capsule than an I.M. injection. A
single dose of Tigan 300 mg oral capsule provided a plasma concentration profile
of trimethobenzamide similar to Tigan 200 mg I.M. The relative bioavailability of
the capsule formulation compared to the solution is 100%. The mean elimination
half-life of trimethobenzamide is 7 to 9 hours.
Special Populations
Gender
Systemic exposure to trimethobenzamide was similar between men (N=40) and
women (N=28).
Race
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African
Americans (N=12).
INDICATIONS
Tigan® is indicated for the treatment of postoperative nausea and vomiting and
for nausea associated with gastroenteritis.
CONTRAINDICATIONS
Use of the injectable form of Tigan® in children, the suppositories in premature or
newborn infants, and use of any dosage form in patients with known
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hypersensitivity to trimethobenzamide are contraindicated. Since the
suppositories contain benzocaine they should not be used in patients known to
be sensitive to this or similar local anesthetics.
WARNINGS
Caution should be exercised when administering Tigan® to children for the
treatment of vomiting. Antiemetics are not recommended for treatment of
uncomplicated vomiting in children and their use should be limited to prolonged
vomiting of known etiology. There are two principal reasons for caution:
1. The extrapyramidal symptoms which can occur secondary to Tigan® may be
confused with the central nervous system signs of an undiagnosed primary
disease responsible for the vomiting, e.g., Reye’s syndrome or other
encephalopathy.
2. It has been suspected that drugs with hepatotoxic potential, such as Tigan®,
may unfavorably alter the course of Reye’s syndrome. Such drugs should
therefore be avoided in children whose signs and symptoms (vomiting) could
represent Reye’s syndrome.
Tigan® may produce drowsiness. Patients should not operate motor vehicles or
other dangerous machinery until their individual responses have been
determined.
Usage in Pregnancy: Trimethobenzamide hydrochloride was studied in
reproduction experiments in rats and rabbits and no teratogenicity was
suggested. The only effects observed were an increased percentage of
embryonic resorptions or stillborn pups in rats administered 20 mg and 100
mg/kg and increased resorptions in rabbits receiving 100 mg/kg. In each study
these adverse effects were attributed to one or two dams. The relevance to
humans is not known. Since there is no adequate experience in pregnant or
lactating women who have received this drug, safety in pregnancy or in nursing
mothers has not been established.
Usage with Alcohol: Concomitant use of alcohol with Tigan® may result in an
adverse drug interaction.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
During the course of acute febrile illness, encephalitides, gastroenteritis,
dehydration and electrolyte imbalance, especially in children and the elderly or
debilitated, CNS reactions such as opisthotonos, convulsions, coma and
extrapyramidal symptoms have been reported with and without use of Tigan®
(trimethobenzamide hydrochloride) or other antiemetic agents. In such disorders
caution should be exercised in administering Tigan®, particularly to patients who
have recently received other CNS-acting agents (phenothiazines, barbiturates,
belladonna derivatives). Primary emphasis should be directed toward the
restoration of body fluids and electrolyte balance, the relief of fever and relief of
the causative disease process. Overhydration should be avoided since it may
result in cerebral edema.
The antiemetic effects of Tigan® may render diagnosis more difficult in such
conditions as appendicitis and obscure signs of toxicity due to overdosage of
other drugs.
ADVERSE REACTIONS
There have been reports of hypersensitivity reactions and Parkinson-like
symptoms. There have been instances of hypotension reported following
parenteral administration to surgical patients. There have been reports of blood
dyscrasias, blurring of vision, coma, convulsions, depression of mood, diarrhea,
disorientation, dizziness, drowsiness, headache, jaundice, muscle cramps and
opisthotonos. If these occur, the administration of the drug should be
discontinued. Allergic-type skin reactions have been observed; therefore, the
drug should be discontinued at the first sign of sensitization. While these
symptoms will usually disappear spontaneously, symptomatic treatment may be
indicated in some cases.
DOSAGE AND ADMINISTRATION
(See WARNINGS and PRECAUTIONS.)
Dosage should be adjusted according to the indication for therapy, severity of
symptoms and the response of the patient.
CAPSULES, 300 mg
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Usual Adult Dosage
One 300 mg capsule t.i.d. or q.i.d.
SUPPOSITORIES, 200 mg (not to be used in premature or newborn infants)
Usual Adult Dosage
One suppository (200 mg) t.i.d. or q.i.d.
Usual Children's Dosage
Under 30 lbs: One-half suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One-half to one suppository (100 to 200 mg) t.i.d. or
q.i.d.
SUPPOSITORIES, PEDIATRIC, 100 mg (not to be used in premature or
newborn infants)
Usual Children's Dosage
Under 30 lbs: One suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One to two suppositories (100 to 200 mg) t.i.d. or q.i.d.
INJECTABLE, 100 mg/mL (not for use in children)
Usual Adult Dosage
2 mL (200 mg) t.i.d. or q.i.d. intramuscularly.
NOTE: The injectable form is intended for intramuscular administration only; it is
not recommended for intravenous use.
Intramuscular administration may cause pain, stinging, burning, redness and
swelling at the site of injection. Such effects may be minimized by deep injection
into the upper outer quadrant of the gluteal region, and by avoiding the escape of
solution along the route.
Rx Only
STORAGE
Store at 25°C (77°F).
Excursions permitted to 15–30°C (59–86°F).
[See USP Controlled Room Temperature]
HOW SUPPLIED
Capsules, 300 mg trimethobenzamide hydrochloride each, bottles of 100 and
500
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 61570-079-01 300 mg 100’s
NDC 61570-079-05 300 mg 500’s
Suppositories, Pediatric, 100 mg, boxes of 10
Suppositories, 200 mg, boxes of 10 and 50
NDC 61570-503-10 100 mg (box of 10)
NDC 61570-504-10 200 mg (box of 10)
NDC 61570-504-50 200 mg (box of 50)
Single-Dose Vials, 2 mL , trays of 25
NDC 61570-543-25 200 mg/mL in 2 mL Single-Dose Vials
Multi-Dose Vials, 20 mL
NDC 61570-541-20 100 mg/mL in 20 mL Multi-Dose Vials
Prescribing Information as of November 2004.
Distributed By: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Manufactured By: King Pharmaceuticals, Inc., Bristol, TN 37620
Rev. 11/04
3000437
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 61570-543-25
25 x 2 mL Single-Dose Vials
Injection
200 mg/2mL
Tigan Steri-Vial 2 mL
3-5/32"L x 3-5/32"W x 1-25/64"H
Tray, 25 pack
3000358
X
PMS
280 Blue
PMS
Black
Unvarnished
Area
Tigan®
(trimethobenzamide HCl)
NOT FOR USE IN CHILDREN.
FOR I.M. USE ONLY (preferably by deep IM Injection).
Each 2 mL of solution contains 200 mg trimethobenzamide hydrochloride com-
pounded with 1 mg sodium citrate and 0.4 mg citric acid as buffers, and sodium
hydroxide to adjust pH to approximately 5.0.
Dosage: See accompanying prescribing information.
Store at 25° C (77° F) (see insert).
Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Manufactured by: King Pharmaceuticals, Inc., Bristol, TN 37620
Lot and exp. date
3000358
998
FPO
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b)(4)
(b)(4)
Supplier to insert
live RSS bar code
(01)0036157054301.
NDC 61570-543-01
200 mg/2 mL
Tigan
®
(trimethobenzamide HCl)
Injection
For IM Use Only
Not for Use in Children
Dist. by: Monarch
Pharmaceuticals, Inc.
Bristol, TN 37620
(A wholly owned
subsidiary of King
Pharmaceuticals, Inc.)
Tigan Steri-Vial 2 mL
1-3/4" x 9/16"
Label
3000349
n/a
PMS
280 Blue
PMS
Black
Unvarnished
Area
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b)(4)
(b)(4)
|
custom-source
|
2025-02-12T13:44:14.941224
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017530s021,022,023lbl.pdf', 'application_number': 17530, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
11,017
|
Str
uctural F
ormula
Diaßeta® (glyburide) Tablets USP
1.25, 2.5 and 5 mg
DESCRIPTION
Diaßeta® (glyburide) is an oral blood-glucose-lowering drug of the sulfonylurea class. It is a
white, crystalline compound, formulated as tablets of 1.25 mg, 2.5 mg, and 5 mg strengths for
oral administration. Diaßeta tablets USP contain the active ingredient glyburide and the
following inactive ingredients: dibasic calcium phosphate USP, magnesium stearate NF,
microcrystalline cellulose NF, sodium alginate NF, talc USP. Diaßeta 1.25 mg tablets USP also
contain D&C Yellow #10 Aluminum Lake and FD&C Red #40 Aluminum Lake. Diaßeta 2.5 mg
tablets USP also contain FD&C Red #40 Aluminum Lake. Diaßeta 5 mg tablets USP also
contain D&C Yellow #10 Aluminum Lake, and FD&C Blue #1. Chemically, Diaßeta is
identified as 1-[[p-[2-(5-Chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclohexylurea.
The CAS Registry Number is 10238-21-8.
The structural formula is:
The molecular weight is 493.99. The aqueous solubility of Diaßeta increases with pH as a result
of salt formation.
CLINICAL PHARMACOLOGY
Diaßeta appears to lower the blood glucose acutely by stimulating the release of insulin from the
pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism
by which Diaßeta lowers blood glucose during long-term administration has not been clearly
established.
With chronic administration in Type II diabetic patients, the blood glucose lowering effect
persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic
effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
In addition to its blood glucose lowering actions, Diaßeta produces a mild diuresis by
enhancement of renal free water clearance. Clinical experience to date indicates an extremely
low incidence of disulfiram-like reactions in patients while taking Diaßeta.
Pharmacokinetics
Single-dose studies with Diaßeta in normal subjects demonstrate significant absorption within
one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four
hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time
curve, increase in proportion to corresponding increases in dose. Multiple-dose studies with
Diaßeta in diabetic patients demonstrate drug level concentration-time curves similar to single-
dose studies, indicating no build-up of drug in tissue depots. The decrease of glyburide in the
serum of normal healthy individuals is biphasic, the terminal half-life being about 10 hours. In
1
single-dose studies in fasting normal subjects, the degree and duration of blood glucose lowering
is proportional to the dose administered and to the area under the drug level concentration-time
curve. The blood glucose lowering effect persists for 24 hours following single morning doses in
non-fasting diabetic patients. Under conditions of repeated administration in diabetic patients,
however, there is no reliable correlation between blood drug levels and fasting blood glucose
levels. A one-year study of diabetic patients treated with Diaßeta showed no reliable correlation
between administered dose and serum drug level.
The major metabolite of Diaßeta is the 4-trans-hydroxy derivative. A second metabolite, the 3
cis-hydroxy derivative, also occurs. These metabolites contribute no significant hypoglycemic
action since they are only weakly active (1/400th and 1/40th, respectively, as glyburide) in
rabbits.
Diaßeta is excreted as metabolites in the bile and urine, approximately 50% by each route. This
dual excretory pathway is qualitatively different from that of other sulfonylureas, which are
excreted primarily in the urine.
Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding
sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding
exhibited by Diaßeta is predominantly non-ionic, whereas that of other sulfonylureas
(chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as
phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum
proteins to a far greater extent than the non-ionic binding Diaßeta. It has not been shown that this
difference in protein binding will result in fewer drug-drug interactions with Diaßeta in clinical
use.
INDICATIONS AND USAGE
Diaßeta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
type 2 diabetes mellitus.
CONTRAINDICATIONS
Diaßeta is contraindicated in patients:
1. With known hypersensitivity to the drug or any of its excipients.
2. With type 1 diabetes mellitus or diabetic ketoacidosis, with or without coma.
These conditions should be treated with insulin.
3. Treated with bosentan.
WARNINGS
SPECIAL WARNING ON INCREASED
RISK OF CARDIOVASCULAR MORTALITY
The administration of oral hypoglycemic drugs has been reported to be associated with
increased cardiovascular mortality as compared to treatment with diet alone or diet plus
insulin. This warning is based on the study conducted by the University Group Diabetes
Program (UGDP), a long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in
2
patients with non-insulin-dependent diabetes. The study involved 823 patients who were
randomly assigned to one of four treatment groups (Diabetes 19 (supp. 2): 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of
tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2
1/2 times that of patients treated with diet alone. A significant increase in total mortality
was not observed, but the use of tolbutamide was discontinued based on the increase in
cardiovascular mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these results, the
findings of the UGDP study provide an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of Diaßeta and of alternative modes of
therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study,
it is prudent from a safety standpoint to consider that this warning may also apply to other
oral hypoglycemic drugs in this class, in view of their close similarities in mode of action
and chemical structure.
Persons allergic to other sulfonamide derivatives may develop an allergic reaction to glyburide
as well.
PRECAUTIONS
General
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence
of macrovascular risk reduction with Diaßeta or any other anti-diabetic drug.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper
patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Severe
renal or hepatic insufficiency may cause elevated blood levels of Diaßeta and the latter may also
diminish gluconeogenic capacity, both of which increase the risk of serious, prolonged
hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or
pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-
lowering drugs. Hypoglycemia may be difficult to recognize in patients with autonomic
neuropathy, the elderly, and in people who are taking beta-adrenergic blocking drugs or other
sympatholytic agents.
Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged
exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Loss
of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed to
stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it
may be necessary to discontinue Diaßeta and administer insulin.
The effectiveness of any oral hypoglycemic drug, including Diaßeta, in lowering blood glucose
to a desired level decreases in many patients over a period of time, which may be due to
progression of the severity of the diabetes or to diminished responsiveness to the drug. This
3
phenomenon is known as secondary failure, to distinguish it from primary failure in which the
drug is ineffective in an individual patient when first given.
Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD)
deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Diaßeta belongs to
the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a
non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia
has also been reported in patients who did not have known G6PD deficiency.
Information for Patients
Patients should be informed of the potential risks and advantages of Diaßeta and of alternative
modes of therapy. They should also be informed about the importance of adherence to dietary
instructions, of a regular exercise program, and of regular testing of blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its
development should be explained to patients and responsible family members. Primary and secondary
failure should also be explained.
Laboratory Tests
Periodic fasting blood glucose measurements should be performed to monitor therapeutic
response. A glycosylated hemoglobin determination should also be performed periodically.
Drug Interactions
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including
nonsteroidal anti-inflammatory agents, ACE inhibitors, disopyramide, fluoxetine, clarithromycin,
and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol,
probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such
drugs are administered to a patient receiving Diaßeta, the patient should be observed closely for
hypoglycemia. When such drugs are withdrawn from a patient receiving Diaßeta, the patient
should be observed closely for loss of control.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with the intravenous,
topical or vaginal preparations of miconazole is not known.
A possible interaction between glyburide and fluoroquinolone antibiotics has been reported
resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this
interaction is not known.
Possible interactions between glyburide and coumarin derivatives have been reported that may
either potentiate or weaken the effects of coumarin derivatives. The mechanism of these
interactions is not known.
Rifampin may worsen glucose control of glyburide because rifampin can significantly induce
metabolic isozymes of glyburide such as CYP2C9 and 3A4.
4
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,
estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel
blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Diaßeta,
the patient should be closely observed for loss of control. When such drugs are withdrawn from a
patient receiving Diaßeta, the patient should be observed closely for hypoglycemia.
An increased incidence of elevated liver enzymes was observed in patients receiving glyburide
concomitantly with bosentan. Therefore this combination should not be used. (See
CONTRAINDICATIONS.)
Diaßeta may increase cyclosporine plasma concentration and potentially lead to its increased
toxicity. Monitoring and dosage adjustment of cyclosporine are therefore recommended when
both drugs are coadministered.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Diaßeta is non-mutagenic when studied in the Salmonella microsome test (Ames test) and in the
DNA damage/alkaline elution assay. Studies in rats at doses up to 300 mg/kg/day for 18 months
showed no carcinogenic effects.
No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity
study of glyburide in mice.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Diaßeta has been shown to affect the maturation of the long bones (humerus and femur) in rat
pups when given in doses 6250 times the maximum recommended human dose. These effects,
which were seen during the period of lactation and not during organogenesis, are a shortening of
the bones with effects to various structures of the long bones, especially in humerus and femur.
There are no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, Diaßeta should be used during
pregnancy only if the potential benefit justifies the risk to the fetus. Because recent information
suggests that abnormal blood glucose levels during pregnancy are associated with a higher
incidence of congenital abnormalities, many experts recommend that insulin be used during
pregnancy to maintain blood glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives. If Diaßeta is
used during pregnancy, it should be discontinued at least two weeks before the expected delivery
date.
Nursing Mothers
Although it is not known whether Diaßeta is excreted in human milk, some sulfonylureas are
known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants
5
may exist, a decision should be made whether to discontinue nursing or to discontinue
administering the drug, taking into account the importance of the drug to the mother. If Diaßeta
is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy
should be considered.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
In US clinical studies of glyburide, 1406 of 2897 patients were ≥60 years and 515 patients were
≥70 years. Differences in safety and efficacy were not determined between these patients and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and
maintenance dosing should be conservative to avoid hypoglycemic reactions.
In three published studies of 20 to 51 subjects each, mixed results were seen in comparing the
pharmacokinetics of glyburide in elderly versus younger subjects. However, observed
pharmacodynamic differences indicate the necessity for dosage titration to a specified
therapeutic response.
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.
In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency,
the initial dosing, dose increments, and maintenance dosage should be conservative to avoid
hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people
who are taking beta-adrenergic blocking drugs or other sympatholytic agents. (See
PRECAUTIONS, General; and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE Sections.
Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely which may
progress to liver failure; Diaßeta should be discontinued if this occurs. Liver function
abnormalities, including isolated transaminase elevations, have been reported. Gastrointestinal
disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and
occur in 1.8% of treated patients. They tend to be dose-related and may disappear when dosage is
reduced.
Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and
morbilliform or maculopapular eruptions, occur in 1.5% of treated patients. These may be
6
transient and may disappear despite continued use of Diaßeta; if skin reactions persist, the drug
should be discontinued.
Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally
may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia have been
reported with sulfonylureas.
Metabolic Reactions: Hepatic porphyria reactions have been reported with sulfonylureas;
however, these have not been reported with Diaßeta. Disulfiram-like reactions have been
reported very rarely with Diaßeta. Cases of hyponatremia have been reported with glyburide and
all other sulfonylureas, most often in patients who are on other medications or have medical
conditions known to cause hyponatremia or increase release of antidiuretic hormone. The
syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with
certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the
peripheral (antidiuretic) action of ADH and/or increase release of ADH.
Other Reactions: Changes in accommodation and/or blurred vision have been reported with
glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose
levels.
In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia
and vasculitis have been reported.
OVERDOSAGE
Overdosage of sulfonylureas, including Diaßeta, can produce hypoglycemia. Mild hypoglycemic
symptoms without loss of consciousness or neurologic findings should be treated aggressively
with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should
continue until the physician is assured that the patient is out of danger. Severe hypoglycemic
reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute
medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or
suspected, the patient should be given a rapid intravenous injection of concentrated (50%)
glucose solution. This should be followed by a continuous infusion of a more dilute (10%)
glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.
Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may
recur after apparent clinical recovery.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with Diaßeta or any
other hypoglycemic agent. The patient’s fasting blood glucose must be measured periodically to
determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate
lowering of blood glucose at the maximum recommended dose of medication; and to detect
secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of
effectiveness. Periodic glycosylated hemoglobin determinations should be performed.
7
Short-term administration of Diaßeta may be sufficient during periods of transient loss of control
in patients usually controlled well on diet.
1.
Usual Starting Dose
The usual starting dose of Diaßeta as initial therapy is 2.5 to 5 mg daily, administered
with breakfast or the first main meal. Those patients who may be more sensitive to
hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS Section for
patients at increased risk). Failure to follow an appropriate dosage regimen may
precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug
regimen are more prone to exhibit unsatisfactory response to therapy.
Transfer of patients from other oral antidiabetic regimens to Diaßeta should be done
conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients
from oral hypoglycemic agents other than chlorpropamide, to Diaßeta, no transition
period and no initial priming dose is necessary. When transferring patients from
chlorpropamide, particular care should be exercised during the first two weeks because
the prolonged retention of chlorpropamide in the body and subsequent overlapping drug
effects may provoke hypoglycemia.
Bioavailability studies have demonstrated that Glynase®* PresTab®* Tablets 3 mg are
not bioequivalent to Diaßeta Tablets USP 5 mg. Therefore, these products are not
substitutable and patients should be retitrated if transferred.
Some Type II diabetic patients being treated with insulin may respond satisfactorily to
Diaßeta. If the insulin dose is less than 20 units daily, substitution of Diaßeta 2.5 to 5 mg
as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily,
the patient may be placed directly on Diaßeta 5 mg daily as a single dose. If the insulin
dose is more than 40 units daily, a transition period is required for conversion to Diaßeta.
In these patients, insulin dosage is decreased by 50% and Diaßeta 5 mg daily is started.
Please refer to Usual Maintenance Dose for further explanation.
2.
Usual Maintenance Dose
The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as
a single dose or in divided doses (See Dosage Interval Section). Dosage increases should
be made in increments of no more than 2.5 mg at weekly intervals based upon the
patient’s blood glucose response.
No exact dosage relationship exists between Diaßeta and the other oral hypoglycemic
agents. Although patients may be transferred from the maximum dose of other
sulfonylureas, the maximum starting dose of 5 mg of Diaßeta should be observed. A
maintenance dose of 5 mg Diaßeta provides approximately the same degree of blood
glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750
mg acetohexamide, or 1000 to 1500 mg tolbutamide.
When transferring patients receiving more than 40 units of insulin daily, they may be
started on a daily dose of Diaßeta 5 mg concomitantly with a 50% reduction in insulin
8
dose. Progressive withdrawal of insulin and increase of Diaßeta in increments of 1.25 to
2.5 mg every 2 to 10 days is then carried out. During this conversion period when both
insulin and Diaßeta are being used, hypoglycemia may rarely occur. During insulin
withdrawal, patients should self-test their blood for glucose and their urine for acetone at
least 3 times daily and report results to their physician. Self-testing of urinary glucose is a
less desirable alternative. The appearance of persistent acetonuria with glycosuria
indicates that the patient is a Type I diabetic who requires insulin therapy.
3.
Maximum Dose
Daily doses of more than 20 mg are not recommended.
4.
Dosage Interval
Once-a-day therapy is usually satisfactory, based upon usual meal patterns and a 10 hour
half-life of Diaßeta. Some patients, particularly those receiving more than 10 mg daily,
may have a more satisfactory response with twice-a-day dosage.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or
hepatic function, the initial and maintenance dosing should be conservative to avoid
hypoglycemic reactions. (See PRECAUTIONS Section.)
HOW SUPPLIED
Diaßeta (glyburide) tablets USP are available in the following strengths and package sizes:
1.25 mg (peach, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score
line between the “Dia” and the “ß” on one side and plain on the other side).
Bottles of 50
(NDC 0039-0053-05)
2.5 mg (pink, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score line
between the “Dia” and “ß” on one side and plain on the other side).
Bottles of 100
(NDC 0039-0051-10)
Bottles of 500
(NDC 0039-0051-50)
5 mg (green, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score line
between the “Dia” and “ß” on one side and plain on the other side).
Bottles of 100
(NDC 0039-0052-10)
Bottles of 500
(NDC 0039-0052-50)
Bottles of 1000
(NDC 0039-0052-70)
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room
Temperature].
Dispense in well-closed containers with safety closures.
Rx only
Revised XXXXXX
9
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
*Trademarks of their respective owners, not affiliated with sanofi-aventis.
©2009 sanofi-aventis U.S. LLC
10
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017532s030lbl.pdf', 'application_number': 17532, 'submission_type': 'SUPPL ', 'submission_number': 30}
|
11,014
|
NDA 17-531/S-010
Tigan®
(trimethobenzamide hydrochloride)
Capsules/Suppositories/Injectable
DESCRIPTION
Chemically, trimethobenzamide HCl is N-[p-[2-(dimethylamino)ethoxy]benzyl]-3,4,5-
trimethoxybenzamide monohydrochloride. It has a molecular weight of 424.93 and the following
structural formula:
(CH3)2N-CH2CH2O
CH2NHC
OCH3
OCH3
OCH3
O
• HCl
Capsules: Each 300-mg Tigan® capsule for oral use contains trimethobenzamide hydrochloride
equivalent to 300 mg. The capsule has an opaque purple cap marked “Tigan” and an opaque purple
body marked “M079”.
Inactive Ingredients: D&C Red No. 28, FD&C Blue No. 1, lactose, magnesium stearate, starch and
titanium dioxide.
Suppositories (200 mg): Each suppository contains 200 mg trimethobenzamide hydrochloride and 2%
benzocaine in a base compounded with polysorbate 80, white beeswax and propylene glycol
monostearate.
Suppositories, Pediatric (100 mg): Each suppository contains 100 mg trimethobenzamide
hydrochloride and 2% benzocaine in a base compounded with polysorbate 80, white beeswax and
propylene glycol monostearate.
Ampuls: Each 2-mL ampul contains 200 mg trimethobenzamide hydrochloride compounded with 0.2%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
parabens (methyl and propyl) as preservatives, 1 mg sodium citrate and 0.4 mg citric acid as buffers and
pH adjusted to approximately 5.0 with sodium hydroxide.
Multi-Dose Vials: Each mL contains 100 mg trimethobenzamide hydrochloride compounded with
0.45% phenol as preservative, 0.5 mg sodium citrate and 0.2 mg citric acid as buffers and pH adjusted
to approximately 5.0 with sodium hydroxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Tigan® as determined in animals is obscure, but may involve the
chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are
conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly
inhibited. In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is
inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate.
Pharmacokinetics
The pharmacokinetics of trimethobenzamide have been studied in healthy adult subjects. Following
administration of 200 mg (100 mg/mL) Tigan I.M. injection, the time to reach maximum plasma
concentration (Tmax) was about half an hour, about 15 minutes longer for Tigan 300 mg oral capsule
than an I.M. injection. A single dose of Tigan 300 mg oral capsule provided a plasma concentration
profile of trimethobenzamide similar to Tigan 200 mg I.M. The relative bioavailability of the capsule
formulation compared to the solution is 100%. The mean elimination half-life of trimethobenzamide is
7 to 9 hours.
Special Populations
Gender
Systemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
Race
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12).
INDICATIONS
Tigan® is indicated for the treatment of postoperative nausea and vomiting and for nausea associated
with gastroenteritis.
CONTRAINDICATIONS
Use of the injectable form of Tigan® in children, the suppositories in premature or newborn infants, and
use of any dosage form in patients with known hypersensitivity to trimethobenzamide are
contraindicated. Since the suppositories contain benzocaine they should not be used in patients known
to be sensitive to this or similar local anesthetics.
WARNINGS
Caution should be exercised when administering Tigan® to children for the treatment of vomiting.
Antiemetics are not recommended for treatment of uncomplicated vomiting in children and their use
should be limited to prolonged vomiting of known etiology. There are three principal reasons for
caution:
1. The extrapyramidal symptoms which can occur secondary to Tigan® may be confused with
the central nervous system signs of an undiagnosed primary disease responsible for the
vomiting, e.g., Reye’s syndrome or other encephalopathy.
2. It has been suspected that drugs with hepatotoxic potential, such as Tigan®, may unfavorably
alter the course of Reye’s syndrome. Such drugs should therefore be avoided in children
whose signs and symptoms (vomiting) could represent Reye’s syndrome.
Tigan® may produce drowsiness. Patients should not operate motor vehicles or other dangerous
machinery until their individual responses have been determined.
Usage in Pregnancy: Trimethobenzamide hydrochloride was studied in reproduction experiments in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
rats and rabbits and no teratogenicity was suggested. The only effects observed were an increased
percentage of embryonic resorptions or stillborn pups in rats administered 20 mg and 100 mg/kg and
increased resorptions in rabbits receiving 100 mg/kg. In each study these adverse effects were attributed
to one or two dams. The relevance to humans is not known. Since there is no adequate experience in
pregnant or lactating women who have received this drug, safety in pregnancy or in nursing mothers has
not been established.
Usage with Alcohol: Concomitant use of alcohol with Tigan® may result in an adverse drug
interaction.
PRECAUTIONS
During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and electrolyte
imbalance, especially in children and the elderly or debilitated, CNS reactions such as opisthotonos,
convulsions, coma and extrapyramidal symptoms have been reported with and without use of Tigan®
(trimethobenzamide hydrochloride) or other antiemetic agents. In such disorders caution should be
exercised in administering Tigan®, particularly to patients who have recently received other CNS-
acting agents (phenothiazines, barbiturates, belladonna derivatives). Primary emphasis should be
directed toward the restoration of body fluids and electrolyte balance, the relief of fever and relief of the
causative disease process. Overhydration should be avoided since it may result in cerebral edema.
The antiemetic effects of Tigan® may render diagnosis more difficult in such conditions as appendicitis
and obscure signs of toxicity due to overdosage of other drugs.
ADVERSE REACTIONS
There have been reports of hypersensitivity reactions and Parkinson-like symptoms. There have been
instances of hypotension reported following parenteral administration to surgical patients. There have
been reports of blood dyscrasias, blurring of vision, coma, convulsions, depression of mood, diarrhea,
disorientation, dizziness, drowsiness, headache, jaundice, muscle cramps and opisthotonos. If these
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
occur, the administration of the drug should be discontinued. Allergic-type skin reactions have been
observed; therefore, the drug should be discontinued at the first sign of sensitization. While these
symptoms will usually disappear spontaneously, symptomatic treatment may be indicated in some
cases.
DOSAGE AND ADMINISTRATION
(See WARNINGS and PRECAUTIONS.)
Dosage should be adjusted according to the indication for therapy, severity of symptoms and the
response of the patient.
CAPSULES, 300 mg
Usual Adult Dosage
One 300 mg capsule t.i.d. or q.i.d.
SUPPOSITORIES, 200 mg (not to be used in premature or newborn infants)
Usual Adult Dosage
One suppository (200 mg) t.i.d. or q.i.d.
Usual Children's Dosage
Under 30 lbs: One-half suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One-half to one suppository (100 to 200 mg) t.i.d. or q.i.d.
SUPPOSITORIES, PEDIATRIC, 100 mg (not to be used in premature or newborn infants)
Usual Children's Dosage
Under 30 lbs: One suppository (100 mg) t.i.d. or q.i.d.
30 to 90 lbs: One to two suppositories (100 to 200 mg) t.i.d. or q.i.d.
INJECTABLE, 100 mg/mL (not for use in children)
Usual Adult Dosage
2 mL (200 mg) t.i.d. or q.i.d. intramuscularly.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
NOTE: The injectable form is intended for intramuscular administration only; it is not recommended for
intravenous use.
Intramuscular administration may cause pain, stinging, burning, redness and swelling at the site of
injection. Such effects may be minimized by deep injection into the upper outer quadrant of the gluteal
region, and by avoiding the escape of solution along the route.
Rx Only
STORAGE
Store at 25°C (77°F).
Excursions permitted to 15–30°C (59–86°F).
[See USP Controlled Room Temperature]
HOW SUPPLIED
Capsules, 300 mg trimethobenzamide hydrochloride each, bottles of 100 and 500
NDC 61570-079-01 300 mg 100’s
NDC 61570-079-05 300 mg 500’s
Suppositories, Pediatric, 100 mg, boxes of 10
Suppositories, 200 mg, boxes of 10 and 50
NDC 61570-503-10 100 mg (box of 10)
NDC 61570-504-10 200 mg (box of 10)
NDC 61570-504-50 200 mg (box of 50)
Ampuls, 2 mL, boxes of 10
NDC 61570-540-02 100 mg/mL in 2 mL ampul
Multi-Dose Vials, 20 mL
NDC 61570-541-20 100 mg/mL in 20 mL Multi-Dose Vials
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-010
Distributed By: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
Manufactured By: King Pharmaceuticals, Inc., Bristol, TN 37620
Rev. 5/01
0934128
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/
---------------------
Robert Temple
12/13/01 06:36:45 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/2002/17531S010lbl.pdf', 'application_number': 17531, 'submission_type': 'SUPPL ', 'submission_number': 10}
|
11,015
|
NDA 17-531/S-012
Page 3
Tigan®
(trimethobenzamide hydrochloride)
Capsules
DESCRIPTION
Chemically, trimethobenzamide HCl is N-[p-[2-(dimethylamino)ethoxy]benzyl]-3,4,5-
trimethoxybenzamide monohydrochloride. It has a molecular weight of 424.93 and the
following structural formula:
(CH3)2N-CH2CH2O
CH2NHC
OCH3
OCH3
OCH3
O
• HCl
Capsules: Each 300-mg Tigan® capsule for oral use contains trimethobenzamide
hydrochloride equivalent to 300 mg. The capsule has an opaque purple cap marked “Tigan”
and an opaque purple body marked “M079”.
Inactive Ingredients: D&C Red No. 28, FD&C Blue No. 1, lactose, magnesium stearate,
starch and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Tigan® as determined in animals is obscure, but may involve the
chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic
impulses are conveyed to the vomiting center; direct impulses to the vomiting center
apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide HCl, the
emetic response to apomorphine is inhibited, while little or no protection is afforded against
emesis induced by intragastric copper sulfate.
Pharmacokinetics
The pharmacokinetics of trimethobenzamide have been studied in healthy adult subjects.
Following administration of 200 mg (100 mg/mL) Tigan I.M. injection, the time to reach
maximum plasma concentration (Tmax) was about half an hour, about 15 minutes longer for
Tigan 300 mg oral capsule than an I.M. injection. A single dose of Tigan 300 mg oral capsule
provided a plasma concentration profile of trimethobenzamide similar to Tigan 200 mg I.M.
The relative bioavailability of the capsule formulation compared to the solution is 100%. The
mean elimination half-life of trimethobenzamide is 7 to 9 hours. Between 30 – 50% of a
single dose in humans is excreted unchanged in the urine within 48-72 hours. The metabolic
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-012
Page 4
disposition of trimethobenzamide in humans is not known. Specifically, it is not known if
active metabolites are generated in humans.
Special Populations
Age
The clearance of trimethobenzamide is not known in patients with renal impairment.
However, it may be advisable to consider reduction in the dosing of trimethobenzamide in
elderly patients with renal impairment considering that a substantial amount of excretion and
elimination of trimethobenzamide occurs via the kidney and that elderly patients may have
various degrees of renal impairment. (See PRECAUTIONS: General and DOSAGE AND
ADMINISTRATION).
Gender
Systemic exposure to trimethobenzamide was similar between men (N=40) and women
(N=28).
Race
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans
(N=12).
Renal Impairment
The clearance of trimethobenzamide is not known in patients with renal impairment.
However, it may be advisable to consider reduction in the dosing of trimethobenzamide in
patients with renal impairment considering that a substantial amount of excretion and
elimination of trimethobenzamide occurs via the kidney. (See PRECAUTIONS: General and
DOSAGE AND ADMINISTRATION).
INDICATIONS
Tigan® is indicated for the treatment of postoperative nausea and vomiting and for nausea
associated with gastroenteritis.
CONTRAINDICATIONS
Use of any dosage form in patients with known hypersensitivity to trimethobenzamide is
contraindicated.
WARNINGS
Caution should be exercised when administering Tigan® to children for the treatment of
vomiting. Antiemetics are not recommended for treatment of uncomplicated vomiting in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-012
Page 5
children and their use should be limited to prolonged vomiting of known etiology. There are
two principal reasons for caution:
1. The extrapyramidal symptoms which can occur secondary to Tigan® may be confused
with the central nervous system signs of an undiagnosed primary disease responsible
for the vomiting, e.g., Reye’s syndrome or other encephalopathy.
2. It has been suspected that drugs with hepatotoxic potential, such as Tigan®, may
unfavorably alter the course of Reye’s syndrome. Such drugs should therefore be
avoided in children whose signs and symptoms (vomiting) could represent Reye’s
syndrome.
Tigan® may produce drowsiness. Patients should not operate motor vehicles or other
dangerous machinery until their individual responses have been determined.
Usage in Pregnancy: Trimethobenzamide hydrochloride was studied in reproduction
experiments in rats and rabbits and no teratogenicity was suggested. The only effects
observed were an increased percentage of embryonic resorptions or stillborn pups in rats
administered 20 mg and 100 mg/kg and increased resorptions in rabbits receiving 100 mg/kg.
In each study these adverse effects were attributed to one or two dams. The relevance to
humans is not known. Since there is no adequate experience in pregnant or lactating women
who have received this drug, safety in pregnancy or in nursing mothers has not been
established.
Usage with Alcohol: Concomitant use of alcohol with Tigan® may result in an adverse drug
interaction.
PRECAUTIONS
During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and
electrolyte imbalance, especially in children and the elderly or debilitated, CNS reactions
such as opisthotonos, convulsions, coma and extrapyramidal symptoms have been reported
with and without use of Tigan® (trimethobenzamide hydrochloride) or other antiemetic agents.
In such disorders caution should be exercised in administering Tigan®, particularly to patients
who have recently received other CNS-acting agents (phenothiazines, barbiturates,
belladonna derivatives). Primary emphasis should be directed toward the restoration of body
fluids and electrolyte balance, the relief of fever and relief of the causative disease process.
Overhydration should be avoided since it may result in cerebral edema.
The antiemetic effects of Tigan® may render diagnosis more difficult in such conditions as
appendicitis and obscure signs of toxicity due to overdosage of other drugs.
General
Adjustment of Dose in Renal Failure
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-012
Page 6
A substantial route of elimination of unchanged trimethobenzamide is via the kidney. Dosage
adjustment should be considered in patients with reduced renal function including some
elderly patients. (See CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
Geriatric Use
Clinical studies of trimethobenzamide hydrochloride did not include sufficient numbers of
patients aged 65 and over to determine whether they respond differently from younger
patients. Although there are studies reported in the literature that included elderly patients >
65 years old with younger patients, it is not known if there are differences in efficacy or safety
parameters for elderly and non-elderly patients treated with trimethobenzamide. 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. (See CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION).
ADVERSE REACTIONS
There have been reports of hypersensitivity reactions and Parkinson-like symptoms. There
have been instances of hypotension reported following parenteral administration to surgical
patients. There have been reports of blood dyscrasias, blurring of vision, coma, convulsions,
depression of mood, diarrhea, disorientation, dizziness, drowsiness, headache, jaundice,
muscle cramps and opisthotonos. If these occur, the administration of the drug should be
discontinued. Allergic-type skin reactions have been observed; therefore, the drug should be
discontinued at the first sign of sensitization. While these symptoms will usually disappear
spontaneously, symptomatic treatment may be indicated in some cases.
DOSAGE AND ADMINISTRATION
(See WARNINGS and PRECAUTIONS.)
Dosage should be adjusted according to the indication for therapy, severity of symptoms and
the response of the patient.
Geriatric Patients
Dose adjustment such as reducing the total dose administered at each dosing or increasing
the dosing interval should be considered in elderly patients with renal impairment (creatinine
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-531/S-012
Page 7
clearance ≤ 70 mL/min/1.73m²). Final dose adjustment should be based upon integration of
clinical efficacy and safety considerations. (See CLINICAL PHARMACOLOGY and
PRECAUTIONS).
Patients with Renal Impairment
In subjects with renal impairment (creatinine clearance ≤ 70 mL/min/1.73m²), dose
adjustment such as reducing the total dose administered at each dosing or increasing the
dosing interval should be considered. (See CLINICAL PHARMACOLOGY and
PRECAUTIONS).
CAPSULES, 300 mg
Usual Adult Dosage
One 300 mg capsule t.i.d. or q.i.d.
STORAGE
Store at 25°C (77°F).
Excursions permitted to 15–30°C (59–86°F).
[See USP Controlled Room Temperature]
HOW SUPPLIED
Capsules, 300 mg trimethobenzamide hydrochloride each, bottles of 100
NDC 61570-079-01 300 mg 100’s
Rx Only
Prescribing Information as of August 2007.
Distributed By: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
(A wholly owned subsidiary of King Pharmaceuticals, Inc.)
Manufactured By: King Pharmaceuticals, Inc., Bristol, TN 37620
3000834-C
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/2008/017531s012lbl.pdf', 'application_number': 17531, 'submission_type': 'SUPPL ', 'submission_number': 12}
|
11,016
|
Che
mical Str
ucture
Diaßeta®
(glyburide USP)
Tablets 1.25, 2.5 and 5 mg
DESCRIPTION
Diaßeta® (glyburide USP) is an oral blood-glucose-lowering drug of the sulfonylurea class. It is a
white, crystalline compound, formulated as tablets of 1.25 mg, 2.5 mg, and 5 mg strengths for
oral administration. Diaßeta tablets contain the active ingredient glyburide and the following
inactive ingredients: dibasic calcium phosphate USP, magnesium stearate NF, microcrystalline
cellulose NF, sodium alginate NF, talc USP. Diaßeta 1.25 mg tablets also contain D&C Yellow
#10 Aluminum Lake and FD&C Red #40 Aluminum Lake. Diaßeta 2.5 mg tablets also contain
FD&C Red #40 Aluminum Lake. Diaßeta 5 mg tablets also contain D&C Yellow #10 Aluminum
Lake, and FD&C Blue #1. Chemically, Diaßeta is identified as 1-[[p-[2-(5-Chloro-o
anisamido)ethyl]phenyl]sulfonyl]-3-cyclohexylurea.
The CAS Registry Number is 10238-21-8.
The structural formula is:
The molecular weight is 493.99. The aqueous solubility of Diaßeta increases with pH as a result
of salt formation.
CLINICAL PHARMACOLOGY
Diaßeta appears to lower the blood glucose acutely by stimulating the release of insulin from the
pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism
by which Diaßeta lowers blood glucose during long-term administration has not been clearly
established.
With chronic administration in Type II diabetic patients, the blood glucose lowering effect
persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic
effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
In addition to its blood glucose lowering actions, Diaßeta produces a mild diuresis by
enhancement of renal free water clearance. Clinical experience to date indicates an extremely
low incidence of disulfiram-like reactions in patients while taking Diaßeta.
Pharmacokinetics
Single-dose studies with Diaßeta in normal subjects demonstrate significant absorption within
one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four
hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
curve, increase in proportion to corresponding increases in dose. Multiple-dose studies with
Diaßeta in diabetic patients demonstrate drug level concentration-time curves similar to single-
dose studies, indicating no build-up of drug in tissue depots. The decrease of glyburide in the
serum of normal healthy individuals is biphasic, the terminal half-life being about 10 hours. In
single-dose studies in fasting normal subjects, the degree and duration of blood glucose lowering
is proportional to the dose administered and to the area under the drug level concentration-time
curve. The blood glucose lowering effect persists for 24 hours following single morning doses in
non-fasting diabetic patients. Under conditions of repeated administration in diabetic patients,
however, there is no reliable correlation between blood drug levels and fasting blood glucose
levels. A one-year study of diabetic patients treated with Diaßeta showed no reliable correlation
between administered dose and serum drug level.
The major metabolite of Diaßeta is the 4-trans-hydroxy derivative. A second metabolite, the 3
cis-hydroxy derivative, also occurs. These metabolites contribute no significant hypoglycemic
action since they are only weakly active (1/400th and 1/40th, respectively, as glyburide) in
rabbits.
Diaßeta is excreted as metabolites in the bile and urine, approximately 50% by each route. This
dual excretory pathway is qualitatively different from that of other sulfonylureas, which are
excreted primarily in the urine.
Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding
sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding
exhibited by Diaßeta is predominantly non-ionic, whereas that of other sulfonylureas
(chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as
phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum
proteins to a far greater extent than the non-ionic binding Diaßeta. It has not been shown that this
difference in protein binding will result in fewer drug-drug interactions with Diaßeta in clinical
use.
INDICATIONS AND USAGE
Diaßeta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
type 2 diabetes mellitus.
CONTRAINDICATIONS
Diaßeta is contraindicated in patients:
1. With known hypersensitivity to the drug or any of its excipients.
2. With diabetic ketoacidosis, with or without coma.
This condition should be treated with insulin.
3. Treated with bosentan.
WARNINGS
SPECIAL WARNING ON INCREASED
2
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RISK OF CARDIOVASCULAR MORTALITY
The administration of oral hypoglycemic drugs has been reported to be associated with
increased cardiovascular mortality as compared to treatment with diet alone or diet plus
insulin. This warning is based on the study conducted by the University Group Diabetes
Program (UGDP), a long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in
patients with non-insulin-dependent diabetes. The study involved 823 patients who were
randomly assigned to one of four treatment groups (Diabetes 19 (supp. 2): 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of
tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2
1/2 times that of patients treated with diet alone. A significant increase in total mortality
was not observed, but the use of tolbutamide was discontinued based on the increase in
cardiovascular mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these results, the
findings of the UGDP study provide an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of Diaßeta and of alternative modes of
therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study,
it is prudent from a safety standpoint to consider that this warning may also apply to other
oral hypoglycemic drugs in this class, in view of their close similarities in mode of action
and chemical structure.
PRECAUTIONS
General
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence
of macrovascular risk reduction with Diaßeta or any other anti-diabetic drug.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper
patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal
or hepatic insufficiency may cause elevated blood levels of Diaßeta and the latter may also
diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic
reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary
insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-
adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur
when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or
when more than one glucose-lowering drug is used. Loss of control of blood glucose: When a
patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or
surgery, a loss of control may occur. At such times, it may be necessary to discontinue Diaßeta
and administer insulin.
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The effectiveness of any oral hypoglycemic drug, including Diaßeta, in lowering blood glucose
to a desired level decreases in many patients over a period of time, which may be due to
progression of the severity of the diabetes or to diminished responsiveness to the drug. This
phenomenon is known as secondary failure, to distinguish it from primary failure in which the
drug is ineffective in an individual patient when first given.
Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD)
deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Diaßeta belongs to
the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a
non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia
has also been reported in patients who did not have known G6PD deficiency.
Information for Patients
Patients should be informed of the potential risks and advantages of Diaßeta and of alternative
modes of therapy. They should also be informed about the importance of adherence to dietary
instructions, of a regular exercise program, and of regular testing of blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its
development should be explained to patients and responsible family members. Primary and secondary
failure should also be explained.
Laboratory Tests
Periodic fasting blood glucose measurements should be performed to monitor therapeutic
response. A glycosylated hemoglobin determination should also be performed periodically.
Drug Interactions
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including
nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates,
sulfonamides, chloramphenicol, probenecid, monoamine oxidase inhibitors, beta adrenergic
blocking agents, and clarithromycin. When such drugs are administered to a patient receiving
Diaßeta, the patient should be observed closely for hypoglycemia. When such drugs are
withdrawn from a patient receiving Diaßeta, the patient should be observed closely for loss of
control.
A possible interaction between glyburide and fluoroquinolone antibiotics has been reported
resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this
interaction is not known.
Possible interactions between glyburide and coumarin derivatives have been reported that may
either potentiate or weaken the effects of coumarin derivatives. The mechanism of these
interactions is not known.
4
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Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,
estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel
blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Diaßeta,
the patient should be closely observed for loss of control. When such drugs are withdrawn from a
patient receiving Diaßeta, the patient should be observed closely for hypoglycemia. A potential
interaction between oral miconazole and oral hypoglycemic agents leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with the intravenous,
topical or vaginal preparations of miconazole is not known.
An increased incidence of elevated liver enzymes was observed in patients receiving glyburide
concomitantly with bosentan. Therefore this combination should not be used. (See
CONTRAINDICATIONS.)
Diaßeta may increase cyclosporine plasma concentration and potentially lead to its increased
toxicity. Monitoring and dosage adjustment of cyclosporine are therefore recommended when
both drugs are coadministered.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Diaßeta is non-mutagenic when studied in the Salmonella microsome test (Ames test) and in the
DNA damage/alkaline elution assay. Studies in rats at doses up to 300 mg/kg/day for 18 months
showed no carcinogenic effects.
No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity
study of glyburide in mice.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Diaßeta has been shown to affect the maturation of the long bones (humerus and femur) in rat
pups when given in doses 6250 times the maximum recommended human dose. These effects,
which were seen during the period of lactation and not during organogenesis, are a shortening of
the bones with effects to various structures of the long bones, especially in humerus and femur.
There are no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, Diaßeta should be used during
pregnancy only if the potential benefit justifies the risk to the fetus. Because recent information
suggests that abnormal blood glucose levels during pregnancy are associated with a higher
incidence of congenital abnormalities, many experts recommend that insulin be used during
pregnancy to maintain blood glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives. If Diaßeta is
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used during pregnancy, it should be discontinued at least two weeks before the expected delivery
date.
Nursing Mothers
Although it is not known whether Diaßeta is excreted in human milk, some sulfonylureas are
known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants
may exist, a decision should be made whether to discontinue nursing or to discontinue
administering the drug, taking into account the importance of the drug to the mother. If Diaßeta
is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy
should be considered.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
In US clinical studies of glyburide, 1406 of 2897 patients were ≥60 years and 515 patients were
≥70 years. Differences in safety and efficacy were not determined between these patients and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and
maintenance dosing should be conservative to avoid hypoglycemic reactions.
In three published studies of 20 to 51 subjects each, mixed results were seen in comparing the
pharmacokinetics of glyburide in elderly versus younger subjects. However, observed
pharmacodynamic differences indicate the necessity for dosage titration to a specified
therapeutic response.
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.
In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency,
the initial dosing, dose increments, and maintenance dosage should be conservative to avoid
hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people
who are taking beta-adrenergic blocking drugs or other sympatholytic agents. (See
PRECAUTIONS, General; and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE Sections.
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Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely; Diaßeta should
be discontinued if this occurs. Liver function abnormalities, including isolated transaminase
elevations, have been reported. Gastrointestinal disturbances, e.g., nausea, epigastric fullness,
and heartburn, are the most common reactions and occur in 1.8% of treated patients. They tend
to be dose-related and may disappear when dosage is reduced.
Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and
morbilliform or maculopapular eruptions, occur in 1.5% of treated patients. These may be
transient and may disappear despite continued use of Diaßeta; if skin reactions persist, the drug
should be discontinued.
Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally
may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia have been
reported with sulfonylureas.
Metabolic Reactions: Hepatic porphyria reactions have been reported with sulfonylureas;
however, these have not been reported with Diaßeta. Disulfiram-like reactions have been
reported very rarely with Diaßeta. Cases of hyponatremia have been reported with glyburide and
all other sulfonylureas, most often in patients who are on other medications or have medical
conditions known to cause hyponatremia or increase release of antidiuretic hormone. The
syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with
certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the
peripheral (antidiuretic) action of ADH and/or increase release of ADH.
Other Reactions: Changes in accommodation and/or blurred vision have been reported with
glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose
levels.
In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia
and vasculitis have been reported.
OVERDOSAGE
Overdosage of sulfonylureas, including Diaßeta, can produce hypoglycemia. Mild hypoglycemic
symptoms without loss of consciousness or neurologic findings should be treated aggressively
with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should
continue until the physician is assured that the patient is out of danger. Severe hypoglycemic
reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute
medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or
suspected, the patient should be given a rapid intravenous injection of concentrated (50%)
glucose solution. This should be followed by a continuous infusion of a more dilute (10%)
glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.
Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may
recur after apparent clinical recovery.
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DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with Diaßeta or any
other hypoglycemic agent. The patient’s fasting blood glucose must be measured periodically to
determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate
lowering of blood glucose at the maximum recommended dose of medication; and to detect
secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of
effectiveness. Periodic glycosylated hemoglobin determinations should be performed.
Short-term administration of Diaßeta may be sufficient during periods of transient loss of control
in patients usually controlled well on diet.
1.
Usual Starting Dose
The usual starting dose of Diaßeta as initial therapy is 2.5 to 5 mg daily, administered
with breakfast or the first main meal. Those patients who may be more sensitive to
hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS Section for
patients at increased risk). Failure to follow an appropriate dosage regimen may
precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug
regimen are more prone to exhibit unsatisfactory response to therapy.
Transfer of patients from other oral antidiabetic regimens to Diaßeta should be done
conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients
from oral hypoglycemic agents other than chlorpropamide, to Diaßeta, no transition
period and no initial priming dose is necessary. When transferring patients from
chlorpropamide, particular care should be exercised during the first two weeks because
the prolonged retention of chlorpropamide in the body and subsequent overlapping drug
effects may provoke hypoglycemia.
Bioavailability studies have demonstrated that Glynase®* PresTab®* Tablets 3 mg are
not bioequivalent to Diaßeta Tablets 5 mg. Therefore, these products are not substitutable
and patients should be retitrated if transferred.
Some Type II diabetic patients being treated with insulin may respond satisfactorily to
Diaßeta. If the insulin dose is less than 20 units daily, substitution of Diaßeta 2.5 to 5 mg
as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily,
the patient may be placed directly on Diaßeta 5 mg daily as a single dose. If the insulin
dose is more than 40 units daily, a transition period is required for conversion to Diaßeta.
In these patients, insulin dosage is decreased by 50% and Diaßeta 5 mg daily is started.
Please refer to Usual Maintenance Dose for further explanation.
2.
Usual Maintenance Dose
The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as
a single dose or in divided doses (See Dosage Interval Section). Dosage increases should
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For current labeling information, please visit https://www.fda.gov/drugsatfda
be made in increments of no more than 2.5 mg at weekly intervals based upon the
patient’s blood glucose response.
No exact dosage relationship exists between Diaßeta and the other oral hypoglycemic
agents. Although patients may be transferred from the maximum dose of other
sulfonylureas, the maximum starting dose of 5 mg of Diaßeta should be observed. A
maintenance dose of 5 mg Diaßeta provides approximately the same degree of blood
glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750
mg acetohexamide, or 1000 to 1500 mg tolbutamide.
When transferring patients receiving more than 40 units of insulin daily, they may be
started on a daily dose of Diaßeta 5 mg concomitantly with a 50% reduction in insulin
dose. Progressive withdrawal of insulin and increase of Diaßeta in increments of 1.25 to
2.5 mg every 2 to 10 days is then carried out. During this conversion period when both
insulin and Diaßeta are being used, hypoglycemia may rarely occur. During insulin
withdrawal, patients should self-test their blood for glucose and their urine for acetone at
least 3 times daily and report results to their physician. Self-testing of urinary glucose is a
less desirable alternative. The appearance of persistent acetonuria with glycosuria
indicates that the patient is a Type I diabetic who requires insulin therapy.
3.
Maximum Dose
Daily doses of more than 20 mg are not recommended.
4.
Dosage Interval
Once-a-day therapy is usually satisfactory, based upon usual meal patterns and a 10 hour
half-life of Diaßeta. Some patients, particularly those receiving more than 10 mg daily,
may have a more satisfactory response with twice-a-day dosage.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or
hepatic function, the initial and maintenance dosing should be conservative to avoid
hypoglycemic reactions. (See PRECAUTIONS Section.)
HOW SUPPLIED
Diaßeta (glyburide USP) tablets are available in the following strengths and package sizes:
1.25 mg (peach, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score
line between the “Dia” and the “ß” on one side and plain on the other side).
Bottles of 50
(NDC 0039-0053-05)
2.5 mg (pink, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score line
between the “Dia” and “ß” on one side and plain on the other side).
Bottles of 100
(NDC 0039-0051-10)
Bottles of 500
(NDC 0039-0051-50)
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5 mg (green, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score line
between the “Dia” and “ß” on one side and plain on the other side).
Bottles of 100
(NDC 0039-0052-10)
Bottles of 500
(NDC 0039-0052-50)
Bottles of 1000
(NDC 0039-0052-70)
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room
Temperature].
Dispense in well-closed containers with safety closures.
Rx only
Revised February 2009
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
*Trademarks of their respective owners, not affiliated with sanofi-aventis.
©2009 sanofi-aventis U.S. LLC
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custom-source
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2025-02-12T13:44:15.490456
|
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11,018
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Diaßeta® (glyburide) Tablets USP
1.25, 2.5 and 5 mg
DESCRIPTION
Diaßeta® (glyburide) is an oral blood-glucose-lowering drug of the sulfonylurea class. It is a
white, crystalline compound, formulated as tablets of 1.25 mg, 2.5 mg, and 5 mg strengths for
oral administration. Diaßeta tablets USP contain the active ingredient glyburide and the
following inactive ingredients: dibasic calcium phosphate USP, magnesium stearate NF,
microcrystalline cellulose NF, sodium alginate NF, talc USP. Diaßeta 1.25 mg tablets USP also
contain D&C Yellow #10 Aluminum Lake and FD&C Red #40 Aluminum Lake. Diaßeta 2.5 mg
tablets USP also contain FD&C Red #40 Aluminum Lake. Diaßeta 5 mg tablets USP also
contain D&C Yellow #10 Aluminum Lake, and FD&C Blue #1. Chemically, Diaßeta is
identified as 1-[[p-[2-(5-Chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclohexylurea.
The CAS Registry Number is 10238-21-8.
The structural formula is: structural formula
The molecular weight is 493.99. The aqueous solubility of Diaßeta increases with pH as a result
of salt formation.
CLINICAL PHARMACOLOGY
Diaßeta appears to lower the blood glucose acutely by stimulating the release of insulin from the
pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism
by which Diaßeta lowers blood glucose during long-term administration has not been clearly
established.
With chronic administration in Type II diabetic patients, the blood glucose lowering effect
persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic
effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
In addition to its blood glucose lowering actions, Diaßeta produces a mild diuresis by
enhancement of renal free water clearance. Clinical experience to date indicates an extremely
low incidence of disulfiram-like reactions in patients while taking Diaßeta.
Pharmacokinetics
Single-dose studies with Diaßeta in normal subjects demonstrate significant absorption within
one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four
hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time
curve, increase in proportion to corresponding increases in dose. Multiple-dose studies with
Diaßeta in diabetic patients demonstrate drug level concentration-time curves similar to single-
dose studies, indicating no build-up of drug in tissue depots. The decrease of glyburide in the
1
Reference ID: 3389297
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
serum of normal healthy individuals is biphasic, the terminal half-life being about 10 hours. In
single-dose studies in fasting normal subjects, the degree and duration of blood glucose lowering
is proportional to the dose administered and to the area under the drug level concentration-time
curve. The blood glucose lowering effect persists for 24 hours following single morning doses in
non-fasting diabetic patients. Under conditions of repeated administration in diabetic patients,
however, there is no reliable correlation between blood drug levels and fasting blood glucose
levels. A one-year study of diabetic patients treated with Diaßeta showed no reliable correlation
between administered dose and serum drug level.
The major metabolite of Diaßeta is the 4-trans-hydroxy derivative. A second metabolite, the 3
cis-hydroxy derivative, also occurs. These metabolites contribute no significant hypoglycemic
action since they are only weakly active (1/400th and 1/40th, respectively, as glyburide) in
rabbits.
Diaßeta is excreted as metabolites in the bile and urine, approximately 50% by each route. This
dual excretory pathway is qualitatively different from that of other sulfonylureas, which are
excreted primarily in the urine.
Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding
sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding
exhibited by Diaßeta is predominantly non-ionic, whereas that of other sulfonylureas
(chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as
phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum
proteins to a far greater extent than the non-ionic binding Diaßeta. It has not been shown that this
difference in protein binding will result in fewer drug-drug interactions with Diaßeta in clinical
use.
INDICATIONS AND USAGE
Diaßeta is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
type 2 diabetes mellitus.
CONTRAINDICATIONS
Diaßeta is contraindicated in patients:
1. With known hypersensitivity to the drug or any of its excipients.
2. With type 1 diabetes mellitus or diabetic ketoacidosis, with or without coma.
These conditions should be treated with insulin.
3. Treated with bosentan.
WARNINGS
SPECIAL WARNING ON INCREASED
RISK OF CARDIOVASCULAR MORTALITY
The administration of oral hypoglycemic drugs has been reported to be associated with
increased cardiovascular mortality as compared to treatment with diet alone or diet plus
insulin. This warning is based on the study conducted by the University Group Diabetes
Program (UGDP), a long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in
2
Reference ID: 3389297
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients with non-insulin-dependent diabetes. The study involved 823 patients who were
randomly assigned to one of four treatment groups (Diabetes 19 (supp. 2): 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of
tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2
1/2 times that of patients treated with diet alone. A significant increase in total mortality
was not observed, but the use of tolbutamide was discontinued based on the increase in
cardiovascular mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these results, the
findings of the UGDP study provide an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of Diaßeta and of alternative modes of
therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study,
it is prudent from a safety standpoint to consider that this warning may also apply to other
oral hypoglycemic drugs in this class, in view of their close similarities in mode of action
and chemical structure.
Persons allergic to other sulfonamide derivatives may develop an allergic reaction to glyburide
as well.
PRECAUTIONS
General
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence
of macrovascular risk reduction with Diaßeta or any other anti-diabetic drug.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper
patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Severe
renal or hepatic insufficiency may cause elevated blood levels of Diaßeta and the latter may also
diminish gluconeogenic capacity, both of which increase the risk of serious, prolonged
hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or
pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-
lowering drugs. Hypoglycemia may be difficult to recognize in patients with autonomic
neuropathy, the elderly, and in people who are taking beta-adrenergic blocking drugs or other
sympatholytic agents.
Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged
exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Loss
of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed to
stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it
may be necessary to discontinue Diaßeta and administer insulin.
The effectiveness of any oral hypoglycemic drug, including Diaßeta, in lowering blood glucose
to a desired level decreases in many patients over a period of time, which may be due to
progression of the severity of the diabetes or to diminished responsiveness to the drug. This
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phenomenon is known as secondary failure, to distinguish it from primary failure in which the
drug is ineffective in an individual patient when first given.
Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD)
deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Diaßeta belongs to
the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a
non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia
has also been reported in patients who did not have known G6PD deficiency.
Information for Patients
Patients should be informed of the potential risks and advantages of Diaßeta and of alternative
modes of therapy. They should also be informed about the importance of adherence to dietary
instructions, of a regular exercise program, and of regular testing of blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its
development should be explained to patients and responsible family members. Primary and secondary
failure should also be explained.
Laboratory Tests
Periodic fasting blood glucose measurements should be performed to monitor therapeutic
response. A glycosylated hemoglobin determination should also be performed periodically.
Drug Interactions
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including
nonsteroidal anti-inflammatory agents, ACE inhibitors, disopyramide, fluoxetine, clarithromycin,
and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol,
probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such
drugs are administered to a patient receiving Diaßeta, the patient should be observed closely for
hypoglycemia. When such drugs are withdrawn from a patient receiving Diaßeta, the patient
should be observed closely for loss of control.
An increased incidence of elevated liver enzymes was observed in patients receiving glyburide
concomitantly with bosentan. Therefore concomitant administration of Diaßeta and bosentan is
contraindicated (see CONTRAINDICATIONS).
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with the intravenous,
topical or vaginal preparations of miconazole is not known.
A possible interaction between glyburide and fluoroquinolone antibiotics has been reported
resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this
interaction is not known.
Possible interactions between glyburide and coumarin derivatives have been reported that may
either potentiate or weaken the effects of coumarin derivatives. The mechanism of these
interactions is not known.
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Rifampin may worsen glucose control of glyburide because rifampin can significantly induce
metabolic isozymes of glyburide such as CYP2C9 and 3A4.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,
estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel
blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Diaßeta,
the patient should be closely observed for loss of control. When such drugs are withdrawn from a
patient receiving Diaßeta, the patient should be observed closely for hypoglycemia.
Diaßeta may increase cyclosporine plasma concentration and potentially lead to its increased
toxicity. Monitoring and dosage adjustment of cyclosporine are therefore recommended when
both drugs are coadministered.
Colesevelam: Concomitant administration of colesevelam and glyburide resulted in reductions in
glyburide AUC and Cmax of 32% and 47%, respectively. When glyburide was administered
1 hour before colesevelam, the reductions in glyburide AUC and Cmax were 20% and 15%,
respectively, and not significantly changed (-7% and 4%, respectively) when administered
4 hours before colesevelam. Therefore, glyburide should be administered at least 4 hours prior to
colesevelam.
Glyburide is mainly metabolized by CYP 2C9 and to a lesser extent by CYP 3A4. There is a
potential for drug-drug interaction when glyburide is coadministered with inducers or inhibitors
of CYP 2C9, which should be taken into account when considering concomitant therapy.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Diaßeta is non-mutagenic when studied in the Salmonella microsome test (Ames test) and in the
DNA damage/alkaline elution assay. Studies in rats at doses up to 300 mg/kg/day for 18 months
showed no carcinogenic effects.
No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity
study of glyburide in mice.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Diaßeta has been shown to affect the maturation of the long bones (humerus and femur) in rat
pups when given in doses 6250 times the maximum recommended human dose. These effects,
which were seen during the period of lactation and not during organogenesis, are a shortening of
the bones with effects to various structures of the long bones, especially in humerus and femur.
There are no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, Diaßeta should be used during
pregnancy only if the potential benefit justifies the risk to the fetus. Because recent information
suggests that abnormal blood glucose levels during pregnancy are associated with a higher
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incidence of congenital abnormalities, many experts recommend that insulin be used during
pregnancy to maintain blood glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives. If Diaßeta is
used during pregnancy, it should be discontinued at least two weeks before the expected delivery
date.
Nursing Mothers
Although it is not known whether Diaßeta is excreted in human milk, some sulfonylureas are
known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants
may exist, a decision should be made whether to discontinue nursing or to discontinue
administering the drug, taking into account the importance of the drug to the mother. If Diaßeta
is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy
should be considered.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
In US clinical studies of glyburide, 1406 of 2897 patients were ≥60 years and 515 patients were
≥70 years. Differences in safety and efficacy were not determined between these patients and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and
maintenance dosing should be conservative to avoid hypoglycemic reactions.
In three published studies of 20 to 51 subjects each, mixed results were seen in comparing the
pharmacokinetics of glyburide in elderly versus younger subjects. However, observed
pharmacodynamic differences indicate the necessity for dosage titration to a specified
therapeutic response.
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.
In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency,
the initial dosing, dose increments, and maintenance dosage should be conservative to avoid
hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people
who are taking beta-adrenergic blocking drugs or other sympatholytic agents. (See
PRECAUTIONS, General; and DOSAGE AND ADMINISTRATION.)
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ADVERSE REACTIONS
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE Sections.
Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely which may
progress to liver failure; Diaßeta should be discontinued if this occurs. Liver function
abnormalities, including isolated transaminase elevations, have been reported. Gastrointestinal
disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and
occur in 1.8% of treated patients. They tend to be dose-related and may disappear when dosage is
reduced.
Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and
morbilliform or maculopapular eruptions, occur in 1.5% of treated patients. These may be
transient and may disappear despite continued use of Diaßeta; if skin reactions persist, the drug
should be discontinued.
Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally
may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia have been
reported with sulfonylureas.
Metabolic Reactions: Hepatic porphyria reactions have been reported with sulfonylureas;
however, these have not been reported with Diaßeta. Disulfiram-like reactions have been
reported very rarely with Diaßeta. Cases of hyponatremia have been reported with glyburide and
all other sulfonylureas, most often in patients who are on other medications or have medical
conditions known to cause hyponatremia or increase release of antidiuretic hormone. The
syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with
certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the
peripheral (antidiuretic) action of ADH and/or increase release of ADH.
Other Reactions: Changes in accommodation and/or blurred vision have been reported with
glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose
levels.
In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia
and vasculitis have been reported.
OVERDOSAGE
Overdosage of sulfonylureas, including Diaßeta, can produce hypoglycemia. Mild hypoglycemic
symptoms without loss of consciousness or neurologic findings should be treated aggressively
with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should
continue until the physician is assured that the patient is out of danger. Severe hypoglycemic
reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute
medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or
suspected, the patient should be given a rapid intravenous injection of concentrated (50%)
glucose solution. This should be followed by a continuous infusion of a more dilute (10%)
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glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.
Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may
recur after apparent clinical recovery.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with Diaßeta or any
other hypoglycemic agent. The patient’s fasting blood glucose must be measured periodically to
determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate
lowering of blood glucose at the maximum recommended dose of medication; and to detect
secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of
effectiveness. Periodic glycosylated hemoglobin determinations should be performed.
Short-term administration of Diaßeta may be sufficient during periods of transient loss of control
in patients usually controlled well on diet.
1.
Usual Starting Dose
The usual starting dose of Diaßeta as initial therapy is 2.5 to 5 mg daily, administered
with breakfast or the first main meal. Those patients who may be more sensitive to
hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS Section for
patients at increased risk). Failure to follow an appropriate dosage regimen may
precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug
regimen are more prone to exhibit unsatisfactory response to therapy.
Transfer of patients from other oral antidiabetic regimens to Diaßeta should be done
conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients
from oral hypoglycemic agents other than chlorpropamide, to Diaßeta, no transition
period and no initial priming dose is necessary. When transferring patients from
chlorpropamide, particular care should be exercised during the first two weeks because
the prolonged retention of chlorpropamide in the body and subsequent overlapping drug
effects may provoke hypoglycemia.
Bioavailability studies have demonstrated that Glynase®* PresTab®* Tablets 3 mg are
not bioequivalent to Diaßeta Tablets USP 5 mg. Therefore, these products are not
substitutable and patients should be retitrated if transferred.
Some Type II diabetic patients being treated with insulin may respond satisfactorily to
Diaßeta. If the insulin dose is less than 20 units daily, substitution of Diaßeta 2.5 to 5 mg
as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily,
the patient may be placed directly on Diaßeta 5 mg daily as a single dose. If the insulin
dose is more than 40 units daily, a transition period is required for conversion to Diaßeta.
In these patients, insulin dosage is decreased by 50% and Diaßeta 5 mg daily is started.
Please refer to Usual Maintenance Dose for further explanation.
When colesevelam is coadministered with glyburide, maximum plasma concentration and
total exposure to glyburide is reduced. Therefore, Diaßeta should be administered at least
4 hours prior to colesevelam.
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2.
Usual Maintenance Dose
The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as
a single dose or in divided doses (See Dosage Interval Section). Dosage increases should
be made in increments of no more than 2.5 mg at weekly intervals based upon the
patient’s blood glucose response.
No exact dosage relationship exists between Diaßeta and the other oral hypoglycemic
agents. Although patients may be transferred from the maximum dose of other
sulfonylureas, the maximum starting dose of 5 mg of Diaßeta should be observed. A
maintenance dose of 5 mg Diaßeta provides approximately the same degree of blood
glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750
mg acetohexamide, or 1000 to 1500 mg tolbutamide.
When transferring patients receiving more than 40 units of insulin daily, they may be
started on a daily dose of Diaßeta 5 mg concomitantly with a 50% reduction in insulin
dose. Progressive withdrawal of insulin and increase of Diaßeta in increments of 1.25 to
2.5 mg every 2 to 10 days is then carried out. During this conversion period when both
insulin and Diaßeta are being used, hypoglycemia may rarely occur. During insulin
withdrawal, patients should self-test their blood for glucose and their urine for acetone at
least 3 times daily and report results to their physician. Self-testing of urinary glucose is a
less desirable alternative. The appearance of persistent acetonuria with glycosuria
indicates that the patient is a Type I diabetic who requires insulin therapy.
3.
Maximum Dose
Daily doses of more than 20 mg are not recommended.
4.
Dosage Interval
Once-a-day therapy is usually satisfactory, based upon usual meal patterns and a 10 hour
half-life of Diaßeta. Some patients, particularly those receiving more than 10 mg daily,
may have a more satisfactory response with twice-a-day dosage.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or
hepatic function, the initial and maintenance dosing should be conservative to avoid
hypoglycemic reactions. (See PRECAUTIONS Section.)
HOW SUPPLIED
Diaßeta (glyburide) tablets USP are available in the following strengths and package sizes:
1.25 mg (peach, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score
line between the “Dia” and the “ß” on one side and plain on the other side).
Bottles of 50
(NDC 0039-0053-05)
2.5 mg (pink, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score line
between the “Dia” and “ß” on one side and plain on the other side).
Bottles of 100
(NDC 0039-0051-10)
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5 mg (green, capsule-shaped, flat faced, beveled edge tablet debossed “Dia ß” with a score line
between the “Dia” and “ß” on one side and plain on the other side).
Bottles of 100
(NDC 0039-0052-10)
Bottles of 1000
(NDC 0039-0052-70)
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room
Temperature].
Dispense in well-closed containers with safety closures.
Rx only
Revised October 2013
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
*Trademarks of their respective owners, not affiliated with sanofi-aventis.
©2013 sanofi-aventis U.S. LLC
10
Reference ID: 3389297
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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.
/s/
AMY G EGAN
10/15/2013
Reference ID: 3389297
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:15.785019
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017532Orig1s034lbl.pdf', 'application_number': 17532, 'submission_type': 'SUPPL ', 'submission_number': 34}
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SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 1 DRAFT LABELING
XXXXXXXX
PRODUCT INFORMATION
DIPROSONE®
brand of betamethasone
dipropionate
Cream, USP 0.05%
(potency expressed as betamethasone)
For Dermatologic Use Only -
Not for Ophthalmic Use
DESCRIPTION DIPROSONE Cream contains betamethasone dipropionate, USP, a
synthetic adrenocorticosteroid, for dermatologic use. Betamethasone, an analog of
prednisolone, has high corticosteroid activity and slight mineralocorticoid activity.
Betamethasone dipropionate is the 17, 21-dipropionate ester of betamethasone.
Chemically, betamethasone dipropionate is 9-Fluoro-11β,17,21-trihydroxy-16β-
methylpregna-1,4-diene-3,20-dione
17,21-dipropionate,
with
the
empirical
formula
C28H37FO7, a molecular weight of 504.6, and the following structural formula:
Betamethasone dipropionate is a white to creamy white, odorless crystalline
powder, insoluble in water.
Each gram of DIPROSONE Cream 0.05% contains: 0.643 mg betamethasone
dipropionate, USP (equivalent to 0.5 mg betamethasone) in a hydrophilic emollient cream
consisting of purified water, USP; mineral oil, USP; white petrolatum, USP; ceteareth-30;
cetearyl alcohol 70/30 (7.2%); sodium phosphate monobasic monohydrate R; and
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SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 2 DRAFT LABELING
phosphoric acid, NF; chlorocresol and propylene glycol, USP as preservatives. May also
contain sodium hydroxide R to adjust pH to approximately 5.0.
CLINICAL PHARMACOLOGY The corticosteroids are a class of compounds comprising
steroid hormones, secreted by the adrenal cortex and their synthetic analogs. In
pharmacologic doses corticosteroids are used primarily for their anti-inflammatory and/or
immunosuppressive effects.
Topical corticosteroids, such as betamethasone dipropionate, are effective in the
treatment of corticosteroid-responsive dermatoses primarily because of their anti-
inflammatory, antipruritic, and vasoconstrictive actions. However, while the physiologic,
pharmacologic, and clinical effects of the corticosteroids are well known, the exact
mechanisms of their actions in each disease are uncertain. 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 increase percutaneous absorption. Occlusive
dressings substantially increase the percutaneous absorption of topical corticosteroids.
(See DOSAGE AND ADMINISTRATION.)
Once absorbed through the skin, topical corticosteroids are handled through
pharmacokinetic
pathways
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.
Sixty-three pediatric patients ages 1 to 12 years, with atopic dermatitis, were
enrolled in an open-label, hypothalamic-pituitary-adrenal (HPA) axis safety study.
DIPROSONE Cream was applied twice daily for 2 to 3 weeks over a mean body surface
area of 40% (range 35% to 90%). In 10 of 43 (23%) evaluable patients, adrenal
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SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 3 DRAFT LABELING
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.
Studies performed with DIPROSONE Cream indicate that it is in the medium
range of potency as compared with other topical corticosteroids.
INDICATIONS AND USAGE DIPROSONE Cream is a medium-potency corticosteroid
indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-
responsive dermatoses in patients 13 years and older.
CONTRAINDICATIONS DIPROSONE Cream is contraindicated in patients who are
hypersensitive to betamethasone dipropionate, to other corticosteroids, or to any
ingredient in this preparation.
PRECAUTIONS General 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.
Conditions which augment systemic absorption include the application of the more
potent steroids, use over large surface areas, prolonged use, and the addition of occlusive
dressings. Use of more than one corticosteroid-containing product at the same time may
increase
total
systemic
glucocorticoid
exposure.
(See
DOSAGE
AND
ADMINISTRATION.)
Therefore, patients receiving a large dose of a potent topical steroid applied to a
large surface area should be evaluated periodically for evidence of HPA axis suppression
by using the urinary-free cortisol and ACTH stimulation 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 steroid.
Recovery of HPA axis function is generally prompt and complete upon
discontinuation of the drug. In an open-label pediatric study of 43 evaluable patients, of
the 10 subjects who showed evidence of suppression, 2 subjects were tested 2 weeks
after discontinuation of DIPROSONE cream, 0.05%, and 1 of the 2 (50%) had complete
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SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 4 DRAFT LABELING
recovery of HPA axis function. Infrequently, signs and symptoms of steroid withdrawal
may occur, requiring supplemental systemic corticosteroids.
Pediatric
patients
may
absorb
proportionally
larger
amounts
of
topical
corticosteroids and thus be more susceptible to systemic toxicity. (See PRECAUTIONS -
Pediatric Use.)
If irritation develops, topical corticosteroids should be discontinued and appropriate
therapy instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or
antibacterial agent should be instituted. If a favorable response does not occur promptly,
the corticosteroid should be discontinued until the infection has been adequately
controlled.
Information for Patients This information is intended to aid in the safe and effective use
of this medication. It is not a disclosure of all possible adverse or intended effects.
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. Patients should be advised not to use this medication 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 as to
be occlusive. (See DOSAGE AND ADMINISTRATION.)
4. Patients should report any signs of local adverse reactions.
5. Other corticosteroid-containing products should not be used with DIPROSONE Cream
without first talking to your physician.
Laboratory Tests The following tests may be helpful in evaluating HPA axis suppression:
Urinary-free cortisol test
ACTH stimulation test
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SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 5 DRAFT LABELING
Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies
have not been performed to evaluate the carcinogenic potential of betamethasone
dipropionate.
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 0.5 and 4 fold the
estimated maximum human dose based on a mg/m2 comparison, respectively.
Pregnancy: Teratogenic effects: Pregnancy Category C: Corticosteroids are generally
teratogenic in laboratory animals when administered systemically at relatively low dosage
levels.
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 0.03 fold the
estimated maximum human dose based on a mg/m2 comparison. The abnormalities
observed included umbilical hernias, cephalocele and cleft palates.
Some corticosteroids have been shown to be teratogenic after dermal application in
laboratory animals. There are no adequate and well-controlled studies in pregnant women
on teratogenic effects from topically applied corticosteroids. Therefore, topical
corticosteroids should be used during pregnancy only if the potential benefit justifies the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 6 DRAFT LABELING
potential risk to the fetus. Drugs of this class should not be used extensively on pregnant
patients, in large amounts, or for prolonged periods of time.
Nursing Mothers It is not known whether topical administration of corticosteroids could
result in sufficient systemic absorption to produce detectable quantities in breast milk.
Systemically administered corticosteroids are secreted into breast milk in quantities not
likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised
when topical corticosteroids are prescribed for a nursing woman.
Pediatric Use Use of DIPROSONE cream, 0.05%, in pediatric patients 12 years of age
and younger is not recommended. (See CLINICAL PHARMACOLOGY and ADVERSE
REACTIONS Sections.)
In an open-label study, 10 of 43 (23%) evaluable pediatric patients (aged 2 years –
12 years old) using DIPROSONE Cream for treatment of atopic dermatitis for 2-3 weeks
demonstrated HPA axis suppression. The proportion of patients with adrenal suppression
in this study was progressively greater, the younger the age group. (See CLINICAL
PHARMACOLOGY - Pharmacokinetics.)
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 area to body weight ratio. The study described above supports this
premise, as suppression in 9-12 year olds, 6-8 year olds, and 2-5 year olds was 14%,
23%, and 30%, respectively.
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and
intracranial hypertension have been reported in pediatric patients receiving topical
corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear
growth retardation, delayed weight gain, low plasma cortisol levels, and absence of
response to ACTH stimulation. Manifestations of intracranial hypertension include bulging
fontanelles, headaches, and bilateral papilledema.
Administration of topical corticosteroids to pediatric patients should be limited to the
least amount compatible with an effective therapeutic regimen. Chronic corticosteroid
therapy may interfere with the growth and development of pediatric patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 7 DRAFT LABELING
ADVERSE REACTIONS The following local adverse reactions are reported infrequently
when DIPROSONE Cream is used as recommended in the DOSAGE AND
ADMINISTRATION section. These reactions are listed in an approximate decreasing
order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis,
acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis,
maceration of the skin, secondary infection, skin atrophy, striae, miliaria.
Adverse reactions reported to be possibly or probably related to treatment with
DIPROSONE cream during a pediatric clinical study include signs of skin atrophy
(bruising, shininess). Skin atrophy occurred in 3 of 63 (5%) patients, a 3-year old, a 5-
year old, and a 7-year old.
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.
OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts
to produce systemic effects. (See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Apply a thin film of DIPROSONE Cream 0.05% to the affected skin areas once daily. In
some cases, a twice-daily dosage may be necessary.
DIPROSONE Cream is not to be used with occlusive dressings.
HOW SUPPLIED DIPROSONE Cream 0.05% is supplied in 15-g (NDC 0085-0853-02)
and 45-g (NDC 0085-0853-03) tubes; boxes of one.
Store DIPROSONE Cream between 2°° and 30°°C (36°° and 86°°F).
Schering Corporation
Kenilworth, NJ 07033 USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SCH 11460
SECTION 2
DIPROSONE CREAM PAGE 8 DRAFT LABELING
Rev. 5/01
B-XXXXXXXX
YYYYYYYYYT
Copyright © 1974, 1991, 1999, 2001
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
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/
---------------------
Jonathan Wilkin
10/3/01 10:03:45 AM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:15.993078
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/17536s18lbl.pdf', 'application_number': 17536, 'submission_type': 'SUPPL ', 'submission_number': 18}
|
11,019
|
Roche Logo
KLONOPIN® TABLETS
(clonazepam)
KLONOPIN® WAFERS
(clonazepam orally disintegrating tablets)
Rx only
DESCRIPTION
Klonopin, a benzodiazepine, is available as scored tablets with a K-shaped perforation
containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation
containing 1 mg or 2 mg of clonazepam. Each tablet also contains lactose, magnesium
stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5
mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. 2
Lake.
Klonopin is also available as an orally disintegrating tablet containing 0.125 mg, 0.25
mg, 0.5 mg, 1 mg or 2 mg clonazepam. Each orally disintegrating tablet also contains
gelatin, mannitol, methylparaben sodium, propylparaben sodium and xanthan gum.
Chemically,
clonazepam
is
5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4
benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of
315.72 and the following structural formula: Chemical Structure of clonazepam
CLINICAL PHARMACOLOGY
Pharmacodynamics: The precise mechanism by which clonazepam exerts its antiseizure
and antipanic effects is unknown, although it is believed to be related to its ability to
enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory
neurotransmitter in the central nervous system. Convulsions produced in rodents by
pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are
convulsions produced by photic stimulation in susceptible baboons. A taming effect in
aggressive primates, muscle weakness and hypnosis are also produced. In humans,
clonazepam is capable of suppressing the spike and wave discharge in absence seizures
(petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in
minor motor seizures.
Pharmacokinetics: Clonazepam is rapidly and completely absorbed after oral
administration. The absolute bioavailability of clonazepam is about 90%. Maximum
plasma concentrations of clonazepam are reached within 1 to 4 hours after oral
administration. Clonazepam is approximately 85% bound to plasma proteins.
Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being
excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group
to the 4-amino derivative. This derivative can be acetylated, hydroxylated and
glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in
clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically
30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the
dosing range. There is no evidence that clonazepam induces its own metabolism or that
of other drugs in humans.
Pharmacokinetics in Demographic Subpopulations and in Disease States: Controlled
studies examining the influence of gender and age on clonazepam pharmacokinetics have
not been conducted, nor have the effects of renal or liver disease on clonazepam
pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is
possible that liver disease will impair clonazepam elimination. Thus, caution should be
exercised when administering clonazepam to these patients.
Clinical Trials: Panic Disorder: The effectiveness of Klonopin in the treatment of panic
disorder was demonstrated in two double-blind, placebo-controlled studies of adult
outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without
agoraphobia. In these studies, Klonopin was shown to be significantly more effective
than placebo in treating panic disorder on change from baseline in panic attack frequency,
the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global
Impression Improvement Score.
Study 1 was a 9-week, fixed-dose study involving Klonopin doses of 0.5, 1, 2, 3 or 4
mg/day or placebo. This study was conducted in four phases: a 1-week placebo lead-in, a
3-week upward titration, a 6-week fixed dose and a 7-week discontinuance phase. A
significant difference from placebo was observed consistently only for the 1 mg/day
group. The difference between the 1 mg dose group and placebo in reduction from
baseline in the number of full panic attacks was approximately 1 panic attack per week.
At endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic
attacks, compared to 56% of placebo-treated patients.
Study 2 was a 6-week, flexible-dose study involving Klonopin in a dose range of 0.5 to 4
mg/day or placebo. This study was conducted in three phases: a 1-week placebo lead-in, a
6-week optimal-dose and a 6-week discontinuance phase. The mean clonazepam dose
during the optimal dosing period was 2.3 mg/day. The difference between Klonopin and
placebo in reduction from baseline in the number of full panic attacks was approximately
1 panic attack per week. At endpoint, 62% of patients receiving clonazepam were free of
full panic attacks, compared to 37% of placebo-treated patients.
Subgroup analyses did not indicate that there were any differences in treatment outcomes
as a function of race or gender.
Page 2 of 19
INDICATIONS AND USAGE
Seizure Disorders: Klonopin is useful alone or as an adjunct in the treatment of the
Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In
patients with absence seizures (petit mal) who have failed to respond to succinimides,
Klonopin may be useful.
In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often
within 3 months of administration. In some cases, dosage adjustment may reestablish
efficacy.
Panic Disorder: Klonopin 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 Klonopin was established in two 6- to 9-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, ie, 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.
The effectiveness of Klonopin in long-term use, that is, for more than 9 weeks, has not
been systematically studied in controlled clinical trials. The physician who elects to use
Klonopin for extended periods should periodically reevaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Klonopin should not be used in patients with a history of sensitivity to benzodiazepines,
nor in patients with clinical or biochemical evidence of significant liver disease. It may
be used in patients with open angle glaucoma who are receiving appropriate therapy but
is contraindicated in acute narrow angle glaucoma.
WARNINGS
Interference With Cognitive and Motor Performance: Since Klonopin produces CNS
depression, patients receiving this drug should be cautioned against engaging in
hazardous occupations requiring mental alertness, such as operating machinery or driving
a motor vehicle. They should also be warned about the concomitant use of alcohol or
other CNS-depressant drugs during Klonopin therapy (see PRECAUTIONS: Drug
Interactions and Information for Patients).
Page 3 of 19
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including Klonopin,
increase the risk of suicidal thoughts or behavior in patients taking these drugs for any
indication. Patients treated with any AED for any indication should be monitored for the
emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual
changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy)
of 11 different AEDs showed that patients randomized to one of the AEDs had
approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal
thinking or behavior compared to patients randomized to placebo. In these trials, which
had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal
behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24%
among 16,029 placebo-treated patients, representing an increase of approximately one
case of suicidal thinking or behavior for every 530 patients treated. There were four
suicides in drug-treated patients in the trials and none in placebo-treated patients, but the
number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as
one week after starting drug treatment with AEDs and persisted for the duration of
treatment assessed. Because most trials included in the analysis did not extend beyond 24
weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the
data analyzed. The finding of increased risk with AEDs of varying mechanisms of action
and across a range of indications suggests that the risk applies to all AEDs used for any
indication. The risk did not vary substantially by age (5-100 years) in the clinical trials
analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1
Risk by Indication for Antiepileptic Drugs in the Pooled
Analysis
Indication
Placebo
Patients with
Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events per 1000
Patients
Epilepsy
Psychiatric
Other
Total
1.0
5.7
1.0
2.4
3.4
8.5
1.8
4.3
3.5
1.5
1.9
1.8
2.4
2.9
0.9
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy
than in clinical trials for psychiatric or other conditions, but the absolute risk differences
were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Klonopin or any other AED must balance the risk of
suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other
illnesses for which AEDs are prescribed are themselves associated with morbidity and
Page 4 of 19
mortality and an increased risk of suicidal thoughts and behavior. Should suicidal
thoughts and behavior emerge during treatment, the prescriber needs to consider whether
the emergence of these symptoms in any given patient may be related to the illness being
treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of
suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of the signs and symptoms of depression, any unusual changes
in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about
self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Pregnancy Risks: Data from several sources raise concerns about the use of Klonopin
during pregnancy.
Animal Findings: In three studies in which Klonopin was administered orally to pregnant
rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the
maximum recommended human dose of 20 mg/day for seizure disorders and equivalent
to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period
of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused
sternebrae and limb defects) was observed in a low, non-dose-related incidence in
exposed litters from all dosage groups. Reductions in maternal weight gain occurred at
dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one
study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were
observed in mice and rats following administration during organogenesis of oral doses up
to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum
recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the
maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).
General Concerns and Considerations About Anticonvulsants: Recent reports suggest an
association between the use of anticonvulsant drugs by women with epilepsy and an
elevated incidence of birth defects in children born to these women. Data are more
extensive with respect to diphenylhydantoin and phenobarbital, but these are also the
most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a
possible similar association with the use of all known anticonvulsant drugs.
In children of women treated with drugs for epilepsy, reports suggesting an elevated
incidence of birth defects cannot be regarded as adequate to prove a definite cause and
effect relationship. There are intrinsic methodologic problems in obtaining adequate data
on drug teratogenicity in humans; the possibility also exists that other factors (eg, genetic
factors or the epileptic condition itself) may be more important than drug therapy in
leading to birth defects. The great majority of mothers on anticonvulsant medication
deliver normal infants. It is important to note that anticonvulsant drugs should not be
discontinued in patients in whom the drug is administered to prevent seizures because of
the strong possibility of precipitating status epilepticus with attendant hypoxia and threat
to life. In individual cases where the severity and frequency of the seizure disorder are
such that the removal of medication does not pose a serious threat to the patient,
Page 5 of 19
discontinuation of the drug may be considered prior to and during pregnancy; however, it
cannot be said with any confidence that even mild seizures do not pose some hazards to
the developing embryo or fetus.
General Concerns About Benzodiazepines: An increased risk of congenital
malformations associated with the use of benzodiazepine drugs has been suggested in
several studies.
There may also be non-teratogenic risks associated with the use of benzodiazepines
during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding
difficulties, and hypothermia in children born to mothers who have been receiving
benzodiazepines late in pregnancy. In addition, children born to mothers receiving
benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal
symptoms during the postnatal period.
Advice Regarding the Use of Klonopin in Women of Childbearing Potential: In general,
the use of Klonopin in women of childbearing potential, and more specifically during
known pregnancy, should be considered only when the clinical situation warrants the risk
to the fetus.
The specific considerations addressed above regarding the use of anticonvulsants for
epilepsy in women of childbearing potential should be weighed in treating or counseling
these women.
Because of experience with other members of the benzodiazepine class, Klonopin is
assumed to be capable of causing an increased risk of congenital abnormalities when
administered to a pregnant woman during the first trimester. Because use of these drugs
is rarely a matter of urgency in the treatment of panic disorder, their use during the first
trimester should almost always be avoided. The possibility that a woman of childbearing
potential may be pregnant at the time of institution of therapy should be considered. 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. Patients should
also be advised that if they become pregnant during therapy or intend to become
pregnant, they should communicate with their physician about the desirability of
discontinuing the drug.
Withdrawal Symptoms: Withdrawal symptoms of the barbiturate type have occurred
after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
PRECAUTIONS
General: Worsening of Seizures: When used in patients in whom several different types
of seizure disorders coexist, Klonopin may increase the incidence or precipitate the onset
of generalized tonic-clonic seizures (grand mal). This may require the addition of
appropriate anticonvulsants or an increase in their dosages. The concomitant use of
valproic acid and Klonopin may produce absence status.
Laboratory Testing During Long-Term Therapy: Periodic blood counts and liver function
tests are advisable during long-term therapy with Klonopin.
Page 6 of 19
Risks of Abrupt Withdrawal: The abrupt withdrawal of Klonopin, particularly in those
patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore,
when discontinuing Klonopin, gradual withdrawal is essential. While Klonopin is being
gradually withdrawn, the simultaneous substitution of another anticonvulsant may be
indicated.
Caution in Renally Impaired Patients: Metabolites of Klonopin are excreted by the
kidneys; to avoid their excess accumulation, caution should be exercised in the
administration of the drug to patients with impaired renal function.
Hypersalivation: Klonopin may produce an increase in salivation. This should be
considered before giving the drug to patients who have difficulty handling secretions.
Because of this and the possibility of respiratory depression, Klonopin should be used
with caution in patients with chronic respiratory diseases.
Information for Patients: Patients should be instructed to take Klonopin only as
prescribed. Physicians are advised to discuss the following issues with patients for whom
they prescribe Klonopin:
Dose Changes: To assure the safe and effective use of benzodiazepines, patients should
be informed that, since benzodiazepines may produce psychological and physical
dependence, it is advisable that they consult with their physician before either increasing
the dose or abruptly discontinuing this drug.
Interference With Cognitive and Motor Performance: Because benzodiazepines have the
potential to impair judgment, thinking or motor skills, patients should be cautioned about
operating hazardous machinery, including automobiles, until they are reasonably certain
that Klonopin therapy does not affect them adversely.
Suicidal Thinking and Behavior: Patients, their caregivers, and families should be
counseled that AEDs, including Klonopin, may increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of
symptoms of depression, any unusual changes in mood or behavior, or the emergence of
suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be
reported immediately to healthcare providers.
Pregnancy: Patients should be advised to notify their physician if they become pregnant
or intend to become pregnant during therapy with Klonopin (see WARNINGS:
Pregnancy Risks). Patients should be encouraged to enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry
is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS:
Pregnancy).
Nursing: Patients should be advised not to breastfeed an infant if they are taking
Klonopin.
Page 7 of 19
Concomitant Medication: Patients should be advised to inform their physicians if they are
taking, or plan to take, any prescription or over-the-counter drugs, since there is a
potential for interactions.
Alcohol: Patients should be advised to avoid alcohol while taking Klonopin.
Drug Interactions: Effect of Clonazepam on the Pharmacokinetics of Other Drugs:
Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine
or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not
been investigated.
Effect of Other Drugs on the Pharmacokinetics of Clonazepam: Literature reports suggest
that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam
pharmacokinetics.
In a study in which the 2 mg clonazepam orally disintegrating tablet was administered
with and without propantheline (an anticholinergic agent with multiple effects on the GI
tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax of
clonazepam was 20% lower when the orally disintegrating tablet was given with
propantheline compared to when it was given alone.
Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450
inducers, such as phenytoin, carbamazepine and phenobarbital, induce clonazepam
metabolism, causing an approximately 30% decrease in plasma clonazepam levels.
Although clinical studies have not been performed, based on the involvement of the
cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme
system, notably oral antifungal agents, should be used cautiously in patients receiving
clonazepam.
Pharmacodynamic Interactions: The CNS-depressant action of the benzodiazepine class
of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics,
antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of
antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and
by other anticonvulsant drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not
been conducted with clonazepam.
The data currently available are not sufficient to determine the genotoxic potential of
clonazepam.
In a two-generation fertility study in which clonazepam was given orally to rats at 10 and
100 mg/kg/day (low dose approximately 5 times and 24 times the maximum
recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic
disorder, respectively, on a mg/m2 basis), there was a decrease in the number of
pregnancies and in the number of offspring surviving until weaning.
Pregnancy: Teratogenic Effects: Pregnancy Category D (see WARNINGS: Pregnancy
Risks).
Page 8 of 19
To provide information regarding the effects of in utero exposure to Klonopin, physicians
are advised to recommend that pregnant patients taking Klonopin enroll in the NAAED
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334,
and must be done by patients themselves. Information on this registry can also be found
at the website http://www.aedpregnancyregistry.org/.
Labor and Delivery: The effect of Klonopin on labor and delivery in humans has not
been specifically studied; however, perinatal complications have been reported in
children born to mothers who have been receiving benzodiazepines late in pregnancy,
including findings suggestive of either excess benzodiazepine exposure or of withdrawal
phenomena (see WARNINGS: Pregnancy Risks).
Nursing Mothers: Mothers receiving Klonopin should not breastfeed their infants.
Pediatric Use: Because of the possibility that adverse effects on physical or mental
development could become apparent only after many years, a benefit-risk consideration
of the long-term use of Klonopin is important in pediatric patients being treated for
seizure
disorder
(see
INDICATIONS
AND
USAGE
and
DOSAGE
AND
ADMINISTRATION).
Safety and effectiveness in pediatric patients with panic disorder below the age of 18
have not been established.
Geriatric Use: Clinical studies of Klonopin 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.
Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will
impair clonazepam elimination. Metabolites of Klonopin are excreted by the kidneys; to
avoid their excess accumulation, caution should be exercised in the administration of the
drug to patients with impaired renal function. Because elderly patients are more likely to
have decreased hepatic and/or renal function, care should be taken in dose selection, and
it may be useful to assess hepatic and/or renal function at the time of dose selection.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients
generally should be started on low doses of Klonopin and observed closely.
ADVERSE REACTIONS
The adverse experiences for Klonopin are provided separately for patients with seizure
disorders and with panic disorder.
Seizure Disorders: The most frequently occurring side effects of Klonopin are referable
to CNS depression. Experience in treatment of seizures has shown that drowsiness has
occurred in approximately 50% of patients and ataxia in approximately 30%. In some
cases, these may diminish with time; behavior problems have been noted in
approximately 25% of patients. Others, listed by system, are:
Page 9 of 19
Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia,
dysarthria, dysdiadochokinesis, ‘‘glassy-eyed’’ appearance, headache, hemiparesis,
hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo
Psychiatric: Confusion, depression, amnesia, hallucinations, hysteria, increased libido,
insomnia, psychosis,(the behavior effects are more likely to occur in patients with a
history of psychiatric disturbances). The following paradoxical reactions have been
observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility,
anxiety, sleep disturbances, nightmares and vivid dreams
Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper
respiratory passages
Cardiovascular: Palpitations
Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis,
gastritis, increased appetite, nausea, sore gums
Genitourinary: Dysuria, enuresis, nocturia, urinary retention
Musculoskeletal: Muscle weakness, pains
Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss
or gain
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline
phosphatase
Panic Disorder: Adverse events during exposure to Klonopin were obtained by
spontaneous report and 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 events into a smaller number of standardized event categories. In the tables and
tabulations that follow, CIGY dictionary terminology has been used to classify reported
adverse events, except in certain cases in which redundant terms were collapsed into
more meaningful terms, as noted below.
The stated frequencies of adverse events represent the proportion of individuals who
experienced, at least once, a treatment-emergent adverse event of the type listed. An
event was considered treatment-emergent if it occurred for the first time or worsened
while receiving therapy following baseline evaluation.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials:
Adverse Events Associated With Discontinuation of Treatment:
Overall, the incidence of discontinuation due to adverse events was 17% in Klonopin
compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most
Page 10 of 19
common events (≥1%) associated with discontinuation and a dropout rate twice or greater
for Klonopin than that of placebo included the following:
Table 2
Most Common Adverse Events (≥1%) Associated with
Discontinuation of Treatment
Adverse Event
Klonopin (N=574)
Placebo (N=294)
Somnolence
7%
1%
Depression
4%
1%
Dizziness
1%
<1%
Nervousness
1%
0%
Ataxia
1%
0%
Intellectual Ability Reduced
1%
0%
Adverse Events Occurring at an Incidence of 1% or More Among Klonopin-Treated
Patients:
Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent
adverse events that occurred during acute therapy of panic disorder from a pool of two 6-
to 9-week trials. Events reported in 1% or more of patients treated with Klonopin (doses
ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in
placebo-treated patients are included.
The prescriber should be aware that the figures in Table 3 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 in the
population studied.
Table 3
Treatment-Emergent Adverse Event Incidence in 6- to 9
Week Placebo-Controlled Clinical Trials*
Clonazepam Maximum Daily Dose
Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Central & Peripheral Nervous
System
Somnolence†
Dizziness
Coordination Abnormal†
Ataxia†
Dysarthria†
26
5
1
2
0
35
5
2
1
0
50
12
7
8
4
36
8
9
8
3
37
8
6
5
2
10
4
0
0
0
Psychiatric
Page 11 of 19
Clonazepam Maximum Daily Dose
Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Depression
7
6
8
8
7
1
Memory Disturbance
2
5
2
5
4
2
Nervousness
1
4
3
4
3
2
Intellectual Ability Reduced
0
2
4
3
2
0
Emotional Lability
0
1
2
2
1
1
Libido Decreased
0
1
3
1
1
0
Confusion
0
2
2
1
1
0
Respiratory System
Upper Respiratory Tract
Infection†
10
10
7
6
8
4
Sinusitis
4
2
8
4
4
3
Rhinitis
3
2
4
2
2
1
Coughing
2
2
4
0
2
0
Pharyngitis
1
1
3
2
2
1
Bronchitis
1
0
2
2
1
1
Gastrointestinal System
Constipation†
0
1
5
3
2
2
Appetite Decreased
1
1
0
3
1
1
Abdominal Pain†
2
2
2
0
1
1
Page 12 of 19
Clonazepam Maximum Daily Dose
Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Body as a Whole
Fatigue
Allergic Reaction
9
3
6
1
7
4
7
2
7
2
4
1
Musculoskeletal
Myalgia
2
1
4
0
1
1
Resistance Mechanism
Disorders
Influenza
3
2
5
5
4
3
Urinary System
Micturition Frequency
Urinary Tract Infection†
1
0
2
0
2
2
1
2
1
1
0
0
Vision Disorders
Blurred Vision
1
2
3
0
1
1
Reproductive Disorders‡
Female
Dysmenorrhea
Colpitis
Male
Ejaculation Delayed
Impotence
0
4
0
3
6
0
0
0
5
2
2
2
2
1
2
1
3
1
1
1
2
1
0
0
* Events reported by at least 1% of patients treated with Klonopin and for which the
incidence was greater than that for placebo.
† Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel) for
adverse event incidence was ≤0.10.
‡ Denominators for events in gender-specific systems are: n= 240 (clonazepam), 102
(placebo) for male, and 334 (clonazepam), 192 (placebo) for female.
Page 13 of 19
Commonly Observed Adverse Events:
Table 4
Incidence of Most Commonly Observed Adverse Events* in
Acute Therapy in Pool of 6- to 9-Week Trials
Adverse Event
(Roche Preferred Term)
Clonazepam
(N=574)
Placebo
(N=294)
Somnolence
37%
10%
Depression
7%
1%
Coordination Abnormal
6%
0%
Ataxia
5%
0%
* Treatment-emergent events for which the incidence in the clonazepam patients was
≥5% and at least twice that in the placebo patients.
Treatment-Emergent Depressive Symptoms:
In the pool of two short-term placebo-controlled trials, adverse events classified under the
preferred term “depression” were reported in 7% of Klonopin-treated patients compared
to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these
same trials, adverse events classified under the preferred term “depression” were reported
as leading to discontinuation in 4% of Klonopin-treated patients compared to 1% of
placebo-treated patients. While these findings are noteworthy, Hamilton Depression
Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D
scores in the clonazepam group than the placebo group suggesting that clonazepam
treated patients were not experiencing a worsening or emergence of clinical depression.
Other Adverse Events Observed During the Premarketing Evaluation of Klonopin in
Panic Disorder:
Following is a list of modified CIGY terms that reflect treatment-emergent adverse
events reported by patients treated with Klonopin at multiple doses during clinical trials.
All reported events are included except those already listed in Table 3 or elsewhere in
labeling, those events for which a drug cause was remote, those event terms which were
so general as to be uninformative, and events reported only once and which did not have
a substantial probability of being acutely life-threatening. It is important to emphasize
that, although the events occurred during treatment with Klonopin, they were not
necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency. These adverse events were reported infrequently, which is defined as
occurring in 1/100 to 1/1000 patients.
Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever,
shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain,
cellulitis, inflammation localized
Cardiovascular Disorders: chest pain, hypotension postural
Page 14 of 19
Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness,
feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness,
hyperactivity, hypoesthesia, tongue thick, twitching
Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation,
stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel
movements frequent, pain pelvic, dyspepsia, hemorrhoids
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
Heart Rate and Rhythm Disorders: palpitation
Metabolic and Nutritional Disorders: thirst, gout
Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain
leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis,
arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee
Platelet, Bleeding and Clotting Disorders: bleeding dermal
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization,
dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased,
aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal,
illusion, nightmares, sleep disorder, suicide ideation, yawning
Reproductive Disorders, Female: breast pain, menstrual irregularity
Reproductive Disorders, Male: ejaculation decreased
Resistance Mechanism Disorders: infection mycotic, infection viral, infection
streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis
Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed,
pneumonia, pleurisy
Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact,
flushing, pruritus, pustular reaction, skin burns, skin disorder
Special Senses Other, Disorders: taste loss
Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder
dysfunction, urinary retention, urinary tract bleeding, urine discoloration
Vascular (Extracardiac) Disorders: thrombophlebitis leg
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual
field defect, xerophthalmia
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Clonazepam is a Schedule IV controlled substance.
Physical and Psychological Dependence: Withdrawal symptoms, similar in character to
those noted with barbiturates and alcohol (eg, convulsions, psychosis, hallucinations,
Page 15 of 19
behavioral disorder, tremor, abdominal and muscle cramps) have occurred following
abrupt discontinuance of clonazepam. The more severe withdrawal symptoms have
usually been limited to those patients who received excessive doses over an extended
period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia)
have been reported following abrupt discontinuance of benzodiazepines taken
continuously at therapeutic levels for several months. Consequently, after extended
therapy, abrupt discontinuation should generally be avoided and a gradual dosage
tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone
individuals (such as drug addicts or alcoholics) should be under careful surveillance when
receiving clonazepam or other psychotropic agents because of the predisposition of such
patients to habituation and dependence.
Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see
CLINICAL PHARMACOLOGY: Clinical Trials), patients were gradually withdrawn
during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance
period was associated with good tolerability and a very modest clinical deterioration,
without evidence of a significant rebound phenomenon. However, there are not sufficient
data from adequate and well-controlled long-term clonazepam studies in patients with
panic disorder to accurately estimate the risks of withdrawal symptoms and dependence
that may be associated with such use.
OVERDOSAGE
Human Experience: Symptoms of clonazepam overdosage, like those produced by other
CNS depressants, include somnolence, confusion, coma and diminished reflexes.
Overdose Management: Treatment includes monitoring of respiration, pulse and blood
pressure, general supportive measures and immediate gastric lavage. Intravenous fluids
should be administered and an adequate airway maintained. Hypotension may be
combated by the use of levarterenol or metaraminol. Dialysis is of no known value.
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete
or partial reversal of the sedative effects of benzodiazepines and may be used in
situations when an overdose with a benzodiazepine is known or suspected. Prior to the
administration of flumazenil, necessary measures should be instituted to secure airway,
ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a
substitute for, proper management of benzodiazepine overdose. Patients treated with
flumazenil should be monitored for resedation, respiratory depression and other residual
benzodiazepine effects for an appropriate period after treatment. The prescriber should
be aware of a risk of seizure in association with flumazenil treatment, particularly in
long-term benzodiazepine users and in cyclic antidepressant overdose. The complete
flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and
PRECAUTIONS, should be consulted prior to use.
Flumazenil is not indicated in patients with epilepsy who have been treated with
benzodiazepines. Antagonism of the benzodiazepine effect in such patients may
provoke seizures.
Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.
Page 16 of 19
DOSAGE AND ADMINISTRATION
Clonazepam is available as a tablet or an orally disintegrating tablet (wafer). The tablets
should be administered with water by swallowing the tablet whole. The orally
disintegrating tablet should be administered as follows: After opening the pouch, peel
back the foil on the blister. Do not push tablet through foil. Immediately upon opening
the blister, using dry hands, remove the tablet and place it in the mouth. Tablet
disintegration occurs rapidly in saliva so it can be easily swallowed with or without
water.
Seizure Disorders: Adults: The initial dose for adults with seizure disorders should not
exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of
0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects
preclude any further increase. Maintenance dosage must be individualized for each
patient depending upon response. Maximum recommended daily dose is 20 mg.
The use of multiple anticonvulsants may result in an increase of depressant adverse
effects. This should be considered before adding Klonopin to an existing anticonvulsant
regimen.
Pediatric Patients: Klonopin is administered orally. In order to minimize drowsiness, the
initial dose for infants and children (up to 10 years of age or 30 kg of body weight)
should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in
two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg
every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has
been reached, unless seizures are controlled or side effects preclude further increase.
Whenever possible, the daily dose should be divided into three equal doses. If doses are
not equally divided, the largest dose should be given before retiring.
Geriatric Patients: There is no clinical trial experience with Klonopin in seizure disorder
patients 65 years of age and older. In general, elderly patients should be started on low
doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
Panic Disorder: Adults: The initial dose for adults with panic disorder is 0.25 mg bid. An
increase to the target dose for most patients of 1 mg/day may be made after 3 days. The
recommended dose of 1 mg/day is based on the results from a fixed dose study in which
the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study
were less effective than the 1 mg/day dose and were associated with more adverse
effects. Nevertheless, it is possible that some individual patients may benefit from doses
of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased
in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or
until side effects make further increases undesired. To reduce the inconvenience of
somnolence, administration of one dose at bedtime may be desirable.
Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every
3 days, until the drug is completely withdrawn.
There is no body of evidence available to answer the question of how long the patient
treated with clonazepam should remain on it. Therefore, the physician who elects to use
Page 17 of 19
Klonopin for extended periods should periodically reevaluate the long-term usefulness of
the drug for the individual patient.
Pediatric Patients: There is no clinical trial experience with Klonopin in panic disorder
patients under 18 years of age.
Geriatric Patients: There is no clinical trial experience with Klonopin in panic disorder
patients 65 years of age and older. In general, elderly patients should be started on low
doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
HOW SUPPLIED
Klonopin tablets are available as scored tablets with a K-shaped perforation—0.5 mg,
orange (NDC 0004-0068-01); and unscored tablets with a K-shaped perforation—1 mg,
blue (NDC 0004-0058-01); 2 mg, white (NDC 0004-0098-01)—bottles of 100.
Imprint on tablets:
0.5 mg — 1/2 KLONOPIN (front)
ROCHE (scored side)
1 mg — 1 KLONOPIN (front)
ROCHE (reverse side) tablets pictured
2 mg — 2 KLONOPIN (front)
ROCHE (reverse side) tablets pictured
Klonopin Wafers (clonazepam orally disintegrating tablets) are white, round and
debossed with the tablet strength expressed as a fraction or whole number (1/8, 1/4, 1/2,
1, or 2). The tablets are available in blister packages of 60 (10 pouches/carton) as
follows:
0.125 mg debossed 1/8, (NDC 0004-0279-22)
0.25 mg debossed 1/4, (NDC 0004-0280-22)
0.5 mg debossed 1/2, (NDC 0004-0281-22)
1 mg debossed 1, (NDC 0004-0282-22)
2 mg debossed 2, (NDC 0004-0283-22)
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
PI Revised: 4/2009
Page 18 of 19
|
custom-source
|
2025-02-12T13:44:16.038734
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017533s045,020813s005lbl.pdf', 'application_number': 17533, 'submission_type': 'SUPPL ', 'submission_number': 45}
|
11,020
|
NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Labeling Text October 2013
KLONOPIN TABLETS
(clonazepam)
Rx only
DESCRIPTION
Klonopin, a benzodiazepine, is available as scored tablets with a K-shaped perforation
containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation
containing 1 mg or 2 mg of clonazepam. Each tablet also contains lactose, magnesium
stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5
mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. 2
Lake.
Chemically,
clonazepam
is
5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4
benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of
315.72 and the following structural formula: structural formula
CLINICAL PHARMACOLOGY
Pharmacodynamics: The precise mechanism by which clonazepam exerts its antiseizure
and antipanic effects is unknown, although it is believed to be related to its ability to
enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory
neurotransmitter in the central nervous system. Convulsions produced in rodents by
pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are
convulsions produced by photic stimulation in susceptible baboons. A taming effect in
aggressive primates, muscle weakness and hypnosis are also produced. In humans,
clonazepam is capable of suppressing the spike and wave discharge in absence seizures
(petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in
minor motor seizures.
Pharmacokinetics: Clonazepam is rapidly and completely absorbed after oral
administration. The absolute bioavailability of clonazepam is about 90%. Maximum
plasma concentrations of clonazepam are reached within 1 to 4 hours after oral
administration. Clonazepam is approximately 85% bound to plasma proteins.
Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being
excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group
Reference ID: 3398090
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Labeling Text October 2013
to the 4-amino derivative. This derivative can be acetylated, hydroxylated and
glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in
clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically
30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the
dosing range. There is no evidence that clonazepam induces its own metabolism or that
of other drugs in humans.
Pharmacokinetics in Demographic Subpopulations and in Disease States: Controlled
studies examining the influence of gender and age on clonazepam pharmacokinetics have
not been conducted, nor have the effects of renal or liver disease on clonazepam
pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is
possible that liver disease will impair clonazepam elimination. Thus, caution should be
exercised when administering clonazepam to these patients.
Clinical Trials: Panic Disorder: The effectiveness of Klonopin in the treatment of panic
disorder was demonstrated in two double-blind, placebo-controlled studies of adult
outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without
agoraphobia. In these studies, Klonopin was shown to be significantly more effective
than placebo in treating panic disorder on change from baseline in panic attack frequency,
the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global
Impression Improvement Score.
Study 1 was a 9-week, fixed-dose study involving Klonopin doses of 0.5, 1, 2, 3 or 4
mg/day or placebo. This study was conducted in four phases: a 1-week placebo lead-in, a
3-week upward titration, a 6-week fixed dose and a 7-week discontinuance phase. A
significant difference from placebo was observed consistently only for the 1 mg/day
group. The difference between the 1 mg dose group and placebo in reduction from
baseline in the number of full panic attacks was approximately 1 panic attack per week.
At endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic
attacks, compared to 56% of placebo-treated patients.
Study 2 was a 6-week, flexible-dose study involving Klonopin in a dose range of 0.5 to 4
mg/day or placebo. This study was conducted in three phases: a 1-week placebo lead-in, a
6-week optimal-dose and a 6-week discontinuance phase. The mean clonazepam dose
during the optimal dosing period was 2.3 mg/day. The difference between Klonopin and
placebo in reduction from baseline in the number of full panic attacks was approximately
1 panic attack per week. At endpoint, 62% of patients receiving clonazepam were free of
full panic attacks, compared to 37% of placebo-treated patients.
Subgroup analyses did not indicate that there were any differences in treatment outcomes
as a function of race or gender.
INDICATIONS AND USAGE
Seizure Disorders: Klonopin is useful alone or as an adjunct in the treatment of the
Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In
patients with absence seizures (petit mal) who have failed to respond to succinimides,
Klonopin may be useful.
Reference ID: 3398090
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Labeling Text October 2013
In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often
within 3 months of administration. In some cases, dosage adjustment may reestablish
efficacy.
Panic Disorder: Klonopin 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 Klonopin was established in two 6- to 9-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, ie, 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.
The effectiveness of Klonopin in long-term use, that is, for more than 9 weeks, has not
been systematically studied in controlled clinical trials. The physician who elects to use
Klonopin for extended periods should periodically reevaluate the long-term usefulness of
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Klonopin should not be used in patients with a history of sensitivity to benzodiazepines,
nor in patients with clinical or biochemical evidence of significant liver disease. It may
be used in patients with open angle glaucoma who are receiving appropriate therapy but
is contraindicated in acute narrow angle glaucoma.
WARNINGS
Interference With Cognitive and Motor Performance: Since Klonopin produces CNS
depression, patients receiving this drug should be cautioned against engaging in
hazardous occupations requiring mental alertness, such as operating machinery or driving
a motor vehicle. They should also be warned about the concomitant use of alcohol or
other CNS-depressant drugs during Klonopin therapy (see PRECAUTIONS: Drug
Interactions and Information for Patients).
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including Klonopin,
increase the risk of suicidal thoughts or behavior in patients taking these drugs for any
indication. Patients treated with any AED for any indication should be monitored for the
emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual
changes in mood or behavior.
Reference ID: 3398090
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Labeling Text October 2013
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy)
of 11 different AEDs showed that patients randomized to one of the AEDs had
approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal
thinking or behavior compared to patients randomized to placebo. In these trials, which
had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal
behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24%
among 16,029 placebo-treated patients, representing an increase of approximately one
case of suicidal thinking or behavior for every 530 patients treated. There were four
suicides in drug-treated patients in the trials and none in placebo-treated patients, but the
number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as
one week after starting drug treatment with AEDs and persisted for the duration of
treatment assessed. Because most trials included in the analysis did not extend beyond 24
weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the
data analyzed. The finding of increased risk with AEDs of varying mechanisms of action
and across a range of indications suggests that the risk applies to all AEDs used for any
indication. The risk did not vary substantially by age (5-100 years) in the clinical trials
analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1
Risk by Indication for Antiepileptic Drugs in the Pooled
Analysis
Indication
Placebo
Patients with
Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events per 1000
Patients
Epilepsy
Psychiatric
Other
Total
1.0
5.7
1.0
2.4
3.4
8.5
1.8
4.3
3.5
1.5
1.9
1.8
2.4
2.9
0.9
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy
than in clinical trials for psychiatric or other conditions, but the absolute risk differences
were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Klonopin or any other AED must balance the risk of
suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other
illnesses for which AEDs are prescribed are themselves associated with morbidity and
mortality and an increased risk of suicidal thoughts and behavior. Should suicidal
thoughts and behavior emerge during treatment, the prescriber needs to consider whether
the emergence of these symptoms in any given patient may be related to the illness being
treated.
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Patients, their caregivers, and families should be informed that AEDs increase the risk of
suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of the signs and symptoms of depression, any unusual changes
in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about
self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Pregnancy Risks: Data from several sources raise concerns about the use of Klonopin
during pregnancy.
Animal Findings: In three studies in which Klonopin was administered orally to pregnant
rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the
maximum recommended human dose of 20 mg/day for seizure disorders and equivalent
to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period
of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused
sternebrae and limb defects) was observed in a low, non-dose-related incidence in
exposed litters from all dosage groups. Reductions in maternal weight gain occurred at
dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one
study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were
observed in mice and rats following administration during organogenesis of oral doses up
to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum
recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the
maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).
General Concerns and Considerations About Anticonvulsants: Recent reports suggest an
association between the use of anticonvulsant drugs by women with epilepsy and an
elevated incidence of birth defects in children born to these women. Data are more
extensive with respect to diphenylhydantoin and phenobarbital, but these are also the
most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a
possible similar association with the use of all known anticonvulsant drugs.
In children of women treated with drugs for epilepsy, reports suggesting an elevated
incidence of birth defects cannot be regarded as adequate to prove a definite cause and
effect relationship. There are intrinsic methodologic problems in obtaining adequate data
on drug teratogenicity in humans; the possibility also exists that other factors (eg, genetic
factors or the epileptic condition itself) may be more important than drug therapy in
leading to birth defects. The great majority of mothers on anticonvulsant medication
deliver normal infants. It is important to note that anticonvulsant drugs should not be
discontinued in patients in whom the drug is administered to prevent seizures because of
the strong possibility of precipitating status epilepticus with attendant hypoxia and threat
to life. In individual cases where the severity and frequency of the seizure disorder are
such that the removal of medication does not pose a serious threat to the patient,
discontinuation of the drug may be considered prior to and during pregnancy; however, it
cannot be said with any confidence that even mild seizures do not pose some hazards to
the developing embryo or fetus.
General Concerns About Benzodiazepines: An increased risk of congenital
malformations associated with the use of benzodiazepine drugs has been suggested in
several studies.
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There may also be non-teratogenic risks associated with the use of benzodiazepines
during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding
difficulties, and hypothermia in children born to mothers who have been receiving
benzodiazepines late in pregnancy. In addition, children born to mothers receiving
benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal
symptoms during the postnatal period.
Advice Regarding the Use of Klonopin in Women of Childbearing Potential: In general,
the use of Klonopin in women of childbearing potential, and more specifically during
known pregnancy, should be considered only when the clinical situation warrants the risk
to the fetus.
The specific considerations addressed above regarding the use of anticonvulsants for
epilepsy in women of childbearing potential should be weighed in treating or counseling
these women.
Because of experience with other members of the benzodiazepine class, Klonopin is
assumed to be capable of causing an increased risk of congenital abnormalities when
administered to a pregnant woman during the first trimester. Because use of these drugs
is rarely a matter of urgency in the treatment of panic disorder, their use during the first
trimester should almost always be avoided. The possibility that a woman of childbearing
potential may be pregnant at the time of institution of therapy should be considered. 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. Patients should
also be advised that if they become pregnant during therapy or intend to become
pregnant, they should communicate with their physician about the desirability of
discontinuing the drug.
Withdrawal Symptoms: Withdrawal symptoms of the barbiturate type have occurred
after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
PRECAUTIONS
General: Worsening of Seizures: When used in patients in whom several different types
of seizure disorders coexist, Klonopin may increase the incidence or precipitate the onset
of generalized tonic-clonic seizures (grand mal). This may require the addition of
appropriate anticonvulsants or an increase in their dosages. The concomitant use of
valproic acid and Klonopin may produce absence status.
Laboratory Testing During Long-Term Therapy: Periodic blood counts and liver function
tests are advisable during long-term therapy with Klonopin.
Risks of Abrupt Withdrawal: The abrupt withdrawal of Klonopin, particularly in those
patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore,
when discontinuing Klonopin, gradual withdrawal is essential. While Klonopin is being
gradually withdrawn, the simultaneous substitution of another anticonvulsant may be
indicated.
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Caution in Renally Impaired Patients: Metabolites of Klonopin are excreted by the
kidneys; to avoid their excess accumulation, caution should be exercised in the
administration of the drug to patients with impaired renal function.
Hypersalivation: Klonopin may produce an increase in salivation. This should be
considered before giving the drug to patients who have difficulty handling secretions.
Because of this and the possibility of respiratory depression, Klonopin should be used
with caution in patients with chronic respiratory diseases.
Information for Patients: A Klonopin Medication Guide must be given to the patient
each time Klonopin is dispensed, as required by law. Patients should be instructed to take
Klonopin only as prescribed. Physicians are advised to discuss the following issues with
patients for whom they prescribe Klonopin:
Dose Changes: To assure the safe and effective use of benzodiazepines, patients should
be informed that, since benzodiazepines may produce psychological and physical
dependence, it is advisable that they consult with their physician before either increasing
the dose or abruptly discontinuing this drug.
Interference With Cognitive and Motor Performance: Because benzodiazepines have the
potential to impair judgment, thinking or motor skills, patients should be cautioned about
operating hazardous machinery, including automobiles, until they are reasonably certain
that Klonopin therapy does not affect them adversely.
Suicidal Thinking and Behavior: Patients, their caregivers, and families should be
counseled that AEDs, including Klonopin, may increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of
symptoms of depression, any unusual changes in mood or behavior, or the emergence of
suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be
reported immediately to healthcare providers.
Pregnancy: Patients should be advised to notify their physician if they become pregnant
or intend to become pregnant during therapy with Klonopin (see WARNINGS:
Pregnancy Risks). Patients should be encouraged to enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry
is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS:
Pregnancy).
Nursing: Patients should be advised not to breastfeed an infant if they are taking
Klonopin.
Concomitant Medication: Patients should be advised to inform their physicians if they are
taking, or plan to take, any prescription or over-the-counter drugs, since there is a
potential for interactions.
Alcohol: Patients should be advised to avoid alcohol while taking Klonopin.
Drug Interactions: Effect of Clonazepam on the Pharmacokinetics of Other Drugs:
Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine
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or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not
been investigated.
Effect of Other Drugs on the Pharmacokinetics of Clonazepam: Literature reports suggest
that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam
pharmacokinetics.
In a study in which the 2 mg clonazepam orally disintegrating tablet was administered
with and without propantheline (an anticholinergic agent with multiple effects on the GI
tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax of
clonazepam was 20% lower when the orally disintegrating tablet was given with
propantheline compared to when it was given alone.
Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450
inducers, such as phenytoin, carbamazepine and phenobarbital, induce clonazepam
metabolism, causing an approximately 30% decrease in plasma clonazepam levels.
Although clinical studies have not been performed, based on the involvement of the
cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme
system, notably oral antifungal agents, should be used cautiously in patients receiving
clonazepam.
Pharmacodynamic Interactions: The CNS-depressant action of the benzodiazepine class
of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics,
antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of
antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and
by other anticonvulsant drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not
been conducted with clonazepam.
The data currently available are not sufficient to determine the genotoxic potential of
clonazepam.
In a two-generation fertility study in which clonazepam was given orally to rats at 10 and
100 mg/kg/day (low dose approximately 5 times and 24 times the maximum
recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic
disorder, respectively, on a mg/m2 basis), there was a decrease in the number of
pregnancies and in the number of offspring surviving until weaning.
Pregnancy: Teratogenic Effects: Pregnancy Category D (see WARNINGS: Pregnancy
Risks).
To provide information regarding the effects of in utero exposure to Klonopin, physicians
are advised to recommend that pregnant patients taking Klonopin enroll in the NAAED
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334,
and must be done by patients themselves. Information on this registry can also be found
at the website http://www.aedpregnancyregistry.org/.
Labor and Delivery: The effect of Klonopin on labor and delivery in humans has not
been specifically studied; however, perinatal complications have been reported in
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children born to mothers who have been receiving benzodiazepines late in pregnancy,
including findings suggestive of either excess benzodiazepine exposure or of withdrawal
phenomena (see WARNINGS: Pregnancy Risks).
Nursing Mothers: Mothers receiving Klonopin should not breastfeed their infants.
Pediatric Use: Because of the possibility that adverse effects on physical or mental
development could become apparent only after many years, a benefit-risk consideration
of the long-term use of Klonopin is important in pediatric patients being treated for
seizure
disorder
(see
INDICATIONS
AND
USAGE
and
DOSAGE
AND
ADMINISTRATION).
Safety and effectiveness in pediatric patients with panic disorder below the age of 18
have not been established.
Geriatric Use: Clinical studies of Klonopin 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.
Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will
impair clonazepam elimination. Metabolites of Klonopin are excreted by the kidneys; to
avoid their excess accumulation, caution should be exercised in the administration of the
drug to patients with impaired renal function. Because elderly patients are more likely to
have decreased hepatic and/or renal function, care should be taken in dose selection, and
it may be useful to assess hepatic and/or renal function at the time of dose selection.
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients
generally should be started on low doses of Klonopin and observed closely.
ADVERSE REACTIONS
The adverse experiences for Klonopin are provided separately for patients with seizure
disorders and with panic disorder.
Seizure Disorders: The most frequently occurring side effects of Klonopin are referable
to CNS depression. Experience in treatment of seizures has shown that drowsiness has
occurred in approximately 50% of patients and ataxia in approximately 30%. In some
cases, these may diminish with time; behavior problems have been noted in
approximately 25% of patients. Others, listed by system, are:
Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia,
dysarthria, dysdiadochokinesis, ‘‘glassy-eyed’’ appearance, headache, hemiparesis,
hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo
Psychiatric: Confusion, depression, amnesia, hallucinations, hysteria, increased libido,
insomnia, psychosis (the behavior effects are more likely to occur in patients with a
Reference ID: 3398090
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history of psychiatric disturbances). The following paradoxical reactions have been
observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility,
anxiety, sleep disturbances, nightmares and vivid dreams
Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper
respiratory passages
Cardiovascular: Palpitations
Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis,
gastritis, increased appetite, nausea, sore gums
Genitourinary: Dysuria, enuresis, nocturia, urinary retention
Musculoskeletal: Muscle weakness, pains
Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss
or gain
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline
phosphatase
Panic Disorder: Adverse events during exposure to Klonopin were obtained by
spontaneous report and 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 events into a smaller number of standardized event categories. In the tables and
tabulations that follow, CIGY dictionary terminology has been used to classify reported
adverse events, except in certain cases in which redundant terms were collapsed into
more meaningful terms, as noted below.
The stated frequencies of adverse events represent the proportion of individuals who
experienced, at least once, a treatment-emergent adverse event of the type listed. An
event was considered treatment-emergent if it occurred for the first time or worsened
while receiving therapy following baseline evaluation.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials:
Adverse Events Associated With Discontinuation of Treatment:
Overall, the incidence of discontinuation due to adverse events was 17% in Klonopin
compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most
common events (≥1%) associated with discontinuation and a dropout rate twice or greater
for Klonopin than that of placebo included the following:
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Table 2
Most Common Adverse Events (≥1%) Associated with
Discontinuation of Treatment
Adverse Event
Klonopin (N=574)
Placebo (N=294)
Somnolence
7%
1%
Depression
4%
1%
Dizziness
1%
<1%
Nervousness
1%
0%
Ataxia
1%
0%
Intellectual Ability Reduced
1%
0%
Adverse Events Occurring at an Incidence of 1% or More Among Klonopin-Treated
Patients:
Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent
adverse events that occurred during acute therapy of panic disorder from a pool of two 6
to 9-week trials. Events reported in 1% or more of patients treated with Klonopin (doses
ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in
placebo-treated patients are included.
The prescriber should be aware that the figures in Table 3 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 in the
population studied.
Table 3
Treatment-Emergent Adverse Event Incidence in 6- to 9
Week Placebo-Controlled Clinical Trials*
Clonazepam Maximum Daily Dose
Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Central & Peripheral Nervous
System
Somnolence†
26
35
50
36
37
10
Dizziness
5
5
12
8
8
4
Coordination Abnormal†
1
2
7
9
6
0
Ataxia†
2
1
8
8
5
0
Dysarthria†
0
0
4
3
2
0
Psychiatric
Depression
Memory Disturbance
7
2
6
5
8
2
8
5
7
4
1
2
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Clonazepam Maximum Daily Dose
Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Nervousness
1
4
3
4
3
2
Intellectual Ability Reduced
0
2
4
3
2
0
Emotional Lability
0
1
2
2
1
1
Libido Decreased
0
1
3
1
1
0
Confusion
0
2
2
1
1
0
Respiratory System
Upper Respiratory Tract
Infection†
10
10
7
6
8
4
Sinusitis
4
2
8
4
4
3
Rhinitis
3
2
4
2
2
1
Coughing
2
2
4
0
2
0
Pharyngitis
1
1
3
2
2
1
Bronchitis
1
0
2
2
1
1
Gastrointestinal System
Constipation†
0
1
5
3
2
2
Appetite Decreased
1
1
0
3
1
1
Abdominal Pain†
2
2
2
0
1
1
Reference ID: 3398090
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FDA Approved Labeling Text October 2013
Clonazepam Maximum Daily Dose
Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Body as a Whole
Fatigue
Allergic Reaction
9
3
6
1
7
4
7
2
7
2
4
1
Musculoskeletal
Myalgia
2
1
4
0
1
1
Resistance Mechanism
Disorders
Influenza
3
2
5
5
4
3
Urinary System
Micturition Frequency
Urinary Tract Infection†
1
0
2
0
2
2
1
2
1
1
0
0
Vision Disorders
Blurred Vision
1
2
3
0
1
1
Reproductive Disorders‡
Female
Dysmenorrhea
0
6
5
2
3
2
Colpitis
Male
4
0
2
1
1
1
Ejaculation Delayed
0
0
2
2
1
0
Impotence
3
0
2
1
1
0
* Events reported by at least 1% of patients treated with Klonopin and for which the
incidence was greater than that for placebo.
† Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel) for
adverse event incidence was ≤0.10.
‡ Denominators for events in gender-specific systems are: n=240 (clonazepam), 102
(placebo) for male, and 334 (clonazepam), 192 (placebo) for female.
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Commonly Observed Adverse Events:
Table 4
Incidence of Most Commonly Observed Adverse Events* in
Acute Therapy in Pool of 6- to 9-Week Trials
Adverse Event
(Genentech Preferred Term)
Clonazepam
(N=574)
Placebo
(N=294)
Somnolence
37%
10%
Depression
7%
1%
Coordination Abnormal
6%
0%
Ataxia
5%
0%
* Treatment-emergent events for which the incidence in the clonazepam patients was
≥5% and at least twice that in the placebo patients.
Treatment-Emergent Depressive Symptoms:
In the pool of two short-term placebo-controlled trials, adverse events classified under the
preferred term “depression” were reported in 7% of Klonopin-treated patients compared
to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these
same trials, adverse events classified under the preferred term “depression” were reported
as leading to discontinuation in 4% of Klonopin-treated patients compared to 1% of
placebo-treated patients. While these findings are noteworthy, Hamilton Depression
Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D
scores in the clonazepam group than the placebo group suggesting that clonazepam
treated patients were not experiencing a worsening or emergence of clinical depression.
Other Adverse Events Observed During the Premarketing Evaluation of Klonopin in
Panic Disorder:
Following is a list of modified CIGY terms that reflect treatment-emergent adverse
events reported by patients treated with Klonopin at multiple doses during clinical trials.
All reported events are included except those already listed in Table 3 or elsewhere in
labeling, those events for which a drug cause was remote, those event terms which were
so general as to be uninformative, and events reported only once and which did not have
a substantial probability of being acutely life-threatening. It is important to emphasize
that, although the events occurred during treatment with Klonopin, they were not
necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency. These adverse events were reported infrequently, which is defined as
occurring in 1/100 to 1/1000 patients.
Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever,
shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain,
cellulitis, inflammation localized
Cardiovascular Disorders: chest pain, hypotension postural
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Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness,
feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness,
hyperactivity, hypoesthesia, tongue thick, twitching
Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation,
stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel
movements frequent, pain pelvic, dyspepsia, hemorrhoids
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
Heart Rate and Rhythm Disorders: palpitation
Metabolic and Nutritional Disorders: thirst, gout
Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain
leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis,
arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee
Platelet, Bleeding and Clotting Disorders: bleeding dermal
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization,
dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased,
aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal,
illusion, nightmares, sleep disorder, suicide ideation, yawning
Reproductive Disorders, Female: breast pain, menstrual irregularity
Reproductive Disorders, Male: ejaculation decreased
Resistance Mechanism Disorders: infection mycotic, infection viral, infection
streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis
Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed,
pneumonia, pleurisy
Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact,
flushing, pruritus, pustular reaction, skin burns, skin disorder
Special Senses Other, Disorders: taste loss
Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder
dysfunction, urinary retention, urinary tract bleeding, urine discoloration
Vascular (Extracardiac) Disorders: thrombophlebitis leg
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual
field defect, xerophthalmia
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Clonazepam is a Schedule IV controlled substance.
Physical and Psychological Dependence: Withdrawal symptoms, similar in character to
those noted with barbiturates and alcohol (eg, convulsions, psychosis, hallucinations,
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NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Labeling Text October 2013
behavioral disorder, tremor, abdominal and muscle cramps) have occurred following
abrupt discontinuance of clonazepam. The more severe withdrawal symptoms have
usually been limited to those patients who received excessive doses over an extended
period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia)
have been reported following abrupt discontinuance of benzodiazepines taken
continuously at therapeutic levels for several months. Consequently, after extended
therapy, abrupt discontinuation should generally be avoided and a gradual dosage
tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone
individuals (such as drug addicts or alcoholics) should be under careful surveillance when
receiving clonazepam or other psychotropic agents because of the predisposition of such
patients to habituation and dependence.
Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see
CLINICAL PHARMACOLOGY: Clinical Trials), patients were gradually withdrawn
during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance
period was associated with good tolerability and a very modest clinical deterioration,
without evidence of a significant rebound phenomenon. However, there are not sufficient
data from adequate and well-controlled long-term clonazepam studies in patients with
panic disorder to accurately estimate the risks of withdrawal symptoms and dependence
that may be associated with such use.
OVERDOSAGE
Human Experience: Symptoms of clonazepam overdosage, like those produced by other
CNS depressants, include somnolence, confusion, coma and diminished reflexes.
Overdose Management: Treatment includes monitoring of respiration, pulse and blood
pressure, general supportive measures and immediate gastric lavage. Intravenous fluids
should be administered and an adequate airway maintained. Hypotension may be
combated by the use of levarterenol or metaraminol. Dialysis is of no known value.
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete
or partial reversal of the sedative effects of benzodiazepines and may be used in
situations when an overdose with a benzodiazepine is known or suspected. Prior to the
administration of flumazenil, necessary measures should be instituted to secure airway,
ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a
substitute for, proper management of benzodiazepine overdose. Patients treated with
flumazenil should be monitored for resedation, respiratory depression and other residual
benzodiazepine effects for an appropriate period after treatment. The prescriber should
be aware of a risk of seizure in association with flumazenil treatment, particularly in
long-term benzodiazepine users and in cyclic antidepressant overdose. The complete
flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and
PRECAUTIONS, should be consulted prior to use.
Flumazenil is not indicated in patients with epilepsy who have been treated with
benzodiazepines. Antagonism of the benzodiazepine effect in such patients may
provoke seizures.
Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.
Reference ID: 3398090
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NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Labeling Text October 2013
DOSAGE AND ADMINISTRATION
Clonazepam is available as a tablet. The tablets should be administered with water by
swallowing the tablet whole.
Seizure Disorders: Adults: The initial dose for adults with seizure disorders should not
exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of
0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects
preclude any further increase. Maintenance dosage must be individualized for each
patient depending upon response. Maximum recommended daily dose is 20 mg.
The use of multiple anticonvulsants may result in an increase of depressant adverse
effects. This should be considered before adding Klonopin to an existing anticonvulsant
regimen.
Pediatric Patients: Klonopin is administered orally. In order to minimize drowsiness, the
initial dose for infants and children (up to 10 years of age or 30 kg of body weight)
should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in
two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg
every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has
been reached, unless seizures are controlled or side effects preclude further increase.
Whenever possible, the daily dose should be divided into three equal doses. If doses are
not equally divided, the largest dose should be given before retiring.
Geriatric Patients: There is no clinical trial experience with Klonopin in seizure disorder
patients 65 years of age and older. In general, elderly patients should be started on low
doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
Panic Disorder: Adults: The initial dose for adults with panic disorder is 0.25 mg bid. An
increase to the target dose for most patients of 1 mg/day may be made after 3 days. The
recommended dose of 1 mg/day is based on the results from a fixed dose study in which
the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study
were less effective than the 1 mg/day dose and were associated with more adverse
effects. Nevertheless, it is possible that some individual patients may benefit from doses
of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased
in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or
until side effects make further increases undesired. To reduce the inconvenience of
somnolence, administration of one dose at bedtime may be desirable.
Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every
3 days, until the drug is completely withdrawn.
There is no body of evidence available to answer the question of how long the patient
treated with clonazepam should remain on it. Therefore, the physician who elects to use
Klonopin for extended periods should periodically reevaluate the long-term usefulness of
the drug for the individual patient.
Pediatric Patients: There is no clinical trial experience with Klonopin in panic disorder
patients under 18 years of age.
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NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Labeling Text October 2013
Geriatric Patients: There is no clinical trial experience with Klonopin in panic disorder
patients 65 years of age and older. In general, elderly patients should be started on low
doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
HOW SUPPLIED
Klonopin tablets are available as scored tablets with a K-shaped perforation—0.5 mg,
orange (NDC 0004-0068-01); and unscored tablets with a K-shaped perforation—1 mg,
blue (NDC 0004-0058-01); 2 mg, white (NDC 0004-0098-01)—bottles of 100.
Imprint on tablets: usage illustration
0.5 mg — 1/2 KLONOPIN (front)
ROCHE (scored side)
1 mg — 1 KLONOPIN (front)
ROCHE (reverse side) usage illustration
2 mg — 2 KLONOPIN (front)
ROCHE (reverse side) usage illustration
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). company logo
Revised: Month Year
© xxxx Genentech, Inc. All rights reserved.
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NDA 017533 Klonopin (clonazepam) tablets
FDA Approved Medication Guide October 2013
Medication Guide
KLONOPIN (KLON-oh-pin)
(clonazepam)
Tablets
Read this Medication Guide before you start taking KLONOPIN and each time
you get a refill. There may be new information. This information does not take the
place of talking to your healthcare provider about your medical condition or
treatment.
KLONOPIN can cause serious side effects. Because stopping KLONOPIN
suddenly can also cause serious problems, do not stop taking KLONOPIN without
talking to your healthcare provider first.
What is the most important information I should know about KLONOPIN?
Do not stop taking KLONOPIN without first talking to your healthcare
provider. Stopping KLONOPIN suddenly can cause serious problems.
KLONOPIN can cause serious side effects, including:
1. KLONOPIN can slow your thinking and motor skills
• Do not drive, operate heavy machinery, or do other dangerous activities
until you know how KLONOPIN affects you.
• Do not drink alcohol or take other drugs that may make you sleepy or
dizzy while taking KLONOPIN until you talk to your healthcare
provider. When taken with alcohol or drugs that cause sleepiness or
dizziness, KLONOPIN may make your sleepiness or dizziness worse.
2. Like other antiepileptic drugs, KLONOPIN may cause suicidal thoughts
or actions in a very small number of people, about 1 in 500.
Call a healthcare provider right away if you have any of these
symptoms, especially if they are new, worse, or worry you:
•
thoughts about suicide or dying
•
attempt to commit suicide
•
new or worse depression
•
new or worse anxiety
•
feeling 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
Reference ID: 3398090
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3.
How can I watch for early symptoms of suicidal thoughts and actions?
• Pay attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are
worried about symptoms.
Suicidal thoughts or actions can be caused by things other than medicines. If
you have suicidal thoughts or actions, your healthcare provider may check
for other causes.
Do not stop KLONOPIN without first talking to a healthcare provider.
Stopping KLONOPIN suddenly can cause serious problems. Stopping
KLONOPIN suddenly can cause seizures that will not stop (status
epilepticus).
KLONOPIN may harm your unborn or developing baby.
• If you take KLONOPIN during pregnancy, your baby is at risk for serious
birth defects. These defects can happen as early as in the first month of
pregnancy, even before you know you are pregnant. Birth defects may
occur even in children born to women who are not taking any medicines
and do not have other risk factors.
• Children born to mothers receiving benzodiazepine medications (including
KLONOPIN) late in pregnancy may be at some risk of experiencing
breathing problems, feeding problems, hypothermia, and withdrawal
symptoms.
• Tell your healthcare provider right away if you become pregnant while
taking KLONOPIN. You and your healthcare provider should decide if
you will take KLONOPIN while you are pregnant.
• If you become pregnant while taking KLONOPIN, talk to your healthcare
provider about registering with the North American Antiepileptic Drug
Pregnancy Registry. You can register by calling 1-888-233-2334. The
purpose of this registry is to collect information about the safety of
antiepileptic drugs during pregnancy.
• KLONOPIN can pass into breast milk. Talk to your healthcare provider
about the best way to feed your baby if you take KLONOPIN. You and
your healthcare provider should decide if you will take KLONOPIN or
breast feed. You should not do both.
4. KLONOPIN can cause abuse and dependence.
• Do not stop taking KLONOPIN all of a sudden. Stopping KLONOPIN
suddenly can cause seizures that do not stop, hearing or seeing things that
are not there (hallucinations), shaking, and stomach and muscle cramps.
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o Talk to your doctor about slowly stopping KLONOPIN to avoid
getting sick with withdrawal symptoms.
o Physical dependence is not the same as drug addiction. Your
healthcare provider can tell you more about the differences
between physical dependence and drug addiction.
KLONOPIN is a federally controlled substance (C-IV) because it can be
abused or lead to dependence. Keep KLONOPIN in a safe place to prevent
misuse and abuse. Selling or giving away KLONOPIN may harm others, and
is against the law. Tell your doctor if you have ever abused or been
dependent on alcohol, prescription medicines or street drugs.
What is KLONOPIN?
KLONOPIN is a prescription medicine used alone or with other medicines to
treat:
• certain types of seizure disorders (epilepsy) in adults and children
• panic disorder with or without fear of open spaces (agoraphobia) in adults
It is not known if KLONOPIN is safe or effective in treating panic disorder in
children younger than 18 years old.
Who should not take KLONOPIN?
Do not take KLONOPIN if you:
• are allergic to benzodiazepines
• have significant liver disease
• have an eye disease called acute narrow angle glaucoma
Ask your healthcare provider if you are not sure if you have any of the
problems listed above.
What should I tell my healthcare provider before taking KLONOPIN?
Before you take KLONOPIN, tell your healthcare provider if you:
• have liver or kidney problems
• have lung problems (respiratory disease)
• have or have had depression, mood problems, or suicidal thoughts or
behavior
• have any other medical conditions
Tell your healthcare provider about all the medicines you take, including
prescription and non-prescription medicines, vitamins, and herbal supplements.
Taking KLONOPIN with certain other medicines can cause side effects or affect
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how well they work. Do not start or stop other medicines without talking to your
healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare
provider and pharmacist when you get a new medicine.
How should I take KLONOPIN?
• Take KLONOPIN exactly as your healthcare provider tells you.
KLONOPIN is available as a tablet.
• Do not stop taking KLONOPIN without first talking to your healthcare
provider. Stopping KLONOPIN suddenly can cause serious problems.
• KLONOPIN tablets should be taken with water and swallowed whole.
• If you take too much KLONOPIN, call your healthcare provider or local
Poison Control Center right away.
What should I avoid while taking KLONOPIN?
• KLONOPIN can slow your thinking and motor skills. Do not drive,
operate heavy machinery, or do other dangerous activities until you know
how KLONOPIN affects you.
• Do not drink alcohol or take other drugs that may make you sleepy or
dizzy while taking KLONOPIN until you talk to your healthcare
provider. When taken with alcohol or drugs that cause sleepiness or
dizziness, KLONOPIN may make your sleepiness or dizziness worse.
What are the possible side effects of KLONOPIN?
See “What is the most important information I should know about
KLONOPIN?”
KLONOPIN can also make your seizures happen more often or make them worse.
Call your healthcare provider right away if your seizures get worse while taking
KLONOPIN.
The most common side effects of KLONOPIN include:
• Drowsiness
• Problems with walking and coordination
• Dizziness
• Depression
• Fatigue
• Problems with memory
These are not all the possible side effects of KLONOPIN. For more information,
ask your healthcare provider or pharmacist.
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Tell your healthcare provider if you have any side effect that bothers you or that
does not go away.
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 KLONOPIN?
• Store KLONOPIN between 59°F to 86°F (15°C to 30°C)
Keep KLONOPIN and all medicines out of the reach of children.
General Information about KLONOPIN
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use KLONOPIN for a condition for which it was not
prescribed. Do not give KLONOPIN to other people, even if they have the same
symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about
KLONOPIN. If you would like more information, talk with your healthcare
provider. You can ask your pharmacist or healthcare provider for information
about KLONOPIN that is written for health professionals.
For more information, go to www.gene.com/gene/products/information/klonopin
or call 1-888-835-2555.
What are the ingredients in KLONOPIN?
Active ingredient: clonazepam
Inactive ingredients:
• Tablets:
o 0.5 mg tablets contain lactose, magnesium stearate,
microcrystalline cellulose, corn starch, FD&C Yellow No. 6 Lake
o 1 mg tablets contain lactose, magnesium stearate, microcrystalline
cellulose, corn starch, FD&C Blue No. 1 Lake and FD&C Blue
No. 2 Lake
o 2 mg tablets contain lactose, magnesium stearate, microcrystalline
cellulose, corn starch
Issued: Month Year
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Reference ID: 3398090
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company logo
© 2013 Genentech, Inc. All rights reserved.
For additional copies of this Medication Guide, please call 1-877-436-3683 or visit
www.gene.com/gene/products/information/klonopin.
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Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
1
2
KLONOPIN TABLETS
3
(clonazepam)
4
KLONOPIN WAFERS
5
(clonazepam orally disintegrating tablets)
6
Rx only
7
DESCRIPTION
8
Klonopin, a benzodiazepine, is available as scored tablets with a K-shaped perforation
9
containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation
10
containing 1 mg or 2 mg of clonazepam. Each tablet also contains lactose, magnesium
11
stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5
12
mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. 2
13
Lake.
14
Klonopin is also available as an orally disintegrating tablet containing 0.125 mg, 0.25
15
mg, 0.5 mg, 1 mg or 2 mg clonazepam. Each orally disintegrating tablet also contains
16
gelatin, mannitol, methylparaben sodium, propylparaben sodium and xanthan gum.
17
Chemically,
clonazepam
is
5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4
18
benzodiazepin-2-one. It is a light yellow crystalline powder. It has a molecular weight of
19
315.72 and the following structural formula: structural formula
20
21
CLINICAL PHARMACOLOGY
22
Pharmacodynamics: The precise mechanism by which clonazepam exerts its antiseizure
23
and antipanic effects is unknown, although it is believed to be related to its ability to
24
enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory
25
neurotransmitter in the central nervous system. Convulsions produced in rodents by
26
pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are
27
convulsions produced by photic stimulation in susceptible baboons. A taming effect in
28
aggressive primates, muscle weakness and hypnosis are also produced. In humans,
29
clonazepam is capable of suppressing the spike and wave discharge in absence seizures
30
(petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in
31
minor motor seizures.
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Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
32
Pharmacokinetics: Clonazepam is rapidly and completely absorbed after oral
33
administration. The absolute bioavailability of clonazepam is about 90%. Maximum
34
plasma concentrations of clonazepam are reached within 1 to 4 hours after oral
35
administration. Clonazepam is approximately 85% bound to plasma proteins.
36
Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being
37
excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group
38
to the 4-amino derivative. This derivative can be acetylated, hydroxylated and
39
glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in
40
clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically
41
30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the
42
dosing range. There is no evidence that clonazepam induces its own metabolism or that
43
of other drugs in humans.
44
Pharmacokinetics in Demographic Subpopulations and in Disease States: Controlled
45
studies examining the influence of gender and age on clonazepam pharmacokinetics have
46
not been conducted, nor have the effects of renal or liver disease on clonazepam
47
pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is
48
possible that liver disease will impair clonazepam elimination. Thus, caution should be
49
exercised when administering clonazepam to these patients.
50
Clinical Trials: Panic Disorder: The effectiveness of Klonopin in the treatment of panic
51
disorder was demonstrated in two double-blind, placebo-controlled studies of adult
52
outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without
53
agoraphobia. In these studies, Klonopin was shown to be significantly more effective
54
than placebo in treating panic disorder on change from baseline in panic attack frequency,
55
the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global
56
Impression Improvement Score.
57
Study 1 was a 9-week, fixed-dose study involving Klonopin doses of 0.5, 1, 2, 3 or 4
58
mg/day or placebo. This study was conducted in four phases: a 1-week placebo lead-in, a
59
3-week upward titration, a 6-week fixed dose and a 7-week discontinuance phase. A
60
significant difference from placebo was observed consistently only for the 1 mg/day
61
group. The difference between the 1 mg dose group and placebo in reduction from
62
baseline in the number of full panic attacks was approximately 1 panic attack per week.
63
At endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic
64
attacks, compared to 56% of placebo-treated patients.
65
Study 2 was a 6-week, flexible-dose study involving Klonopin in a dose range of 0.5 to 4
66
mg/day or placebo. This study was conducted in three phases: a 1-week placebo lead-in, a
67
6-week optimal-dose and a 6-week discontinuance phase. The mean clonazepam dose
68
during the optimal dosing period was 2.3 mg/day. The difference between Klonopin and
69
placebo in reduction from baseline in the number of full panic attacks was approximately
70
1 panic attack per week. At endpoint, 62% of patients receiving clonazepam were free of
71
full panic attacks, compared to 37% of placebo-treated patients.
72
Subgroup analyses did not indicate that there were any differences in treatment outcomes
73
as a function of race or gender.
Reference ID: 3398090
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Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
74
INDICATIONS AND USAGE
75
Seizure Disorders: Klonopin is useful alone or as an adjunct in the treatment of the
76
Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In
77
patients with absence seizures (petit mal) who have failed to respond to succinimides,
78
Klonopin may be useful.
79
In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often
80
within 3 months of administration. In some cases, dosage adjustment may reestablish
81
efficacy.
82
Panic Disorder: Klonopin is indicated for the treatment of panic disorder, with or
83
without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the
84
occurrence of unexpected panic attacks and associated concern about having additional
85
attacks, worry about the implications or consequences of the attacks, and/or a significant
86
change in behavior related to the attacks.
87
The efficacy of Klonopin was established in two 6- to 9-week trials in panic disorder
88
patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see
89
CLINICAL PHARMACOLOGY: Clinical Trials).
90
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a
91
discrete period of intense fear or discomfort in which four (or more) of the following
92
symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations,
93
pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4)
94
sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or
95
discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or
96
faint; (9) derealization (feelings of unreality) or depersonalization (being detached from
97
oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or
98
tingling sensations); (13) chills or hot flushes.
99
The effectiveness of Klonopin in long-term use, that is, for more than 9 weeks, has not
100
been systematically studied in controlled clinical trials. The physician who elects to use
101
Klonopin for extended periods should periodically reevaluate the long-term usefulness of
102
the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
103
CONTRAINDICATIONS
104
Klonopin should not be used in patients with a history of sensitivity to benzodiazepines,
105
nor in patients with clinical or biochemical evidence of significant liver disease. It may
106
be used in patients with open angle glaucoma who are receiving appropriate therapy but
107
is contraindicated in acute narrow angle glaucoma.
108
WARNINGS
109
Interference With Cognitive and Motor Performance: Since Klonopin produces CNS
110
depression, patients receiving this drug should be cautioned against engaging in
111
hazardous occupations requiring mental alertness, such as operating machinery or driving
112
a motor vehicle. They should also be warned about the concomitant use of alcohol or
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FDA Approved Labeling Text October 2013
113
other CNS-depressant drugs during Klonopin therapy (see PRECAUTIONS: Drug
114
Interactions and Information for Patients).
115
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including Klonopin,
116
increase the risk of suicidal thoughts or behavior in patients taking these drugs for any
117
indication. Patients treated with any AED for any indication should be monitored for the
118
emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual
119
changes in mood or behavior.
120
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy)
121
of 11 different AEDs showed that patients randomized to one of the AEDs had
122
approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal
123
thinking or behavior compared to patients randomized to placebo. In these trials, which
124
had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal
125
behavior or ideation among 27,863 AED-treated patients was 0.43% compared to 0.24%
126
among 16,029 placebo-treated patients, representing an increase of approximately one
127
case of suicidal thinking or behavior for every 530 patients treated. There were four
128
suicides in drug-treated patients in the trials and none in placebo-treated patients, but the
129
number is too small to allow any conclusion about drug effect on suicide.
130
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as
131
one week after starting drug treatment with AEDs and persisted for the duration of
132
treatment assessed. Because most trials included in the analysis did not extend beyond 24
133
weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
134
The risk of suicidal thoughts or behavior was generally consistent among drugs in the
135
data analyzed. The finding of increased risk with AEDs of varying mechanisms of action
136
and across a range of indications suggests that the risk applies to all AEDs used for any
137
indication. The risk did not vary substantially by age (5-100 years) in the clinical trials
138
analyzed.
139
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
140
Table 1
Risk by Indication for Antiepileptic Drugs in the Pooled
141
Analysis
Indication
Placebo
Patients with
Events Per
1000 Patients
Drug Patients
with Events Per
1000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events per 1000
Patients
Epilepsy
Psychiatric
Other
Total
1.0
5.7
1.0
2.4
3.4
8.5
1.8
4.3
3.5
1.5
1.9
1.8
2.4
2.9
0.9
1.9
142
143
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy
144
than in clinical trials for psychiatric or other conditions, but the absolute risk differences
145
were similar for the epilepsy and psychiatric indications.
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146
Anyone considering prescribing Klonopin or any other AED must balance the risk of
147
suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other
148
illnesses for which AEDs are prescribed are themselves associated with morbidity and
149
mortality and an increased risk of suicidal thoughts and behavior. Should suicidal
150
thoughts and behavior emerge during treatment, the prescriber needs to consider whether
151
the emergence of these symptoms in any given patient may be related to the illness being
152
treated.
153
Patients, their caregivers, and families should be informed that AEDs increase the risk of
154
suicidal thoughts and behavior and should be advised of the need to be alert for the
155
emergence or worsening of the signs and symptoms of depression, any unusual changes
156
in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about
157
self-harm. Behaviors of concern should be reported immediately to healthcare providers.
158
Pregnancy Risks: Data from several sources raise concerns about the use of Klonopin
159
during pregnancy.
160
Animal Findings: In three studies in which Klonopin was administered orally to pregnant
161
rabbits at doses of 0.2, 1, 5 or 10 mg/kg/day (low dose approximately 0.2 times the
162
163
maximum recommended human dose of 20 mg/day for seizure disorders and equivalent
to the maximum dose of 4 mg/day for panic disorder, on a mg/m2 basis) during the period
164
of organogenesis, a similar pattern of malformations (cleft palate, open eyelid, fused
165
sternebrae and limb defects) was observed in a low, non-dose-related incidence in
166
exposed litters from all dosage groups. Reductions in maternal weight gain occurred at
167
dosages of 5 mg/kg/day or greater and reduction in embryo-fetal growth occurred in one
168
study at a dosage of 10 mg/kg/day. No adverse maternal or embryo-fetal effects were
169
observed in mice and rats following administration during organogenesis of oral doses up
170
to 15 mg/kg/day or 40 mg/kg/day, respectively (4 and 20 times the maximum
171
172
recommended human dose of 20 mg/day for seizure disorders and 20 and 100 times the
maximum dose of 4 mg/day for panic disorder, respectively, on a mg/m2 basis).
173
General Concerns and Considerations About Anticonvulsants: Recent reports suggest an
174
association between the use of anticonvulsant drugs by women with epilepsy and an
175
elevated incidence of birth defects in children born to these women. Data are more
176
extensive with respect to diphenylhydantoin and phenobarbital, but these are also the
177
most commonly prescribed anticonvulsants; less systematic or anecdotal reports suggest a
178
possible similar association with the use of all known anticonvulsant drugs.
179
In children of women treated with drugs for epilepsy, reports suggesting an elevated
180
incidence of birth defects cannot be regarded as adequate to prove a definite cause and
181
effect relationship. There are intrinsic methodologic problems in obtaining adequate data
182
on drug teratogenicity in humans; the possibility also exists that other factors (eg, genetic
183
factors or the epileptic condition itself) may be more important than drug therapy in
184
leading to birth defects. The great majority of mothers on anticonvulsant medication
185
deliver normal infants. It is important to note that anticonvulsant drugs should not be
186
discontinued in patients in whom the drug is administered to prevent seizures because of
187
the strong possibility of precipitating status epilepticus with attendant hypoxia and threat
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188
to life. In individual cases where the severity and frequency of the seizure disorder are
189
such that the removal of medication does not pose a serious threat to the patient,
190
discontinuation of the drug may be considered prior to and during pregnancy; however, it
191
cannot be said with any confidence that even mild seizures do not pose some hazards to
192
the developing embryo or fetus.
193
General Concerns About Benzodiazepines: An increased risk of congenital
194
malformations associated with the use of benzodiazepine drugs has been suggested in
195
several studies.
196
There may also be non-teratogenic risks associated with the use of benzodiazepines
197
during pregnancy. There have been reports of neonatal flaccidity, respiratory and feeding
198
difficulties, and hypothermia in children born to mothers who have been receiving
199
benzodiazepines late in pregnancy. In addition, children born to mothers receiving
200
benzodiazepines late in pregnancy may be at some risk of experiencing withdrawal
201
symptoms during the postnatal period.
202
Advice Regarding the Use of Klonopin in Women of Childbearing Potential: In general,
203
the use of Klonopin in women of childbearing potential, and more specifically during
204
known pregnancy, should be considered only when the clinical situation warrants the risk
205
to the fetus.
206
The specific considerations addressed above regarding the use of anticonvulsants for
207
epilepsy in women of childbearing potential should be weighed in treating or counseling
208
these women.
209
Because of experience with other members of the benzodiazepine class, Klonopin is
210
assumed to be capable of causing an increased risk of congenital abnormalities when
211
administered to a pregnant woman during the first trimester. Because use of these drugs
212
is rarely a matter of urgency in the treatment of panic disorder, their use during the first
213
trimester should almost always be avoided. The possibility that a woman of childbearing
214
potential may be pregnant at the time of institution of therapy should be considered. If
215
this drug is used during pregnancy, or if the patient becomes pregnant while taking this
216
drug, the patient should be apprised of the potential hazard to the fetus. Patients should
217
also be advised that if they become pregnant during therapy or intend to become
218
pregnant, they should communicate with their physician about the desirability of
219
discontinuing the drug.
220
Withdrawal Symptoms: Withdrawal symptoms of the barbiturate type have occurred
221
after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
222
PRECAUTIONS
223
General: Worsening of Seizures: When used in patients in whom several different types
224
of seizure disorders coexist, Klonopin may increase the incidence or precipitate the onset
225
of generalized tonic-clonic seizures (grand mal). This may require the addition of
226
appropriate anticonvulsants or an increase in their dosages. The concomitant use of
227
valproic acid and Klonopin may produce absence status.
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228
Laboratory Testing During Long-Term Therapy: Periodic blood counts and liver function
229
tests are advisable during long-term therapy with Klonopin.
230
Risks of Abrupt Withdrawal: The abrupt withdrawal of Klonopin, particularly in those
231
patients on long-term, high-dose therapy, may precipitate status epilepticus. Therefore,
232
when discontinuing Klonopin, gradual withdrawal is essential. While Klonopin is being
233
gradually withdrawn, the simultaneous substitution of another anticonvulsant may be
234
indicated.
235
Caution in Renally Impaired Patients: Metabolites of Klonopin are excreted by the
236
kidneys; to avoid their excess accumulation, caution should be exercised in the
237
administration of the drug to patients with impaired renal function.
238
Hypersalivation: Klonopin may produce an increase in salivation. This should be
239
considered before giving the drug to patients who have difficulty handling secretions.
240
Because of this and the possibility of respiratory depression, Klonopin should be used
241
with caution in patients with chronic respiratory diseases.
242
Information for Patients: A Klonopin Medication Guide must be given to the patient
243
each time Klonopin is dispensed, as required by law. Patients should be instructed to take
244
Klonopin only as prescribed. Physicians are advised to discuss the following issues with
245
patients for whom they prescribe Klonopin:
246
Dose Changes: To assure the safe and effective use of benzodiazepines, patients should
247
be informed that, since benzodiazepines may produce psychological and physical
248
dependence, it is advisable that they consult with their physician before either increasing
249
the dose or abruptly discontinuing this drug.
250
Interference With Cognitive and Motor Performance: Because benzodiazepines have the
251
potential to impair judgment, thinking or motor skills, patients should be cautioned about
252
operating hazardous machinery, including automobiles, until they are reasonably certain
253
that Klonopin therapy does not affect them adversely.
254
Suicidal Thinking and Behavior: Patients, their caregivers, and families should be
255
counseled that AEDs, including Klonopin, may increase the risk of suicidal thoughts and
256
behavior and should be advised of the need to be alert for the emergence or worsening of
257
symptoms of depression, any unusual changes in mood or behavior, or the emergence of
258
suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be
259
reported immediately to healthcare providers.
260
Pregnancy: Patients should be advised to notify their physician if they become pregnant
261
or intend to become pregnant during therapy with Klonopin (see WARNINGS:
262
Pregnancy Risks). Patients should be encouraged to enroll in the North American
263
Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry
264
is collecting information about the safety of antiepileptic drugs during pregnancy. To
265
enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS:
266
Pregnancy).
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267
Nursing: Patients should be advised not to breastfeed an infant if they are taking
268
Klonopin.
269
Concomitant Medication: Patients should be advised to inform their physicians if they are
270
taking, or plan to take, any prescription or over-the-counter drugs, since there is a
271
potential for interactions.
272
Alcohol: Patients should be advised to avoid alcohol while taking Klonopin.
273
Drug Interactions: Effect of Clonazepam on the Pharmacokinetics of Other Drugs:
274
Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine
275
or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not
276
been investigated.
277
Effect of Other Drugs on the Pharmacokinetics of Clonazepam: Literature reports suggest
278
that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam
279
pharmacokinetics.
280
In a study in which the 2 mg clonazepam orally disintegrating tablet was administered
281
with and without propantheline (an anticholinergic agent with multiple effects on the GI
282
tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax of
283
clonazepam was 20% lower when the orally disintegrating tablet was given with
284
propantheline compared to when it was given alone.
285
Fluoxetine does not affect the pharmacokinetics of clonazepam. Cytochrome P-450
286
inducers, such as phenytoin, carbamazepine and phenobarbital, induce clonazepam
287
metabolism, causing an approximately 30% decrease in plasma clonazepam levels.
288
Although clinical studies have not been performed, based on the involvement of the
289
cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme
290
system, notably oral antifungal agents, should be used cautiously in patients receiving
291
clonazepam.
292
Pharmacodynamic Interactions: The CNS-depressant action of the benzodiazepine class
293
of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics,
294
antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of
295
antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and
296
by other anticonvulsant drugs.
297
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not
298
been conducted with clonazepam.
299
The data currently available are not sufficient to determine the genotoxic potential of
300
clonazepam.
301
In a two-generation fertility study in which clonazepam was given orally to rats at 10 and
302
100 mg/kg/day (low dose approximately 5 times and 24 times the maximum
303
304
recommended human dose of 20 mg/day for seizure disorder and 4 mg/day for panic
disorder, respectively, on a mg/m2 basis), there was a decrease in the number of
305
pregnancies and in the number of offspring surviving until weaning.
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306
Pregnancy: Teratogenic Effects: Pregnancy Category D (see WARNINGS: Pregnancy
307
Risks).
308
To provide information regarding the effects of in utero exposure to Klonopin, physicians
309
are advised to recommend that pregnant patients taking Klonopin enroll in the NAAED
310
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334,
311
and must be done by patients themselves. Information on this registry can also be found
312
at the website http://www.aedpregnancyregistry.org/.
313
Labor and Delivery: The effect of Klonopin on labor and delivery in humans has not
314
been specifically studied; however, perinatal complications have been reported in
315
children born to mothers who have been receiving benzodiazepines late in pregnancy,
316
including findings suggestive of either excess benzodiazepine exposure or of withdrawal
317
phenomena (see WARNINGS: Pregnancy Risks).
318
Nursing Mothers: Mothers receiving Klonopin should not breastfeed their infants.
319
Pediatric Use: Because of the possibility that adverse effects on physical or mental
320
development could become apparent only after many years, a benefit-risk consideration
321
of the long-term use of Klonopin is important in pediatric patients being treated for
322
seizure
disorder
(see
INDICATIONS
AND
USAGE
and
DOSAGE
AND
323
ADMINISTRATION).
324
Safety and effectiveness in pediatric patients with panic disorder below the age of 18
325
have not been established.
326
Geriatric Use: Clinical studies of Klonopin did not include sufficient numbers of subjects
327
aged 65 and over to determine whether they respond differently from younger subjects.
328
Other reported clinical experience has not identified differences in responses between the
329
elderly and younger patients. In general, dose selection for an elderly patient should be
330
cautious, usually starting at the low end of the dosing range, reflecting the greater
331
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or
332
other drug therapy.
333
Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will
334
impair clonazepam elimination. Metabolites of Klonopin are excreted by the kidneys; to
335
avoid their excess accumulation, caution should be exercised in the administration of the
336
drug to patients with impaired renal function. Because elderly patients are more likely to
337
have decreased hepatic and/or renal function, care should be taken in dose selection, and
338
it may be useful to assess hepatic and/or renal function at the time of dose selection.
339
Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients
340
generally should be started on low doses of Klonopin and observed closely.
341
ADVERSE REACTIONS
342
The adverse experiences for Klonopin are provided separately for patients with seizure
343
disorders and with panic disorder.
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344
Seizure Disorders: The most frequently occurring side effects of Klonopin are referable
345
to CNS depression. Experience in treatment of seizures has shown that drowsiness has
346
occurred in approximately 50% of patients and ataxia in approximately 30%. In some
347
cases, these may diminish with time; behavior problems have been noted in
348
approximately 25% of patients. Others, listed by system, are:
349
Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia,
350
dysarthria, dysdiadochokinesis, ‘‘glassy-eyed’’ appearance, headache, hemiparesis,
351
hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo
352
Psychiatric: Confusion, depression, amnesia, hallucinations, hysteria, increased libido,
353
insomnia, psychosis (the behavior effects are more likely to occur in patients with a
354
history of psychiatric disturbances). The following paradoxical reactions have been
355
observed: excitability, irritability, aggressive behavior, agitation, nervousness, hostility,
356
anxiety, sleep disturbances, nightmares and vivid dreams
357
Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper
358
respiratory passages
359
Cardiovascular: Palpitations
360
Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
361
Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis,
362
gastritis, increased appetite, nausea, sore gums
363
Genitourinary: Dysuria, enuresis, nocturia, urinary retention
364
Musculoskeletal: Muscle weakness, pains
365
Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss
366
or gain
367
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia
368
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline
369
phosphatase
370
Panic Disorder: Adverse events during exposure to Klonopin were obtained by
371
spontaneous report and recorded by clinical investigators using terminology of their own
372
choosing. Consequently, it is not possible to provide a meaningful estimate of the
373
proportion of individuals experiencing adverse events without first grouping similar types
374
of events into a smaller number of standardized event categories. In the tables and
375
tabulations that follow, CIGY dictionary terminology has been used to classify reported
376
adverse events, except in certain cases in which redundant terms were collapsed into
377
more meaningful terms, as noted below.
378
The stated frequencies of adverse events represent the proportion of individuals who
379
experienced, at least once, a treatment-emergent adverse event of the type listed. An
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380
event was considered treatment-emergent if it occurred for the first time or worsened
381
while receiving therapy following baseline evaluation.
382
383
384
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials:
385
Adverse Events Associated With Discontinuation of Treatment:
386
Overall, the incidence of discontinuation due to adverse events was 17% in Klonopin
387
compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most
388
common events (≥1%) associated with discontinuation and a dropout rate twice or greater
389
for Klonopin than that of placebo included the following:
390
Table 2
Most Common Adverse Events (≥1%) Associated with
391
Discontinuation of Treatment
Adverse Event
Klonopin (N=574)
Placebo (N=294)
Somnolence
7%
1%
Depression
4%
1%
Dizziness
1%
<1%
Nervousness
1%
0%
Ataxia
1%
0%
Intellectual Ability Reduced
1%
0%
392
Adverse Events Occurring at an Incidence of 1% or More Among Klonopin-Treated
393
Patients:
394
Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent
395
adverse events that occurred during acute therapy of panic disorder from a pool of two 6
396
to 9-week trials. Events reported in 1% or more of patients treated with Klonopin (doses
397
ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in
398
placebo-treated patients are included.
399
The prescriber should be aware that the figures in Table 3 cannot be used to predict the
400
incidence of side effects in the course of usual medical practice where patient
401
characteristics and other factors differ from those that prevailed in the clinical trials.
402
Similarly, the cited frequencies cannot be compared with figures obtained from other
403
clinical investigations involving different treatments, uses and investigators. The cited
404
figures, however, do provide the prescribing physician with some basis for estimating the
405
relative contribution of drug and nondrug factors to the side effect incidence in the
406
population studied.
407
Table 3
Treatment-Emergent Adverse Event Incidence in 6- to 9
408
Week Placebo-Controlled Clinical Trials*
Clonazepam Maximum Daily Dose
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Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Central & Peripheral Nervous
System
Somnolence†
26
35
50
36
37
10
Dizziness
5
5
12
8
8
4
Coordination Abnormal†
1
2
7
9
6
0
Ataxia†
2
1
8
8
5
0
Dysarthria†
0
0
4
3
2
0
Psychiatric
Depression
7
6
8
8
7
1
Memory Disturbance
2
5
2
5
4
2
Nervousness
1
4
3
4
3
2
Intellectual Ability Reduced
0
2
4
3
2
0
Emotional Lability
0
1
2
2
1
1
Libido Decreased
0
1
3
1
1
0
Confusion
0
2
2
1
1
0
Respiratory System
Upper Respiratory Tract
Infection†
10
10
7
6
8
4
Sinusitis
4
2
8
4
4
3
Rhinitis
3
2
4
2
2
1
Coughing
2
2
4
0
2
0
Pharyngitis
1
1
3
2
2
1
Bronchitis
1
0
2
2
1
1
Gastrointestinal System
Constipation†
0
1
5
3
2
2
Appetite Decreased
1
1
0
3
1
1
Abdominal Pain†
2
2
2
0
1
1
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Clonazepam Maximum Daily Dose
Adverse Event
by Body System
<1mg
n=96
%
1-<2mg
n=129
%
2-<3mg
n=113
%
≥3mg
n=235
%
All
Klonopin
Groups
N=574
%
Placebo
N=294
%
Body as a Whole
Fatigue
Allergic Reaction
9
3
6
1
7
4
7
2
7
2
4
1
Musculoskeletal
Myalgia
2
1
4
0
1
1
Resistance Mechanism
Disorders
Influenza
3
2
5
5
4
3
Urinary System
Micturition Frequency
Urinary Tract Infection†
1
0
2
0
2
2
1
2
1
1
0
0
Vision Disorders
Blurred Vision
1
2
3
0
1
1
Reproductive Disorders‡
Female
Dysmenorrhea
0
6
5
2
3
2
Colpitis
Male
4
0
2
1
1
1
Ejaculation Delayed
0
0
2
2
1
0
Impotence
3
0
2
1
1
0
409
* Events reported by at least 1% of patients treated with Klonopin and for which the
410
incidence was greater than that for placebo.
411
† Indicates that the p-value for the dose-trend test (Cochran-Mantel-Haenszel) for
412
adverse event incidence was ≤0.10.
413
‡ Denominators for events in gender-specific systems are: n=240 (clonazepam), 102
414
(placebo) for male, and 334 (clonazepam), 192 (placebo) for female.
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415
Commonly Observed Adverse Events:
416
Table 4
Incidence of Most Commonly Observed Adverse Events* in
417
Acute Therapy in Pool of 6- to 9-Week Trials
Adverse Event
(Genentech Preferred Term)
Clonazepam
(N=574)
Placebo
(N=294)
Somnolence
37%
10%
Depression
7%
1%
Coordination Abnormal
6%
0%
Ataxia
5%
0%
418
* Treatment-emergent events for which the incidence in the clonazepam patients was
419
≥5% and at least twice that in the placebo patients.
420
Treatment-Emergent Depressive Symptoms:
421
In the pool of two short-term placebo-controlled trials, adverse events classified under the
422
preferred term “depression” were reported in 7% of Klonopin-treated patients compared
423
to 1% of placebo-treated patients, without any clear pattern of dose relatedness. In these
424
same trials, adverse events classified under the preferred term “depression” were reported
425
as leading to discontinuation in 4% of Klonopin-treated patients compared to 1% of
426
placebo-treated patients. While these findings are noteworthy, Hamilton Depression
427
Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D
428
scores in the clonazepam group than the placebo group suggesting that clonazepam
429
treated patients were not experiencing a worsening or emergence of clinical depression.
430
Other Adverse Events Observed During the Premarketing Evaluation of Klonopin in
431
Panic Disorder:
432
Following is a list of modified CIGY terms that reflect treatment-emergent adverse
433
events reported by patients treated with Klonopin at multiple doses during clinical trials.
434
All reported events are included except those already listed in Table 3 or elsewhere in
435
labeling, those events for which a drug cause was remote, those event terms which were
436
so general as to be uninformative, and events reported only once and which did not have
437
a substantial probability of being acutely life-threatening. It is important to emphasize
438
that, although the events occurred during treatment with Klonopin, they were not
439
necessarily caused by it.
440
Events are further categorized by body system and listed in order of decreasing
441
frequency. These adverse events were reported infrequently, which is defined as
442
occurring in 1/100 to 1/1000 patients.
443
Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever,
444
shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain,
445
cellulitis, inflammation localized
446
Cardiovascular Disorders: chest pain, hypotension postural
Reference ID: 3398090
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
447
Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness,
448
feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness,
449
hyperactivity, hypoesthesia, tongue thick, twitching
450
Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation,
451
stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel
452
movements frequent, pain pelvic, dyspepsia, hemorrhoids
453
Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
454
Heart Rate and Rhythm Disorders: palpitation
455
Metabolic and Nutritional Disorders: thirst, gout
456
Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain
457
leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis,
458
arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee
459
Platelet, Bleeding and Clotting Disorders: bleeding dermal
460
Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization,
461
dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased,
462
aggressive reaction, apathy, attention lack, excitement, feeling mad, hunger abnormal,
463
illusion, nightmares, sleep disorder, suicide ideation, yawning
464
Reproductive Disorders, Female: breast pain, menstrual irregularity
465
Reproductive Disorders, Male: ejaculation decreased
466
Resistance Mechanism Disorders: infection mycotic, infection viral, infection
467
streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis
468
Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed,
469
pneumonia, pleurisy
470
Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact,
471
flushing, pruritus, pustular reaction, skin burns, skin disorder
472
Special Senses Other, Disorders: taste loss
473
Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder
474
dysfunction, urinary retention, urinary tract bleeding, urine discoloration
475
Vascular (Extracardiac) Disorders: thrombophlebitis leg
476
Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual
477
field defect, xerophthalmia
478
DRUG ABUSE AND DEPENDENCE
479
Controlled Substance Class: Clonazepam is a Schedule IV controlled substance.
Reference ID: 3398090
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
480
Physical and Psychological Dependence: Withdrawal symptoms, similar in character to
481
those noted with barbiturates and alcohol (eg, convulsions, psychosis, hallucinations,
482
behavioral disorder, tremor, abdominal and muscle cramps) have occurred following
483
abrupt discontinuance of clonazepam. The more severe withdrawal symptoms have
484
usually been limited to those patients who received excessive doses over an extended
485
period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia)
486
have been reported following abrupt discontinuance of benzodiazepines taken
487
continuously at therapeutic levels for several months. Consequently, after extended
488
therapy, abrupt discontinuation should generally be avoided and a gradual dosage
489
tapering schedule followed (see DOSAGE AND ADMINISTRATION). Addiction-prone
490
individuals (such as drug addicts or alcoholics) should be under careful surveillance when
491
receiving clonazepam or other psychotropic agents because of the predisposition of such
492
patients to habituation and dependence.
493
Following the short-term treatment of patients with panic disorder in Studies 1 and 2 (see
494
CLINICAL PHARMACOLOGY: Clinical Trials), patients were gradually withdrawn
495
during a 7-week downward-titration (discontinuance) period. Overall, the discontinuance
496
period was associated with good tolerability and a very modest clinical deterioration,
497
without evidence of a significant rebound phenomenon. However, there are not sufficient
498
data from adequate and well-controlled long-term clonazepam studies in patients with
499
panic disorder to accurately estimate the risks of withdrawal symptoms and dependence
500
that may be associated with such use.
501
OVERDOSAGE
502
Human Experience: Symptoms of clonazepam overdosage, like those produced by other
503
CNS depressants, include somnolence, confusion, coma and diminished reflexes.
504
Overdose Management: Treatment includes monitoring of respiration, pulse and blood
505
pressure, general supportive measures and immediate gastric lavage. Intravenous fluids
506
should be administered and an adequate airway maintained. Hypotension may be
507
combated by the use of levarterenol or metaraminol. Dialysis is of no known value.
508
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete
509
or partial reversal of the sedative effects of benzodiazepines and may be used in
510
situations when an overdose with a benzodiazepine is known or suspected. Prior to the
511
administration of flumazenil, necessary measures should be instituted to secure airway,
512
ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a
513
substitute for, proper management of benzodiazepine overdose. Patients treated with
514
flumazenil should be monitored for resedation, respiratory depression and other residual
515
benzodiazepine effects for an appropriate period after treatment. The prescriber should
516
be aware of a risk of seizure in association with flumazenil treatment, particularly in
517
long-term benzodiazepine users and in cyclic antidepressant overdose. The complete
518
flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and
519
PRECAUTIONS, should be consulted prior to use.
Reference ID: 3398090
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
520
Flumazenil is not indicated in patients with epilepsy who have been treated with
521
benzodiazepines. Antagonism of the benzodiazepine effect in such patients may
522
provoke seizures.
523
Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.
524
DOSAGE AND ADMINISTRATION
525
Clonazepam is available as a tablet or an orally disintegrating tablet (wafer). The tablets
526
should be administered with water by swallowing the tablet whole. The orally
527
disintegrating tablet should be administered as follows: After opening the pouch, peel
528
back the foil on the blister. Do not push tablet through foil. Immediately upon opening
529
the blister, using dry hands, remove the tablet and place it in the mouth. Tablet
530
disintegration occurs rapidly in saliva so it can be easily swallowed with or without
531
water.
532
533
Seizure Disorders: Adults: The initial dose for adults with seizure disorders should not
534
exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of
535
0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects
536
preclude any further increase. Maintenance dosage must be individualized for each
537
patient depending upon response. Maximum recommended daily dose is 20 mg.
538
The use of multiple anticonvulsants may result in an increase of depressant adverse
539
effects. This should be considered before adding Klonopin to an existing anticonvulsant
540
regimen.
541
Pediatric Patients: Klonopin is administered orally. In order to minimize drowsiness, the
542
initial dose for infants and children (up to 10 years of age or 30 kg of body weight)
543
should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05 mg/kg/day given in
544
two or three divided doses. Dosage should be increased by no more than 0.25 to 0.5 mg
545
every third day until a daily maintenance dose of 0.1 to 0.2 mg/kg of body weight has
546
been reached, unless seizures are controlled or side effects preclude further increase.
547
Whenever possible, the daily dose should be divided into three equal doses. If doses are
548
not equally divided, the largest dose should be given before retiring.
549
Geriatric Patients: There is no clinical trial experience with Klonopin in seizure disorder
550
patients 65 years of age and older. In general, elderly patients should be started on low
551
doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
552
Panic Disorder: Adults: The initial dose for adults with panic disorder is 0.25 mg bid. An
553
increase to the target dose for most patients of 1 mg/day may be made after 3 days. The
554
recommended dose of 1 mg/day is based on the results from a fixed dose study in which
555
the optimal effect was seen at 1 mg/day. Higher doses of 2, 3 and 4 mg/day in that study
556
were less effective than the 1 mg/day dose and were associated with more adverse
557
effects. Nevertheless, it is possible that some individual patients may benefit from doses
558
of up to a maximum dose of 4 mg/day, and in those instances, the dose may be increased
559
in increments of 0.125 to 0.25 mg bid every 3 days until panic disorder is controlled or
Reference ID: 3398090
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
560
until side effects make further increases undesired. To reduce the inconvenience of
561
somnolence, administration of one dose at bedtime may be desirable.
562
Treatment should be discontinued gradually, with a decrease of 0.125 mg bid every
563
3 days, until the drug is completely withdrawn.
564
There is no body of evidence available to answer the question of how long the patient
565
treated with clonazepam should remain on it. Therefore, the physician who elects to use
566
Klonopin for extended periods should periodically reevaluate the long-term usefulness of
567
the drug for the individual patient.
568
Pediatric Patients: There is no clinical trial experience with Klonopin in panic disorder
569
patients under 18 years of age.
570
Geriatric Patients: There is no clinical trial experience with Klonopin in panic disorder
571
patients 65 years of age and older. In general, elderly patients should be started on low
572
doses of Klonopin and observed closely (see PRECAUTIONS: Geriatric Use).
573
HOW SUPPLIED
574
Klonopin tablets are available as scored tablets with a K-shaped perforation—0.5 mg,
575
orange (NDC 0004-0068-01); and unscored tablets with a K-shaped perforation—1 mg,
576
blue (NDC 0004-0058-01); 2 mg, white (NDC 0004-0098-01)—bottles of 100.
577
Imprint on tablets: usage illustration
578
0.5 mg — 1/2 KLONOPIN (front)
579
ROCHE (scored side)
580
1 mg — 1 KLONOPIN (front)
581
ROCHE (reverse side) usage illustration
582
2 mg — 2 KLONOPIN (front)
583
ROCHE (reverse side) usage illustration
584
Klonopin Wafers (clonazepam orally disintegrating tablets) are white, round and
585
debossed with the tablet strength expressed as a fraction or whole number (1/8, 1/4, 1/2,
586
1, or 2). The tablets are available in blister packages of 60 (10 pouches/carton) as
587
follows:
Reference ID: 3398090
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved Labeling Text October 2013
588
0.125 mg debossed 1/8, (NDC 0004-0279-22)
589
0.25 mg debossed 1/4, (NDC 0004-0280-22)
590
0.5 mg debossed 1/2, (NDC 0004-0281-22)
591
1 mg debossed 1, (NDC 0004-0282-22)
592
2 mg debossed 2, (NDC 0004-0283-22)
593
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
594
comp
any logo
597
Revised: Month Year
598
© xxxx Genentech, Inc. All rights reserved.
Reference ID: 3398090
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Klonopin (clonazepam) tablets NDA 017533
Klonopin (clonazepam) wafers NDA 020813
FDA Approved MG Text October 2013
1
Medication Guide
2
KLONOPIN (KLON-oh-pin)
3
(clonazepam)
4
Tablets and Wafers
5
6
Read this Medication Guide before you start taking KLONOPIN and each time
7
you get a refill. There may be new information. This information does not take the
8
place of talking to your healthcare provider about your medical condition or
9
treatment.
10
KLONOPIN can cause serious side effects. Because stopping KLONOPIN
11
suddenly can also cause serious problems, do not stop taking KLONOPIN without
12
talking to your healthcare provider first.
13
What is the most important information I should know about KLONOPIN?
14
Do not stop taking KLONOPIN without first talking to your healthcare
15
provider. Stopping KLONOPIN suddenly can cause serious problems.
16
KLONOPIN can cause serious side effects, including:
17
1. KLONOPIN can slow your thinking and motor skills
18
•
Do not drive, operate heavy machinery, or do other dangerous activities
19
until you know how KLONOPIN affects you.
20
•
Do not drink alcohol or take other drugs that may make you sleepy or
21
dizzy while taking KLONOPIN until you talk to your healthcare
22
provider. When taken with alcohol or drugs that cause sleepiness or
23
dizziness, KLONOPIN may make your sleepiness or dizziness worse.
24
2. Like other antiepileptic drugs, KLONOPIN may cause suicidal thoughts
25
or actions in a very small number of people, about 1 in 500.
26
Call a healthcare provider right away if you have any of these
27
symptoms, especially if they are new, worse, or worry you:
28
•
thoughts about suicide or dying
29
•
attempt to commit suicide
30
•
new or worse depression
31
•
new or worse anxiety
32
•
feeling agitated or restless
33
•
panic attacks
34
•
trouble sleeping (insomnia)
35
•
new or worse irritability
36
•
acting aggressive, being angry, or violent
37
•
acting on dangerous impulses
38
•
an extreme increase in activity and talking (mania)
Reference ID: 3398090
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
•
other unusual changes in behavior or mood
40
How can I watch for early symptoms of suicidal thoughts and actions?
41
• Pay attention to any changes, especially sudden changes, in mood,
42
behaviors, thoughts, or feelings.
43
•
Keep all follow-up visits with your healthcare provider as scheduled.
44
Call your healthcare provider between visits as needed, especially if you are
45
worried about symptoms.
46
47
Suicidal thoughts or actions can be caused by things other than medicines. If
48
you have suicidal thoughts or actions, your healthcare provider may check
49
for other causes.
50
Do not stop KLONOPIN without first talking to a healthcare provider.
51
Stopping KLONOPIN suddenly can cause serious problems. Stopping
52
KLONOPIN suddenly can cause seizures that will not stop (status
53
epilepticus).
54
3. KLONOPIN may harm your unborn or developing baby.
55
• If you take KLONOPIN during pregnancy, your baby is at risk for serious
56
birth defects. These defects can happen as early as in the first month of
57
pregnancy, even before you know you are pregnant. Birth defects may
58
occur even in children born to women who are not taking any medicines
59
and do not have other risk factors.
60
• Children born to mothers receiving benzodiazepine medications (including
61
KLONOPIN) late in pregnancy may be at some risk of experiencing
62
breathing problems, feeding problems, hypothermia, and withdrawal
63
symptoms.
64
• Tell your healthcare provider right away if you become pregnant while
65
taking KLONOPIN. You and your healthcare provider should decide if
66
you will take KLONOPIN while you are pregnant.
67
• If you become pregnant while taking KLONOPIN, talk to your healthcare
68
provider about registering with the North American Antiepileptic Drug
69
Pregnancy Registry. You can register by calling 1-888-233-2334. The
70
purpose of this registry is to collect information about the safety of
71
antiepileptic drugs during pregnancy.
72
• KLONOPIN can pass into breast milk. Talk to your healthcare provider
73
about the best way to feed your baby if you take KLONOPIN. You and
74
your healthcare provider should decide if you will take KLONOPIN or
75
breast feed. You should not do both.
76
4. KLONOPIN can cause abuse and dependence.
Reference ID: 3398090
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
77
• Do not stop taking KLONOPIN all of a sudden. Stopping KLONOPIN
78
suddenly can cause seizures that do not stop, hearing or seeing things that
79
are not there (hallucinations), shaking, and stomach and muscle cramps.
80
o Talk to your doctor about slowly stopping KLONOPIN to avoid
81
getting sick with withdrawal symptoms.
82
o Physical dependence is not the same as drug addiction. Your
83
healthcare provider can tell you more about the differences
84
between physical dependence and drug addiction.
85
KLONOPIN is a federally controlled substance (C-IV) because it can be
86
abused or lead to dependence. Keep KLONOPIN in a safe place to prevent
87
misuse and abuse. Selling or giving away KLONOPIN may harm others, and
88
is against the law. Tell your doctor if you have ever abused or been
89
dependent on alcohol, prescription medicines or street drugs.
90
What is KLONOPIN?
91
KLONOPIN is a prescription medicine used alone or with other medicines to
92
treat:
93
• certain types of seizure disorders (epilepsy) in adults and children
94
• panic disorder with or without fear of open spaces (agoraphobia) in adults
95
It is not known if KLONOPIN is safe or effective in treating panic disorder in
96
children younger than 18 years old.
97
Who should not take KLONOPIN?
98
Do not take KLONOPIN if you:
99
• are allergic to benzodiazepines
100
• have significant liver disease
101
• have an eye disease called acute narrow angle glaucoma
102
Ask your healthcare provider if you are not sure if you have any of the
103
problems listed above.
104
What should I tell my healthcare provider before taking KLONOPIN?
105
Before you take KLONOPIN, tell your healthcare provider if you:
106
• have liver or kidney problems
107
• have lung problems (respiratory disease)
108
• have or have had depression, mood problems, or suicidal thoughts or
109
behavior
110
• have any other medical conditions
111
Reference ID: 3398090
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
112
Tell your healthcare provider about all the medicines you take, including
113
prescription and non-prescription medicines, vitamins, and herbal supplements.
114
Taking KLONOPIN with certain other medicines can cause side effects or affect
115
how well they work. Do not start or stop other medicines without talking to your
116
healthcare provider.
117
Know the medicines you take. Keep a list of them and show it to your healthcare
118
provider and pharmacist when you get a new medicine.
119
How should I take KLONOPIN?
120
• Take KLONOPIN exactly as your healthcare provider tells you.
121
KLONOPIN is available as a tablet or as an orally disintegrating tablet
122
(wafer).
123
• Do not stop taking KLONOPIN without first talking to your healthcare
124
provider. Stopping KLONOPIN suddenly can cause serious problems.
125
• KLONOPIN tablets should be taken with water and swallowed whole.
126
• KLONOPIN wafers can be taken with or without water.
127
o Do not open the pouch until you are ready to take KLONOPIN.
128
o After opening the pouch, peel back the foil on the blister pack.
129
o Do not push the wafer through the foil.
130
o After opening the blister pack, with dry hands, take the wafer and
131
place it in your mouth.
132
o The wafer will melt quickly.
133
• If you take too much KLONOPIN, call your healthcare provider or local
134
Poison Control Center right away.
135
What should I avoid while taking KLONOPIN?
136
• KLONOPIN can slow your thinking and motor skills. Do not drive,
137
operate heavy machinery, or do other dangerous activities until you know
138
how KLONOPIN affects you.
139
•
Do not drink alcohol or take other drugs that may make you sleepy or
140
dizzy while taking KLONOPIN until you talk to your healthcare
141
provider. When taken with alcohol or drugs that cause sleepiness or
142
dizziness, KLONOPIN may make your sleepiness or dizziness worse.
143
What are the possible side effects of KLONOPIN?
144
See “What is the most important information I should know about
145
KLONOPIN?”
146
KLONOPIN can also make your seizures happen more often or make them worse.
147
Call your healthcare provider right away if your seizures get worse while taking
148
KLONOPIN.
149
The most common side effects of KLONOPIN include:
Reference ID: 3398090
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
150
• Drowsiness
151
• Problems with walking and coordination
152
• Dizziness
153
• Depression
154
• Fatigue
155
• Problems with memory
156
These are not all the possible side effects of KLONOPIN. For more information,
157
ask your healthcare provider or pharmacist.
158
Tell your healthcare provider if you have any side effect that bothers you or that
159
does not go away.
160
Call your doctor for medical advice about side effects. You may report side
161
effects to FDA at 1-800-FDA-1088.
162
How should I store KLONOPIN?
163
• Store KLONOPIN between 59°F to 86°F (15°C to 30°C)
164
Keep KLONOPIN and all medicines out of the reach of children.
165
General Information about KLONOPIN
166
Medicines are sometimes prescribed for purposes other than those listed in a
167
Medication Guide. Do not use KLONOPIN for a condition for which it was not
168
prescribed. Do not give KLONOPIN to other people, even if they have the same
169
symptoms that you have. It may harm them.
170
This Medication Guide summarizes the most important information about
171
KLONOPIN. If you would like more information, talk with your healthcare
172
provider. You can ask your pharmacist or healthcare provider for information
173
about KLONOPIN that is written for health professionals.
174
For more information, go to www.gene.com/gene/products/information/klonopin
175
or call 1-888-835-2555.
176
What are the ingredients in KLONOPIN?
177
Active ingredient: clonazepam
178
Inactive ingredients:
179
• Tablets:
180
o 0.5 mg tablets contain lactose, magnesium stearate,
181
microcrystalline cellulose, corn starch, FD&C Yellow No. 6 Lake
182
o 1 mg tablets contain lactose, magnesium stearate, microcrystalline
183
cellulose, corn starch, FD&C Blue No. 1 Lake and FD&C Blue
184
No. 2 Lake
185
o 2 mg tablets contain lactose, magnesium stearate, microcrystalline
186
cellulose, corn starch
Reference ID: 3398090
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
187
• Wafers: gelatin, mannitol, methylparaben sodium, propylparaben sodium
188
189
and xanthan gum
190
Issued: Month Year
191
This Medication Guide has been approved by the U.S. Food and Drug
192
Administration.
193
company logo
195
© 2013 Genentech, Inc. All rights reserved.
196
For additional copies of this Medication Guide, please call 1-877-436-3683 or visit
197
www.gene.com/gene/products/information/klonopin.
Reference ID: 3398090
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:16.263633
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017533s053,020813s009lbl.pdf', 'application_number': 17533, 'submission_type': 'SUPPL ', 'submission_number': 53}
|
11,022
|
SINEMET
®
(carbidopa levodopa)
Tablets
DESCRIPTION
SINEMET® (carbidopa levodopa) is a combination of carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound,
slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (—)-L-α
hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is
C10H14N2O4•H2O, and its structural formula is: structural formula
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a
molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β-(3,4-dihydroxybenzene)
propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is: structural formula
SINEMET is supplied as tablets in three strengths:
SINEMET 25-100, containing 25 mg of carbidopa and 100 mg of levodopa.
SINEMET 10-100, containing 10 mg of carbidopa and 100 mg of levodopa.
SINEMET 25-250, containing 25 mg of carbidopa and 250 mg of levodopa.
Inactive ingredients are hydroxypropyl cellulose, pregelatinized starch, crospovidone, microcrystalline
cellulose, and magnesium stearate. SINEMET 10-100 and 25-250 Tablets also contain FD&C Blue
#2/Indigo Carmine AL. SINEMET 25-100 Tablets also contain D&C Yellow #10 Lake.
CLINICAL PHARMACOLOGY
Mechanism of Action
Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous
system affecting the mobility and control of the skeletal muscular system. Its characteristic features
include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa
therapies, may permit the patient better mobility.
Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine
in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease
apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor
of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.
This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacodynamics
W hen levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues
so that only a small portion of a given dose is transported unchanged to the central nervous system. For
this reason, large doses of levodopa are required for adequate therapeutic effect, and these may often be
accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed
in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of
levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and
does not affect the metabolism of levodopa within the central nervous system.
The incidence of levodopa-induced nausea and vomiting is less with SINEMET than with levodopa. In
many patients, this reduction in nausea and vomiting will permit more rapid dosage titration.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa
with levodopa makes more levodopa available for transport to the brain.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and,
when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and
decreases plasma and urinary dopamine and homovanillic acid.
The plasma half-life of levodopa is about 50 minutes, without carbidopa. W hen carbidopa and
levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. At steady
state, the bioavailability of carbidopa from SINEMET tablets is approximately 99% relative to the
concomitant administration of carbidopa and levodopa.
In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced
greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the
two drugs at separate times.
Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of
levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of
pyridoxine; therefore, SINEMET can be given to patients receiving supplemental pyridoxine (vitamin B6).
Special Populations
Geriatric: A study in eight young healthy subjects (21-22 yr) and eight elderly healthy subjects (69-76
yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects
following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of
levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study
in forty patients with Parkinson’s disease, there was a correlation between age of patients and the
increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa
decarboxylase. AUC of levodopa was increased by 28% in elderly patients (≥ 65 yr) compared to young
patients (< 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients
(≥ 65 yr) compared to young patients (< 65 yr) (see PRECAUTIONS, Geriatric Use).
The AUC of carbidopa was increased in elderly subjects (n=10, 65-76 yr) by 29% compared to young
subjects (n=24, 23-64 yr) following IV administration of 50 mg levodopa with carbidopa (50 mg). This
increase is not considered a clinically significant impact.
INDICATIONS AND USAGE
SINEMET is indicated in the treatment of Parkinson's disease, post-encephalitic parkinsonism, and
symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.
Carbidopa allows patients treated for Parkinson's disease to use much lower doses of levodopa. Some
patients who responded poorly to levodopa have improved on SINEMET. This is most likely due to
decreased peripheral decarboxylation of levodopa caused by administration of carbidopa rather than by a
primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the
intrinsic efficacy of levodopa.
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Reference ID: 3594908
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Carbidopa may also reduce nausea and vomiting and permit more rapid titration of levodopa.
CONTRAINDICATIONS
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with SINEMET. These
inhibitors must be discontinued at least two weeks prior to initiating therapy with SINEMET. SINEMET may
be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with
selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS, Drug Interactions).
SINEMET is contraindicated in patients with known hypersensitivity to any component of this drug, and
in patients with narrow-angle glaucoma.
WARNINGS
When SINEMET is to be given to patients who are being treated with levodopa, levodopa must
be discontinued at least twelve hours before therapy with SINEMET is started. In order to reduce
adverse reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION
section before initiating therapy.
The addition of carbidopa with levodopa in the form of SINEMET reduces the peripheral effects
(nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the
adverse reactions due to the central effects of levodopa. Because carbidopa permits more levodopa to
reach the brain and more dopamine to be formed, certain adverse central nervous system (CNS) effects,
e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with SINEMET than
with levodopa alone.
All patients should be observed carefully for the development of depression with concomitant suicidal
tendencies.
SINEMET should be administered cautiously to patients with severe cardiovascular or pulmonary
disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering SINEMET to patients with a history of
myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac
function should be monitored with particular care during the period of initial dosage adjustment, in a facility
with provisions for intensive cardiac care.
As with levodopa, treatment with SINEMET may increase the possibility of upper gastrointestinal
hemorrhage in patients with a history of peptic ulcer.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking SINEMET alone or with other dopaminergic drugs have reported suddenly falling
asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of
motor vehicles). Road traffic accidents attributed to sudden sleep onset have been reported. Although
many patients reported somnolence while on dopaminergic medications, there have been reports of road
traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning
signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.
Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre
existing somnolence, although some patients may not give such a history. For this reason, prescribers
should reassess patients for drowsiness or sleepiness especially since some of the events occur well after
the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or
sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients
should be advised to exercise caution while driving or operating machines during treatment with
SINEMET. Patients who have already experienced somnolence or an episode of sudden sleep onset
should not participate in these activities during treatment with SINEMET.
Before initiating treatment with SINEMET, advise patients about the potential to develop drowsiness
and ask specifically about factors that may increase the risk for somnolence with SINEMET such as the
use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing
SINEMET in patients who report significant daytime sleepiness or episodes of falling asleep during
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
activities that require active participation (e.g., conversations, eating, etc.). If treatment with SINEMET
continues, patients should be advised not to drive and to avoid other potentially dangerous activities that
might result in harm if the patients become somnolent. There is insufficient information to establish that
dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Hyperpyrexia and Confusion
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been
reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as
levodopa, carbidopa levodopa, or carbidopa levodopa extended release. Therefore, patients should be
observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the
patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental
status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating,
hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis,
myoglobinuria, and increased serum myoglobin have been reported.
The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic
infection, etc.) is essential. This may be especially complex if the clinical presentation includes both
serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever, and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring
and 2) treatment of any concomitant serious medical problems for which specific treatments are available.
Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in
the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are
recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with SINEMET provided the
intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular
pressure during therapy.
Dyskinesia
Levodopa alone, as well as SINEMET, is associated with dyskinesias. The occurrence of dyskinesias
may require dosage reduction.
Hallucinations / Psychotic-Like Behavior
Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In
general, hallucinations present shortly after the initiation of therapy and may be responsive to dose
reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep
disorder (insomnia) and excessive dreaming.
SINEMET may have similar effects on thinking and behavior. This abnormal thinking and behavior may
present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion,
psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with SINEMET, because of
the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may
exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of SINEMET.
Impulse Control / Compulsive Behaviors
Reports of patients taking dopaminergic medications (medications that increase central dopaminergic
tone), suggest that patients may experience an intense urge to gamble, increased sexual urges, intense
urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. In
some cases, although not all, these urges were reported to have stopped when the dose was reduced or
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is
important for prescribers to specifically ask patients or the caregivers about the development of new or
increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with
SINEMET. Physicians should consider dose reduction or stopping the medication if a patient develops
such urges while taking SINEMET [see Information for Patients].
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to
approximately 6-fold higher) of developing melanoma than the general population. W hether the increased
risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s
disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently
and on a regular basis when using SINEMET for any indication. Ideally, periodic skin examinations should
be performed by appropriately qualified individuals (e.g., dermatologists).
Information for Patients
The patient should be informed that SINEMET is an immediate-release formulation of carbidopa
levodopa that is designed to begin release of ingredients within 30 minutes. It is important that SINEMET
be taken at regular intervals according to the schedule outlined by the physician. The patient should be
cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson
medications, including other carbidopa levodopa preparations, without first consulting the physician.
Patients should be advised that sometimes a ‘wearing-off’ effect may occur at the end of the dosing
interval. The physician should be notified if such response poses a problem to lifestyle.
Patients should be advised that occasionally, dark color (red, brown, or black) may appear in saliva,
urine, or sweat after ingestion of SINEMET. Although the color appears to be clinically insignificant,
garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also
delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multivitamin
tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce the
clinical effectiveness of the levodopa or carbidopa levodopa therapy.
Patients should be alerted to the possibility of sudden onset of sleep during daily activities, in some
cases without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Patients should be advised to exercise caution while driving or operating machinery and that if
they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities.
(See W ARNINGS, Falling Asleep During Activities of Daily Living and Somnolence.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment of
Parkinson’s disease, including SINEMET. Although it is not proven that the medications caused these
events, these urges were reported to have stopped in some cases when the dose was reduced or the
medication was stopped. Prescribers should ask patients about the development of new or increased
gambling urges, sexual urges or other urges while being treated with SINEMET. Patients should inform
their physician if they experience new or increased gambling urges, increased sexual urges, or other
intense urges while taking SINEMET. Physicians should consider dose reduction or stopping the
medication if a patient develops such urges while taking SINEMET (See PRECAUTIONS, Impulse Control
/ Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline
phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase (LDH), and bilirubin. Abnormalities in
blood urea nitrogen (BUN) and positive Coombs test have also been reported. Commonly, levels of blood
urea nitrogen, creatinine, and uric acid are lower during administration of SINEMET than with levodopa.
SINEMET may cause a false-positive reaction for urinary ketone bodies when a test tape is used for
determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative
tests may result with the use of glucose-oxidase methods of testing for glucosuria.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cases of falsely diagnosed pheochromocytoma in patients on carbidopa levodopa therapy have been
reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of
catecholamines and their metabolites in patients on levodopa or carbidopa levodopa therapy.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with SINEMET.
Symptomatic postural hypotension occurred when SINEMET was added to the treatment of a patient
receiving antihypertensive drugs. Therefore, when therapy with SINEMET is started, dosage adjustment of
the antihypertensive drug may be required.
For patients receiving MAO inhibitors (Type A or B), see CONTRAINDICATIONS. Concomitant therapy
with selegiline and carbidopa levodopa may be associated with severe orthostatic hypotension not
attributable to carbidopa levodopa alone (see CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting
from the concomitant use of tricyclic antidepressants and SINEMET.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid
may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in
Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking
these drugs with SINEMET should be carefully observed for loss of therapeutic response.
Use of SINEMET with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other drugs
known to deplete monoamine stores is not recommended.
SINEMET and iron salts or multivitamins containing iron salts should be coadministered with caution.
Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of
carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying,
metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic
properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year bioassay of SINEMET, no evidence of carcinogenicity was found in rats receiving doses
of approximately two times the maximum daily human dose of carbidopa and four times the maximum
daily human dose of levodopa.
In reproduction studies with SINEMET, no effects on fertility were found in rats receiving doses of
approximately two times the maximum daily human dose of carbidopa and four times the maximum daily
human dose of levodopa.
Pregnancy
Pregnancy Category C. No teratogenic effects were observed in a study in mice receiving up to 20 times
the maximum recommended human dose of SINEMET. There was a decrease in the number of live pups
delivered by rats receiving approximately two times the maximum recommended human dose of
carbidopa and approximately five times the maximum recommended human dose of levodopa during
organogenesis. SINEMET caused both visceral and skeletal malformations in rabbits at all doses and
ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended
human dose of carbidopa/levodopa to 20 times/10 times the maximum recommended human dose of
carbidopa/levodopa.
There are no adequate or well-controlled studies in pregnant women. It has been reported from
individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized.
Carbidopa concentrations in fetal tissue appeared to be minimal. Use of SINEMET in women of
childbearing potential requires that the anticipated benefits of the drug be weighed against possible
hazards to mother and child.
Nursing Mothers
Levodopa has been detected in human milk. Caution should be exercised when SINEMET is
administered to a nursing woman.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients
below the age of 18 is not recommended.
Geriatric Use
In the clinical efficacy trials for SINEMET, almost half of the patients were older than 65, but few were
older than 75. No overall meaningful differences in safety or effectiveness were observed between these
subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions
such as hallucinations cannot be ruled out. There is no specific dosing recommendation based upon
clinical pharmacology data as SINEMET is titrated as tolerated for clinical effect.
ADVERSE REACTIONS
The most common adverse reactions reported with SINEMET have included dyskinesias, such as
choreiform, dystonic, and other involuntary movements, and nausea.
The following other adverse reactions have been reported with SINEMET:
Body as a Whole
Chest pain, asthenia.
Cardiovascular
Cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension,
syncope, phlebitis, palpitation.
Gastrointestinal
Dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea,
constipation, dyspepsia, dry mouth, taste alterations.
Hematologic
Agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia.
Hypersensitivity
Angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like
reactions).
Musculoskeletal
Back pain, shoulder pain, muscle cramps.
Nervous System/Psychiatric
Psychotic episodes including delusions, hallucinations, and paranoid ideation, bradykinetic episodes
("on-off" phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including
nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal
tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control
symptoms. Convulsions also have occurred; however, a causal relationship with SINEMET has not been
established.
Respiratory
Dyspnea, upper respiratory infection.
Skin
Rash, increased sweating, alopecia, dark sweat.
Urogenital
Urinary tract infection, urinary frequency, dark urine.
Laboratory Tests
Decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT
(ALT), LDH, bilirubin, BUN, Coombs test; elevated serum glucose; white blood cells, bacteria, and blood in
the urine.
Other adverse reactions that have been reported with levodopa alone and with various carbidopa
levodopa formulations, and may occur with SINEMET are:
Body as a Whole
Abdominal pain and distress, fatigue.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cardiovascular
Myocardial infarction.
Gastrointestinal
Gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue,
heartburn, hiccups.
Metabolic
Edema, weight gain, weight loss.
Musculoskeletal
Leg pain.
Nervous System/Psychiatric
Ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental
acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early
sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased
tremor, numbness, muscle twitching, activation of latent Horner's syndrome, peripheral neuropathy.
Respiratory
Pharyngeal pain, cough.
Skin
Malignant melanoma (see also CONTRAINDICATIONS), flushing.
Special Senses
Oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital
Urinary retention, urinary incontinence, priapism.
Miscellaneous
Bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation.
Laboratory Tests
Decreased white blood cell count and serum potassium; increased serum creatinine and uric acid;
protein and glucose in urine.
OVERDOSAGE
Management of acute overdosage with SINEMET is the same as management of acute overdosage
with levodopa. Pyridoxine is not effective in reversing the actions of SINEMET.
General supportive measures should be employed, along with immediate gastric lavage. Intravenous
fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic
monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if
required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have
taken other drugs as well as SINEMET should be taken into consideration. To date, no experience has
been reported with dialysis; hence, its value in overdosage is not known.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant
proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are
expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of
800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of
carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a
significant proportion of mice are expected to die to 3360 mg/kg.
DOSAGE AND ADMINISTRATION
The optimum daily dosage of SINEMET must be determined by careful titration in each patient.
SINEMET tablets are available in a 1:4 ratio of carbidopa to levodopa (SINEMET 25-100) as well as 1:10
ratio (SINEMET 25-250 and SINEMET 10-100). Tablets of the two ratios may be given separately or
combined as needed to provide the optimum dosage.
Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 to 100
mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and
vomiting.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Usual Initial Dosage
Dosage is best initiated with one tablet of SINEMET 25-100 three times a day. This dosage schedule
provides 75 mg of carbidopa per day. Dosage may be increased by one tablet every day or every other
day, as necessary, until a dosage of eight tablets of SINEMET 25-100 a day is reached.
If SINEMET 10-100 is used, dosage may be initiated with one tablet three or four times a day.
However, this will not provide an adequate amount of carbidopa for many patients. Dosage may be
increased by one tablet every day or every other day until a total of eight tablets (2 tablets q.i.d.) is
reached.
How to Transfer Patients from Levodopa
Levodopa must be discontinued at least twelve hours before starting SINEMET. A daily dosage
of SINEMET should be chosen that will provide approximately 25% of the previous levodopa dosage.
Patients who are taking less than 1500 mg of levodopa a day should be started on one tablet of SINEMET
25-100 three or four times a day. The suggested starting dosage for most patients taking more than
1500 mg of levodopa is one tablet of SINEMET 25-250 three or four times a day.
Maintenance
Therapy should be individualized and adjusted according to the desired therapeutic response. At least
70 to 100 mg of carbidopa per day should be provided. W hen a greater proportion of carbidopa is
required, one tablet of SINEMET 25-100 may be substituted for each tablet of SINEMET 10-100. W hen
more levodopa is required, SINEMET 25-250 should be substituted for SINEMET 25-100 or SINEMET 10
100. If necessary, the dosage of carbidopa levodopa 25-250 may be increased by one-half or one tablet
every day or every other day to a maximum of eight tablets a day. Experience with total daily dosages of
carbidopa greater than 200 mg is limited.
Because both therapeutic and adverse responses occur more rapidly with SINEMET than with
levodopa alone, patients should be monitored closely during the dose adjustment period. Specifically,
involuntary movements will occur more rapidly with SINEMET than with levodopa. The occurrence of
involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of
excess dosage in some patients.
Addition of Other Antiparkinsonian Medications
Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be
used concomitantly while SINEMET is being administered, although dosage adjustments may be required.
Interruption of Therapy
Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and
withdrawal of SINEMET. Patients should be observed carefully if abrupt reduction or discontinuation of
SINEMET is required, especially if the patient is receiving neuroleptics. (See W ARNINGS.)
If general anesthesia is required, SINEMET may be continued as long as the patient is permitted to
take fluids and medication by mouth. If therapy is interrupted temporarily, the patient should be observed
for symptoms resembling NMS, and the usual daily dosage may be administered as soon as the patient is
able to take oral medication.
HOW SUPPLIED
No. 3916A — SINEMET 25-100 Tablets are yellow, round, uncoated tablets, that are coded “650” on
one side and plain on the other. They are supplied as follows:
NDC 0006-3916-68 bottles of 100.
No. 3915 — SINEMET 10-100 Tablets are light dapple-blue, round, uncoated tablets, that are coded
“647” on one side and plain on the other. They are supplied as follows:
NDC 0006-3915-68 bottles of 100.
No. 3917 — SINEMET 25-250 Tablets are light dapple-blue, round, uncoated tablets, that are coded
“654” on one side and plain on the other. They are supplied as follows:
NDC 0006-3917-68 bottles of 100.
9
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Storage and Handling
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Store in a tightly closed container, protected from light and moisture.
Dispense in a tightly closed, light-resistant container. company logo
Manufactured by:
Mylan Pharmaceuticals, Inc.
Morgantown, W V 26505, USA
Copyright 1996-2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: 07/2014
uspi-mk0295b-t-1406r003
Rx Only
10
Reference ID: 3594908
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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2025-02-12T13:44:16.327050
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/017555s056s068s071lbl.pdf', 'application_number': 17555, 'submission_type': 'SUPPL ', 'submission_number': 56}
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11,024
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SINEMET
®
(carbidopa levodopa)
Tablets
DESCRIPTION
SINEMET® (carbidopa levodopa) is a combination of carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound,
slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (—)-L-α
hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is
C10H14N2O4•H2O, and its structural formula is: structural formula
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a
molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β-(3,4-dihydroxybenzene)
propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is: structural formula
SINEMET is supplied as tablets in three strengths:
SINEMET 25-100, containing 25 mg of carbidopa and 100 mg of levodopa.
SINEMET 10-100, containing 10 mg of carbidopa and 100 mg of levodopa.
SINEMET 25-250, containing 25 mg of carbidopa and 250 mg of levodopa.
Inactive ingredients are hydroxypropyl cellulose, pregelatinized starch, crospovidone, microcrystalline
cellulose, and magnesium stearate. SINEMET 10-100 and 25-250 Tablets also contain FD&C Blue
#2/Indigo Carmine AL. SINEMET 25-100 Tablets also contain D&C Yellow #10 Lake.
CLINICAL PHARMACOLOGY
Mechanism of Action
Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous
system affecting the mobility and control of the skeletal muscular system. Its characteristic features
include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa
therapies, may permit the patient better mobility.
Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine
in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease
apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor
of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.
This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacodynamics
W hen levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues
so that only a small portion of a given dose is transported unchanged to the central nervous system. For
this reason, large doses of levodopa are required for adequate therapeutic effect, and these may often be
accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed
in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of
levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and
does not affect the metabolism of levodopa within the central nervous system.
The incidence of levodopa-induced nausea and vomiting is less with SINEMET than with levodopa. In
many patients, this reduction in nausea and vomiting will permit more rapid dosage titration.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of carbidopa
with levodopa makes more levodopa available for transport to the brain.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and,
when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and
decreases plasma and urinary dopamine and homovanillic acid.
The plasma half-life of levodopa is about 50 minutes, without carbidopa. W hen carbidopa and
levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. At steady
state, the bioavailability of carbidopa from SINEMET tablets is approximately 99% relative to the
concomitant administration of carbidopa and levodopa.
In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced
greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the
two drugs at separate times.
Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of
levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of
pyridoxine; therefore, SINEMET can be given to patients receiving supplemental pyridoxine (vitamin B6).
Special Populations
Geriatric: A study in eight young healthy subjects (21-22 yr) and eight elderly healthy subjects (69-76
yr) showed that the absolute bioavailability of levodopa was similar between young and elderly subjects
following oral administration of levodopa and carbidopa. However, the systemic exposure (AUC) of
levodopa was increased by 55% in elderly subjects compared to young subjects. Based on another study
in forty patients with Parkinson’s disease, there was a correlation between age of patients and the
increase of AUC of levodopa following administration of levodopa and an inhibitor of peripheral dopa
decarboxylase. AUC of levodopa was increased by 28% in elderly patients (≥ 65 yr) compared to young
patients (< 65 yr). Additionally, mean value of Cmax for levodopa was increased by 24% in elderly patients
(≥ 65 yr) compared to young patients (< 65 yr) (see PRECAUTIONS, Geriatric Use).
The AUC of carbidopa was increased in elderly subjects (n=10, 65-76 yr) by 29% compared to young
subjects (n=24, 23-64 yr) following IV administration of 50 mg levodopa with carbidopa (50 mg). This
increase is not considered a clinically significant impact.
INDICATIONS AND USAGE
SINEMET is indicated in the treatment of Parkinson's disease, post-encephalitic parkinsonism, and
symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.
Carbidopa allows patients treated for Parkinson's disease to use much lower doses of levodopa. Some
patients who responded poorly to levodopa have improved on SINEMET. This is most likely due to
decreased peripheral decarboxylation of levodopa caused by administration of carbidopa rather than by a
primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the
intrinsic efficacy of levodopa.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carbidopa may also reduce nausea and vomiting and permit more rapid titration of levodopa.
CONTRAINDICATIONS
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with SINEMET. These
inhibitors must be discontinued at least two weeks prior to initiating therapy with SINEMET. SINEMET may
be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with
selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS, Drug Interactions).
SINEMET is contraindicated in patients with known hypersensitivity to any component of this drug, and
in patients with narrow-angle glaucoma.
WARNINGS
When SINEMET is to be given to patients who are being treated with levodopa, levodopa must
be discontinued at least twelve hours before therapy with SINEMET is started. In order to reduce
adverse reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION
section before initiating therapy.
The addition of carbidopa with levodopa in the form of SINEMET reduces the peripheral effects
(nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the
adverse reactions due to the central effects of levodopa. Because carbidopa permits more levodopa to
reach the brain and more dopamine to be formed, certain adverse central nervous system (CNS) effects,
e.g., dyskinesias (involuntary movements), may occur at lower dosages and sooner with SINEMET than
with levodopa alone.
All patients should be observed carefully for the development of depression with concomitant suicidal
tendencies.
SINEMET should be administered cautiously to patients with severe cardiovascular or pulmonary
disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering SINEMET to patients with a history of
myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac
function should be monitored with particular care during the period of initial dosage adjustment, in a facility
with provisions for intensive cardiac care.
As with levodopa, treatment with SINEMET may increase the possibility of upper gastrointestinal
hemorrhage in patients with a history of peptic ulcer.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking SINEMET alone or with other dopaminergic drugs have reported suddenly falling
asleep without prior warning of sleepiness while engaged in activities of daily living (includes operation of
motor vehicles). Road traffic accidents attributed to sudden sleep onset have been reported. Although
many patients reported somnolence while on dopaminergic medications, there have been reports of road
traffic accidents attributed to sudden onset of sleep in which the patient did not perceive any warning
signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.
Sudden onset of sleep has been reported to occur as long as one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre
existing somnolence, although some patients may not give such a history. For this reason, prescribers
should reassess patients for drowsiness or sleepiness especially since some of the events occur well after
the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or
sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients
should be advised to exercise caution while driving or operating machines during treatment with
SINEMET. Patients who have already experienced somnolence or an episode of sudden sleep onset
should not participate in these activities during treatment with SINEMET.
Before initiating treatment with SINEMET, advise patients about the potential to develop drowsiness
and ask specifically about factors that may increase the risk for somnolence with SINEMET such as the
use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing
SINEMET in patients who report significant daytime sleepiness or episodes of falling asleep during
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
activities that require active participation (e.g., conversations, eating, etc.). If treatment with SINEMET
continues, patients should be advised not to drive and to avoid other potentially dangerous activities that
might result in harm if the patients become somnolent. There is insufficient information to establish that
dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Hyperpyrexia and Confusion
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been
reported in association with dose reductions or withdrawal of certain antiparkinsonian agents such as
levodopa, carbidopa levodopa, or carbidopa levodopa extended release. Therefore, patients should be
observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the
patient is receiving neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental
status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating,
hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis,
myoglobinuria, and increased serum myoglobin have been reported.
The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic
infection, etc.) is essential. This may be especially complex if the clinical presentation includes both
serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever, and primary central nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring
and 2) treatment of any concomitant serious medical problems for which specific treatments are available.
Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are often used in
the treatment of NMS; however, their effectiveness has not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function are
recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with SINEMET provided the
intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular
pressure during therapy.
Dyskinesia
Levodopa alone, as well as SINEMET, is associated with dyskinesias. The occurrence of dyskinesias
may require dosage reduction.
Hallucinations / Psychotic-Like Behavior
Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In
general, hallucinations present shortly after the initiation of therapy and may be responsive to dose
reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser extent sleep
disorder (insomnia) and excessive dreaming.
SINEMET may have similar effects on thinking and behavior. This abnormal thinking and behavior may
present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion,
psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with SINEMET, because of
the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may
exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of SINEMET.
Impulse Control / Compulsive Behaviors
Reports of patients taking dopaminergic medications (medications that increase central dopaminergic
tone), suggest that patients may experience an intense urge to gamble, increased sexual urges, intense
urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. In
some cases, although not all, these urges were reported to have stopped when the dose was reduced or
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is
important for prescribers to specifically ask patients or the caregivers about the development of new or
increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with
SINEMET. Physicians should consider dose reduction or stopping the medication if a patient develops
such urges while taking SINEMET [see Information for Patients].
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to
approximately 6-fold higher) of developing melanoma than the general population. W hether the increased
risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s
disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently
and on a regular basis when using SINEMET for any indication. Ideally, periodic skin examinations should
be performed by appropriately qualified individuals (e.g., dermatologists).
Information for Patients
The patient should be informed that SINEMET is an immediate-release formulation of carbidopa
levodopa that is designed to begin release of ingredients within 30 minutes. It is important that SINEMET
be taken at regular intervals according to the schedule outlined by the physician. The patient should be
cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson
medications, including other carbidopa levodopa preparations, without first consulting the physician.
Patients should be advised that sometimes a ‘wearing-off’ effect may occur at the end of the dosing
interval. The physician should be notified if such response poses a problem to lifestyle.
Patients should be advised that occasionally, dark color (red, brown, or black) may appear in saliva,
urine, or sweat after ingestion of SINEMET. Although the color appears to be clinically insignificant,
garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also
delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multivitamin
tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce the
clinical effectiveness of the levodopa or carbidopa levodopa therapy.
Patients should be alerted to the possibility of sudden onset of sleep during daily activities, in some
cases without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Patients should be advised to exercise caution while driving or operating machinery and that if
they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities.
(See W ARNINGS, Falling Asleep During Activities of Daily Living and Somnolence.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment of
Parkinson’s disease, including SINEMET. Although it is not proven that the medications caused these
events, these urges were reported to have stopped in some cases when the dose was reduced or the
medication was stopped. Prescribers should ask patients about the development of new or increased
gambling urges, sexual urges or other urges while being treated with SINEMET. Patients should inform
their physician if they experience new or increased gambling urges, increased sexual urges, or other
intense urges while taking SINEMET. Physicians should consider dose reduction or stopping the
medication if a patient develops such urges while taking SINEMET (See PRECAUTIONS, Impulse Control
/ Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline
phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase (LDH), and bilirubin. Abnormalities in
blood urea nitrogen (BUN) and positive Coombs test have also been reported. Commonly, levels of blood
urea nitrogen, creatinine, and uric acid are lower during administration of SINEMET than with levodopa.
SINEMET may cause a false-positive reaction for urinary ketone bodies when a test tape is used for
determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative
tests may result with the use of glucose-oxidase methods of testing for glucosuria.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cases of falsely diagnosed pheochromocytoma in patients on carbidopa levodopa therapy have been
reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of
catecholamines and their metabolites in patients on levodopa or carbidopa levodopa therapy.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with SINEMET.
Symptomatic postural hypotension occurred when SINEMET was added to the treatment of a patient
receiving antihypertensive drugs. Therefore, when therapy with SINEMET is started, dosage adjustment of
the antihypertensive drug may be required.
For patients receiving MAO inhibitors (Type A or B), see CONTRAINDICATIONS. Concomitant therapy
with selegiline and carbidopa levodopa may be associated with severe orthostatic hypotension not
attributable to carbidopa levodopa alone (see CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting
from the concomitant use of tricyclic antidepressants and SINEMET.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid
may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in
Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking
these drugs with SINEMET should be carefully observed for loss of therapeutic response.
Use of SINEMET with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other drugs
known to deplete monoamine stores is not recommended.
SINEMET and iron salts or multivitamins containing iron salts should be coadministered with caution.
Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of
carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying,
metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic
properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year bioassay of SINEMET, no evidence of carcinogenicity was found in rats receiving doses
of approximately two times the maximum daily human dose of carbidopa and four times the maximum
daily human dose of levodopa.
In reproduction studies with SINEMET, no effects on fertility were found in rats receiving doses of
approximately two times the maximum daily human dose of carbidopa and four times the maximum daily
human dose of levodopa.
Pregnancy
Pregnancy Category C. No teratogenic effects were observed in a study in mice receiving up to 20 times
the maximum recommended human dose of SINEMET. There was a decrease in the number of live pups
delivered by rats receiving approximately two times the maximum recommended human dose of
carbidopa and approximately five times the maximum recommended human dose of levodopa during
organogenesis. SINEMET caused both visceral and skeletal malformations in rabbits at all doses and
ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended
human dose of carbidopa/levodopa to 20 times/10 times the maximum recommended human dose of
carbidopa/levodopa.
There are no adequate or well-controlled studies in pregnant women. It has been reported from
individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized.
Carbidopa concentrations in fetal tissue appeared to be minimal. Use of SINEMET in women of
childbearing potential requires that the anticipated benefits of the drug be weighed against possible
hazards to mother and child.
Nursing Mothers
Levodopa has been detected in human milk. Caution should be exercised when SINEMET is
administered to a nursing woman.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients
below the age of 18 is not recommended.
Geriatric Use
In the clinical efficacy trials for SINEMET, almost half of the patients were older than 65, but few were
older than 75. No overall meaningful differences in safety or effectiveness were observed between these
subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions
such as hallucinations cannot be ruled out. There is no specific dosing recommendation based upon
clinical pharmacology data as SINEMET is titrated as tolerated for clinical effect.
ADVERSE REACTIONS
The most common adverse reactions reported with SINEMET have included dyskinesias, such as
choreiform, dystonic, and other involuntary movements, and nausea.
The following other adverse reactions have been reported with SINEMET:
Body as a Whole
Chest pain, asthenia.
Cardiovascular
Cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension,
syncope, phlebitis, palpitation.
Gastrointestinal
Dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea,
constipation, dyspepsia, dry mouth, taste alterations.
Hematologic
Agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia.
Hypersensitivity
Angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like
reactions).
Musculoskeletal
Back pain, shoulder pain, muscle cramps.
Nervous System/Psychiatric
Psychotic episodes including delusions, hallucinations, and paranoid ideation, bradykinetic episodes
("on-off" phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities including
nightmares, insomnia, paresthesia, headache, depression with or without development of suicidal
tendencies, dementia, pathological gambling, increased libido including hypersexuality, impulse control
symptoms. Convulsions also have occurred; however, a causal relationship with SINEMET has not been
established.
Respiratory
Dyspnea, upper respiratory infection.
Skin
Rash, increased sweating, alopecia, dark sweat.
Urogenital
Urinary tract infection, urinary frequency, dark urine.
Laboratory Tests
Decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT
(ALT), LDH, bilirubin, BUN, Coombs test; elevated serum glucose; white blood cells, bacteria, and blood in
the urine.
Other adverse reactions that have been reported with levodopa alone and with various carbidopa
levodopa formulations, and may occur with SINEMET are:
Body as a Whole
Abdominal pain and distress, fatigue.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cardiovascular
Myocardial infarction.
Gastrointestinal
Gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue,
heartburn, hiccups.
Metabolic
Edema, weight gain, weight loss.
Musculoskeletal
Leg pain.
Nervous System/Psychiatric
Ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental
acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early
sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased
tremor, numbness, muscle twitching, activation of latent Horner's syndrome, peripheral neuropathy.
Respiratory
Pharyngeal pain, cough.
Skin
Malignant melanoma (see also CONTRAINDICATIONS), flushing.
Special Senses
Oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital
Urinary retention, urinary incontinence, priapism.
Miscellaneous
Bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation.
Laboratory Tests
Decreased white blood cell count and serum potassium; increased serum creatinine and uric acid;
protein and glucose in urine.
OVERDOSAGE
Management of acute overdosage with SINEMET is the same as management of acute overdosage
with levodopa. Pyridoxine is not effective in reversing the actions of SINEMET.
General supportive measures should be employed, along with immediate gastric lavage. Intravenous
fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic
monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if
required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have
taken other drugs as well as SINEMET should be taken into consideration. To date, no experience has
been reported with dialysis; hence, its value in overdosage is not known.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant
proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are
expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of
800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of
carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a
significant proportion of mice are expected to die to 3360 mg/kg.
DOSAGE AND ADMINISTRATION
The optimum daily dosage of SINEMET must be determined by careful titration in each patient.
SINEMET tablets are available in a 1:4 ratio of carbidopa to levodopa (SINEMET 25-100) as well as 1:10
ratio (SINEMET 25-250 and SINEMET 10-100). Tablets of the two ratios may be given separately or
combined as needed to provide the optimum dosage.
Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 to 100
mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and
vomiting.
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Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Usual Initial Dosage
Dosage is best initiated with one tablet of SINEMET 25-100 three times a day. This dosage schedule
provides 75 mg of carbidopa per day. Dosage may be increased by one tablet every day or every other
day, as necessary, until a dosage of eight tablets of SINEMET 25-100 a day is reached.
If SINEMET 10-100 is used, dosage may be initiated with one tablet three or four times a day.
However, this will not provide an adequate amount of carbidopa for many patients. Dosage may be
increased by one tablet every day or every other day until a total of eight tablets (2 tablets q.i.d.) is
reached.
How to Transfer Patients from Levodopa
Levodopa must be discontinued at least twelve hours before starting SINEMET. A daily dosage
of SINEMET should be chosen that will provide approximately 25% of the previous levodopa dosage.
Patients who are taking less than 1500 mg of levodopa a day should be started on one tablet of SINEMET
25-100 three or four times a day. The suggested starting dosage for most patients taking more than
1500 mg of levodopa is one tablet of SINEMET 25-250 three or four times a day.
Maintenance
Therapy should be individualized and adjusted according to the desired therapeutic response. At least
70 to 100 mg of carbidopa per day should be provided. W hen a greater proportion of carbidopa is
required, one tablet of SINEMET 25-100 may be substituted for each tablet of SINEMET 10-100. W hen
more levodopa is required, SINEMET 25-250 should be substituted for SINEMET 25-100 or SINEMET 10
100. If necessary, the dosage of carbidopa levodopa 25-250 may be increased by one-half or one tablet
every day or every other day to a maximum of eight tablets a day. Experience with total daily dosages of
carbidopa greater than 200 mg is limited.
Because both therapeutic and adverse responses occur more rapidly with SINEMET than with
levodopa alone, patients should be monitored closely during the dose adjustment period. Specifically,
involuntary movements will occur more rapidly with SINEMET than with levodopa. The occurrence of
involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of
excess dosage in some patients.
Addition of Other Antiparkinsonian Medications
Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may be
used concomitantly while SINEMET is being administered, although dosage adjustments may be required.
Interruption of Therapy
Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and
withdrawal of SINEMET. Patients should be observed carefully if abrupt reduction or discontinuation of
SINEMET is required, especially if the patient is receiving neuroleptics. (See W ARNINGS.)
If general anesthesia is required, SINEMET may be continued as long as the patient is permitted to
take fluids and medication by mouth. If therapy is interrupted temporarily, the patient should be observed
for symptoms resembling NMS, and the usual daily dosage may be administered as soon as the patient is
able to take oral medication.
HOW SUPPLIED
No. 3916A — SINEMET 25-100 Tablets are yellow, round, uncoated tablets, that are coded “650” on
one side and plain on the other. They are supplied as follows:
NDC 0006-3916-68 bottles of 100.
No. 3915 — SINEMET 10-100 Tablets are light dapple-blue, round, uncoated tablets, that are coded
“647” on one side and plain on the other. They are supplied as follows:
NDC 0006-3915-68 bottles of 100.
No. 3917 — SINEMET 25-250 Tablets are light dapple-blue, round, uncoated tablets, that are coded
“654” on one side and plain on the other. They are supplied as follows:
NDC 0006-3917-68 bottles of 100.
9
Reference ID: 3594908
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Storage and Handling
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Store in a tightly closed container, protected from light and moisture.
Dispense in a tightly closed, light-resistant container. company logo
Manufactured by:
Mylan Pharmaceuticals, Inc.
Morgantown, W V 26505, USA
Copyright 1996-2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: 07/2014
uspi-mk0295b-t-1406r003
Rx Only
10
Reference ID: 3594908
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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FDA Approved Labeling Text for NDA 017555
Dated 1/31/11 company logo
SINEMET®
(carbidopa-levodopa)
Tablets
DESCRIPTION
SINEMET® (carbidopa-levodopa) is a combination of carbidopa and levodopa for the treatment of
Parkinson's disease and syndrome.
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound,
slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (—)-L-α
hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is
C10H14N2O4•H2O, and its structural formula is:
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular weight of 226.3.
Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a
molecular weight of 197.2. It is designated chemically as (—)-L-α-amino-β-(3,4-dihydroxybenzene)
propanoic acid. Its empirical formula is C9H11NO4, and its structural formula is:
SINEMET is supplied as tablets in three strengths:
SINEMET 25-100, containing 25 mg of carbidopa and 100 mg of levodopa.
SINEMET 10-100, containing 10 mg of carbidopa and 100 mg of levodopa.
SINEMET 25-250, containing 25 mg of carbidopa and 250 mg of levodopa.
Inactive ingredients are hydroxypropyl cellulose, pregelatinized starch, crospovidone, microcrystalline
cellulose, and magnesium stearate. SINEMET 10-100 and 25-250 Tablets also contain FD&C Blue
#2/Indigo Carmine AL. SINEMET 25-100 Tablets also contain D&C Yellow #10 Lake.
CLINICAL PHARMACOLOGY
Mechanism of Action
Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous
system affecting the mobility and control of the skeletal muscular system. Its characteristic features
include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa
therapies, may permit the patient better mobility.
Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine
in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease
Reference ID: 2898568
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET® (carbidopa-levodopa)
apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor
of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.
This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.
Pharmacodynamics
When levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral
tissues so that only a small portion of a given dose is transported unchanged to the central nervous
system. For this reason, large doses of levodopa are required for adequate therapeutic effect, and these
may often be accompanied by nausea and other adverse reactions, some of which are attributable to
dopamine formed in extracerebral tissues.
Since levodopa competes with certain amino acids for transport across the gut wall, the absorption of
levodopa may be impaired in some patients on a high protein diet.
Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier
and does not affect the metabolism of levodopa within the central nervous system.
The incidence of levodopa-induced nausea and vomiting is less with SINEMET than with levodopa. In
many patients, this reduction in nausea and vomiting will permit more rapid dosage titration.
Since its decarboxylase inhibiting activity is limited to extracerebral tissues, administration of
carbidopa with levodopa makes more levodopa available for transport to the brain.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and,
when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and
decreases plasma and urinary dopamine and homovanillic acid.
The plasma half-life of levodopa is about 50 minutes, without carbidopa. When carbidopa and
levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. At steady
state, the bioavailability of carbidopa from SINEMET tablets is approximately 99% relative to the
concomitant administration of carbidopa and levodopa.
In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced
greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the
two drugs at separate times.
Pyridoxine hydrochloride (vitamin B6), in oral doses of 10 mg to 25 mg, may reverse the effects of
levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of
pyridoxine; therefore, SINEMET can be given to patients receiving supplemental pyridoxine (vitamin B6).
INDICATIONS AND USAGE
SINEMET is indicated in the treatment of the symptoms of idiopathic Parkinson's disease (paralysis
agitans), post-encephalitic parkinsonism, and symptomatic parkinsonism which may follow injury to the
nervous system by carbon monoxide intoxication and/or manganese intoxication. SINEMET is indicated
in these conditions to permit the administration of lower doses of levodopa with reduced nausea and
vomiting, with more rapid dosage titration, with a somewhat smoother response, and with supplemental
pyridoxine (vitamin B6).
In some patients a somewhat smoother antiparkinsonian effect results from therapy with SINEMET
than with levodopa. However, patients with markedly irregular ("on-off") responses to levodopa have not
been shown to benefit from SINEMET.
Although the administration of carbidopa permits control of parkinsonism and Parkinson's disease with
much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other
than in reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat
smoother response to levodopa.
Certain patients who responded poorly to levodopa have improved when SINEMET was substituted.
This is most likely due to decreased peripheral decarboxylation of levodopa which results from
administration of carbidopa rather than to a primary effect of carbidopa on the nervous system. Carbidopa
has not been shown to enhance the intrinsic efficacy of levodopa in parkinsonian syndromes.
In considering whether to give SINEMET to patients already on levodopa who have nausea and/or
vomiting, the practitioner should be aware that, while many patients may be expected to improve, some
do not. Since one cannot predict which patients are likely to improve, this can only be determined by a
trial of therapy. It should be further noted that in controlled trials comparing SINEMET with levodopa,
Reference ID: 2898568
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET® (carbidopa-levodopa)
about half of the patients with nausea and/or vomiting on levodopa improved spontaneously despite
being retained on the same dose of levodopa during the controlled portion of the trial.
CONTRAINDICATIONS
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with SINEMET. These
inhibitors must be discontinued at least two weeks prior to initiating therapy with SINEMET. SINEMET
may be administered concomitantly with the manufacturer's recommended dose of an MAO inhibitor with
selectivity for MAO type B (e.g., selegiline HCl) (see PRECAUTIONS, Drug Interactions).
SINEMET is contraindicated in patients with known hypersensitivity to any component of this drug,
and in patients with narrow-angle glaucoma.
Because levodopa may activate a malignant melanoma, SINEMET should not be used in patients with
suspicious, undiagnosed skin lesions or a history of melanoma.
WARNINGS
When SINEMET is to be given to patients who are being treated with levodopa, levodopa must
be discontinued at least twelve hours before therapy with SINEMET is started. In order to reduce
adverse reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION
section before initiating therapy.
The addition of carbidopa with levodopa in the form of SINEMET reduces the peripheral effects
(nausea, vomiting) due to decarboxylation of levodopa; however, carbidopa does not decrease the
adverse reactions due to the central effects of levodopa. Because carbidopa permits more levodopa to
reach the brain and more dopamine to be formed, certain adverse CNS effects, e.g., dyskinesias
(involuntary movements), may occur at lower dosages and sooner with SINEMET than with levodopa
alone.
Levodopa alone, as well as SINEMET, is associated with dyskinesias. The occurrence of dyskinesias
may require dosage reduction.
As with levodopa, SINEMET may cause mental disturbances. These reactions are thought to be due
to increased brain dopamine following administration of levodopa. All patients should be observed
carefully for the development of depression with concomitant suicidal tendencies. Patients with past or
current psychoses should be treated with caution.
SINEMET should be administered cautiously to patients with severe cardiovascular or pulmonary
disease, bronchial asthma, renal, hepatic or endocrine disease.
As with levodopa, care should be exercised in administering SINEMET to patients with a history of
myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac
function should be monitored with particular care during the period of initial dosage adjustment, in a
facility with provisions for intensive cardiac care.
As with levodopa, treatment with SINEMET may increase the possibility of upper gastrointestinal
hemorrhage in patients with a history of peptic ulcer.
Neuroleptic Malignant Syndrome (NMS)
Sporadic cases of a symptom complex resembling NMS have been reported in association with dose
reductions or withdrawal of therapy with SINEMET. Therefore, patients should be observed carefully
when the dosage of SINEMET is reduced abruptly or discontinued, especially if the patient is receiving
neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered consciousness, mental
status changes; other disturbances, such as autonomic dysfunction, tachycardia, tachypnea, sweating,
hyper- or hypotension; laboratory findings, such as creatine phosphokinase elevation, leukocytosis,
myoglobinuria, and increased serum myoglobin have been reported.
The early diagnosis of this condition is important for the appropriate management of these patients.
Considering NMS as a possible diagnosis and ruling out other acute illnesses (e.g., pneumonia, systemic
infection, etc.) is essential. This may be especially complex if the clinical presentation includes both
serious medical illness and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, drug fever, and primary central nervous system (CNS) pathology.
Reference ID: 2898568
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET® (carbidopa-levodopa)
The management of NMS should include: 1) intensive symptomatic treatment and medical monitoring
and 2) treatment of any concomitant serious medical problems for which specific treatments are
available. Dopamine agonists, such as bromocriptine, and muscle relaxants, such as dantrolene, are
often used in the treatment of NMS, however, their effectiveness has not been demonstrated in controlled
studies.
PRECAUTIONS
General
As with levodopa, periodic evaluations of hepatic, hematopoietic, cardiovascular, and renal function
are recommended during extended therapy.
Patients with chronic wide-angle glaucoma may be treated cautiously with SINEMET provided the
intraocular pressure is well-controlled and the patient is monitored carefully for changes in intraocular
pressure during therapy.
Dopaminergic agents, including levodopa, may be associated with somnolence and very rarely
episodes of sudden onset of sleep. In some cases, these episodes may occur without awareness or
warning during daily activities. Patients must be informed of this and advised to exercise caution while
driving or operating machines while being treated with dopaminergic agents, including levodopa. Patients
who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or
operating machines (see Information for Patients).
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to
approximately 6-fold higher) of developing melanoma than the general population. Whether the increased
risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s
disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently
and on a regular basis when using SINEMET for any indication. Ideally, periodic skin examinations
should be performed by appropriately qualified individuals (e.g., dermatologists).
Information for Patients
The patient should be informed that SINEMET is an immediate-release formulation of carbidopa
levodopa that is designed to begin release of ingredients within 30 minutes. It is important that SINEMET
be taken at regular intervals according to the schedule outlined by the physician. The patient should be
cautioned not to change the prescribed dosage regimen and not to add any additional antiparkinson
medications, including other carbidopa-levodopa preparations, without first consulting the physician.
Patients should be advised that sometimes a ‘wearing-off’ effect may occur at the end of the dosing
interval. The physician should be notified if such response poses a problem to lifestyle.
Patients should be advised that occasionally, dark color (red, brown, or black) may appear in saliva,
urine, or sweat after ingestion of SINEMET. Although the color appears to be clinically insignificant,
garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity also
delays stomach emptying, thus delaying the absorption of levodopa. Iron salts (such as in multivitamin
tablets) may also reduce the amount of levodopa available to the body. The above factors may reduce
the clinical effectiveness of the levodopa or carbidopa-levodopa therapy.
Patients should be alerted to the possibility of sudden onset of sleep during daily activities, in some
cases without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Patients should be advised to exercise caution while driving or operating machinery and that if
they have experienced somnolence and/or sudden sleep onset, they must refrain from these activities.
(See PRECAUTIONS, General.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment of
Parkinson’s disease, including SINEMET. Although it is not proven that the medications caused these
events, these urges were reported to have stopped in some cases when the dose was reduced or the
medication was stopped. Prescribers should ask patients about the development of new or increased
Reference ID: 2898568
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For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET® (carbidopa-levodopa)
gambling urges, sexual urges or other urges while being treated with SINEMET. Patients should inform
their physician if they experience new or increased gambling urges, increased sexual urges, or other
intense urges while taking SINEMET. Physicians should consider dose reduction or stopping the
medication if a patient develops such urges while taking SINEMET.
NOTE: The suggested advice to patients being treated with SINEMET is intended to aid in the safe
and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline
phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin. Abnormalities in blood urea
nitrogen and positive Coombs test have also been reported. Commonly, levels of blood urea nitrogen,
creatinine, and uric acid are lower during administration of SINEMET than with levodopa.
SINEMET may cause a false-positive reaction for urinary ketone bodies when a test tape is used for
determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative
tests may result with the use of glucose-oxidase methods of testing for glucosuria.
Cases of falsely diagnosed pheochromocytoma in patients on carbidopa-levodopa therapy have been
reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of
catecholamines and their metabolites in patients on levodopa or carbidopa-levodopa therapy.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with SINEMET.
Symptomatic postural hypotension occurred when SINEMET was added to the treatment of a patient
receiving antihypertensive drugs. Therefore, when therapy with SINEMET is started, dosage adjustment
of the antihypertensive drug may be required.
For patients receiving MAO inhibitors (Type A or B), see CONTRAINDICATIONS. Concomitant
therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension
not attributable to carbidopa-levodopa alone (see CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting
from the concomitant use of tricyclic antidepressants and SINEMET.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid
may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in
Parkinson's disease have been reported to be reversed by phenytoin and papaverine. Patients taking
these drugs with SINEMET should be carefully observed for loss of therapeutic response.
Iron salts may reduce the bioavailability of levodopa and carbidopa. The clinical relevance is unclear.
Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying,
metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic
properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year bioassay of SINEMET, no evidence of carcinogenicity was found in rats receiving doses
of approximately two times the maximum daily human dose of carbidopa and four times the maximum
daily human dose of levodopa.
In reproduction studies with SINEMET, no effects on fertility were found in rats receiving doses of
approximately two times the maximum daily human dose of carbidopa and four times the maximum daily
human dose of levodopa.
Pregnancy
Pregnancy Category C. No teratogenic effects were observed in a study in mice receiving up to 20 times
the maximum recommended human dose of SINEMET. There was a decrease in the number of live pups
delivered by rats receiving approximately two times the maximum recommended human dose of
carbidopa and approximately five times the maximum recommended human dose of levodopa during
organogenesis. SINEMET caused both visceral and skeletal malformations in rabbits at all doses and
ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended
human dose of carbidopa/levodopa to 20 times/10 times the maximum recommended human dose of
carbidopa/levodopa.
There are no adequate or well-controlled studies in pregnant women. It has been reported from
individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized.
Carbidopa concentrations in fetal tissue appeared to be minimal. Use of SINEMET in women of
childbearing potential requires that the anticipated benefits of the drug be weighed against possible
hazards to mother and child.
Reference ID: 2898568
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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
SINEMET® (carbidopa-levodopa)
Nursing Mothers
In a study of one nursing mother with Parkinson’s disease, excretion of levodopa in human breast milk
was reported. Therefore, caution should be exercised when SINEMET is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients
below the age of 18 is not recommended.
ADVERSE REACTIONS
The most common adverse reactions reported with SINEMET have included dyskinesias, such as
choreiform, dystonic, and other involuntary movements, and nausea.
The following other adverse reactions have been reported with SINEMET:
Body as a Whole
Chest pain, asthenia.
Cardiovascular
Cardiac irregularities, hypotension, orthostatic effects including orthostatic hypotension, hypertension,
syncope, phlebitis, palpitation.
Gastrointestinal
Dark saliva, gastrointestinal bleeding, development of duodenal ulcer, anorexia, vomiting, diarrhea,
constipation, dyspepsia, dry mouth, taste alterations.
Hematologic
Agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, leukopenia.
Hypersensitivity
Angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions (including pemphigus-like
reactions).
Musculoskeletal
Back pain, shoulder pain, muscle cramps.
Nervous System/Psychiatric
Psychotic episodes including delusions, hallucinations, and paranoid ideation, neuroleptic malignant
syndrome (NMS, see WARNINGS), bradykinetic episodes ("on-off" phenomenon), confusion, agitation,
dizziness, somnolence, dream abnormalities including nightmares, insomnia, paresthesia, headache,
depression with or without development of suicidal tendencies, dementia, pathological gambling,
increased libido including hypersexuality, impulse control symptoms. Convulsions also have occurred;
however, a causal relationship with SINEMET has not been established.
Respiratory
Dyspnea, upper respiratory infection.
Skin
Rash, increased sweating, alopecia, dark sweat.
Urogenital
Urinary tract infection, urinary frequency, dark urine.
Laboratory Tests
Decreased hemoglobin and hematocrit; abnormalities in alkaline phosphatase, SGOT (AST), SGPT
(ALT), lactic dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs test; elevated serum glucose;
white blood cells, bacteria, and blood in the urine.
Other adverse reactions that have been reported with levodopa alone and with various carbidopa
levodopa formulations, and may occur with SINEMET are:
Body as a Whole
Abdominal pain and distress, fatigue.
Cardiovascular
Myocardial infarction.
Reference ID: 2898568
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET® (carbidopa-levodopa)
Gastrointestinal
Gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning sensation of the tongue,
heartburn, hiccups.
Metabolic
Edema, weight gain, weight loss.
Musculoskeletal
Leg pain.
Nervous System/Psychiatric
Ataxia, extrapyramidal disorder, falling, anxiety, gait abnormalities, nervousness, decreased mental
acuity, memory impairment, disorientation, euphoria, blepharospasm (which may be taken as an early
sign of excess dosage; consideration of dosage reduction may be made at this time), trismus, increased
tremor, numbness, muscle twitching, activation of latent Horner's syndrome, peripheral neuropathy.
Respiratory
Pharyngeal pain, cough.
Skin
Malignant melanoma (see also CONTRAINDICATIONS), flushing.
Special Senses
Oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital
Urinary retention, urinary incontinence, priapism.
Miscellaneous
Bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, sense of stimulation.
Laboratory Tests
Decreased white blood cell count and serum potassium; increased serum creatinine and uric acid;
protein and glucose in urine.
OVERDOSAGE
Management of acute overdosage with SINEMET is the same as management of acute overdosage
with levodopa. Pyridoxine is not effective in reversing the actions of SINEMET.
General supportive measures should be employed, along with immediate gastric lavage. Intravenous
fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic
monitoring should be instituted and the patient carefully observed for the development of arrhythmias; if
required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have
taken other drugs as well as SINEMET should be taken into consideration. To date, no experience has
been reported with dialysis; hence, its value in overdosage is not known.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant
proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are
expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800
mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa.
The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant
proportion of mice are expected to die to 3360 mg/kg.
DOSAGE AND ADMINISTRATION
The optimum daily dosage of SINEMET must be determined by careful titration in each patient.
SINEMET tablets are available in a 1:4 ratio of carbidopa to levodopa (SINEMET 25-100) as well as 1:10
ratio (SINEMET 25-250 and SINEMET 10-100). Tablets of the two ratios may be given separately or
combined as needed to provide the optimum dosage.
Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 to
100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea
and vomiting.
Usual Initial Dosage
Dosage is best initiated with one tablet of SINEMET 25-100 three times a day. This dosage schedule
provides 75 mg of carbidopa per day. Dosage may be increased by one tablet every day or every other
day, as necessary, until a dosage of eight tablets of SINEMET 25-100 a day is reached.
Reference ID: 2898568
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET® (carbidopa-levodopa)
If SINEMET 10-100 is used, dosage may be initiated with one tablet three or four times a day.
However, this will not provide an adequate amount of carbidopa for many patients. Dosage may be
increased by one tablet every day or every other day until a total of eight tablets (2 tablets q.i.d.) is
reached.
How to Transfer Patients from Levodopa
Levodopa must be discontinued at least twelve hours before starting SINEMET. A daily dosage
of SINEMET should be chosen that will provide approximately 25% of the previous levodopa dosage.
Patients who are taking less than 1500 mg of levodopa a day should be started on one tablet of
SINEMET 25-100 three or four times a day. The suggested starting dosage for most patients taking more
than 1500 mg of levodopa is one tablet of SINEMET 25-250 three or four times a day.
Maintenance
Therapy should be individualized and adjusted according to the desired therapeutic response. At least
70 to 100 mg of carbidopa per day should be provided. When a greater proportion of carbidopa is
required, one tablet of SINEMET 25-100 may be substituted for each tablet of SINEMET 10-100. When
more levodopa is required, SINEMET 25-250 should be substituted for SINEMET 25-100 or SINEMET
10-100. If necessary, the dosage of carbidopa/levodopa 25-250 may be increased by one-half or one
tablet every day or every other day to a maximum of eight tablets a day. Experience with total daily
dosages of carbidopa greater than 200 mg is limited.
Because both therapeutic and adverse responses occur more rapidly with SINEMET than with
levodopa alone, patients should be monitored closely during the dose adjustment period. Specifically,
involuntary movements will occur more rapidly with SINEMET than with levodopa. The occurrence of
involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of
excess dosage in some patients.
Addition of Other Antiparkinsonian Medications
Standard drugs for Parkinson's disease, other than levodopa without a decarboxylase inhibitor, may
be used concomitantly while SINEMET is being administered, although dosage adjustments may be
required.
Interruption of Therapy
Sporadic cases of a symptom complex resembling Neuroleptic Malignant Syndrome (NMS) have been
associated with dose reductions and withdrawal of SINEMET. Patients should be observed carefully if
abrupt reduction or discontinuation of SINEMET is required, especially if the patient is receiving
neuroleptics. (See WARNINGS.)
If general anesthesia is required, SINEMET may be continued as long as the patient is permitted to
take fluids and medication by mouth. If therapy is interrupted temporarily, the patient should be observed
for symptoms resembling NMS, and the usual daily dosage may be administered as soon as the patient
is able to take oral medication.
HOW SUPPLIED
No. 3916A — SINEMET 25-100 Tablets are yellow, round, uncoated tablets, that are coded “650” on
one side and plain on the other. They are supplied as follows:
NDC 0006-3916-68 bottles of 100.
No. 3915 — SINEMET 10-100 Tablets are light dapple-blue, round, uncoated tablets, that are coded
“647” on one side and plain on the other. They are supplied as follows:
NDC 0006-3915-68 bottles of 100.
No. 3917 — SINEMET 25-250 Tablets are light dapple-blue, round, uncoated tablets, that are coded
“654” on one side and plain on the other. They are supplied as follows:
NDC 0006-3917-68 bottles of 100.
Storage and Handling
Reference ID: 2898568
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SINEMET® (carbidopa-levodopa)
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Store in a tightly closed container, protected from light and moisture.
Dispense in a tightly closed, light-resistant container.
Rx Only
Manufactured for: company logo
By:
Mylan Pharmaceuticals, Inc.
Morgantown, WV 26505, USA
Issued Month Year
January 2011
Copyright © 1996 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved
Reference ID: 2898568
9
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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2025-02-12T13:44:16.432782
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017555s070lbl.pdf', 'application_number': 17555, 'submission_type': 'SUPPL ', 'submission_number': 70}
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11,027
|
DANOCRINE®
Brand of DANAZOL
CAPSULES, USP
DESCRIPTION
DANOCRINE, brand of danazol, is a synthetic steroid derived from ethisterone. It is a
white to pale yellow crystalline powder, practically insoluble or insoluble in water, and
sparingly soluble in alcohol. Chemically, danazol is 17α-Pregna-2,4-dien-20-yno [2,3-d]
isoxazol-17-ol. The molecular formula is C22H27NO2. It has a molecular weight of 337.46
and the following structural formula: structural formula
Danocrine capsules for oral administration contain 50 mg, 100 mg or 200 mg danazol.
Inactive Ingredients: Corn Starch, Lactose, Magnesium Stearate, Talc. Capsules 50 mg, 100
mg and 200 mg contain D&C Yellow #10, FD&C Red #40, Gelatin, Silicon Dioxide,
Sodium Lauryl Sulfate, Titanium Dioxide. The 50 mg and 200 mg capsules also contain
D&C Red #28.
CLINICAL PHARMACOLOGY
DANOCRINE suppresses the pituitary-ovarian axis. This suppression is probably a
combination of depressed hypothalamic-pituitary response to lowered estrogen production,
the alteration of sex steroid metabolism, and interaction of danazol with sex hormone
receptors. The only other demonstrable hormonal effect is weak androgenic activity.
DANOCRINE depresses the output of both follicle-stimulating hormone (FSH) and
luteinizing hormone (LH).
Recent evidence suggests a direct inhibitory effect at gonadal sites and a binding of
DANOCRINE to receptors of gonadal steroids at target organs. In addition, DANOCRINE
has been shown to significantly decrease IgG, IgM and IgA levels, as well as phospholipid
and IgG isotope autoantibodies in patients with endometriosis and associated elevations of
autoantibodies, suggesting this could be another mechanism by which it facilitates
regression of the disease.
1
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the treatment of endometriosis, DANOCRINE alters the normal and ectopic endometrial
tissue so that it becomes inactive and atrophic. Complete resolution of endometrial lesions
occurs in the majority of cases.
Changes in vaginal cytology and cervical mucus reflect the suppressive effect of
DANOCRINE on the pituitary-ovarian axis.
In the treatment of fibrocystic breast disease, DANOCRINE usually produces partial to
complete disappearance of nodularity and complete relief of pain and tenderness. Changes
in the menstrual pattern may occur.
Generally, the pituitary-suppressive action of DANOCRINE is reversible. Ovulation and
cyclic bleeding usually return within 60 to 90 days when therapy with DANOCRINE is
discontinued.
In the treatment of hereditary angioedema, DANOCRINE at effective doses prevents
attacks of the disease characterized by episodic edema of the abdominal viscera,
extremities, face, and airway which may be disabling and, if the airway is involved, fatal. In
addition, DANOCRINE corrects partially or completely the primary biochemical
abnormality of hereditary angioedema by increasing the levels of the deficient C1 esterase
inhibitor (C1EI). As a result of this action the serum levels of the C4 component of the
complement system are also increased.
Pharmacokinetics
Absorption: After oral administration of a 400 mg dose to healthy male volunteers, peak
plasma concentrations of danazol are reached between 2 and 8 hours, with a median Tmax
value of 4 hours. Steady state conditions are observed following 6 days of twice daily
dosing of DANOCRINE.
The pharmacokinetic parameters for DANOCRINE after administering a 400 mg oral dose
to healthy males are summarized in the following table:
Parameters
Mean ± SD (n=15)
Cmax (ng/mL)
69.6 ± 29.9
Tmax (h)
2.47 ± 1.62
AUC0-∞ (ng*h/mL)
601 ± 181
t1/2 (h)
9.70 ± 3.29
Total Body Clearance (L/h)
727 ± 221
The pharmacokinetic parameters for DANOCRINE after oral administration of 100, 200
and 400 mg single doses to healthy female volunteers are summarized in the following
table:
Reference ID: 3061327
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dose (mg)
Mean Cmax ± SD
(ng/mL)
Mean Tmax (h)
Mean AUC0-∞ ± SD
(ng*h/mL)
Fasting
Fed
Fasting
Fed
Fasting
Fed
100
45.9 ±23.9
113.8 ±
46.0
1-8
2-6
484 ± 263
741 ± 265
200
63.8 ± 27.7
159 ± 57.3
1-6
2-4
681 ± 363
1252 ±
307
400
60.4 ± 30.0
253.7 ±
105.5
1-6
2-4
754 ± 443
1851 ±
605
Dose proportionality: Bioavailability studies indicate that blood levels do not increase
proportionally with increases in the administered dose.
Single dose administration of DANOCRINE in healthy female volunteers found that a 4
fold increase in dose produced only a 1.6 and 2.5-fold increase in AUC and a 1.3 and 2.2
fold increase in Cmax in the fasted and fed state, respectively. A similar degree of non-dose
proportionality was observed at steady state.
Food Effect: Single dose administration of 100 mg and 200 mg capsules of DANOCRINE
to female volunteers showed that both the extent of availability and the maximum plasma
concentration increased by 3 to 4 fold, respectively, following a meal (> 30 grams of fat),
when compared to the fasted state. Further, food also delayed mean time to peak
concentration of DANOCRINE by about 30 minutes. Even after multiple dosing under less
extreme food/fasting conditions, there remained approximately a 2 to 2.5 fold difference in
bioavailability between the fed and fasted states.
Distribution: Danazol is lipophilic and can partition into cell membranes, indicating the
likelihood of distribution into deep tissue compartments.
Metabolism and Excretion: Danazol appears to be metabolized and the metabolites are
eliminated by renal and fecal pathways. The two primary metabolites excreted in the urine
are 2-hydroxymethyl danazol and ethisterone. At least ten different products were identified
in feces.
The reported elimination half-life of danazol is variable across studies. The mean half-life
of danazol in healthy males is 9.7 h. After 6 months of 200 mg three times a day dosing in
endometriosis patients, the half-life of danazol was reported as 23.7 hours.
INDICATIONS AND USAGE
Endometriosis. DANOCRINE is indicated for the treatment of endometriosis amenable to
hormonal management.
Fibrocystic Breast Disease. Most cases of symptomatic fibrocystic breast disease may be
treated by simple measures (e.g., padded brassieres and analgesics).
Reference ID: 3061327
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In infrequent patients, symptoms of pain and tenderness may be severe enough to warrant
treatment by suppression of ovarian function. DANOCRINE is usually effective in
decreasing nodularity, pain, and tenderness. It should be stressed to the patient that this
treatment is not innocuous in that it involves considerable alterations of hormone levels
and that recurrence of symptoms is very common after cessation of therapy.
Hereditary Angioedema. DANOCRINE is indicated for the prevention of attacks of
angioedema of all types (cutaneous, abdominal, laryngeal) in males and females.
CONTRAINDICATIONS
DANOCRINE should not be administered to patients with:
1.
Undiagnosed abnormal genital bleeding.
2.
Markedly impaired hepatic, renal, or cardiac function.
3.
Pregnancy. (See WARNINGS.)
4.
Breast feeding.
5.
Porphyria−DANOCRINE can induce ALA synthetase activity and hence
porphyrin metabolism.
6.
Androgen-dependent tumor.
7.
Active thrombosis or thromboembolic disease and history of such events.
8.
Hypersensitivity to danazol.
WARNINGS
Use of danazol in pregnancy is contraindicated. A sensitive test (e.g., beta subunit test
if available) capable of determining early pregnancy is recommended immediately
prior to start of therapy. Additionally a non-hormonal method of contraception
should be used during therapy. If a patient becomes pregnant while taking danazol,
administration of the drug should be discontinued and the patient should be apprised
of the potential risk to the fetus. Exposure to danazol in utero may result in
androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion,
urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received.
(See PRECAUTIONS: Pregnancy, Teratogenic
Effects.)
Thromboembolism, thrombotic and thrombophlebitic events including sagittal sinus
thrombosis and life-threatening or fatal strokes have been reported.
Experience with long-term therapy with danazol is limited. Peliosis hepatis and benign
hepatic adenoma have been observed with long-term use. Peliosis hepatis and hepatic
adenoma may be silent until complicated by acute, potentially life-threatening
intraabdominal hemorrhage. The physician therefore should be alert to this possibility.
Attempts should be made to determine the lowest dose that will provide adequate
protection. If the drug was begun at a time of exacerbation of hereditary angioneurotic
edema due to trauma, stress or other cause, periodic attempts to decrease or withdraw
therapy should be considered.
Danazol has been associated with several cases of benign intracranial hypertension also
4
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
known as pseudotumor cerebri. Early signs and symptoms of benign intracranial
hypertension include papilledema, headache, nausea and vomiting, and visual disturbances.
Patients with these symptoms should be screened for papilledema and, if present, the
patients should be advised to discontinue danazol immediately and be referred to a
neurologist for further diagnosis and care.
A temporary alteration of lipoproteins in the form of decreased high density lipoproteins
and possibly increased low density lipoproteins has been reported during danazol therapy.
These alterations may be marked, and prescribers should consider the potential impact on
the risk of atherosclerosis and coronary artery disease in accordance with the potential
benefit of the therapy to the patient.
Before initiating therapy of fibrocystic breast disease with DANOCRINE, carcinoma of the
breast should be excluded. However, nodularity, pain, tenderness due to fibrocystic breast
disease may prevent recognition of underlying carcinoma before treatment is begun.
Therefore, if any nodule persists or enlarges during treatment, carcinoma should be
considered and ruled out.
Patients should be watched closely for signs of androgenic effects some of which may not
be reversible even when drug administration is stopped.
PRECAUTIONS
Because DANOCRINE may cause some degree of fluid retention, conditions that might be
influenced by this factor, such as epilepsy, migraine, or cardiac or renal dysfunction,
polycythemia and hypertension require careful observation. Use with caution in patients
with diabetes mellitus.
Since hepatic dysfunction manifested by modest increases in serum transaminases levels
has been reported in patients treated with DANOCRINE, periodic liver function tests should
be performed (see WARNINGS and ADVERSE REACTIONS).
Administration of danazol has been reported to cause exacerbation of the manifestations of
acute intermittent porphyria. (See CONTRAINDICATIONS.)
Laboratory monitoring of the hematologic state should be considered.
Drug Interactions:
Prolongation of prothrombin time occurs in patients stabilized on warfarin.
Therapy with danazol may cause an increase in carbamazepine levels in patients taking both
drugs.
Danazol can cause insulin resistance. Caution should be exercised when used with
antidiabetic drugs.
Reference ID: 3061327
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Danazol may raise the plasma levels of cyclosporin and tacrolimus, leading to an increase
of the renal toxicity of these drugs. Monitoring of systemic concentrations of these drugs
and appropriate dose adjustments may be needed when used concomitantly with danazol.
Danazol can increase the calcemic response to synthetic vitamin D analogs in primary
hypoparathyroidism.
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of
danazol with statins such as simvastatin, atorvastatin and lovastatin. Caution should be
exercised if used concomitantly. Consult the product labeling for statin drugs for specific
information on dose restrictions in presence of danazol.
Laboratory Tests: Danazol treatment may interfere with laboratory determinations of
testosterone, androstenedione and dehydroepiandrosterone. Other metabolic events include
a reduction in thyroid binding globulin and T4 with increased uptake of T3, but without
disturbance of thyroid stimulating hormone or of free thyroxin index.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Current data are insufficient
to assess the carcinogenicity of danazol.
Pregnancy, Teratogenic Effects: (See CONTRAINDICATIONS.) Pregnancy
Category X. DANOCRINE administered orally to pregnant rats from the 6th through the
15th day of gestation at doses up to 250 mg/kg/day (7-15 times the human dose) did not
result in drug-induced embryotoxicity or teratogenicity, nor difference in litter size, viability
or weight of offspring compared to controls. In rabbits, the administration of DANOCRINE
on days 6-18 of gestation at doses of 60 mg/kg/day and above (2-4 times the human dose)
resulted in inhibition of fetal development.
Nursing Mothers: (See CONTRAINDICATIONS.)
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: Clinical studies of DANOCRINE did not include sufficient numbers of
subjects aged 65 and over to determine the safety and effectiveness of Danocrine in elderly
patients.
ADVERSE REACTIONS
The following events have been reported in association with the use of DANOCRINE:
Androgen like effects include weight gain, acne and seborrhea. Mild hirsutism, edema, hair
loss, voice change, which may take the form of hoarseness, sore throat or of instability or
deepening of pitch, may occur and may persist after cessation of therapy. Hypertrophy of
the clitoris is rare.
Other possible endocrine effects are menstrual disturbances including spotting, alteration of
the timing of the cycle and amenorrhea. Although cyclical bleeding and ovulation usually
6
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
return within 60-90 days after discontinuation of therapy with DANOCRINE, persistent
amenorrhea has occasionally been reported.
Flushing, sweating, vaginal dryness and irritation and reduction in breast size, may reflect
lowering of estrogen. Nervousness and emotional lability have been reported. In the male a
modest reduction in spermatogenesis may be evident during treatment. Abnormalities in
semen volume, viscosity, sperm count, and motility may occur in patients receiving long-
term therapy.
Hepatic dysfunction, as evidenced by reversible elevated serum enzymes and/or jaundice,
has been reported in patients receiving a daily dosage of DANOCRINE of 400 mg or more.
It is recommended that patients receiving DANOCRINE be monitored for hepatic
dysfunction by laboratory tests and clinical observation. Serious hepatic toxicity including
cholestatic jaundice, peliosis hepatis, and hepatic adenoma have been reported. (See
WARNINGS and PRECAUTIONS.)
Abnormalities in laboratory tests may occur during therapy with DANOCRINE including
CPK, glucose tolerance, glucagon, thyroid binding globulin, sex hormone binding globulin,
other plasma proteins, lipids and lipoproteins.
The following reactions have been reported, a causal relationship to the administration of
DANOCRINE has neither been confirmed nor refuted; allergic: urticaria, pruritus and
rarely, nasal congestion; CNS effects: headache, nervousness and emotional lability,
dizziness and fainting, depression, fatigue, sleep disorders, tremor, paresthesias, weakness,
visual disturbances, and rarely, benign intracranial hypertension, anxiety, changes in
appetite, chills, and rarely convulsions, Guillain-Barre syndrome; gastrointestinal:
gastroenteritis, nausea, vomiting, constipation, and rarely, pancreatitis and splenic peliosis;
musculoskeletal: muscle cramps or spasms, or pains, joint pain, joint lockup, joint swelling,
pain in back, neck, or extremities, and rarely, carpal tunnel syndrome which may be
secondary to fluid retention; genitourinary: hematuria, prolonged posttherapy amenorrhea;
hematologic: an increase in red cell and platelet count. Reversible erythrocytosis,
leukocytosis or polycythemia may be provoked. Eosinophilia, leukopenia and
thrombocytopenia have also been noted. Skin: rashes (maculopapular, vesicular, papular,
purpuric, petechial), and rarely, sun sensitivity, Stevens-Johnson syndrome and erythema
multiforme; other: increased insulin requirements in diabetic patients, change in libido,
myocardial infarction, palpitation, tachycardia, elevation in blood pressure, interstitial
pneumonitis, and rarely, cataracts, bleeding gums, fever, pelvic pain, nipple discharge.
Malignant liver tumors have been reported in rare instances, after long-term use.
DOSAGE AND ADMINISTRATION
Endometriosis. In moderate to severe disease, or in patients infertile due to endometriosis, a
starting dose of 800 mg given in two divided doses is recommended. Amenorrhea and rapid
response to painful symptoms is best achieved at this dosage level. Gradual downward
titration to a dose sufficient to maintain amenorrhea may be considered depending upon
patient response. For mild cases, an initial daily dose of 200 mg to 400 mg given in two
7
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
divided doses is recommended and may be adjusted depending on patient response.
Therapy should begin during menstruation. Otherwise, appropriate tests should be
performed to ensure that the patient is not pregnant while on therapy with
DANOCRINE. (See CONTRAINDICATIONS and WARNINGS.) It is essential that
therapy continue uninterrupted for 3 to 6 months but may be extended to 9 months if
necessary. After termination of therapy, if symptoms recur, treatment can be reinstituted.
Fibrocystic Breast Disease. The total daily dosage of DANOCRINE for fibrocystic breast
disease ranges from 100 mg to 400 mg given in two divided doses depending upon patient
response. Therapy should begin during menstruation. Otherwise, appropriate tests
should be performed to ensure that the patient is not pregnant while on therapy with
DANOCRINE. A nonhormonal method of contraception is recommended when
DANOCRINE is administered at this dose, since ovulation may not be suppressed.
In most instances, breast pain and tenderness are significantly relieved by the first month
and eliminated in 2 to 3 months. Usually elimination of nodularity requires 4 to 6 months
of uninterrupted therapy. Regular menstrual patterns irregular menstrual patterns and
amenorrhea each occur in approximately one-third of patients treated with 100 mg of
DANOCRINE. Irregular menstrual patterns and amenorrhea are observed more frequently
with higher doses. Clinical studies have demonstrated that 50% of patients may show
evidence of recurrence of symptoms within one year. In this event, treatment may be
reinstated.
Hereditary Angioedema. The dosage requirements for continuous treatment of hereditary
angioedema with DANOCRINE should be individualized on the basis of the clinical
response of the patient. It is recommended that the patient be started on 200 mg, two or
three times a day. After a favorable initial response is obtained in terms of prevention of
episodes of edematous attacks, the proper continuing dosage should be determined by
decreasing the dosage by 50% or less at intervals of one to three months or longer if
frequency of attacks prior to treatment dictates. If an attack occurs, the daily dosage may be
increased by up to 200 mg. During the dose adjusting phase, close monitoring of the
patient’s response is indicated, particularly if the patient has a history of airway
involvement.
HOW SUPPLIED
Capsules of 200 mg (orange), bottles of 60 (NDC 0024-0305-60).
Capsules of 200 mg (orange), bottles of 100 (NDC 0024-0305-06).
Capsules of 100 mg (yellow), bottles of 100 (NDC 0024-0304-06).
Capsules of 50 mg (orange and white), bottles of 100 (NDC 0024-0303-06).
Store at controlled room temperature, 15° C to 30° C (59° F to 86° F).
Reference ID: 3061327
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
sanofi-aventis U.S. LLC
Bridgewater, New Jersey 08807
Revised December 2011
©2011 sanofi-aventis U.S. LLC
Reference ID: 3061327
9
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/2011/017557s033s039s040s041s042lbl.pdf', 'application_number': 17557, 'submission_type': 'SUPPL ', 'submission_number': 40}
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11,026
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DANOCRINE®
Brand of DANAZOL
CAPSULES, USP
DESCRIPTION
DANOCRINE, brand of danazol, is a synthetic steroid derived from ethisterone. It is a
white to pale yellow crystalline powder, practically insoluble or insoluble in water, and
sparingly soluble in alcohol. Chemically, danazol is 17α-Pregna-2,4-dien-20-yno [2,3-d]
isoxazol-17-ol. The molecular formula is C22H27NO2. It has a molecular weight of 337.46
and the following structural formula: structural formula
Danocrine capsules for oral administration contain 50 mg, 100 mg or 200 mg danazol.
Inactive Ingredients: Corn Starch, Lactose, Magnesium Stearate, Talc. Capsules 50 mg, 100
mg and 200 mg contain D&C Yellow #10, FD&C Red #40, Gelatin, Silicon Dioxide,
Sodium Lauryl Sulfate, Titanium Dioxide. The 50 mg and 200 mg capsules also contain
D&C Red #28.
CLINICAL PHARMACOLOGY
DANOCRINE suppresses the pituitary-ovarian axis. This suppression is probably a
combination of depressed hypothalamic-pituitary response to lowered estrogen production,
the alteration of sex steroid metabolism, and interaction of danazol with sex hormone
receptors. The only other demonstrable hormonal effect is weak androgenic activity.
DANOCRINE depresses the output of both follicle-stimulating hormone (FSH) and
luteinizing hormone (LH).
Recent evidence suggests a direct inhibitory effect at gonadal sites and a binding of
DANOCRINE to receptors of gonadal steroids at target organs. In addition, DANOCRINE
has been shown to significantly decrease IgG, IgM and IgA levels, as well as phospholipid
and IgG isotope autoantibodies in patients with endometriosis and associated elevations of
autoantibodies, suggesting this could be another mechanism by which it facilitates
regression of the disease.
1
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the treatment of endometriosis, DANOCRINE alters the normal and ectopic endometrial
tissue so that it becomes inactive and atrophic. Complete resolution of endometrial lesions
occurs in the majority of cases.
Changes in vaginal cytology and cervical mucus reflect the suppressive effect of
DANOCRINE on the pituitary-ovarian axis.
In the treatment of fibrocystic breast disease, DANOCRINE usually produces partial to
complete disappearance of nodularity and complete relief of pain and tenderness. Changes
in the menstrual pattern may occur.
Generally, the pituitary-suppressive action of DANOCRINE is reversible. Ovulation and
cyclic bleeding usually return within 60 to 90 days when therapy with DANOCRINE is
discontinued.
In the treatment of hereditary angioedema, DANOCRINE at effective doses prevents
attacks of the disease characterized by episodic edema of the abdominal viscera,
extremities, face, and airway which may be disabling and, if the airway is involved, fatal. In
addition, DANOCRINE corrects partially or completely the primary biochemical
abnormality of hereditary angioedema by increasing the levels of the deficient C1 esterase
inhibitor (C1EI). As a result of this action the serum levels of the C4 component of the
complement system are also increased.
Pharmacokinetics
Absorption: After oral administration of a 400 mg dose to healthy male volunteers, peak
plasma concentrations of danazol are reached between 2 and 8 hours, with a median Tmax
value of 4 hours. Steady state conditions are observed following 6 days of twice daily
dosing of DANOCRINE.
The pharmacokinetic parameters for DANOCRINE after administering a 400 mg oral dose
to healthy males are summarized in the following table:
Parameters
Mean ± SD (n=15)
Cmax (ng/mL)
69.6 ± 29.9
Tmax (h)
2.47 ± 1.62
AUC0-∞ (ng*h/mL)
601 ± 181
t1/2 (h)
9.70 ± 3.29
Total Body Clearance (L/h)
727 ± 221
The pharmacokinetic parameters for DANOCRINE after oral administration of 100, 200
and 400 mg single doses to healthy female volunteers are summarized in the following
table:
Reference ID: 3061327
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dose (mg)
Mean Cmax ± SD
(ng/mL)
Mean Tmax (h)
Mean AUC0-∞ ± SD
(ng*h/mL)
Fasting
Fed
Fasting
Fed
Fasting
Fed
100
45.9 ±23.9
113.8 ±
46.0
1-8
2-6
484 ± 263
741 ± 265
200
63.8 ± 27.7
159 ± 57.3
1-6
2-4
681 ± 363
1252 ±
307
400
60.4 ± 30.0
253.7 ±
105.5
1-6
2-4
754 ± 443
1851 ±
605
Dose proportionality: Bioavailability studies indicate that blood levels do not increase
proportionally with increases in the administered dose.
Single dose administration of DANOCRINE in healthy female volunteers found that a 4
fold increase in dose produced only a 1.6 and 2.5-fold increase in AUC and a 1.3 and 2.2
fold increase in Cmax in the fasted and fed state, respectively. A similar degree of non-dose
proportionality was observed at steady state.
Food Effect: Single dose administration of 100 mg and 200 mg capsules of DANOCRINE
to female volunteers showed that both the extent of availability and the maximum plasma
concentration increased by 3 to 4 fold, respectively, following a meal (> 30 grams of fat),
when compared to the fasted state. Further, food also delayed mean time to peak
concentration of DANOCRINE by about 30 minutes. Even after multiple dosing under less
extreme food/fasting conditions, there remained approximately a 2 to 2.5 fold difference in
bioavailability between the fed and fasted states.
Distribution: Danazol is lipophilic and can partition into cell membranes, indicating the
likelihood of distribution into deep tissue compartments.
Metabolism and Excretion: Danazol appears to be metabolized and the metabolites are
eliminated by renal and fecal pathways. The two primary metabolites excreted in the urine
are 2-hydroxymethyl danazol and ethisterone. At least ten different products were identified
in feces.
The reported elimination half-life of danazol is variable across studies. The mean half-life
of danazol in healthy males is 9.7 h. After 6 months of 200 mg three times a day dosing in
endometriosis patients, the half-life of danazol was reported as 23.7 hours.
INDICATIONS AND USAGE
Endometriosis. DANOCRINE is indicated for the treatment of endometriosis amenable to
hormonal management.
Fibrocystic Breast Disease. Most cases of symptomatic fibrocystic breast disease may be
treated by simple measures (e.g., padded brassieres and analgesics).
Reference ID: 3061327
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In infrequent patients, symptoms of pain and tenderness may be severe enough to warrant
treatment by suppression of ovarian function. DANOCRINE is usually effective in
decreasing nodularity, pain, and tenderness. It should be stressed to the patient that this
treatment is not innocuous in that it involves considerable alterations of hormone levels
and that recurrence of symptoms is very common after cessation of therapy.
Hereditary Angioedema. DANOCRINE is indicated for the prevention of attacks of
angioedema of all types (cutaneous, abdominal, laryngeal) in males and females.
CONTRAINDICATIONS
DANOCRINE should not be administered to patients with:
1.
Undiagnosed abnormal genital bleeding.
2.
Markedly impaired hepatic, renal, or cardiac function.
3.
Pregnancy. (See WARNINGS.)
4.
Breast feeding.
5.
Porphyria−DANOCRINE can induce ALA synthetase activity and hence
porphyrin metabolism.
6.
Androgen-dependent tumor.
7.
Active thrombosis or thromboembolic disease and history of such events.
8.
Hypersensitivity to danazol.
WARNINGS
Use of danazol in pregnancy is contraindicated. A sensitive test (e.g., beta subunit test
if available) capable of determining early pregnancy is recommended immediately
prior to start of therapy. Additionally a non-hormonal method of contraception
should be used during therapy. If a patient becomes pregnant while taking danazol,
administration of the drug should be discontinued and the patient should be apprised
of the potential risk to the fetus. Exposure to danazol in utero may result in
androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion,
urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received.
(See PRECAUTIONS: Pregnancy, Teratogenic
Effects.)
Thromboembolism, thrombotic and thrombophlebitic events including sagittal sinus
thrombosis and life-threatening or fatal strokes have been reported.
Experience with long-term therapy with danazol is limited. Peliosis hepatis and benign
hepatic adenoma have been observed with long-term use. Peliosis hepatis and hepatic
adenoma may be silent until complicated by acute, potentially life-threatening
intraabdominal hemorrhage. The physician therefore should be alert to this possibility.
Attempts should be made to determine the lowest dose that will provide adequate
protection. If the drug was begun at a time of exacerbation of hereditary angioneurotic
edema due to trauma, stress or other cause, periodic attempts to decrease or withdraw
therapy should be considered.
Danazol has been associated with several cases of benign intracranial hypertension also
4
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
known as pseudotumor cerebri. Early signs and symptoms of benign intracranial
hypertension include papilledema, headache, nausea and vomiting, and visual disturbances.
Patients with these symptoms should be screened for papilledema and, if present, the
patients should be advised to discontinue danazol immediately and be referred to a
neurologist for further diagnosis and care.
A temporary alteration of lipoproteins in the form of decreased high density lipoproteins
and possibly increased low density lipoproteins has been reported during danazol therapy.
These alterations may be marked, and prescribers should consider the potential impact on
the risk of atherosclerosis and coronary artery disease in accordance with the potential
benefit of the therapy to the patient.
Before initiating therapy of fibrocystic breast disease with DANOCRINE, carcinoma of the
breast should be excluded. However, nodularity, pain, tenderness due to fibrocystic breast
disease may prevent recognition of underlying carcinoma before treatment is begun.
Therefore, if any nodule persists or enlarges during treatment, carcinoma should be
considered and ruled out.
Patients should be watched closely for signs of androgenic effects some of which may not
be reversible even when drug administration is stopped.
PRECAUTIONS
Because DANOCRINE may cause some degree of fluid retention, conditions that might be
influenced by this factor, such as epilepsy, migraine, or cardiac or renal dysfunction,
polycythemia and hypertension require careful observation. Use with caution in patients
with diabetes mellitus.
Since hepatic dysfunction manifested by modest increases in serum transaminases levels
has been reported in patients treated with DANOCRINE, periodic liver function tests should
be performed (see WARNINGS and ADVERSE REACTIONS).
Administration of danazol has been reported to cause exacerbation of the manifestations of
acute intermittent porphyria. (See CONTRAINDICATIONS.)
Laboratory monitoring of the hematologic state should be considered.
Drug Interactions:
Prolongation of prothrombin time occurs in patients stabilized on warfarin.
Therapy with danazol may cause an increase in carbamazepine levels in patients taking both
drugs.
Danazol can cause insulin resistance. Caution should be exercised when used with
antidiabetic drugs.
Reference ID: 3061327
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Danazol may raise the plasma levels of cyclosporin and tacrolimus, leading to an increase
of the renal toxicity of these drugs. Monitoring of systemic concentrations of these drugs
and appropriate dose adjustments may be needed when used concomitantly with danazol.
Danazol can increase the calcemic response to synthetic vitamin D analogs in primary
hypoparathyroidism.
The risk of myopathy and rhabdomyolysis is increased by concomitant administration of
danazol with statins such as simvastatin, atorvastatin and lovastatin. Caution should be
exercised if used concomitantly. Consult the product labeling for statin drugs for specific
information on dose restrictions in presence of danazol.
Laboratory Tests: Danazol treatment may interfere with laboratory determinations of
testosterone, androstenedione and dehydroepiandrosterone. Other metabolic events include
a reduction in thyroid binding globulin and T4 with increased uptake of T3, but without
disturbance of thyroid stimulating hormone or of free thyroxin index.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Current data are insufficient
to assess the carcinogenicity of danazol.
Pregnancy, Teratogenic Effects: (See CONTRAINDICATIONS.) Pregnancy
Category X. DANOCRINE administered orally to pregnant rats from the 6th through the
15th day of gestation at doses up to 250 mg/kg/day (7-15 times the human dose) did not
result in drug-induced embryotoxicity or teratogenicity, nor difference in litter size, viability
or weight of offspring compared to controls. In rabbits, the administration of DANOCRINE
on days 6-18 of gestation at doses of 60 mg/kg/day and above (2-4 times the human dose)
resulted in inhibition of fetal development.
Nursing Mothers: (See CONTRAINDICATIONS.)
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: Clinical studies of DANOCRINE did not include sufficient numbers of
subjects aged 65 and over to determine the safety and effectiveness of Danocrine in elderly
patients.
ADVERSE REACTIONS
The following events have been reported in association with the use of DANOCRINE:
Androgen like effects include weight gain, acne and seborrhea. Mild hirsutism, edema, hair
loss, voice change, which may take the form of hoarseness, sore throat or of instability or
deepening of pitch, may occur and may persist after cessation of therapy. Hypertrophy of
the clitoris is rare.
Other possible endocrine effects are menstrual disturbances including spotting, alteration of
the timing of the cycle and amenorrhea. Although cyclical bleeding and ovulation usually
6
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
return within 60-90 days after discontinuation of therapy with DANOCRINE, persistent
amenorrhea has occasionally been reported.
Flushing, sweating, vaginal dryness and irritation and reduction in breast size, may reflect
lowering of estrogen. Nervousness and emotional lability have been reported. In the male a
modest reduction in spermatogenesis may be evident during treatment. Abnormalities in
semen volume, viscosity, sperm count, and motility may occur in patients receiving long-
term therapy.
Hepatic dysfunction, as evidenced by reversible elevated serum enzymes and/or jaundice,
has been reported in patients receiving a daily dosage of DANOCRINE of 400 mg or more.
It is recommended that patients receiving DANOCRINE be monitored for hepatic
dysfunction by laboratory tests and clinical observation. Serious hepatic toxicity including
cholestatic jaundice, peliosis hepatis, and hepatic adenoma have been reported. (See
WARNINGS and PRECAUTIONS.)
Abnormalities in laboratory tests may occur during therapy with DANOCRINE including
CPK, glucose tolerance, glucagon, thyroid binding globulin, sex hormone binding globulin,
other plasma proteins, lipids and lipoproteins.
The following reactions have been reported, a causal relationship to the administration of
DANOCRINE has neither been confirmed nor refuted; allergic: urticaria, pruritus and
rarely, nasal congestion; CNS effects: headache, nervousness and emotional lability,
dizziness and fainting, depression, fatigue, sleep disorders, tremor, paresthesias, weakness,
visual disturbances, and rarely, benign intracranial hypertension, anxiety, changes in
appetite, chills, and rarely convulsions, Guillain-Barre syndrome; gastrointestinal:
gastroenteritis, nausea, vomiting, constipation, and rarely, pancreatitis and splenic peliosis;
musculoskeletal: muscle cramps or spasms, or pains, joint pain, joint lockup, joint swelling,
pain in back, neck, or extremities, and rarely, carpal tunnel syndrome which may be
secondary to fluid retention; genitourinary: hematuria, prolonged posttherapy amenorrhea;
hematologic: an increase in red cell and platelet count. Reversible erythrocytosis,
leukocytosis or polycythemia may be provoked. Eosinophilia, leukopenia and
thrombocytopenia have also been noted. Skin: rashes (maculopapular, vesicular, papular,
purpuric, petechial), and rarely, sun sensitivity, Stevens-Johnson syndrome and erythema
multiforme; other: increased insulin requirements in diabetic patients, change in libido,
myocardial infarction, palpitation, tachycardia, elevation in blood pressure, interstitial
pneumonitis, and rarely, cataracts, bleeding gums, fever, pelvic pain, nipple discharge.
Malignant liver tumors have been reported in rare instances, after long-term use.
DOSAGE AND ADMINISTRATION
Endometriosis. In moderate to severe disease, or in patients infertile due to endometriosis, a
starting dose of 800 mg given in two divided doses is recommended. Amenorrhea and rapid
response to painful symptoms is best achieved at this dosage level. Gradual downward
titration to a dose sufficient to maintain amenorrhea may be considered depending upon
patient response. For mild cases, an initial daily dose of 200 mg to 400 mg given in two
7
Reference ID: 3061327
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
divided doses is recommended and may be adjusted depending on patient response.
Therapy should begin during menstruation. Otherwise, appropriate tests should be
performed to ensure that the patient is not pregnant while on therapy with
DANOCRINE. (See CONTRAINDICATIONS and WARNINGS.) It is essential that
therapy continue uninterrupted for 3 to 6 months but may be extended to 9 months if
necessary. After termination of therapy, if symptoms recur, treatment can be reinstituted.
Fibrocystic Breast Disease. The total daily dosage of DANOCRINE for fibrocystic breast
disease ranges from 100 mg to 400 mg given in two divided doses depending upon patient
response. Therapy should begin during menstruation. Otherwise, appropriate tests
should be performed to ensure that the patient is not pregnant while on therapy with
DANOCRINE. A nonhormonal method of contraception is recommended when
DANOCRINE is administered at this dose, since ovulation may not be suppressed.
In most instances, breast pain and tenderness are significantly relieved by the first month
and eliminated in 2 to 3 months. Usually elimination of nodularity requires 4 to 6 months
of uninterrupted therapy. Regular menstrual patterns irregular menstrual patterns and
amenorrhea each occur in approximately one-third of patients treated with 100 mg of
DANOCRINE. Irregular menstrual patterns and amenorrhea are observed more frequently
with higher doses. Clinical studies have demonstrated that 50% of patients may show
evidence of recurrence of symptoms within one year. In this event, treatment may be
reinstated.
Hereditary Angioedema. The dosage requirements for continuous treatment of hereditary
angioedema with DANOCRINE should be individualized on the basis of the clinical
response of the patient. It is recommended that the patient be started on 200 mg, two or
three times a day. After a favorable initial response is obtained in terms of prevention of
episodes of edematous attacks, the proper continuing dosage should be determined by
decreasing the dosage by 50% or less at intervals of one to three months or longer if
frequency of attacks prior to treatment dictates. If an attack occurs, the daily dosage may be
increased by up to 200 mg. During the dose adjusting phase, close monitoring of the
patient’s response is indicated, particularly if the patient has a history of airway
involvement.
HOW SUPPLIED
Capsules of 200 mg (orange), bottles of 60 (NDC 0024-0305-60).
Capsules of 200 mg (orange), bottles of 100 (NDC 0024-0305-06).
Capsules of 100 mg (yellow), bottles of 100 (NDC 0024-0304-06).
Capsules of 50 mg (orange and white), bottles of 100 (NDC 0024-0303-06).
Store at controlled room temperature, 15° C to 30° C (59° F to 86° F).
Reference ID: 3061327
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
sanofi-aventis U.S. LLC
Bridgewater, New Jersey 08807
Revised December 2011
©2011 sanofi-aventis U.S. LLC
Reference ID: 3061327
9
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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2025-02-12T13:44:16.728148
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017557s033s039s040s041s042lbl.pdf', 'application_number': 17557, 'submission_type': 'SUPPL ', 'submission_number': 33}
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11,025
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HALOG®(Halcinonide Cream, USP) 0.1%
Page 1 of 6
HALOG - halcinonide cream
®
HALOG
(Halcinonide Cream, USP) 0.1%
For Topical Use Only. Not For Ophthalmic, Oral or Intravaginal Use.
DESCRIPTION
The topical corticosteroids constitute a class of primarily synthetic steroids used as anti
inflammatory and antipruritic agents. The steroids in this class include halcinonide. Halcinonide
is designated chemically as 21-Chloro-9-fluoro-11β,16α, 17-trihydroxypregn-4-ene-3,20-dione
cyclic 16,17-acetal with acetone. Graphic formula:
Each gram of 0.1% HALOG (Halcinonide Cream, USP) contains 1 mg halcinonide in a
specially formulated cream base consisting of cetyl alcohol, dimethicone 350, glyceryl
monostearate NF XII, isopropyl palmitate, polysorbate 60, propylene glycol, purified water, and
titanium dioxide. Structural Formula
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various
laboratory methods, including vasoconstrictor assays, are used to compare and predict
potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to
suggest that a recognizable correlation exists between vasoconstrictor potency and
therapeutic efficacy in man.
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.
Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other
disease processes in the skin increase percutaneous absorption. Occlusive dressings
substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive
dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses (see
DOSAGE AND ADMINISTRATION).
file://\\Fdswa150\nonectd\N17556\S_038\2009-02-09\NDA 17-556, Halog® (halcinonide)... 6/10/2009
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HALOG®(Halcinonide Cream, USP) 0.1%
Page 2 of 6
Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic
pathways 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.
INDICATIONS AND USAGE
HALOG (Halcinonide Cream, USP) 0.1% is indicated for the relief of the inflammatory and
pruritic manifestations of corticosteroid-responsive dermatoses.
CONTRAINDICATIONS
Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to
any of the components of the preparations.
PRECAUTIONS
General
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.
Conditions which augment systemic absorption include the application of the more potent
steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.
Therefore, patients receiving a large dose of any potent topical steroid applied to a large
surface area or under an occlusive dressing should be evaluated periodically for evidence of
HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for
impairment of thermal homeostasis. If HPA axis suppression or elevation of the body
temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency
of application, substitute a less potent steroid, or use a sequential approach when utilizing the
occlusive technique.
Recovery of HPA axis function and thermal homeostasis are generally prompt and complete
upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may
occur, requiring supplemental systemic corticosteroids. Occasionally, a patient may develop a
sensitivity reaction to a particular occlusive dressing material or adhesive and a substitute
material may be necessary.
Children may absorb proportionally larger amounts of topical corticosteroids and thus be more
susceptible to systemic toxicity (see PRECAUTIONS: Pediatric Use).
If irritation develops, topical corticosteroids should be discontinued and appropriate therapy
instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or
antibacterial agent should be instituted. If a favorable response does not occur promptly, the
corticosteroid should be discontinued until the infection has been adequately controlled.
The preparation is not for ophthalmic, oral, or intravaginal use.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HALOG®(Halcinonide Cream, USP) 0.1%
Page 3 of 6
Information for the Patient
Patients using topical corticosteroids should receive the following information and instructions:
• This medication is to be used as directed by the physician. It is for dermatologic use only.
Avoid contact with the eyes.
• Patients should be advised not to use this medication for any disorder other than for
which it was prescribed.
• The treated skin area should not be bandaged or otherwise covered or wrapped as to be
occlusive unless directed by the physician.
• Patients should report any signs of local adverse reactions especially under occlusive
dressing.
• Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic
pants on a child being treated in the diaper area, as these garments may constitute
occlusive dressings.
Laboratory Tests
A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA axis
suppression.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential or
the effect on fertility of topical corticosteroids.
Studies to determine mutagenicity with prednisolone and hydrocortisone showed negative
results.
Pregnancy
Teratogenic Effects: Category C
Corticosteroids are generally teratogenic in laboratory animals when administered systemically
at relatively low dosage levels. The more potent corticosteroids have been shown to be
teratogenic after dermal application in laboratory animals. There are no adequate and well-
controlled studies in pregnant women on teratogenic effects from topically applied
corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. Drugs of this class should not be used
extensively on pregnant patients, in large amounts, or for prolonged periods of time.
Nursing Mothers
It is not known whether topical administration of corticosteroids could result in sufficient
systemic absorption to produce detectable quantities in breast milk. Systemically administered
corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect
on the infant. Nevertheless, caution should be exercised when topical corticosteroids are
administered to a nursing woman.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HALOG®(Halcinonide Cream, USP) 0.1%
Page 4 of 6
Pediatric Use
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 area to body weight ratio.
HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported
in children receiving topical corticosteroids. Manifestations of adrenal suppression in children
include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence
of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging
fontanelles, headaches, and bilateral papilledema.
Administration of topical corticosteroids to children should be limited to the least amount
compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere
with the growth and development of children.
Geriatric Use
Of approximately 3000 patients included in clinical studies of 0.1% HALOG CREAM, 14% were
60 years or older, while 4% were 70 years or older. No overall differences in safety were
observed between these patients and younger patients. Efficacy data have not been evaluated
for differences between elderly 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.
ADVERSE REACTIONS
The following local adverse reactions are reported infrequently with topical corticosteroids, but
may occur more frequently with the use of occlusive dressings (reactions are listed in an
approximate decreasing order of occurrence): burning, itching, irritation, dryness, folliculitis,
hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact
dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria.
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic
effects (see PRECAUTIONS: General).
DOSAGE AND ADMINISTRATION
Apply the 0.1% HALOG (Halcinonide Cream, USP) to the affected area two to three times
daily. Rub in gently.
Occlusive Dressing Technique
Occlusive dressings may be used for the management of psoriasis or other recalcitrant
conditions. Gently rub a small amount of cream into the lesion until it disappears. Reapply the
preparation leaving a thin coating on the lesion, cover with a pliable nonporous film, and seal
the edges. If needed, additional moisture may be provided by covering the lesion with a
dampened clean cotton cloth before the nonporous film is applied or by briefly wetting the
affected area with water immediately prior to applying the medication. The frequency of
changing dressings is best determined on an individual basis. It may be convenient to apply
file://\\Fdswa150\nonectd\N17556\S_038\2009-02-09\NDA 17-556, Halog® (halcinonide)... 6/10/2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
P
roduc
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Chart
HALOG®(Halcinonide Cream, USP) 0.1%
Page 5 of 6
HALOG under an occlusive dressing in the evening and to remove the dressing in the morning
(i.e., 12-hour occlusion). When utilizing the 12-hour occlusion regimen, additional cream
should be applied, without occlusion, during the day. Reapplication is essential at each
dressing change.
If an infection develops, the use of occlusive dressings should be discontinued and appropriate
antimicrobial therapy instituted.
HOW SUPPLIED
HALOG ® (Halcinonide Cream, USP) 0.1% is supplied as:
NDC 10631-094-31 Tubes containing 1.5 g of cream (Physician Samples not for Sale)
NDC 10631-094-20 Tubes containing 30 g of cream
NDC 10631-094-30 Tubes containing 60 g of cream
NDC 10631-094-76 Jars containing 216 g of cream.
Storage
Store at room temperature; avoid excessive heat (104° F).
RANBAXY
Jacksonville, FL 32257 USA
09-XXXX (flat)
09-YYYY (folded)
Revised February 2009
file://\\Fdswa150\nonectd\N17556\S_038\2009-02-09\NDA 17-556, Halog® (halcinonide)... 6/10/2009
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
P
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HALOG®(Halcinonide Cream, USP) 0.1%
Page 6 of 6
file://\\Fdswa150\nonectd\N17556\S_038\2009-02-09\NDA 17-556, Halog® (halcinonide)... 6/10/2009
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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2025-02-12T13:44:16.755899
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017556s038lbl.pdf', 'application_number': 17556, 'submission_type': 'SUPPL ', 'submission_number': 38}
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11,031
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DITROPAN®
(oxybutynin chloride)
Tablets
DESCRIPTION
Each scored biconvex, engraved blue DITROPAN® (oxybutynin chloride) Tablet
contains 5 mg of oxybutynin chloride. Chemically, oxybutynin chloride is d,l
(racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The
empirical formula of oxybutynin chloride is C22H31NO3•HCl. The structural formula
appears below: Structural Formula
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It
is readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN Tablets also contain calcium stearate, FD&C Blue #1 Lake, lactose, and
microcrystalline cellulose.
DITROPAN Tablets are for oral administration.
Therapeutic Category: Antispasmodic, anticholinergic.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and
inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin
chloride exhibits only one fifth of the anticholinergic activity of atropine on the rabbit
detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects
occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin chloride increases bladder (vesical) capacity,
diminishes the frequency of uninhibited contractions of the detrusor muscle, and
delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the
frequency of both incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominately in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in
vitro studies.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Absorption
Following oral administration of DITROPAN, oxybutynin is rapidly absorbed
achieving Cmax within an hour, following which plasma concentration decreases with
an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of
oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for the tablets. Wide
interindividual variation in pharmacokinetic parameters is evident following oral
administration of oxybutynin.
The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in
Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar
in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Three Doses of
DITROPAN 5 mg Administered every 8 Hours (n=23)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
3.6 (2.2)
7.8 (4.1)
Tmax (h)
0.89 (0.34)
0.65 (0.32)
AUCt (ng⋅h/mL)
22.6 (11.3)
35.0 (17.3)
AUCinf (ng⋅h/mL)
24.3 (12.3)
37.3 (18.7)
Gr
aph
0
4
8
12
16
20
24
Time (h)
Figure 1.
Mean R-oxybutynin plasma concentrations following three doses of DITROPAN 5 mg
administered every 8 hours for 1 day in 23 healthy adult volunteers
DITROPAN steady-state pharmacokinetics were also studied in 11 pediatric patients
with detrusor overactivity associated with a neurological condition (e.g., spina bifida).
These pediatric patients were on DITROPAN tablets with total daily dose ranging
from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg). Overall, most patients (86.9%) were
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
taking a total daily DITROPAN dose between 10 mg and 15 mg. Sparse sampling
technique was used to obtain serum samples. When all available data are normalized
to an equivalent of 5 mg twice daily DITROPAN, the mean pharmacokinetic
parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are
summarized in Table 2. The plasma-time concentration profiles for R- and
S-oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin when
all available data are normalized to an equivalent of 5 mg twice daily.
Table 2
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
Parameters In Children Aged 5-15 Following Administration of 7.5 mg to 15 mg Total
Daily Dose of DITROPAN Tablets (N=11)
All Available Data Normalized to an Equivalent of DITROPAN Tablets 5 mg BID or TID at Steady
State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax* (ng/mL)
6.1± 3.2
10.1 ± 7.5
55.4 ± 17.9
28.2 ± 10.0
Tmax (hr)
1.0
1.0
2.0
2.0
AUC**
19.8 ± 7.4
28.4 ± 12.7
238.8 ± 77.6
119.5 ± 50.7
(ng.hr/mL)
*Reflects Cmax for pooled data
**AUC0-end of dosing interval
Gr
ap
h
0
2
4
6
8
10
12
Time (h)
Figure 2.
Mean steady-state (±SD) R-oxybutynin plasma concentrations following
administration of total daily DITROPAN Tablet dose of 7.5 mg to 15 mg (0.22
mg/kg to 0.53 mg/kg) in children 5-15 years of age. – Plot represents all
available data normalized to the equivalent of DITROPAN 5 mg BID or TID at
steady state
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Food Effects
Data in the literature suggests that oxybutynin solution co-administered with food
resulted in a slight delay in absorption and an increase in its bioavailability by
25% (n=18).
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous
or oral administration. The volume of distribution is 193 L after intravenous
administration of 5 mg oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
CLINICAL STUDIES
DITROPAN was well tolerated in patients administered the drug in controlled studies
of 30 days’ duration and in uncontrolled studies in which some of the patients
received the drug for 2 years.
INDICATIONS AND USAGE
DITROPAN® (oxybutynin chloride) is indicated for the relief of symptoms of bladder
instability associated with voiding in patients with uninhibited neurogenic or reflex
neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence,
dysuria).
CONTRAINDICATIONS
DITROPAN® (oxybutynin chloride) is contraindicated in patients with urinary
retention, gastric retention and other severe decreased gastrointestinal motility
conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for
these conditions.
DITROPAN is also contraindicated in patients who have demonstrated
hypersensitivity to the drug substance or other components of the product.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
Central Nervous System Effects
Oxybutynin is associated with anticholinergic central nervous system (CNS) effects
(See ADVERSE REACTIONS). A variety of CNS anticholinergic effects have been
reported, including hallucinations, agitation, confusion and somnolence. Patients
should be monitored for signs of anticholinergic CNS effects, particularly in the first
few months after beginning treatment or increasing the dose. If a patient experiences
anticholinergic CNS effects, dose reduction or drug discontinuation should be
considered.
DITROPAN should be used with caution in patients with preexisting dementia treated
with cholinesterase inhibitors due to the risk of aggravation of symptoms.
General
DITROPAN® (oxybutynin chloride) should be used with caution in the frail elderly,
in patients with hepatic or renal impairment, and in patients with myasthenia gravis.
DITROPAN may aggravate the symptoms of hyperthyroidism, coronary heart
disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia,
hypertension, myasthenia gravis, and prostatic hypertrophy.
Urinary Retention
DITROPAN should be administered with caution to patients with clinically
significant bladder outflow obstruction because of the risk of urinary retention
(see CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN should be administered with caution to patients with gastrointestinal
obstructive
disorders
because
of
the
risk
of
gastric
retention
(see CONTRAINDICATIONS).
Administration of DITROPAN to patients with ulcerative colitis may suppress
intestinal motility to the point of producing a paralytic ileus and precipitate or
aggravate toxic megacolon, a serious complication of the disease.
DITROPAN, like other anticholinergic drugs, may decrease gastrointestinal motility
and should be used with caution in patients with conditions such as ulcerative colitis,
and intestinal atony.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DITROPAN should be used with caution in patients who have gastroesophageal
reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can
cause or exacerbate esophagitis.
Information for Patients
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence), or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other
agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such
effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This
may be of concern for drugs with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 3-4 fold higher
when DITROPAN was administered with ketoconazole, a potent CYP3A4 inhibitor.
Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic
agents
(e.g.,
itraconazole
and
miconazole)
or
macrolide
antibiotics
(e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic
parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions
is not known. Caution should be used when such drugs are co-administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and
160 mg/kg/day showed no evidence of carcinogenicity. These doses are
approximately 6, 25, and 50 times the maximum human exposure, based on surface
area.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella
typhimurium test systems.
Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse
have shown no definite evidence of impaired fertility.
Pregnancy
Category B. Reproduction studies using oxybutynin chloride in the hamster, rabbit,
rat, and mouse have shown no definite evidence of impaired fertility or harm to the
animal fetus. The safety of DITROPAN administered to women who are or who may
become pregnant has not been established. Therefore, DITROPAN should not be
given to pregnant women unless, in the judgment of the physician, the probable
clinical benefits outweigh the possible hazards.
Nursing Mothers
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 DITROPAN is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN administration have been demonstrated for
pediatric
patients
5
years
of
age
and
older
(see
DOSAGE
AND
ADMINISTRATION).
The safety and efficacy of DITROPAN Tablets were studied in 30 children in a 24
week, open-label trial. Patients were aged 5-15 years, all had symptoms of detrusor
overactivity in association with a neurological condition (e.g., spina bifida), all used
clean intermittent catheterization, and all were current users of oxybutynin chloride.
Study results demonstrated that the administration of DITROPAN was associated
with improvement in clinical and urodynamic parameters.
At total daily doses ranging from 5 mg to 15 mg, treatment with DITROPAN Tablets
was associated with an increase from baseline in mean urine volume per
catheterization from 122 mL to 145 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 168 mL, and an increase from
baseline in the mean percentage of catheterizations without a leaking episode from
43% to 61%. Urodynamic results in these patients were consistent with the clinical
results. Treatment with DITROPAN Tablets was associated with an increase from
baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from
baseline in mean detrusor pressure at maximum cystometric capacity from 36 cm
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
T
a
b
l
e
H20 to 33 cm H20, and a reduction in the percentage of patients demonstrating
uninhibited detrusor contractions (of at least 15 cm H20) from 39% to 20%.
As
there
is
insufficient
clinical
data
for
pediatric
populations
under
age 5, DITROPAN is not recommended for this age group.
Geriatric Use
Clinical studies of DITROPAN did not include sufficient numbers of subjects
age 65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses between
healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg
given 2 or 3 times a day has been recommended for the frail elderly due to a
prolongation of the elimination half-life from 2-3 hours to 5 hours.2, 3, 4 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
The safety and efficacy of DITROPAN® (oxybutynin chloride) was evaluated in a
total of 199 patients in three clinical trials. These participants were treated with
DITROPAN 5-20 mg/day for up to 6 weeks. Table 3 shows the incidence of adverse
events judged by investigators to be at least possibly related to treatment and reported
by at least 5% of patients.
The most common adverse events reported by patients receiving DITROPAN
5-20 mg/day were the expected side effects of anticholinergic agents. The incidence
of dry mouth was dose-related.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In addition, the following adverse events were reported by 1 to <5% of patients using
DITROPAN
(5-20
mg/day)
in
all
studies.
Infections
and
Infestations:
nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection;
Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders:
confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye
Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations,
sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and
Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat,
sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders:
diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper,
dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue
Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back
pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria,
pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema
peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased,
blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural
Complications: fall.
Postmarketing Surveillance
Because postmarketing adverse events 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 following additional adverse
events have been reported from worldwide postmarketing experience with
DITROPAN: Psychiatric Disorders: psychotic disorder, agitation, hallucination,
memory impairment; Nervous System Disorders: convulsions; Eye Disorders:
cycloplegia, mydriasis; Cardiac Disorders: tachycardia, QT interval prolongation;
Gastrointestinal
Disorders:
decreased
gastrointestinal
motility;
Skin
and
Subcutaneous Tissue Disorders: rash, decreased sweating; Renal and Urinary
Disorders: impotence; Reproductive System and Breast Disorders: Suppression of
lactation.
OVERDOSAGE
Treatment should be symptomatic and supportive. Activated charcoal as well as a
cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation (e.g., restlessness, tremor, irritability,
convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
arrhythmia, vomiting, and urinary retention. Other symptoms may include
hypotension or hypertension, respiratory failure, paralysis, and coma.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been
reported in a 13-year-old boy who experienced memory loss, and a 34 year old
woman who developed stupor, followed by disorientation and agitation on
awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both
patients fully recovered with symptomatic treatment.
DOSAGE AND ADMINISTRATION
Adults: The usual dose is one 5-mg tablet two to three times a day. The maximum
recommended dose is one 5-mg tablet four times a day. A lower starting dose of
2.5 mg two or three times a day is recommended for the frail elderly.
Pediatric patients over 5 years of age: The usual dose is one 5-mg tablet two times a
day. The maximum recommended dose is one 5-mg tablet three times a day.
HOW SUPPLIED
DITROPAN® (oxybutynin chloride) Tablets are supplied in bottles of 100 tablets
(NDC 17314-9200-1). Blue scored tablets (5 mg) are engraved with DITROPAN on
one side with 92 and 00, separated by a horizontal score, on the other side.
Pharmacist: Dispense in tight, light-resistant container as defined in the USP.
Store at controlled room temperature 59-86°F (15-30°C).
REFERENCES
1. Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal
subjects. Pharm Res. 1991; 8 (Suppl.): S-320.
2. Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in
plasma, and its application to pharmacokinetic studies in young, elderly and frail
elderly volunteers. Xenobiotica. 1992; 22 (7): 859-869.
3. Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in
Geriatric Patients. J. Urol. 1988; 140: 47-50.
4. Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and
Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Instability.
Drugs & Aging. 1995; 6(3): 243-262.
Manufactured by sanofi-aventis U.S. LLC, Kansas City, MO 64137.
Marketed by Ortho Women’s Health & Urology, Division of Ortho-McNeil-Janssen
Pharmaceuticals, Inc., Raritan, NJ 08869
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(OMP Logo)
Revised
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:17.174390
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017577s035lbl.pdf', 'application_number': 17577, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
11,029
|
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
1
DITROPAN®
(oxybutynin chloride)
Tablets and Syrup
DESCRIPTION
Each scored biconvex, engraved blue DITROPAN (oxybutynin chloride) Tablet contains
5 mg of oxybutynin chloride. Each 5 mL of DITROPAN Syrup contains 5 mg of
oxybutynin chloride. Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-
butynyl phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin
chloride is C22H31NO3•HCl. The structural formula appears below:
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is
readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN Tablets
Also contains: calcium stearate, FD&C Blue #1 Lake, lactose, and microcrystalline
cellulose.
DITROPAN Syrup
Also contains: citric acid, FD&C Green #3, glycerin, methylparaben, flavor, sodium
citrate, sorbitol, sucrose, and water.
DITROPAN Tablets and Syrup are for oral administration.
Therapeutic Category: Antispasmodic, anticholinergic.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits
the muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits
only one fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but
four to ten times the antispasmodic activity. No blocking effects occur at skeletal
neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin chloride increases bladder (vesical) capacity, diminishes
the frequency of uninhibited contractions of the detrusor muscle, and delays the initial
desire to void. Oxybutynin chloride thus decreases urgency and the frequency of both
incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominately in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in vitro
studies.
Pharmacokinetics
Absorption
Following oral administration of DITROPAN, oxybutynin is rapidly absorbed achieving
Cmax within an hour, following which plasma concentration decreases with an effective
half-life of approximately 2 to 3 hours. The absolute bioavailability of oxybutynin is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
2
reported to be about 6% (range 1.6 to 10.9%) for both the tablet and syrup. Wide
interindividual variation in pharmacokinetic parameters is evident following oral
administration of oxybutynin.
The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in
Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar in
shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters
Following Three doses of Ditropan 5 mg administered every 8 hours (n=23)
Parameters (units)
R-oxybutynin
S-oxybutynin
Cmax (ng/mL)
3.6 (2.2)
7.8 (4.1)
Tmax (h)
0.89 (0.34)
0.65 (0.32)
AUCt (ng⋅h/mL)
22.6 (11.3)
35.0 (17.3)
AUCinf (ng⋅h/mL)
24.3 (12.3)
37.3 (18.7)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0
4
8
12
16
20
24
Time (h)
Mean Plasma R-Oxybutynin Concentration
(ng/mL)
Oxybutynin 5 mg TID
Figure 1. Mean R-oxybutynin plasma concentrations following three doses of
DITROPAN 5 mg administered every 8 hours for 1 day in 23 healthy adult volunteers
DITROPAN steady-state pharmacokinetics was also studied in 23 pediatric patients
with detrusor overactivity associated with a neurological condition (e.g., spina bifida).
These pediatric patients were on Ditropan tablets (n=11) with total daily dose ranging
from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg) or Ditropan syrup (n=12) with total daily dose
ranging from 5 mg to 22.5 mg (0.26 to 0.75 mg/kg). Overall, most patients (86.9%) were
taking a total daily Ditropan dose between 10 mg and 15 mg. Sparse sampling
technique was used to obtain serum samples. When all available data are normalized to
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
3
an equivalent of 5 mg twice daily Ditropan, the mean pharmacokinetic parameters
derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in
Table 2a (for tablet) and Table 2b (for syrup). The plasma-time concentration profile for
R- and S-oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin
when all available data are normalized to an equivalent of 5 mg twice daily.
Table 2a
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters
In Children Aged 5-15
Following Administration of 7.5 mg to 15 mg Total Daily Dose of Ditropan Tablets (N=11)
All Available Data Normalized to An Equivalent of Ditropan Tablets 5 mg BID or TID at Steady State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax*(ng/mL)
6.1± 3.2
10.1 ± 7.5
55.4 ± 17.9
28.2 ± 10.0
Tmax (hr)
1.0
1.0
2.0
2.0
AUC**
(ng.hr/mL)
19.8 ± 7.4
28.4 ± 12.7
238.8 ± 77.6
119.5 ± 50.7
*Reflects Cmax for pooled data
**AUC0-end of dosing interval
Table 2b
Mean ± SD R- and S-oxybutynin and R- and S-desethyloxybutynin Pharmacokinetic Parameters
In Children Aged 5-15
Following Administration of 5 mg to 22.5 mg Total Daily Dose of Ditropan Syrup (N=12)
All Available Data Normalized to An Equivalent of Ditropan Syrup 5 mg BID or TID at Steady State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax* (ng/mL)
5.7 ± 6.2
7.3 ± 7.3
54.2 ± 34.0
27.8 ± 20.7
Tmax (hr)
1.0
1.0
1.0
1.0
AUC**
(ng.hr/mL)
16.3 ± 17.1
20.2 ± 20.8
209.1 ± 174.2
99.1 ± 87.5
*Reflects Cmax for pooled data
**AUC0-end of dosing interval
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
4
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Time (h)
Mean R-Oxybutynin Plasma
Concentration (ng/mL)
Ditropan Syrup 5 mg
Ditropan IR Tablet 5 mg
Figure 2. Mean steady-state (±SD) R-oxybutynin plasma concentrations following administration
of total daily Ditropan dose of 5 mg to 30 mg (0.21 mg/kg to 0.77 mg/kg) in children 5-15 years of
age. – Plot represents all available data normalized to the equivalent of Ditropan 5 mg BID or
TID at steady state
Food effects
Data in the literature suggests that oxybutynin solution co-administered with food
resulted in a slight delay in absorption and an increase in its bioavailability by 25%
(n=18).1
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous or
oral administration. The volume of distribution is 193 L after intravenous administration
of 5 mg oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
Clinical Studies
DITROPAN was well tolerated in patients administered the drug in controlled studies of
30 days’ duration and in uncontrolled studies in which some of the patients received the
drug for 2 years.
1 Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal subjects. Pharm Res.
1991; 8 (Suppl.): S-320
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
5
INDICATIONS AND USAGE
DITROPAN (oxybutynin chloride) is indicated for the relief of symptoms of bladder
instability associated with voiding in patients with uninhibited neurogenic or reflex
neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence,
dysuria).
CONTRAINDICATIONS
DITROPAN is contraindicated in patients with urinary retention, gastric retention and
other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle
glaucoma and in patients who are at risk for these conditions.
DITROPAN is also contraindicated in patients who have demonstrated hypersensitivity
to the drug substance or other components of the product.
PRECAUTIONS
General
DITROPAN should be used with caution in the frail elderly, in patients with hepatic or
renal impairment, and in patients with myasthenia gravis.
DITROPAN may aggravate the symptoms of hyperthyroidism, coronary heart disease,
congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia, hypertension,
myasthenia gravis, and prostatic hypertrophy.
Urinary Retention
DITROPAN should be administered with caution to patients with clinically significant
bladder outflow obstruction because of the risk of urinary retention (See
CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN should be administered with caution to patients with gastrointestinal
obstructive disorders because of the risk of gastric retention (see
CONTRAINDICATIONS).
Administration of DITROPAN to patients with ulcerative colitis may suppress intestinal
motility to the point of producing a paralytic ileus and precipitate or aggravate toxic
megacolon, a serious complication of the disease.
DITROPAN, like other anticholinergic drugs, may decrease gastrointestinal motility and
should be used with caution in patients with conditions such as ulcerative colitis, and
intestinal atony.
DITROPAN should be used with caution in patients who have gastroesophageal reflux
and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or
exacerbate esophagitis.
Information for Patients
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
6
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence) or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other agents
which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This may be
of concern for drugs with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 3-4 fold higher
when DITROPAN (oxybutynin chloride) was administered with ketoconazole, a potent
CYP3A4 inhibitor.
Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic
agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin
and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax
and AUC). The clinical relevance of such potential interactions is not known. Caution
should be used when such drugs are co-administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and 160 mg/kg/day
showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50
times the maximum human exposure, based on surface area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella
typhimurium test systems.
Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse
have shown no definite evidence of impaired fertility.
Pregnancy
Category B. Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat,
and mouse have shown no definite evidence of impaired fertility or harm to the animal
fetus. The safety of DITROPAN administered to women who are or who may become
pregnant has not been established. Therefore, DITROPAN should not be given to
pregnant women unless, in the judgment of the physician, the probable clinical benefits
outweigh the possible hazards.
Nursing Mothers
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 DITROPAN 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
NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
7
Pediatric Use
The safety and efficacy of DITROPAN (oxybutynin chloride) administration have been
demonstrated for pediatric patients 5 years of age and older (see DOSAGE AND
ADMINISTRATION).
The safety and efficacy of Ditropan Tablets and Ditropan Syrup were studied in 30 and
in 26 children, respectively, in a 24-week, open-label trial. Patients were aged 5-15
years, all had symptoms of detrusor overactivity in association with a neurological
condition (e.g., spina bifida), all used clean intermittent catheterization, and all were
current users of oxybutynin chloride. Study results demonstrated that the administration
of DITROPAN was associated with improvement in clinical and urodynamic parameters.
At total daily doses ranging from 5 mg to 15 mg, treatment with Ditropan Tablets was
associated with an increase from baseline in mean urine volume per catheterization from
122 mL to 145 mL, an increase from baseline in mean urine volume after morning
awakening from 148 mL to 168 mL, and an increase from baseline in the mean
percentage of catheterizations without a leaking episode from 43% to 61%. Urodynamic
results in these patients were consistent with the clinical results. Treatment with
Ditropan Tablets was associated with an increase from baseline in maximum
cystometric capacity from 230 mL to 279 mL, a decrease from baseline in mean detrusor
pressure at maximum cystometric capacity from 36 cm H20 to 33 cm H20, and a
reduction in the percentage of patients demonstrating uninhibited detrusor contractions
(of at least 15 cm H20) from 39% to 20%.
At total daily doses ranging from 5 mg to 30 mg, treatment with Ditropan Syrup was
associated with an increase from baseline in mean urine volume per catheterization from
113 mL to 133 mL, an increase from baseline in mean urine volume after morning
awakening from 143 mL to 165 mL, and an increase from baseline in the mean
percentage of catheterizations without a leaking episode from 34% to 63%. Urodynamic
results were consistent with these clinical results. Treatment with Ditropan Syrup was
associated with an increase from baseline in maximum cystometric capacity from 192
mL to 294 mL, a decrease from baseline in mean detrusor pressure at maximum
cystometric capacity from 46 cm H20 to 37 cm H20, and a reduction in the percentage of
patients demonstrating uninhibited detrusor contractions (of at least 15 cm H20) from
67% to 28%.
As there is insufficient clinical data for pediatric populations under age 5, DITROPAN is
not recommended for this age group.
Geriatric Use
Clinical studies of DITROPAN did not include sufficient numbers of subjects age 65 and
over to determine whether they respond differently from younger patients. Other
reported clinical experience has not identified differences in responses between healthy
elderly and younger patients; however, a lower initial starting dose of 2.5 mg given 2 or 3
times a day has been recommended for the frail elderly due to a prolongation of the
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NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
8
elimination half-life from 2-3 hours to 5 hours.2,3,4 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
The safety and efficacy of DITROPAN (oxybutynin chloride) was evaluated in a total of
199 patients in three clinical trials comparing DITROPAN with DITROPAN XL (see Table
3). These participants were treated with DITROPAN 5-20 mg/day for up to 6 weeks.
Table 3 shows the incidence of adverse events judged by investigator to be at least
possibly related to treatment and reported by at least 5% of patients.
Table 3
Incidence (%) of Adverse Events Reported by > 5% of Patients
Using DITROPAN (5-20 mg/day)
Body System
Adverse Event
DITROPAN
(5-20
mg/day)
(n=199)
General
Abdominal pain
Headache
6.5%
6.0%
Digestive
Dry mouth
Constipation
Nausea
Dyspepsia
Diarrhea
71.4%
12.6%
10.1%
7.0%
5.0%
Nervous
Dizziness
Somnolence
15.6%
12.6%
Special senses
Blurred vision
9.0%
Urogenital
Urination impaired
Post void residuals increase
Urinary tract infection
10.6%
5.0%
5.0%
The most common adverse events reported by patients receiving DITROPAN 5-20
mg/day were the expected side effects of anticholinergic agents. The incidence of dry
mouth was dose-related.
In addition, the following adverse events were reported by 2 to <5% of patients using
DITROPAN (5-20 mg/day) in all studies. General: asthenia, dry nasal and sinus mucous
2 Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application
to pharmacokinetic studies in young, elderly and frail elderly volunteers. Xenobiotica. 1992; 22 (7): 859-
869.
3 Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in Geriatric Patients. J. Urol.
1988; 140: 47-50
4 Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and Pharmacokinetic Properties, and its
Therapeutic Use in Detrusor Instability. Drugs & Aging. 1995; 6 (3): 243-262.
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NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
9
membranes; Cardiovascular: palpitation; Metabolic and Nutritional System: peripheral
edema; Nervous System: insomnia, nervousness, confusion; Skin: dry skin; Special
Senses: dry eyes, taste perversion.
Other adverse events that have been reported include: tachycardia, hallucinations,
cycloplegia, mydriasis, impotence, suppression of lactation, vasodilatation, rash,
decreased gastrointestinal motility, flatulence, urinary retention, convulsions and
decreased sweating.
OVERDOSAGE
Treatment should be symptomatic and supportive. Activated charcoal as well as a
cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation (e.g., restlessness, tremor, irritability,
convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac arrhythmia,
vomiting, and urinary retention. Other symptoms may include hypotension or
hypertension, respiratory failure, paralysis, and coma.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in
a 13 year old boy who experienced memory loss, and a 34 year old woman who
developed stupor, followed by disorientation and agitation on awakening, dilated pupils,
dry skin, cardiac arrhythmia, and retention of urine. Both patients fully recovered with
symptomatic treatment.
DOSAGE AND ADMINISTRATION
Tablets
Adults: The usual dose is one 5-mg tablet two to three times a day. The maximum
recommended dose is one 5-mg tablet four times a day. A lower starting dose of 2.5 mg
two or three times a day is recommended for the frail elderly.
Pediatric patients over 5 years of age: The usual dose is one 5-mg tablet two times a
day. The maximum recommended dose is one 5-mg tablet three times a day.
Syrup
Adults: The usual dose is one teaspoon (5 mg/5 mL) syrup two to three times a day.
The maximum recommended dose is one teaspoon (5 mg/5 mL) syrup four times a day.
A lower starting dose of 2.5 mg two or three times a day is recommended for the frail
elderly.
Pediatric patients over 5 years of age: The usual dose is one teaspoon (5 mg/5 mL)
syrup two times a day. The maximum recommended dose is one teaspoon (5 mg/5mL)
syrup three times a day.
HOW SUPPLIED
DITROPAN (oxybutynin chloride) Tablets are supplied in bottles of 100 tablets (NDC
17314-9200-1). Blue scored tablets (5 mg) are engraved with DITROPAN on one side
with 92 and 00, separated by a horizontal score, on the other side.
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NDA 17-577 DITROPAN (oxybutynin chloride) Tablets (Final Draft submitted 4/9/2003)
NDA 18-211 DITROPAN (oxybutynin chloride) Syrup (Final Draft submitted 4/9/2003)
10
DITROPAN Syrup (5 mg/5 mL) is supplied in bottles of 16 fluid ounces (473 mL) (NDC
17314-9201-4).
Pharmacist: Dispense in tight, light-resistant container as defined in the USP.
Store at controlled room temperature (59-86°F).
Rx ONLY
Manufactured by Aventis Pharmaceuticals, Inc., Kansas City, MO 64137
Distributed and Marketed by Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ 08869.
Edition: 03/03
50017115
Placeholder for Ortho-
McNeil Pharmaceutical,
Inc. Logo
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
1
DITROPAN XL
(oxybutynin chloride)
Extended Release Tablets
DESCRIPTION
DITROPAN XL® (oxybutynin chloride) is an antispasmodic, anticholinergic agent. Each
DITROPAN XL Extended Release Tablet contains 5 mg, 10 mg or 15 mg of oxybutynin chloride
USP, formulated as a once-a-day controlled-release tablet for oral administration. Oxybutynin
chloride is administered as a racemate of R- and S- enantiomers.
Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl
phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin chloride is
C22H31NO3 • HCl.
Its structural formula is:
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is readily
soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN XL also contains the following inert ingredients: cellulose acetate, hydroxypropyl
methylcellulose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, synthetic
iron oxides, titanium dioxide, polysorbate 80, sodium chloride, and butylated hydroxytoluene.
System Components and Performance
DITROPAN XL uses osmotic pressure to deliver oxybutynin chloride at a controlled rate over
approximately 24 hours. The system, which resembles a conventional tablet in appearance,
comprises an osmotically active bilayer core surrounded by a semipermeable membrane. The
bilayer core is composed of a drug layer containing the drug and excipients, and a push layer
containing osmotically active components. There is a precision-laser drilled orifice in the
semipermeable membrane on the drug-layer side of the tablet. In an aqueous environment, such
as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing
the drug to go into suspension and the push layer to expand. This expansion pushes the
suspended drug out through the orifice. The semipermeable membrane controls the rate at
which water permeates into the tablet core, which in turn controls the rate of drug delivery. The
controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or
gastrointestinal motility. The function of DITROPAN XL depends on the existence of an osmotic
gradient between the contents of the bilayer core and the fluid in the gastrointestinal tract. Since
the osmotic gradient remains constant, drug delivery remains essentially constant. The
biologically inert components of the tablet remain intact during gastrointestinal transit and are
eliminated in the feces as an insoluble shell.
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
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2
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the
muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits only one-fifth
of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the
antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or
autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions characterized by
involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin
increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the
detrusor muscle, and delays the initial desire to void. Oxybutynin thus decreases urgency and
the frequency of both incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominantly in the R-isomer. A metabolite, desethyloxybutynin,
has pharmacological activity similar to that of oxybutynin in in vitro studies.
Pharmacokinetics
Absorption
Following the first dose of DITROPAN XL® (oxybutynin chloride), oxybutynin plasma
concentrations rise for 4 to 6 hours; thereafter steady concentrations are maintained for up to 24
hours, minimizing fluctuations between peak and trough concentrations associated with
oxybutynin.
The relative bioavailabilities of R- and S-oxybutynin from DITROPAN XL are 156% and 187%,
respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R- and S-
oxybutynin are summarized in Table 1. The plasma concentration-time profiles for R- and S-
oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters
Following a Single Dose of DITROPAN XL 10 mg (n=43)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
1.0
(0.6)
1.8
(1.0)
Tmax (h)
12.7
(5.4)
11.8
(5.3)
t1/2 (h)
13.2
(6.2)
12.4
(6.1)
AUC(0-48) (ng⋅h/mL)
18.4
(10.3)
34.2
(16.9)
AUCinf (ng⋅h/mL)
21.3
(12.2)
39.5
(21.2)
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April 3, 2003)
3
Figure 1. Mean R-oxybutynin plasma concentrations following a single dose of DITROPAN XL 10 mg and oxybutynin 5 mg
administered every 8 hours (n=23 for each treatment).
Steady-state oxybutynin plasma concentrations are achieved by Day 3 of repeated DITROPAN
XL® (oxybutynin chloride) dosing, with no observed drug accumulation or change in oxybutynin
and desethyloxybutynin pharmacokinetic parameters.
DITROPAN XL steady-state pharmacokinetics was studied in 19 children aged 5-15 years with
detrusor overactivity associated with a neurological condition (e.g. spina bifida). The children
were on DITROPAN XL total daily dose ranging from 5 to 20 mg (0.10 to 0.77 mg/kg). Sparse
sampling technique was used to obtain serum samples. When all available data are normalized
to an equivalent of 5mg per day Ditropan XL, the mean pharmacokinetic parameters derived for
R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. The plasma-
time concentration profiles for R- and S-oxybutynin are similar in shape; Figure 2 shows the
profile for R-oxybutynin when all available data are normalized to an equivalent of 5 mg per day.
Table 2
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5-15
Following Administration of 5 to 20mg Ditropan XL Once Daily (N=19)
All Available Data Normalized To An Equivalent of Ditropan XL 5 mg Once Daily
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax (ng/mL)
0.7 ± 0.4
1.3 ± 0.8
7.8 ± 3.7
4.2 ± 2.3
Tmax (hr)
5.0
5.0
5.0
5.0
AUC (ng.hr/mL)
12.8 ± 7.0
23.7 ± 14.4
125.1 ± 66.7
73.6 ± 47.7
DITROPAN
XL
10 mg QD
oxybutynin 5 mg TID
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4
Figure 2. Mean steady state (±SD) R-oxybutynin plasma concentrations following administration of 5 to 20
mg Ditropan XL once daily in children aged 5-15. - Plot represents all available data normalized to an
equivalent of Ditropan XL 5 mg once daily
Food Effects
The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted
conditions.
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous or oral
administration. The volume of distribution is 193 L after intravenous administration of 5 mg
oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly
CYP3A4 found mostly in the liver and gut wall. Its metabolic products include
phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which
is pharmacologically active. Following DITROPAN XL administration, plasma concentrations of
R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with
oxybutynin.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose
excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as
the metabolite desethyloxybutynin.
Dose Proportionality
Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following
administration of 5-20 mg of DITROPAN XL are dose proportional.
0.0
0.5
1.0
1.5
2.0
0
5
10
15
20
25
Time (hours)
Mean R-Oxybutynin Plasma
Concentration (ng/ml)
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
5
Special Populations
Geriatric: The pharmacokinetics of DITROPAN XL were similar in all patients studied (up to 78
years of age).
Pediatric: The pharmacokinetics of DITROPAN XL (oxybutynin chloride) were evaluated in 19
children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g.,
spina bifida). The pharmacokinetics of DITROPAN XL in these pediatric patients were consistent
with those reported for adults (see Tables 1 and 2, and Figures 1 and 2 above).
Gender: There are no significant differences in the pharmacokinetics of oxybutynin in healthy
male and female volunteers following administration of DITROPAN XL.
Race: Available data suggest that there are no significant differences in the pharmacokinetics of
oxybutynin based on race in healthy volunteers following administration of DITROPAN XL.
Renal Insufficiency: There is no experience with the use of DITROPAN XL in patients with renal
insufficiency.
Hepatic Insufficiency: There is no experience with the use of DITROPAN XL in patients with
hepatic insufficiency.
Drug-Drug Interactions: See PRECAUTIONS: Drug Interactions.
Clinical Studies
DITROPAN XL was evaluated for the treatment of patients with overactive bladder with
symptoms of urge urinary incontinence, urgency, and frequency in three controlled studies and
one open label study. The majority of patients were Caucasian (89.0%) and female (91.9%) with
a mean age of 59 years (range, 18 to 98 years). Entry criteria required that patients have urge or
mixed incontinence (with a predominance of urge) as evidenced by ≥ 6 urge incontinence
episodes per week and ≥ 10 micturitions per day. Study 1 was a forced dose escalation design,
whereas the other studies used a dose adjustment design in which each patient’s final dose was
adjusted to a balance between improvement of incontinence symptoms and tolerability of side
effects. Controlled studies included patients known to be responsive to oxybutynin or other
anticholinergic medications, and these patients were maintained on a final dose for up to 2
weeks.
The efficacy results for the three controlled trials are presented in the following tables and
figures.
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
7
INDICATIONS AND USAGE
DITROPAN XL® (oxybutynin chloride) is a once-daily controlled-release tablet indicated for the
treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and
frequency.
DITROPAN XL is also indicated in the treatment of pediatric patients aged 6 years and older with
symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida).
CONTRAINDICATIONS
DITROPAN XL is contraindicated in patients with urinary retention, gastric retention and other
severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma and in
patients who are at risk for these conditions.
DITROPAN XL is also contraindicated in patients who have demonstrated hypersensitivity to the
drug substance or other components of the product.
PRECAUTIONS
General
DITROPAN XL should be used with caution in patients with hepatic or renal impairment and in
patients with myasthenia gravis due to the risk of symptom aggravation.
Urinary Retention:
DITROPAN XL should be administered with caution to patients with clinically significant bladder
outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS).
Gastrointestinal Disorders:
DITROPAN XL should be administered with caution to patients with gastrointestinal obstructive
disorders because of the risk of gastric retention (see CONTRAINDICATIONS).
DITROPAN XL, like other anticholinergic drugs, may decrease gastrointestinal motility and
should be used with caution in patients with conditions such as ulcerative colitis and intestinal
atony.
DITROPAN XL should be used with caution in patients who have gastroesophageal reflux and/or
who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate
esophagitis.
As with any other nondeformable material, caution should be used when administering
DITROPAN XL to patients with preexisting severe gastrointestinal narrowing (pathologic or
iatrogenic). There have been rare reports of obstructive symptoms in patients with known
strictures in association with the ingestion of other drugs in nondeformable controlled-release
formulations.
Information for Patients
Patients should be informed that heat prostration (fever and heat stroke due to decreased
sweating) can occur when anticholinergics such as oxybutynin chloride are administered in the
presence of high environmental temperature.
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NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
8
Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence) or
blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic
agents such as oxybutynin.
Patients should be informed that DITROPAN XL® (oxybutynin chloride) should be swallowed
whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication
is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The
tablet shell is eliminated from the body; patients should not be concerned if they occasionally
notice in their stool something that looks like a tablet.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which
produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like
effects may increase the frequency and/or severity of such effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly administered
drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs
with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when
DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors
of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and
miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter
oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of
such potential interactions is not known. Caution should be used when such drugs are co-
administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg/day showed
no evidence of carcinogenicity. These doses are approximately 6, 25 and 50 times the maximum
human exposure, based on surface area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, and Salmonella
typhimurium test systems.
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no
definite evidence of impaired fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category B
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no
definite evidence of impaired fertility or harm to the animal fetus. The safety of DITROPAN XL
administration to women who are or who may become pregnant has not been established.
Therefore, DITROPAN XL should not be given to pregnant women unless, in the judgment of the
physician, the probable clinical benefits outweigh the possible hazards.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
9
Nursing Mothers
It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted
in human milk, caution should be exercised when DITROPAN XL® (oxybutynin chloride) is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN XL were studied in 60 children in a 24-week, open-label
trial. Patients were aged 6-15 years, all had symptoms of detrusor overactivity in association with
a neurological condition (e.g., spina bifida), all used clean intermittent catheterization, and all
were current users of oxybutynin chloride. Study results demonstrated that administration of
DITROPAN XL 5 to 20 mg/day was associated with an increase from baseline in mean urine
volume per catheterization from 108 mL to 136 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 189 mL, and an increase from baseline in the
mean percentage of catheterizations without a leaking episode from 34% to 51%.
Urodynamic results were consistent with clinical results. Administration of DITROPAN XL resulted
in an increase from baseline in mean maximum cystometric capacity from 185 mL to 254 mL, a
decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 cm
H2O to 33 cm H2O, and a reduction in the percentage of patients demonstrating uninhibited
detrusor contractions (of at least 15 cm H2O) from 60% to 28%.
DITROPAN XL is not recommended in pediatric patients who can not swallow the tablet whole
without chewing, dividing, or crushing, or in children under the age of 6 (see DOSAGE AND
ADMINISTRATION).
Geriatric Use
The rate and severity of anticholinergic effects reported by patients less than 65 years old and
those 65 years and older were similar (See CLINICAL PHARMACOLOGY, Pharmacokinetics,
Special Populations: Gender).
ADVERSE REACTIONS
Adverse Events with DITROPAN XL®
The safety and efficacy of DITROPAN XL was evaluated in a total of 580 participants who
received DITROPAN XL in clinical trials (429 patients, 151 healthy volunteers). These
participants were treated with 5-30 mg/day for up to 4.5 months. Safety information is provided
for 429 patients from three controlled clinical studies and one open label study (Table 3). The
adverse events are reported regardless of causality.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
10
Table 3
Incidence (%) of Adverse Events Reported by ≥≥≥≥ 5% of Patients
Using DITROPAN XL (5-30 mg/day)
DITROPAN XL
Body System
Adverse Event
5-30 mg/day
(n=429)
General
headache
9.8
asthenia
6.8
pain
6.8
Digestive
dry mouth
60.8
constipation
13.1
diarrhea
9.1
nausea
8.9
dyspepsia
6.8
Nervous
somnolence
11.9
dizziness
6.3
Respiratory
rhinitis
5.6
Special senses
blurred vision
7.7
dry eyes
6.1
Urogenital
urinary tract infection
5.1
The most common adverse events reported by patients receiving 5-30 mg/day
DITROPAN XL® were the expected side effects of anticholinergic agents. The incidence of dry
mouth was dose-related.
The discontinuation rate for all adverse events was 6.8%. The most frequent adverse event
causing early discontinuation of study medication was nausea (1.9%), while discontinuation due
to dry mouth was 1.2%.
In addition, the following adverse events were reported by 2 to < 5% of patients using DITROPAN
XL (oxybutynin chloride) (5-30 mg/day) in all studies. General: abdominal pain, dry nasal and
sinus mucous membranes, accidental injury, back pain, flu syndrome; Cardiovascular:
hypertension, palpitation, vasodilatation; Digestive: flatulence, gastroesophageal reflux;
Musculoskeletal: arthritis; Nervous: insomnia, nervousness, confusion; Respiratory: upper
respiratory tract infection, cough, sinusitis, bronchitis, pharyngitis; Skin: dry skin, rash; Urogenital:
impaired urination (hesitancy), increased post void residual volume, urinary retention, cystitis.
Additional rare adverse events reported from worldwide post-marketing experience with
DITROPAN XL include: peripheral edema, cardiac arrhythmia, tachycardia, hallucinations,
convulsions, and impotence.
Additional adverse events reported with some other oxybutynin chloride formulations include:
cycloplegia, mydriasis, and suppression of lactation.
OVERDOSAGE
The continuous release of oxybutynin from DITROPAN XL (oxybutynin chloride) should be
considered in the treatment of overdosage. Patients should be monitored for at least 24 hours.
Treatment should be symptomatic and supportive. Activated charcoal as well as a cathartic may
be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects including
central nervous system excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and
urinary retention.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
11
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in a 13
year old boy who experienced memory loss, and a 34 year old woman who developed stupor,
followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia,
and retention of urine. Both patients fully recovered with symptomatic treatment.
DOSAGE AND ADMINISTRATION
DITROPAN XL® must be swallowed whole with the aid of liquids, and must not be chewed,
divided, or crushed.
DITROPAN XL® may be administered with or without food.
Adults: The recommended starting dose of DITROPAN XL® is 5 mg once daily. Dosage may be
adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of
30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals.
Pediatric patients aged 6 years of age and older: The recommended starting dose of DITROPAN
XL is 5 mg once daily. Dosage may be adjusted in 5-mg increments to achieve a balance of
efficacy and tolerability (up to a maximum of 20 mg/day).
HOW SUPPLIED
DITROPAN XL® (oxybutynin chloride) Extended Release Tablets are available in three dosage
strengths, 5 mg (pale yellow), 10 mg (pink) and 15 mg (gray) and are imprinted with
“5 XL”, “10 XL” or “15 XL”. DITROPAN XL® (oxybutynin chloride) Extended Release Tablets are
supplied in bottles of 100 tablets.
5 mg
100 count bottle
NDC 17314-8500-1
10 mg
100 count bottle
NDC 17314-8501-1
15 mg
100 count bottle
NDC 17314-8502-1
Storage
Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room
Temperature]. Protect from moisture and humidity.
Rx only
For more information call 1-888-395-1232 or visit www.DitropanXL.com
Manufactured by
ALZA Corporation, Mountain View, CA 94043.
An ALZA OROS
Technology Product
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 20-897: DITROPAN XL® (oxybutynin chloride) Extended Release Tablets – Revised Final Draft (Submitted
April 3, 2003)
12
DITROPAN XL and OROS are registered trademarks of ALZA Corporation.
Distributed and Marketed by
Ortho-McNeil Pharmaceuticals, Inc., Raritan, NJ 08869.
00096532
Edition: 3/03
Placeholder for Ortho-McNeil
Pharmaceuticals, Inc. Logo
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:17.175908
|
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|
11,030
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1
DITROPAN®
(oxybutynin chloride)
Tablets and Syrup
DESCRIPTION
Each scored biconvex, engraved blue DITROPAN® (oxybutynin chloride) Tablet
contains 5 mg of oxybutynin chloride. Each 5 mL of DITROPAN Syrup contains
5 mg of oxybutynin chloride. Chemically, oxybutynin chloride is d,l (racemic)
4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The empirical
formula of oxybutynin chloride is C22H31NO3•HCl. The structural formula appears
below:
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It
is readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN Tablets also contain calcium stearate, FD&C Blue #1 Lake, lactose, and
microcrystalline cellulose.
DITROPAN Syrup also contains citric acid, FD&C Green #3, glycerin,
methylparaben, flavor, sodium citrate, sorbitol, sucrose, and water.
DITROPAN Tablets and Syrup are for oral administration.
Therapeutic Category: Antispasmodic, anticholinergic.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and
inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin
chloride exhibits only one fifth of the anticholinergic activity of atropine on the rabbit
detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects
occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin chloride increases bladder (vesical) capacity,
diminishes the frequency of uninhibited contractions of the detrusor muscle, and
delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the
frequency of both incontinent episodes and voluntary urination.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Antimuscarinic activity resides predominately in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in
vitro studies.
Pharmacokinetics
Absorption
Following oral administration of DITROPAN, oxybutynin is rapidly absorbed
achieving Cmax within an hour, following which plasma concentration decreases with
an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of
oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for both the tablet and
syrup. Wide interindividual variation in pharmacokinetic parameters is evident
following oral administration of oxybutynin.
The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in
Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar
in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Three Doses of
DITROPAN 5 mg Administered every 8 Hours (n=23)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
3.6 (2.2)
7.8 (4.1)
Tmax (h)
0.89 (0.34)
0.65 (0.32)
AUCt (ng⋅h/mL)
22.6 (11.3)
35.0 (17.3)
AUCinf (ng⋅h/mL)
24.3 (12.3)
37.3 (18.7)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0
4
8
12
16
20
24
Time (h)
Mean Plasma R-Oxybutynin
Concentration (ng/mL)
Oxybutynin 5 mg TID
Figure 1.
Mean R-oxybutynin plasma concentrations following three doses of DITROPAN 5 mg
administered every 8 hours for 1 day in 23 healthy adult volunteers
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3
DITROPAN steady-state pharmacokinetics were also studied in 23 pediatric patients
with detrusor overactivity associated with a neurological condition (e.g., spina bifida).
These pediatric patients were on DITROPAN tablets (n=11) with total daily dose
ranging from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg) or DITROPAN syrup (n=12) with
total daily dose ranging from 5 mg to 22.5 mg (0.26 to 0.75 mg/kg). Overall, most
patients (86.9%) were taking a total daily DITROPAN dose between 10 mg and
15 mg. Sparse sampling technique was used to obtain serum samples. When all
available data are normalized to an equivalent of 5 mg twice daily DITROPAN, the
mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and
S-desethyloxybutynin are summarized in Table 2a (for tablet) and Table 2b (for
syrup). The plasma-time concentration profiles for R- and S-oxybutynin are similar in
shape; Figure 2 shows the profile for R-oxybutynin when all available data are
normalized to an equivalent of 5 mg twice daily.
Table 2a
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
Parameters In Children Aged 5-15 Following Administration of 7.5 mg to 15 mg Total
Daily Dose of DITROPAN Tablets (N=11)
All Available Data Normalized to an Equivalent of DITROPAN Tablets 5 mg BID or TID at Steady
State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax* (ng/mL)
6.1± 3.2
10.1 ± 7.5
55.4 ± 17.9
28.2 ± 10.0
Tmax (hr)
1.0
1.0
2.0
2.0
AUC**
(ng.hr/mL)
19.8 ± 7.4
28.4 ± 12.7
238.8 ± 77.6
119.5 ± 50.7
*Reflects Cmax for pooled data
**AUC0-end of dosing interval
Table 2b
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
Parameters In Children Aged 5-15 Following Administration of 5 mg to 22.5 mg Total
Daily Dose of DITROPAN Syrup (N=12)
All Available Data Normalized to an Equivalent of DITROPAN Syrup 5 mg BID or TID at Steady
State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax
* (ng/mL)
5.7 ± 6.2
7.3 ± 7.3
54.2 ± 34.0
27.8 ± 20.7
Tmax (hr)
1.0
1.0
1.0
1.0
AUC**
(ng.hr/mL)
16.3 ± 17.1
20.2 ± 20.8
209.1 ± 174.2
99.1 ± 87.5
*Reflects Cmax for pooled data
**AUC0-end of dosing interval
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For current labeling information, please visit https://www.fda.gov/drugsatfda
4
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Time (h)
Mean R-Oxybutynin Plasma
Concentration (ng/mL)
DITROPAN Syrup 5 mg
DITROPAN IR Tablet 5 mg
Figure 2.
Mean
steady-state
(±SD)
R-oxybutynin
plasma
concentrations
following
administration of total daily DITROPAN dose of 5 mg to 30 mg (0.21 mg/kg to 0.77
mg/kg) in children 5-15 years of age. – Plot represents all available data normalized
to the equivalent of DITROPAN 5 mg BID or TID at steady state
Food Effects
Data in the literature suggests that oxybutynin solution co-administered with food
resulted in a slight delay in absorption and an increase in its bioavailability by
25% (n=18). 1
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous
or oral administration. The volume of distribution is 193 L after intravenous
administration of 5 mg oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
CLINICAL STUDIES
DITROPAN was well tolerated in patients administered the drug in controlled studies
of 30 days’ duration and in uncontrolled studies in which some of the patients
received the drug for 2 years.
INDICATIONS AND USAGE
DITROPAN® (oxybutynin chloride) is indicated for the relief of symptoms of bladder
instability associated with voiding in patients with uninhibited neurogenic or reflex
neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence,
dysuria).
CONTRAINDICATIONS
DITROPAN® (oxybutynin chloride) is contraindicated in patients with urinary
retention, gastric retention and other severe decreased gastrointestinal motility
conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for
these conditions.
DITROPAN is also contraindicated in patients who have demonstrated
hypersensitivity to the drug substance or other components of the product.
PRECAUTIONS
Central Nervous System Effects
Oxybutynin is associated with anticholinergic central nervous system (CNS) effects
(See ADVERSE REACTIONS). A variety of CNS anticholinergic effects have been
reported, including hallucinations, agitation, confusion and somnolence. Patients
should be monitored for signs of anticholinergic CNS effects, particularly in the first
few months after beginning treatment or increasing the dose. If a patient experiences
anticholinergic CNS effects, dose reduction or drug discontinuation should be
considered.
DITROPAN should be used with caution in patients with preexisting dementia treated
with cholinesterase inhibitors due to the risk of aggravation of symptoms.
General
DITROPAN® (oxybutynin chloride) should be used with caution in the frail elderly,
in patients with hepatic or renal impairment, and in patients with myasthenia gravis.
DITROPAN may aggravate the symptoms of hyperthyroidism, coronary heart
disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia,
hypertension, myasthenia gravis, and prostatic hypertrophy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Urinary Retention
DITROPAN should be administered with caution to patients with clinically
significant bladder outflow obstruction because of the risk of urinary retention
(see CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN should be administered with caution to patients with gastrointestinal
obstructive
disorders
because
of
the
risk
of
gastric
retention
(see CONTRAINDICATIONS).
Administration of DITROPAN to patients with ulcerative colitis may suppress
intestinal motility to the point of producing a paralytic ileus and precipitate or
aggravate toxic megacolon, a serious complication of the disease.
DITROPAN, like other anticholinergic drugs, may decrease gastrointestinal motility
and should be used with caution in patients with conditions such as ulcerative colitis,
and intestinal atony.
DITROPAN should be used with caution in patients who have gastroesophageal
reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can
cause or exacerbate esophagitis.
Information for Patients
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence), or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other
agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such
effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This
may be of concern for drugs with a narrow therapeutic index.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Mean oxybutynin chloride plasma concentrations were approximately 3-4 fold higher
when DITROPAN was administered with ketoconazole, a potent CYP3A4 inhibitor.
Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic
agents
(e.g.,
itraconazole
and
miconazole)
or
macrolide
antibiotics
(e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic
parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions
is not known. Caution should be used when such drugs are co-administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and
160 mg/kg/day showed no evidence of carcinogenicity. These doses are
approximately 6, 25, and 50 times the maximum human exposure, based on surface
area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella
typhimurium test systems.
Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse
have shown no definite evidence of impaired fertility.
Pregnancy
Category B. Reproduction studies using oxybutynin chloride in the hamster, rabbit,
rat, and mouse have shown no definite evidence of impaired fertility or harm to the
animal fetus. The safety of DITROPAN administered to women who are or who may
become pregnant has not been established. Therefore, DITROPAN should not be
given to pregnant women unless, in the judgment of the physician, the probable
clinical benefits outweigh the possible hazards.
Nursing Mothers
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 DITROPAN is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN administration have been demonstrated for
pediatric
patients
5
years
of
age
and
older
(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
8
The safety and efficacy of DITROPAN Tablets and DITROPAN Syrup were studied
in 30 and in 26 children, respectively, in a 24-week, open-label trial. Patients were
aged 5-15 years, all had symptoms of detrusor overactivity in association with a
neurological condition (e.g., spina bifida), all used clean intermittent catheterization,
and all were current users of oxybutynin chloride. Study results demonstrated that the
administration of DITROPAN was associated with improvement in clinical and
urodynamic parameters.
At total daily doses ranging from 5 mg to 15 mg, treatment with DITROPAN Tablets
was associated with an increase from baseline in mean urine volume per
catheterization from 122 mL to 145 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 168 mL, and an increase from
baseline in the mean percentage of catheterizations without a leaking episode from
43% to 61%. Urodynamic results in these patients were consistent with the clinical
results. Treatment with DITROPAN Tablets was associated with an increase from
baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from
baseline in mean detrusor pressure at maximum cystometric capacity from 36 cm
H20 to 33 cm H20, and a reduction in the percentage of patients demonstrating
uninhibited detrusor contractions (of at least 15 cm H20) from 39% to 20%.
At total daily doses ranging from 5 mg to 30 mg, treatment with DITROPAN Syrup
was associated with an increase from baseline in mean urine volume per
catheterization from 113 mL to 133 mL, an increase from baseline in mean urine
volume after morning awakening from 143 mL to 165 mL, and an increase from
baseline in the mean percentage of catheterizations without a leaking episode from
34% to 63%. Urodynamic results were consistent with these clinical results.
Treatment with DITROPAN Syrup was associated with an increase from baseline in
maximum cystometric capacity from 192 mL to 294 mL, a decrease from baseline in
mean detrusor pressure at maximum cystometric capacity from 46 cm H20 to 37 cm
H20, and a reduction in the percentage of patients demonstrating uninhibited detrusor
contractions (of at least 15 cm H20) from 67% to 28%.
As
there
is
insufficient
clinical
data
for
pediatric
populations
under
age 5, DITROPAN is not recommended for this age group.
Geriatric Use
Clinical studies of DITROPAN did not include sufficient numbers of subjects
age 65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses between
healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
given 2 or 3 times a day has been recommended for the frail elderly due to a
prolongation of the elimination half-life from 2-3 hours to 5 hours.2, 3, 4 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
The safety and efficacy of DITROPAN® (oxybutynin chloride) was evaluated in a
total of 199 patients in three clinical trials comparing DITROPAN with DITROPAN
XL (see Table 3). These participants were treated with DITROPAN 5-20 mg/day for
up to 6 weeks. Table 3 shows the incidence of adverse events judged by investigators
to be at least possibly related to treatment and reported by at least 5% of patients.
Table 3
Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using DITROPAN (5-20
mg/day)
Body System
Adverse Event
DITROPAN
(5-20 mg/day) (n=199)
Infections and Infestations
Urinary tract infection
6.5%
Psychiatric Disorders
Insomnia
Nervousness
5.5%
6.5%
Nervous System Disorders
Dizziness
Somnolence
Headache
16.6%
14.0%
7.5%
Eye Disorders
Blurred vision
9.6%
Gastrointestinal Disorders
Dry mouth
Constipation
Nausea
Dyspepsia
71.4%
15.1%
11.6%
6.0%
Renal and Urinary Disorders
Urinary Hesitation
Urinary Retention
8.5%
6.0%
The most common adverse events reported by patients receiving DITROPAN
5-20 mg/day were the expected side effects of anticholinergic agents. The incidence
of dry mouth was dose-related.
In addition, the following adverse events were reported by 1 to <5% of patients using
DITROPAN
(5-20
mg/day)
in
all
studies.
Infections
and
Infestations:
nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection;
Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders:
confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye
Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations,
sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and
Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat,
sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders:
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diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper,
dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue
Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back
pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria,
pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema
peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased,
blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural
Complications: fall.
Postmarketing Surveillance
Because postmarketing adverse events 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 following additional adverse
events have been reported from worldwide postmarketing experience with
DITROPAN: Psychiatric Disorders: psychotic disorder, agitation, hallucinations;
Nervous System Disorders: convulsions; Eye disorders: cycloplegia, mydriasis;
Cardiac
Disorders:
tachycardia;
Gastrointestinal
Disorders:
decreased
gastrointestinal motility; Skin and Subcutaneous Tissue Disorders: rash, decreased
sweating; Renal and Urinary Disorders: impotence; Reproductive system and breast
disorders: Suppression of lactation.
OVERDOSAGE
Treatment should be symptomatic and supportive. Activated charcoal as well as a
cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation (e.g., restlessness, tremor, irritability,
convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac
arrhythmia, vomiting, and urinary retention. Other symptoms may include
hypotension or hypertension, respiratory failure, paralysis, and coma.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been
reported in a 13-year-old boy who experienced memory loss, and a 34 year old
woman who developed stupor, followed by disorientation and agitation on
awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both
patients fully recovered with symptomatic treatment.
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DOSAGE AND ADMINISTRATION
Tablets
Adults: The usual dose is one 5-mg tablet two to three times a day. The maximum
recommended dose is one 5-mg tablet four times a day. A lower starting dose of
2.5 mg two or three times a day is recommended for the frail elderly.
Pediatric patients over 5 years of age: The usual dose is one 5-mg tablet two times a
day. The maximum recommended dose is one 5-mg tablet three times a day.
Syrup
Adults: The usual dose is one teaspoon (5 mg/5 mL) of syrup two to three times a
day. The maximum recommended dose is one teaspoon (5 mg/5 mL) of syrup four
times a day. A lower starting dose of 2.5 mg two or three times a day is recommended
for the frail elderly.
Pediatric patients over 5 years of age: The usual dose is one teaspoon (5 mg/5 mL) of
syrup two times a day. The maximum recommended dose is one teaspoon
(5 mg/5mL) of syrup three times a day.
HOW SUPPLIED
DITROPAN® (oxybutynin chloride) Tablets are supplied in bottles of 100 tablets
(NDC 17314-9200-1). Blue scored tablets (5 mg) are engraved with DITROPAN on
one side with 92 and 00, separated by a horizontal score, on the other side.
DITROPAN Syrup (5 mg/5 mL) is supplied in bottles of 16 fluid ounces (473 mL)
(NDC 17314-9201-4).
Pharmacist: Dispense in tight, light-resistant container as defined in the USP.
Store at controlled room temperature 59-86°F (15-30°C).
REFERENCES
1. Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal
subjects. Pharm Res. 1991; 8 (Suppl.): S-320.
2. Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in
plasma, and its application to pharmacokinetic studies in young, elderly and frail
elderly volunteers. Xenobiotica. 1992; 22 (7): 859-869.
3. Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in
Geriatric Patients. J. Urol. 1988; 140: 47-50.
4. Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and
Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Instability.
Drugs & Aging. 1995; 6(3): 243-262.
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12
RX ONLY
Manufactured by sanofi-aventis U.S. LLC, Kansas City, MO 64137.
Distributed and Marketed by Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ 08869
(OMP Logo)
Revised February 2008
50070622
633-20-616-X
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1
DITROPAN XL®
(oxybutynin chloride)
Extended Release Tablets
DESCRIPTION
DITROPAN XL® (oxybutynin chloride) is an antispasmodic, anticholinergic agent.
Each DITROPAN XL Extended Release Tablet contains 5 mg, 10 mg, or 15 mg of
oxybutynin chloride USP, formulated as a once-a-day controlled-release tablet for
oral administration. Oxybutynin chloride is administered as a racemate of R- and
S-enantiomers.
Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl
phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin
chloride is C22H31NO3 • HCl.
Its structural formula is:
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It
is readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN XL also contains the following inert ingredients: cellulose acetate,
hypromellose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide,
synthetic iron oxides, titanium dioxide, polysorbate 80, sodium chloride, and
butylated hydroxytoluene.
System Components and Performance
DITROPAN XL uses osmotic pressure to deliver oxybutynin chloride at a controlled
rate over approximately 24 hours. The system, which resembles a conventional tablet
in appearance, comprises an osmotically active bilayer core surrounded by a
semipermeable membrane. The bilayer core is composed of a drug layer containing
the drug and excipients, and a push layer containing osmotically active components.
There is a precision-laser drilled orifice in the semipermeable membrane on the
drug-layer side of the tablet. In an aqueous environment, such as the gastrointestinal
tract, water permeates through the membrane into the tablet core, causing the drug to
go into suspension and the push layer to expand. This expansion pushes the
suspended drug out through the orifice. The semipermeable membrane controls the
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rate at which water permeates into the tablet core, which in turn controls the rate of
drug delivery. The controlled rate of drug delivery into the gastrointestinal lumen is
thus independent of pH or gastrointestinal motility. The function of DITROPAN XL
depends on the existence of an osmotic gradient between the contents of the bilayer
core and the fluid in the gastrointestinal tract. Since the osmotic gradient remains
constant, drug delivery remains essentially constant. The biologically inert
components of the tablet remain intact during gastrointestinal transit and are
eliminated in the feces as an insoluble shell.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and
inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin
chloride exhibits only one-fifth of the anticholinergic activity of atropine on the rabbit
detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects
occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin increases bladder (vesical) capacity, diminishes the
frequency of uninhibited contractions of the detrusor muscle, and delays the initial
desire to void. Oxybutynin thus decreases urgency and the frequency of both
incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominantly in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in
vitro studies.
Pharmacokinetics
Absorption
Following the first dose of DITROPAN XL® (oxybutynin chloride), oxybutynin
plasma concentrations rise for 4 to 6 hours; thereafter steady concentrations are
maintained for up to 24 hours, minimizing fluctuations between peak and trough
concentrations associated with oxybutynin.
The relative bioavailabilities of R- and S-oxybutynin from DITROPAN XL are
156% and
187%,
respectively,
compared
with
oxybutynin.
The
mean
pharmacokinetic parameters for R- and S-oxybutynin are summarized in Table 1. The
plasma concentration-time profiles for R- and S-oxybutynin are similar in shape;
Figure 1 shows the profile for R-oxybutynin.
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Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single
Dose of DITROPAN XL 10 mg (n=43)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
1.0
(0.6)
1.8
(1.0)
Tmax (h)
12.7
(5.4)
11.8
(5.3)
t1/2 (h)
13.2
(6.2)
12.4
(6.1)
AUC(0-48) (ng⋅h/mL)
18.4
(10.3)
34.2
(16.9)
AUCinf (ng⋅h/mL)
21.3
(12.2)
39.5
(21.2)
Figure 1.
Mean R-oxybutynin plasma concentrations following a single dose of DITROPAN
XL 10 mg and oxybutynin 5 mg administered every 8 hours (n=23 for each
treatment).
Steady-state oxybutynin plasma concentrations are achieved by Day 3 of repeated
DITROPAN XL dosing, with no observed drug accumulation or change in
oxybutynin and desethyloxybutynin pharmacokinetic parameters.
DITROPAN XL steady-state pharmacokinetics were studied in 19 children aged
5-15 years with detrusor overactivity associated with a neurological condition (e.g.
spina bifida). The children were on DITROPAN XL total daily dose ranging from
5 to 20 mg (0.10 to 0.77 mg/kg). Sparse sampling technique was used to obtain serum
samples. When all available data are normalized to an equivalent of 5 mg per day
DITROPAN XL, the mean pharmacokinetic parameters derived for R- and
S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. The
plasma-time concentration profiles for R- and S-oxybutynin are similar in shape;
Figure 2 shows the profile for R-oxybutynin when all available data are normalized to
an equivalent of 5 mg per day.
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Table 2
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin
Pharmacokinetic Parameters in Children Aged 5-15 Following Administration of
5 to 20 mg DITROPAN XL Once Daily (n=19) All Available Data Normalized to an
Equivalent of DITROPAN XL 5 mg Once Daily
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax (ng/mL)
0.7 ± 0.4
1.3 ± 0.8
7.8 ± 3.7
4.2 ± 2.3
Tmax (hr)
5.0
5.0
5.0
5.0
AUC (ng⋅hr/mL)
12.8 ± 7.0
23.7 ± 14.4
125.1 ± 66.7
73.6 ± 47.7
0.0
0.5
1.0
1.5
2.0
0
5
10
15
20
25
Time (hours)
Mean R-Oxybutynin Plasma
Concentration (ng/ml)
Figure 2.
Mean
steady
state
(±SD)
R-oxybutynin plasma
concentrations
following
administration of 5 to 20 mg DITROPAN XL once daily in children aged 5-15. Plot
represents all available data normalized to an equivalent of DITROPAN XL
5 mg once daily.
Food Effects
The rate and extent of absorption and metabolism of oxybutynin are similar under fed
and fasted conditions.
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous
or oral administration. The volume of distribution is 193 L after intravenous
administration of 5 mg oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active. Following DITROPAN XL
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administration, plasma concentrations of R- and S-desethyloxybutynin are 73% and
92%, respectively, of concentrations observed with oxybutynin.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
Dose Proportionality
Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC)
following administration of 5-20 mg of DITROPAN XL are dose proportional.
Special Populations
Geriatric:
The pharmacokinetics of DITROPAN XL were similar in all patients studied (up to
78 years of age).
Pediatric:
The pharmacokinetics of DITROPAN XL were evaluated in 19 children aged
5-15 years with detrusor overactivity associated with a neurological condition
(e.g., spina bifida). The pharmacokinetics of DITROPAN XL in these pediatric
patients were consistent with those reported for adults (see Tables 1 and 2, and
Figures 1 and 2 above).
Gender:
There are no significant differences in the pharmacokinetics of oxybutynin in healthy
male and female volunteers following administration of DITROPAN XL.
Race:
Available data suggest that there are no significant differences in the
pharmacokinetics of oxybutynin based on race in healthy volunteers following
administration of DITROPAN XL.
Renal Insufficiency:
There is no experience with the use of DITROPAN XL in patients with renal
insufficiency.
Hepatic Insufficiency:
There is no experience with the use of DITROPAN XL in patients with hepatic
insufficiency.
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Drug-Drug Interactions:
See PRECAUTIONS: Drug Interactions.
CLINICAL STUDIES
DITROPAN XL® (oxybutynin chloride) was evaluated for the treatment of patients
with overactive bladder with symptoms of urge urinary incontinence, urgency, and
frequency in three controlled studies and one open label study. The majority of
patients were Caucasian (89.0%) and female (91.9%) with a mean age of 59 years
(range, 18 to 98 years). Entry criteria required that patients have urge or mixed
incontinence (with a predominance of urge) as evidenced by ≥ 6 urge incontinence
episodes per week and ≥ 10 micturitions per day. Study 1 was a fixed dose escalation
design, whereas the other studies used a dose adjustment design in which each
patient’s final dose was adjusted to a balance between improvement of incontinence
symptoms and tolerability of side effects. Controlled studies included patients known
to be responsive to oxybutynin or other anticholinergic medications, and these
patients were maintained on a final dose for up to 2 weeks.
The efficacy results for the three controlled trials are presented in the following tables
and figures.
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INDICATIONS AND USAGE
DITROPAN XL® (oxybutynin chloride) is a once-daily controlled-release tablet
indicated for the treatment of overactive bladder with symptoms of urge urinary
incontinence, urgency, and frequency.
DITROPAN XL is also indicated in the treatment of pediatric patients aged 6 years
and older with symptoms of detrusor overactivity associated with a neurological
condition (e.g., spina bifida).
CONTRAINDICATIONS
DITROPAN XL® (oxybutynin chloride) is contraindicated in patients with urinary
retention, gastric retention and other severe decreased gastrointestinal motility
conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for
these conditions.
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DITROPAN XL is also contraindicated in patients who have demonstrated
hypersensitivity to the drug substance or other components of the product.
PRECAUTIONS
Central Nervous System Effects
Oxybutynin is associated with anticholinergic central nervous system (CNS) effects
(See ADVERSE REACTIONS). A variety of CNS anticholinergic effects have
been reported, including hallucinations, agitation, confusion and somnolence.
Patients should be monitored for signs of anticholinergic CNS effects, particularly in
the first few months after beginning treatment or increasing the dose. If a patient
experiences anticholinergic CNS effects, dose reduction or drug discontinuation
should be considered.
DITROPAN XL should be used with caution in patients with preexisting dementia
treated with cholinesterase inhibitors due to the risk of aggravation of symptoms.
General
DITROPAN XL® (oxybutynin chloride) should be used with caution in patients with
hepatic or renal impairment and in patients with myasthenia gravis due to the risk of
symptom aggravation.
Urinary Retention
DITROPAN XL should be administered with caution to patients with clinically
significant bladder outflow obstruction because of the risk of urinary retention (see
CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN XL should be administered with caution to patients with gastrointestinal
obstructive
disorders
because
of
the
risk
of
gastric
retention
(see
CONTRAINDICATIONS).
DITROPAN XL, like other anticholinergic drugs, may decrease gastrointestinal
motility and should be used with caution in patients with conditions such as ulcerative
colitis and intestinal atony.
DITROPAN XL should be used with caution in patients who have gastroesophageal
reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can
cause or exacerbate esophagitis.
As with any other nondeformable material, caution should be used when
administering DITROPAN XL to patients with preexisting severe gastrointestinal
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narrowing (pathologic or iatrogenic). There have been rare reports of obstructive
symptoms in patients with known strictures in association with the ingestion of other
drugs in nondeformable controlled-release formulations.
Information for Patients
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence) or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Patients should be informed that DITROPAN XL should be swallowed whole with
the aid of liquids. Patients should not chew, divide, or crush tablets. The medication is
contained within a nonabsorbable shell designed to release the drug at a controlled
rate. The tablet shell is eliminated from the body; patients should not be concerned if
they occasionally notice in their stool something that looks like a tablet.
DITROPAN XL should be taken at approximately the same time each day.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other
agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such
effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This
may be of concern for drugs with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher
when
DITROPAN
XL
was
administered
with
ketoconazole,
a
potent
CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system,
such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide
antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean
pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such
potential interactions is not known. Caution should be used when such drugs are
co-administered.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and
160 mg/kg/day showed no evidence of carcinogenicity. These doses are
approximately 6, 25, and 50 times the maximum human exposure, based on surface
area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, and Salmonella
typhimurium test systems.
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit
showed no definite evidence of impaired fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category B
Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit
showed no definite evidence of impaired fertility or harm to the animal fetus. The
safety of DITROPAN XL administration to women who are or who may become
pregnant has not been established. Therefore, DITROPAN XL should not be given to
pregnant women unless, in the judgment of the physician, the probable clinical
benefits outweigh the possible hazards.
Nursing Mothers
It is not known whether oxybutynin is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when DITROPAN XL is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN XL were studied in 60 children in a 24-week,
open-label trial. Patients were aged 6-15 years, all had symptoms of detrusor
overactivity in association with a neurological condition (e.g., spina bifida), all used
clean intermittent catheterization, and all were current users of oxybutynin chloride.
Study results demonstrated that administration of DITROPAN XL 5 to 20 mg/day
was associated with an increase from baseline in mean urine volume per
catheterization from 108 mL to 136 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 189 mL, and an increase from
baseline in the mean percentage of catheterizations without a leaking episode from
34% to 51%.
Urodynamic results were consistent with clinical results. Administration of
DITROPAN XL resulted in an increase from baseline in mean maximum cystometric
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capacity from 185 mL to 254 mL, a decrease from baseline in mean detrusor pressure
at maximum cystometric capacity from 44 cm H2O to 33 cm H2O, and a reduction in
the percentage of patients demonstrating uninhibited detrusor contractions (of at least
15 cm H2O) from 60% to 28%.
DITROPAN XL is not recommended in pediatric patients who can not swallow the
tablet whole without chewing, dividing, or crushing, or in children under the age of
6 (See DOSAGE AND ADMINISTRATION).
Geriatric Use
The rate and severity of anticholinergic effects reported by patients less than 65 years
old
and
those
65
years
and
older
were
similar
(see
CLINICAL
PHARMACOLOGY, Pharmacokinetics, Special Populations: Gender Geriatric).
ADVERSE REACTIONS
Adverse Events with DITROPAN XL
The safety and efficacy of DITROPAN XL® (oxybutynin chloride) was evaluated in a
total of 580 participants who received DITROPAN XL in 4 clinical trials
(429 patients) and four pharmacokinetic studies (151 healthy volunteers). The
429 patients were treated with 5-30 mg/day for up to 4.5 months. Three of the
4 clinical trials allowed dose adjustments based on efficacy and adverse events and
one was a fixed dose escalation design. Safety information is provided for
429 patients from these three controlled clinical studies and one open label study in
the first column of Table 3 below.
Adverse events from two additional fixed dose, active controlled, 12 week treatment
duration, postmarketing studies, in which 576 patients were treated with DITROPAN
XL 10 mg/day, are also listed in Table 3 (second column). The adverse events are
reported regardless of causality.
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Table 3
Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using DITROPAN
XL (5-30 mg/day) and % of Corresponding Adverse Events in Two Fixed Dose
(10mg/day) Studies
DITROPAN XL
DITROPAN XL
Body System
Adverse Event
5-30 mg/day
10 mg/day
(n=429)
(n=576)
General
headache
10
6
asthenia
7
3
pain
7
4
Digestive
dry mouth
61
29
constipation
13
7
diarrhea
9
7
nausea
9
2
dyspepsia
7
5
Nervous
somnolence
12
2
dizziness
6
4
Respiratory
rhinitis
6
2
Special senses
blurred vision
8
1
dry eyes
6
3
Urogenital
urinary tract infection
5
5
The most common adverse events reported by the 429 patients receiving 5-30 mg/day
DITROPAN XL were the expected side effects of anticholinergic agents. The
incidence of dry mouth was dose-related.
The discontinuation rate for all adverse events was 6.8% in the 429 patients from the
4 studies of efficacy and safety who received 5-30 mg/day. The most frequent adverse
event causing early discontinuation of study medication was nausea (1.9%), while
discontinuation due to dry mouth was 1.2%.
In addition, the following adverse events were reported by ≥1 to < 5% of all patients
who received DITROPAN XL in the 6 adjustable and fixed dose efficacy and safety
studies. Infections and infestations: nasopharyngitis, upper respiratory tract infection,
sinusitis,
bronchitis,
cystitis;
Psychiatric
disorders:
insomnia,
depression,
nervousness, confusional state; Nervous System Disorders: dysgeusia; Cardiac
disorders: palpitations; Vascular disorders: hypertension; Respiratory, thoracic and
mediastinal disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat;
Gastrointestinal Disorders: gastroesophageal reflux disease, abdominal pain, loose
stools, flatulence, vomiting; Skin and subcutaneous tissue disorders: dry skin,
pruritis; Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain
in extremity; Renal and urinary disorders: urinary retention, urinary hesitation,
dysuria; General disorders and administration site conditions: fatigue, edema
peripheral, asthenia, chest pain; Investigations: blood pressure increased.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
Postmarketing Surveillance
Because postmarketing 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 following additional adverse
drug reactions have been reported from worldwide postmarketing experience with
DITROPAN XL: Psychiatric Disorders: psychotic disorder, agitation, hallucinations;
Nervous System Disorders: convulsions; Cardiac Disorders: arrhythmia; tachycardia;
Vascular Disorders: flushing; Skin and Subcutaneous Tissue Disorders: rash; Renal
and Urinary Disorders: impotence; Injury, poisoning and procedural complications:
fall.
Additional adverse events reported with some other oxybutynin chloride formulations
include: cycloplegia, mydriasis, and suppression of lactation.
OVERDOSAGE
The continuous release of oxybutynin from DITROPAN XL® (oxybutynin chloride)
should be considered in the treatment of overdosage. Patients should be monitored for
at least 24 hours. Treatment should be symptomatic and supportive. Activated
charcoal as well as a cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation, flushing, fever, dehydration, cardiac
arrhythmia, vomiting, and urinary retention.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been
reported in a 13-year-old boy who experienced memory loss, and a 34-year-old
woman who developed stupor, followed by disorientation and agitation on
awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both
patients fully recovered with symptomatic treatment.
DOSAGE AND ADMINISTRATION
DITROPAN XL® (oxybutynin chloride) must be swallowed whole with the aid of
liquids, and must not be chewed, divided, or crushed.
DITROPAN XL may be administered with or without food.
Adults:
The recommended starting dose of DITROPAN XL is 5 or 10 mg once daily at
approximately the same time each day. Dosage may be adjusted in 5-mg increments
to achieve a balance of efficacy and tolerability (up to a maximum of 30 mg/day). In
general, dosage adjustment may proceed at approximately weekly intervals.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Pediatric Patients Aged 6 Years of Age and Older:
The recommended starting dose of DITROPAN XL is 5 mg once daily at
approximately the same time each day. Dosage may be adjusted in 5-mg increments
to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).
HOW SUPPLIED
DITROPAN XL® (oxybutynin chloride) Extended Release Tablets are available in
three dosage strengths, 5 mg (pale yellow), 10 mg (pink), and 15 mg (gray) and are
imprinted with “5 XL”, “10 XL”, or “15 XL”. DITROPAN XL Extended Release
Tablets are supplied in bottles of 100 tablets.
5 mg
100 count bottle
NDC 17314-8500-1
10 mg
100 count bottle
NDC 17314-8501-1
15 mg
100 count bottle
NDC 17314-8502-1
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature]. Protect from moisture and humidity.
Rx Only
For more information call 1-888-395-1232 or visit www.DITROPANXL.com
Manufactured by
ALZA Corporation, Mountain View, CA 94043
Placeholder for ALZA Corporation Logo
An ALZA OROS®
Technology Product
DITROPAN XL® and OROS® are registered trademarks of ALZA Corporation.
Distributed and Marketed by
Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ 08869.
Placeholder for Ortho-McNeil Pharmaceuticals, Inc. Logo
631-10-800-X
Revised February 2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:17.352613
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017577s034,018211s017,020897s018lbl.pdf', 'application_number': 17577, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,028
|
28-Day Regimen
Rx only Product Logo
Patients should be counseled that this product does not protect against HIV-infection (AIDS) and
other sexually transmitted diseases.
Description
OVCON® 50, 28-Day (norethindrone and ethinyl estradiol tablets, USP) provides a continuous regimen for
oral contraception derived from 21 tablets composed of norethindrone and ethinyl estradiol to be followed
by 7 green tablets of inert ingredients. The chemical name for norethindrone is 17-hydroxy-19-nor-17α
pregn-4-en-20-yn-3-one and for ethinyl estradiol the chemical name is 19-nor-17α-pregna-1,3,5(10)-trien
20-yne-3,17-diol. The structural formulas are: Chemical Structure
The active OVCON 50 tablets contain 1 mg norethindrone and 0.05 mg ethinyl estradiol.
OVCON® 50, 28-Day contains the following inactive ingredients: dibasic calcium phosphate, D&C
Yellow No. 10 (aluminum lake), FD&C Blue No. 1 (aluminum lake), FD&C Yellow No. 6 (aluminum
lake), lactose, magnesium stearate, povidone, sodium starch glycolate, starch (corn), and talc.
CLINICAL PHARMACOLOGY
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of
this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which
increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of
implantation).
INDICATIONS AND USAGE
Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product as
a method of contraception. Oral contraceptive products such as OVCON 50, 28-Day, which contain 50 mcg
of estrogen, should not be used unless medically indicated.
Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy rates for users of
combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive
methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent
use of methods can result in lower failure rates.
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TABLE 1
LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR
OF CONTINUOUS USE OF A METHOD
% of Women Experiencing an Accidental Pregnancy in the First Year of Continuous Use
Method
Lowest Expected*
Typical**
(No contraception)
(85)
(85)
Oral contraceptives
combined
0.1
3***
progestin only
0.5
3***
Diaphragm with spermicidal
6
18
cream or jelly
Spermicides alone (foam, creams,
3
21
jellies and vaginal suppositories)
Vaginal sponge
nulliparous
6
18
multiparous
9
28
IUD
0.8-2.0
3#
Condom without spermicides
2
12
Periodic abstinence
1-9
20
(all methods)
Injectable progestogen
0.3-0.4
0.3-0.4
Implants
6 capsules
0.04
0.04
2 rods
0.03
0.03
Female sterilization
0.2
0.4
Male sterilization
0.1
0.15
Reproduced with permission of the Population Council from J. Trussell, et al: Contraceptive failure in the
United States: An update. Studies in Family Planning, 21(1), January-February 1990.
*The authors’ best guess of the percentage of women expected to experience an accidental pregnancy
among couples who initiate a method (not necessarily for the first time) and who use it consistently and
correctly during the first year if they do not stop for any reason other than pregnancy.
**This term represents “typical” couples who initiate use of a method (not necessarily for the first
time), who experience an accidental pregnancy during the first year if they do not stop use for any
reason other than pregnancy.
***Combined typical rate for both combined and progestin only.
#Combined typical rate for both medicated and nonmedicated IUD.
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the following conditions:
•
Thrombophlebitis or thromboembolic disorders
•
A past history of deep vein thrombophlebitis or thromboembolic disorders
•
Cerebrovascular or coronary artery disease
•
Known or suspected carcinoma of the breast
•
Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
•
Undiagnosed abnormal genital bleeding
•
Cholestatic jaundice of pregnancy or jaundice with prior pill use
•
Hepatic adenomas or carcinomas
•
Known or suspected pregnancy
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WARNINGS
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive
use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite
marked in women over 35 years of age. Women who use oral contraceptives should be strongly
advised not to smoke.
The use of oral contraceptives is associated with increased risk of several serious conditions including
myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the
risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The
risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such
as hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to
these risks.
The information contained in this package insert is principally based on studies carried out in patients who
used oral contraceptives with higher formulations of estrogens and progestogens than those in common use
today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and
progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control
studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a
disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among
nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease.
Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease
between oral contraceptive users and nonusers. The attributable risk does provide information about the
actual occurrence of a disease in the population.* For further information, the reader is referred to a text on
epidemiological methods.
*Adapted from Stadel BB: Oral contraceptives and cardio-vascular disease. N Engl J Med, 1981;305:612
618, 672-677; with author’s permission.
1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS
The physician should be alert to the earliest manifestations of thromboembolic thrombotic disorders as
discussed below. Should any of these occur or be suspected the drug should be discontinued immediately.
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is
primarily in smokers or women with other underlying risk factors for coronary artery disease such as
hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for
current oral contraceptive users has been estimated to be two to six. The risk is very low under the age
of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the
incidence of myocardial infarctions in women in their mid-thirties or older, with smoking accounting for
the majority of excess cases. Mortality rates associated with circulatory disease have been shown to
increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 1) among
women who use oral contraceptives.
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FIGURE 1
CIRCULATORY DISEASE MORTALITY RATES PER 100,000
WOMEN-YEARS BY AGE, SMOKING STATUS AND
ORAL CONTRACEPTIVE USE Graph
Layde PM, Beral V: Further analyses of mortality in oral contraceptive users: Royal College of General
Practitioners’ oral contraception study. (Table 5) Lancet 1981;1:541-546.
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes,
hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol
and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives
have been shown to increase blood pressure among users (see section 9 in WARNINGS). Such increases in
risk factors have been associated with an increased risk of heart disease and the risk increases with the
number of risk factors present. Oral contraceptives must be used with caution in women with
cardiovascular disease risk factors.
b. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives
is well established. Case control studies have found the relative risk of users compared to non-users to be 3
for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary
embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.
Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for
new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not
related to length of use and disappears after pill use is stopped.
A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been
reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have
predisposing conditions is twice that of women without such medical conditions. If feasible, oral
contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery
of a type associated with an increase in risk of thromboembolism and during and following prolonged
immobilization. Since the immediate postpartum period is also associated with an increased risk of
thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in
women who elect not to breastfeed.
c. Cerebrovascular diseases
Oral contraceptives have been shown to increase both the relative and attributable risk of cerebrovascular
events (thrombotic and hemorrhagic strokes); although, in general, the risk is greatest among older (>35
years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and
nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive
users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2
for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for
smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe
hypertension. The attributable risk is also greater in older women.
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d. Dose-related risk of vascular disease from oral contraceptives
A positive association has been observed between the amount of estrogen and progestogen in oral
contraceptives and the risk of vascular disease. A decline in serum high density lipoproteins (HDL) has
been reported with many progestational agents. A decline in serum high density lipoproteins has been
associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL
cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen
and progestogen and the nature and absolute amount of progestogens used in the contraceptive. The amount
of both hormones should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For
any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which
contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the
needs of the individual patient. New acceptors of oral contraceptive agents should be started on
preparations containing 0.05 mg or less of estrogen. Products containing 50 mcg estrogen should be used
only when medically indicated.
e. Persistence of risk
There are two studies which have shown persistence of risk of vascular disease for ever-users of oral
contraceptives. In a study in the United States, the risk of developing myocardial infarction after
discontinuing oral contraceptives persists for at least 9 years for women 40-49 years old who had used oral
contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In
another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years
after discontinuation of oral contraceptives, although excess risk was very small. However, both studies
were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.
2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE
One study gathered data from a variety of sources which have estimated the mortality rate associated with
different methods of contraception at different ages (Table 2).
TABLE 2
ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH
CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN,
BY FERTILITY CONTROL METHOD ACCORDING TO AGE
Age
Method of control
15-19
20-24
25-29
30-34
35-39
40-44
and outcome
No fertility control methods*
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives
0.3
0.5
0.9
1.9
13.8
31.6
nonsmoker**
Oral contraceptives
2.2
3.4
6.6
13.5
51.1
117.2
smoker**
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
*Deaths are birth related
**Deaths are method related
Ory HW: Mortality associated with fertility and fertility control: 1983. Fam Plann Perspect 1983;
15:50-56.
These estimates include the combined risk of death associated with contraceptive methods plus the risk
attributable to pregnancy in the event of method failure. Each method of contraception has its specific
benefits and risk. The study concluded that with the exception of oral contraceptive users 35 and older who
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smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low
and below that associated with childbirth.
The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on
data gathered in the 1970s – but not reported until 1983. However, current clinical practice involves the use
of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women
who do not have the various risk factors listed in this labeling.
Because of these changes in practice and, also, because of some limited new data which suggest that the
risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed
(Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol
1985;66:1-4 and Porter JB, Jick H, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol
1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the
topic in 1989. The Committee concluded that although cardiovascular disease risk may be increased with
oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose
formulations), there are greater potential health risks associated with pregnancy in older women and with
the alternative surgical and medical procedures which may be necessary if such women do not have access
to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking
women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral
contraceptives, should take the lowest possible dose formulation that is effective.
3. CARCINOMA OF THE REPRODUCTIVE ORGANS
Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian,
and cervical cancer in women using oral contraceptives. The overwhelming evidence in the literature
suggests that use of oral contraceptives is not associated with an increase in the risk of developing breast
cancer, regardless of the age and parity of first use or with most of the marketed brands and doses. The
Cancer and Steroid Hormone (CASH) study also showed no latent effect on the risk of breast cancer for at
least a decade following long-term use. A few studies have shown a slightly increased relative risk of
developing breast cancer, although the methodology of these studies, which included differences in
examination of users and nonusers and differences in age at start of use, has been questioned.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical
intraepithelial neoplasia in some populations of women.
However, there continues to be controversy about the extent to which such findings may be due to
differences in sexual behavior and other factors.
In spite of many studies of the relationship between oral contraceptive use and breast cancer and cervical
cancers, a cause-and-effect relationship has not been established.
4. HEPATIC NEOPLASIA
Benign hepatic adenomas are associated with oral contraceptive use, although their occurrence is rare in the
United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3
cases/100,000 for users, a risk that increases after four or more years of use. Rupture of hepatic adenomas
may cause death through intra-abdominal hemorrhage.
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8
years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable
risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million
users.
5. OCULAR LESIONS
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives.
Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset
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of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic
measures should be undertaken immediately.
6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used
oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far
as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early
pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for
pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual
abortion.
It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled
out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the
possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use
should be discontinued if pregnancy is confirmed.
7. GALLBLADDER DISEASE
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral
contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing
gallbladder disease among oral contraceptive users may be minimal.
The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing
lower hormonal doses of estrogens and progestogens.
8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS
Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral
contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower
doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin
resistance, this effect varying with different progestational agents.
However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose.
Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while
taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed
earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been
reported in oral contraceptive users.
9. ELEVATED BLOOD PRESSURE
An increase in blood pressure has been reported in women taking oral contraceptives and this increase is
more likely in older oral contraceptive users and with continued use. Data from the Royal College of
General Practitioners and subsequent randomized trials have shown that the incidence of hypertension
increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease should be
encouraged to use another method of contraception. If women elect to use oral contraceptives, they should
be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be
discontinued. For most women, elevated blood pressure will return to normal after stopping oral
contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.
10. HEADACHE
The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent,
persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.
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11. BLEEDING IRREGULARITIES
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives,
especially during the first three months of use. Nonhormonal causes should be considered and adequate
diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in
the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another
formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.
Women with a history of oligomenorrhea or secondary amenorrhea or young women without regular cycles
prior to taking oral contraceptives may again have irregular bleeding or amenorrhea after discontinuation of
oral contraceptives.
PRECAUTIONS
1. SEXUALLY-TRANSMITTED DISEASES
Patients should be counseled that this product does not protect against HIV infection (AIDS) and
other sexually transmitted diseases.
2. PHYSICAL EXAMINATION AND FOLLOW-UP
It is good medical practice for all women to have annual history and physical examinations, including
women using oral contraceptives. The physical examination, however, may be deferred until after initiation
of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical
examination should include special reference to blood pressure, breasts, abdomen and pelvic organs,
including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent
abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with
a strong family history of breast cancer or who have breast nodules should be monitored with particular
care.
3. LIPID DISORDERS
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral
contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias
more difficult.
4. LIVER FUNCTION
If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid
hormones may be poorly metabolized in patients with impaired liver function.
5. FLUID RETENTION
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and
only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.
6. EMOTIONAL DISORDERS
Women with a history of depression should be carefully observed and the drug discontinued if depression
recurs to a serious degree.
Patients becoming significantly depressed while taking oral contraceptives should stop the medication and
use an alternate method of contraception in an attempt to determine whether the symptom is drug related.
7. CONTACT LENSES
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an
ophthalmologist.
8. DRUG INTERACTIONS
Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been
associated with concomitant use of rifampin. A similar association, though less marked, has been suggested
with barbiturates, phenylbutazone, phenytoin sodium, and possibly with griseofulvin, ampicillin, and
tetracyclines.
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9. INTERACTIONS WITH LABORATORY TESTS
Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased
norepinephrine-induced platelet aggregability.
b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone,
as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin
uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids
and corticoids; however, free or biologically active levels remain unchanged.
e. Triglycerides may be increased.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical
significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.
10. CARCINOGENESIS
See WARNINGS section.
11. PREGNANCY
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.
12. NURSING MOTHERS
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few
adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral
contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and
quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but
to use other forms of contraception until she has completely weaned her child.
13. VOMITING AND/OR DIARRHEA
Although a cause-and-effect relationship has not been clearly established, several cases of oral
contraceptive failure have been reported in association with vomiting and/or diarrhea. If significant
gastrointestinal disturbance occurs in any woman receiving contraceptive steroids, the use of a back-up
method of contraception for the remainder of that cycle is recommended.
14. PEDIATRIC USE
Safety and efficacy of OVCON 50 (norethindrone and ethinyl estradiol tablets, USP) have been established
in women of reproductive age. Safety and efficacy are expected to be the same in postpubertal adolescents
under the age of 16 years and in users ages 16 years and older. Use of this product before menarche is not
indicated.
INFORMATION FOR THE PATIENT
See Patient Labeling Printed Below
ADVERSE REACTIONS
An increased risk of the following serious adverse reactions has been associated with the use of oral
contraceptives (see WARNINGS section):
•
Thrombophlebitis
•
Arterial thromboembolism
•
Pulmonary embolism
•
Myocardial infarction
•
Cerebral hemorrhage
•
Cerebral thrombosis
•
Hypertension
•
Gallbladder disease
•
Hepatic adenomas or benign liver tumors
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There is evidence of an association between the following conditions and the use of oral contraceptives,
although additional confirmatory studies are needed:
•
Mesenteric thrombosis
•
Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral contraceptives and are
believed to be drug related:
•
Nausea
•
Vomiting
•
Gastrointestinal symptoms (such as abdominal cramps and bloating)
•
Breakthrough bleeding
•
Spotting
•
Change in menstrual flow
•
Amenorrhea
•
Temporary infertility after discontinuation of treatment
•
Edema
•
Melasma which may persist
•
Breast changes: tenderness, enlargement, and secretion
•
Change in weight (increase or decrease)
•
Change in cervical ectropion and secretion
•
Possible diminution in lactation when given immediately postpartum
•
Cholestatic jaundice
•
Migraine
•
Rash (allergic)
•
Mental depression
•
Reduced tolerance to carbohydrates
•
Vaginal candidiasis
•
Change in corneal curvature (steepening)
•
Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives, and the association has
been neither confirmed nor refuted:
•
Premenstrual syndrome
•
Cataracts
•
Changes in appetite
•
Cystitis-like syndrome
•
Headache
•
Nervousness
•
Dizziness
•
Hirsutism
•
Loss of scalp hair
•
Erythema multiforme
•
Erythema nodosum
•
Hemorrhagic eruption
•
Vaginitis
•
Porphyria
•
Impaired renal function
•
Hemolytic uremic syndrome
•
Budd-Chiari syndrome
•
Acne
•
Changes in libido
•
Colitis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by
young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.
NONCONTRACEPTIVE HEALTH EFFECTS
The following noncontraceptive health benefits related to the use of oral contraceptives are supported by
epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses
exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.
Effects on menses:
•
Increased menstrual cycle regularity
•
Decreased blood loss and decreased incidence of iron deficiency anemia
•
Decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
•
Decreased incidence of functional ovarian cysts
•
Decreased incidence of ectopic pregnancies
Effects from long-term use:
•
Decreased incidence of fibroadenomas and fibrocystic disease of the breast
•
Decreased incidence of acute pelvic inflammatory disease
•
Decreased incidence of endometrial cancer
•
Decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION
The following is a summary of the instructions given to the patient in the “HOW TO TAKE THE PILL”
section of the DETAILED PATIENT PACKAGE INSERT.
The patient is given instructions in five (5) categories.
1. IMPORTANT POINTS TO REMEMBER: The patient is told (a) that she should take one pill
every day at the same time, (b) many women have spotting or light bleeding or gastric distress
during the first one to three cycles, (c) missing pills can also cause spotting or light bleeding, (d)
she should use a back-up method for contraception if she has vomiting or diarrhea or takes some
concomitant medications, and/or if she has trouble remembering the pill, (e) if she has any other
questions, she should consult her physician.
2. BEFORE SHE STARTS TAKING HER PILLS: She should decide what time of day she wishes to
take the pill, check whether her pill pack has 21 or 28 pills, and note the order in which she should
take the pills (diagrammatic drawings of the pill pack are included in the patient insert).
3. WHEN SHE SHOULD START THE FIRST PACK: The Day-One start is listed as the first choice
and the Sunday start (the Sunday after her period starts) is given as the second choice. If she uses
the Sunday start she should use a back-up method in the first cycle if she has intercourse before
she has taken seven pills.
4. WHAT TO DO DURING THE CYCLE: The patient is advised to take one pill at the same time
every day until the pack is empty. If she is on a 21-day regimen, she should wait seven days to
start the next pack. If she is on the 28-day regimen, she should start the next pack the day after the
last inactive tablet and not wait any days between packs.
5. WHAT TO DO IF SHE MISSES A PILL OR PILLS: The patient is given instructions about what
she should do if she misses one, two or more than two pills at varying times in her cycle for both
the Day-One and the Sunday start. The patient is warned that she may become pregnant if she has
unprotected intercourse in the seven days. To avoid this, she must use another birth control
method such as condom, foam, or sponge in these seven days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
OVCON® 50 (norethindrone and ethinyl estradiol tablets, USP) is available in 28-day regimens. Each
package contains 21 round, yellow tablets of 1.0 mg norethindrone and 0.05 mg ethinyl estradiol, imprinted
with WC on one side and 585 on the other. Each capsule shaped, green tablet in the 28-day regimen
contains inert ingredients and is imprinted with WC on one side and 850 on the other.
OVCON® 50, 28-Day
N 0430-0585-14 Carton of 6 blister cards (dispensers)
Store below 30º C (86º F).
References are available upon request.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT PACKAGE INSERT BRIEF SUMMARY
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect
against HIV infection (AIDS) and other sexually transmitted diseases.
Oral contraceptives, also known as “birth control pills” or “the pill”, are taken to prevent pregnancy and
when taken correctly, have a failure rate of about 1% per year when used without missing any pills. The
typical failure rate of large numbers of pill users is less than 3% per year when women who miss pills are
included.
Oral contraceptive use is associated with certain serious diseases that can be life-threatening or may cause
temporary or permanent disability. The risks associated with taking oral contraceptives increase
significantly if you:
•
Smoke
•
Have high blood pressure, diabetes, high cholesterol
•
Have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the breast or
sex organs, jaundice or malignant or benign liver tumors.
You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive
use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite
marked in women over 35 years of age. Women who use oral contraceptives are strongly advised not
to smoke.
Most side effects of the pill are not serious. The most common such effects are nausea, vomiting, bleeding
between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. These
side effects, especially nausea and vomiting, may subside within the first three months of use.
The serious side effects of the pill occur very infrequently, especially if you are in good health and are
young. However, you should know that the following medical conditions have been associated with or
made worse by the pill:
1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a
blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina
pectoris), or other organs of the body. As mentioned above, smoking increases the risk of heart
attacks and strokes and subsequent serious medical consequences.
2. Liver tumors, which may rupture and cause severe bleeding. A possible but not definite
association has been found with the pill and liver cancer. However, liver cancers are extremely
rare. The chance of developing liver cancer from using the pill is thus even rarer.
3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.
The symptoms associated with these serious side effects are discussed in the Detailed Patient Package
Insert given to you with your supply of pills. Notify your doctor or healthcare provider if you notice any
unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some
anticonvulsants and some antibiotics may decrease oral contraceptive effectiveness.
Studies to date of women taking the pill have not shown an increase in the incidence of cancer of the breast
or cervix. There is, however, insufficient evidence to rule out the possibility that the pill may cause such
cancers.
Taking the pill provides some important noncontraceptive effects. These include less painful menstruation,
less menstrual blood loss and anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining
of the uterus.
Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare
provider will take a medical and family history before prescribing oral contraceptives and will examine
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
you. The physical examination may be delayed to another time if you request it and the healthcare provider
believes that it is a good medical practice to postpone it. You should be reexamined at least once a year
while taking oral contraceptives. The Detailed Patient Package Insert gives you further information which
you should read and discuss with your healthcare professional.
DOSAGE AND ADMINISTRATION
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
SEXUALLY-TRANSMITTED DISEASES
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect
against transmission of HIV (AIDS) and other sexually transmitted diseases such as Chlamydia,
genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE
SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late. The more pills you
miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO
THEIR STOMACH DURING THE FIRST 1–3 PACKS OF PILLS.
If you do feel sick to your stomach, do not stop taking the pill. The problem will usually go away.
If it doesn’t go away, check with your doctor or clinic.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you
make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your
stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, for any reason, or IF YOU TAKE SOME
MEDICINES, including some antibiotics, your pills may not work as well.
Use a back-up method (such as condoms, foam, or sponge) until you check with your doctor or
clinic.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic
about how to make pill-taking easier or about using another method of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN
THIS LEAFLET, call your doctor or clinic.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK:
The 28-pill pack has 21 “active” yellow pills (with hormones) to take for 3 weeks, followed by
1 week of “reminder” green pills (without hormones).
3. BE SURE TO HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms, foam, or sponge) to use as a back
up in case you miss pills.
AN EXTRA, FULL PILL PACK.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Package Illustration
Each of the 21 yellow pills contains norethindrone (1 mg) and ethinyl estradiol (0.05 mg).
Each green pill in the 28-day regimen contains inert ingredients.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic
which is the best day for you. Once you have decided which day you will begin taking your pills,
immediately do the following: remove the Brief Summary from the cellophane pouch and look for the Day
Label Sheet attached; peel the label from the sheet which has the start day printed on the left-hand side;
affix the label to the blister card in the designated location. Take your pill daily in the order indicated by the
week number in the illustration above. Pick a time of day which will be easy to remember.
DAY 1 START:
1. Take the first “active” yellow pill of the first pack during the first 24 hours of your period.
2. You will not need to use a back-up method of birth control, since you are starting the pill at the
beginning of your period.
SUNDAY START:
1. Take the first “active” yellow pill of the first pack on the Sunday after your period starts, even if
you are still bleeding. If your period begins on Sunday, start the pack that same day.
2. Use another method of birth control as a back-up method if you have sex anytime from the
Sunday you start your first pack until the next Sunday (7 days). Condoms, foam, or the sponge are
good back-up methods of birth control.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your
stomach (nausea).
Do not skip pills even if you do not have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
28 pills: Start the next pack on the day after your last “reminder” pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 yellow “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take
2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 yellow “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST
use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7
days.
If you MISS 2 yellow “active” pills in a row in THE 3rd WEEK:
If you are a Day 1 Starter:
1. THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday.
On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.
2. You may not have your period this month but this is expected. However, if you miss your period
2 months in a row, call your doctor or clinic because you might be pregnant.
3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST
use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7
days.
If you MISS 3 OR MORE yellow “active” pills in a row (during the first 3 weeks):
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday.
On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.
2. You may not have your period this month but this is expected. However, if you miss your period 2
months in a row, call your doctor or clinic because you might be pregnant.
3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST
use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7
days.
A REMINDER FOR THOSE ON 28-DAY PACKS:
If you forget any of the 7 green “reminder” pills in Week 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE
MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your doctor or clinic.
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect
against HIV infections (AIDS) and other sexually transmitted diseases
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DETAILED PATIENT PACKAGE INSERT
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect
against HIV infection (AIDS) and other sexually transmitted diseases.
INTRODUCTION
You should not use OVCON 50 (norethindrone and ethinyl estradiol tablets, USP), 28-Day, which contains
higher doses of estrogen than other oral contraceptives, unless specifically recommended by your
healthcare provider.
Any woman who considers using oral contraceptives (the “birth control pill” or “the pill”) should
understand the benefits and risks of using this form of birth control.
Although the oral contraceptives have important advantages over other methods of contraception, they have
certain risks that no other method has and some of these risks may continue after you have stopped using
the oral contraceptive. This booklet will give you much of the information you will need to make this
decision and will also help you determine if you are at risk of developing any of the serious side effects of
the pill. It will tell you how to use the pill properly so that it will be as effective as possible. However, this
booklet is not a replacement for a careful discussion between you and your healthcare professional. You
should discuss the information provided in this booklet with him or her, both when you first start taking the
pill and during your revisits. You should also follow your healthcare professional’s advice with regard to
regular check-ups while you are on the pill.
EFFECTIVENESS OF ORAL CONTRACEPTIVES
Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and are more
effective than other nonsurgical methods of birth control. The chance of becoming pregnant is less than 1%
(1 pregnancy per 100 women per year of use) when the pills are used correctly and no pills are missed.
Typical failure rates are actually 3% per year. The chance of becoming pregnant increases with each missed
pill during a menstrual cycle.
In comparison, typical accidental pregnancy rates for other nonsurgical methods of birth control during the
first year of use are as follows:
IUD: 3%
Diaphragm with spermicides: 18%
Spermicides alone: 21%
Vaginal sponge: 18% to 28%
Condom alone: 12%
Periodic abstinence: 20%
Injectable progestogen: 0.3% to 0.4%
Implants: 0.03% to 0.04%
No methods: 85%.
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive
use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite
marked in women over 35 years of age. Women who use oral contraceptives should not smoke.
Some women should not use the pill. For example, you should not take the pill if you are pregnant or think
you may be pregnant. You should also not use the pill if you have or have ever had any of the following
conditions:
•
A history of heart attack or stroke
•
Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
•
A history of blood clots in the deep veins of your legs
•
Chest pain (angina pectoris)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Known or suspected breast cancer or cancer of the lining of the uterus
•
Unexplained vaginal bleeding (until a diagnosis is reached by your doctor)
•
Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous
use of the pill
•
Liver tumor (benign or cancerous)
Tell your healthcare professional if you have ever had any of these conditions. Your healthcare professional
can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have:
•
Breast nodules, fibrocystic disease of the breast or an abnormal breast x-ray or mammogram
•
Diabetes
•
Elevated cholesterol or triglycerides
•
High blood pressure
•
Migraine or other headaches or epilepsy
•
Mental depression
•
Gallbladder, heart, or kidney disease
•
History of scanty or irregular menstrual periods
Women with any of these conditions should be checked often by their healthcare professional if they
choose to use oral contraceptives.
Also, be sure to inform your doctor or healthcare professional if you smoke or are on any medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risk of developing blood clots
Blood clots and blockage of blood vessels are the most serious side effects of taking oral contraceptives. In
particular, a clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a
sudden blocking of the vessel carrying blood to the lungs. Either of these can cause death or disability.
Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or impaired
vision.
If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness, or
have recently delivered a baby, you may be at risk of developing blood clots. You should consult your
doctor about stopping oral contraceptives three to four weeks before surgery and not taking oral
contraceptives for two weeks after surgery or during bed rest. You should also not take oral contraceptives
soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not
breastfeeding. If you are breastfeeding see the section on breastfeeding in General Precautions.
2. Heart attacks and strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels in
the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of these
conditions can cause death or disability.
Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking and
the use of oral contraceptives greatly increase the chances of developing and dying of heart disease.
3. Gallbladder disease
Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease, although
this risk may be related to pills containing high doses of estrogens.
4. Liver tumors
In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver tumors
can rupture and cause fatal internal bleeding. In addition, a possible, but not definite, association has been
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For current labeling information, please visit https://www.fda.gov/drugsatfda
found with the pill and liver cancers in two studies, in which a few women who developed these very rare
cancers were found to have used oral contraceptives for long periods. However, liver cancers in general are
extremely rare and the chance of developing liver cancer from using the pill is thus even rarer.
5. Cancer of the reproductive organs
There is, at present, no confirmed evidence that oral contraceptives increase the risk of cancer of the
reproductive organs and breasts in human studies. Several studies have found no overall increase in the risk
of developing breast cancer. However, women who use oral contraceptives and have a strong family history
of breast cancer, or who have breast nodules or abnormal mammograms, should be closely followed by
their doctors.
Some studies have found an increase in the incidence of cancer of the cervix in women who use oral
contraceptives. However, this finding may be related to factors other than the use of oral contraceptives.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing certain diseases which
may lead to disability or death. An estimate of the number of deaths associated with different methods of
birth control and pregnancy has been calculated and is shown in the following table.
ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH
CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL
METHOD ACCORDING TO AGE
Age
Method of control
15-19
20-24
25-29
30-34
35-39
40-44
and outcome
No fertility control methods*
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives
0.3
0.5
0.9
1.9
13.8
31.6
nonsmoker**
Oral contraceptives
2.2
3.4
6.6
13.5
51.1
117.2
smoker**
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
*Deaths are birth related
**Deaths are method related
It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7-26
deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was
always lower than that associated with pregnancy for any age group, although over the age of 40, the risk
increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age.
However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds
those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of
death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy
(28/100,000 women) in that age group.
The suggestion that women over 40 who don’t smoke should not take oral contraceptives is based on
information from older high-dose pills and on less selective use of pills than is practiced today.
An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral
contraceptive use by healthy, nonsmoking women over 40 years of age may outweigh the possible risks.
However, all women, especially older women, are cautioned to use the lowest dose pill that is effective.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the above table, the risk of death from any birth control method is less than the risk of childbirth, except
for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do
not smoke.
You should discuss this information with your healthcare professional.
WARNING SIGNALS
If any of these adverse conditions occur while you are taking oral contraceptives, call your doctor
immediately:
•
Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in
the lung)
•
Pain in the calf (indicating a possible clot in the leg)
•
Crushing chest pain or heaviness in the chest (indicating a possible heart attack)
•
Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech,
weakness, or numbness in an arm or leg (indicating a possible stroke)
•
Sudden partial or complete loss of vision (indicating a possible clot in the eye)
•
Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor
or healthcare professional to show you how to examine your breasts)
•
Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
•
Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating
severe depression)
•
Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue, loss of
appetite, dark-colored urine, or light-colored bowel movements (indicating possible liver
problems)
•
Abnormal vaginal bleeding (see SIDE EFFECTS OF ORAL CONTRACEPTIVES, 1. Vaginal
bleeding.)
SIDE EFFECTS OF ORAL CONTRACEPTIVES
In addition to the risks and more serious side effects discussed above (see RISKS OF TAKING ORAL
CONTRACEPTIVES, ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD
OR PREGNANCY and WARNING SIGNALS sections), the following may also occur:
1. Vaginal bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may vary
from slight staining between menstrual periods to breakthrough bleeding which is a flow much like a
regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use,
but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and
usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If
the bleeding occurs in more than one cycle or lasts for more than a few days, talk to your doctor or
healthcare professional.
2. Gastrointestinal effects
The most frequent, unpleasant side effects are nausea and vomiting, stomach cramps, bloating, and a
change in appetite.
3. Contact lenses
If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact your
doctor or healthcare professional.
4. Fluid retention
Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may raise
your blood pressure. If you experience fluid retention, contact your doctor or healthcare professional.
5. Melasma
A spotty darkening of the skin is possible, particularly of the face.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Other side effects
Other side effects may include change in appetite, headache, nervousness, depression, dizziness, loss of
scalp hair, rash, and vaginal infections.
If any of these side effects bother you, call your doctor or healthcare professional.
GENERAL PRECAUTIONS
1. Missed periods and use of oral contraceptives before or during early pregnancy
There may be times when you may not menstruate regularly after you have completed taking a cycle of
pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills for
the next cycle but be sure to inform your healthcare professional before doing so. If you have not taken the
pills daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods,
you may be pregnant. Check with your healthcare professional immediately to determine whether you are
pregnant. Do not continue to take oral contraceptives until you are sure you are not pregnant, but continue
to use another method of contraception.
There is no conclusive evidence that oral contraceptive use is associated with an increase in birth defects,
when taken inadvertently during early pregnancy. Previously, a few studies had reported that oral
contraceptives might be associated with birth defects, but these studies have not been confirmed.
Nevertheless, oral contraceptives or any other drugs should not be used during pregnancy unless clearly
necessary and prescribed by your doctor. You should check with your doctor about risks to your unborn
child of any medication taken during pregnancy.
2. While breastfeeding
If you are breastfeeding, consult your doctor before starting oral contraceptives. Some of the drug will be
passed on to the child in the milk. A few adverse effects on the child have been reported, including
yellowing of the skin (jaundice) and breast enlargement. In addition, oral contraceptives may decrease the
amount and quality of your milk. If possible, do not use oral contraceptives while breastfeeding. You
should use another method of contraception since breastfeeding provides only partial protection from
becoming pregnant and this partial protection decreases significantly as you breastfeed for longer periods
of time. You should consider starting oral contraceptives only after you have weaned your child
completely.
3. Laboratory tests
If you are scheduled for any laboratory tests, tell your doctor you are taking birth control pills. Certain
blood tests may be affected by birth control pills.
4. Drug interactions
Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy or
cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as
barbiturates (for example, phenobarbital) and phenytoin (Dilantin® is one brand of this drug),
phenylbutazone (Butazolidin® is one brand) and possibly ampicillin and tetracyclines (several brand
names). You may need to use an additional method of contraception when you take drugs which can make
oral contraceptives less effective.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
SEXUALLY-TRANSMITTED DISEASES
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect
against transmission of HIV (AIDS) and other sexually transmitted diseases such as Chlamydia,
genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE
SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late. The more pills you
miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO
THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS.
If you do feel sick to your stomach, do not stop taking the pill. The problem will usually go away.
If it doesn’t go away, check with your doctor or clinic.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you
make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your
stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, for any reasons, or IF YOU TAKE SOME
MEDICINES, including some antibiotics, your pills may not work as well.
Use a back-up method (such as condoms, foam, or sponge) until you check with your doctor or
clinic.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your doctor or clinic
about how to make pill-taking easier or about using another method of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN
THIS LEAFLET, call your doctor or clinic.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK
The 28-pill pack has 21 “active” yellow pills (with hormones) to take for 3 weeks, followed by 1
week of “reminder” green pills (without hormones).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Package Illustration
Each of the 21 yellow pills contains norethindrone (1 mg) and ethinyl estradiol (0.05 mg).
Each green pill in the 28-day regimen contains inert ingredients.
3. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms, foam, or sponge) to use as a back
up in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. Decide with your doctor or clinic
which is the best day for you. Once you have decided which day you will begin taking your pills,
immediately do the following: remove the Brief Summary from the cellophane pouch and look for the Day
Label Sheet attached; peel the label from the sheet which has the start day printed on the left-hand side;
affix the label to the blister card in the designated location. Take your pill daily in the order indicated by the
week number in the illustration above. Pick a time of day which will be easy to remember.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DAY 1 START:
1. Take the first “active” yellow pill of the first pack during the first 24 hours of your period.
2. You will not need to use a back-up method of birth control, since you are starting the pill at the
beginning of your period.
SUNDAY START:
1. Take the first “active” yellow pill of the first pack on the Sunday after your period starts, even if
you are still bleeding. If your period begins on Sunday, start the pack that same day.
2. Use another method of birth control as a back-up method if you have sex anytime from the
Sunday you start your first pack until the next Sunday (7 days). Condoms, foam, or the sponge are
good back-up methods of birth control.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to your
stomach (nausea).
Do not skip pills even if you do not have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
21 pills: Wait 7 days to start the next pack. You will probably have your period during that week.
Be sure that no more than 7 days pass between 21-day packs.
28 pills: Start the next pack on the day after your last “reminder” pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 yellow “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take
2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 yellow “active” pills in a row in WEEK 1 or WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST
use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7
days.
If you MISS 2 yellow “active” pills in a row in THE 3rd WEEK:
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday.
On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.
2. You may not have your period this month but this is expected. However, if you miss your period 2
months in a row, call your doctor or clinic because you might be pregnant.
3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST
use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7
days.
If you MISS 3 OR MORE yellow “active” pills in a row (during the first 3 weeks):
1. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday.
On Sunday, THROW OUT the rest of the pack and start a new pack of pills that same day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. You may not have your period this month but this is expected. However, if you miss your period 2
months in a row, call your doctor or clinic because you might be pregnant.
3. You MAY BECOME PREGNANT if you have sex in the 7 days after you miss pills. You MUST
use another birth control method (such as condoms, foam, or sponge) as a back-up for those 7
days.
A REMINDER FOR THOSE ON 28-DAY PACKS:
If you forget any of the 7 green “reminder” pills in Week 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE
MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your doctor or clinic.
GENERAL
1. Pregnancy due to pill failure
The incidence of pill failure resulting in pregnancy is approximately 1% (i.e., one pregnancy per 100
women per year) if taken every day as directed, but more typical failure rates are about 3%. If failure does
occur, the risk to the fetus is minimal.
2. Pregnancy after stopping the pill
There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you
had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone
conception until you begin menstruating regularly once you have stopped taking the pill and desire
pregnancy.
There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon
after stopping the pill.
3. Other
a. Overdosage
Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young
children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact
your poison control center, healthcare professional, or nearest emergency room. KEEP THIS DRUG AND
ALL DRUGS OUT OF THE REACH OF CHILDREN.
b. General medical information
Your healthcare professional will take a medical and family history before prescribing oral contraceptives
and will examine you. The physical examination may be delayed to another time if you request it and the
healthcare provider believes that it is a good medical practice to postpone it. You should be reexamined at
least once a year. Be sure to inform your healthcare professional if there is a family history of any of the
conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare
professional, because this is a time to determine if there are early signs of side effects of oral contraceptive
use.
Do not use this drug for any condition other than the one for which it was prescribed. This drug has been
prescribed specifically for you; do not give it to others who may want birth control pills.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NONCONTRACEPTIVE EFFECTS OF ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of oral contraceptives may provide certain benefits. They are:
•
Menstrual cycles may become more regular
•
Blood flow during menstruation may be lighter and less iron may be lost. Therefore, anemia due
to iron deficiency is less likely to occur.
•
Pain or other symptoms during menstruation may be encountered less frequently
•
Ectopic (tubal) pregnancy may occur less frequently
•
Noncancerous cysts or lumps in the breast may occur less frequently
•
Acute pelvic inflammatory disease may occur less frequently
•
Oral contraceptive use may provide some protection against developing two forms of cancer:
cancer of the ovaries and cancer of the lining of the uterus.
If you want more information about birth control pills, ask your doctor or pharmacist. They have a more
technical leaflet called the Professional Labeling, which you may wish to read. Manufacturers Logo
Manufactured by: Warner Chilcott Company, Inc.
Fajardo, PR 00738
Marketed by: Warner Chilcott (US), Inc.
Rockaway, NJ 07866
1-800-521-8813
0585G082
Revised: July 2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:17.378595
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017576s051lbl.pdf', 'application_number': 17576, 'submission_type': 'SUPPL ', 'submission_number': 51}
|
11,032
|
DITROPAN
(oxybutynin chloride)
Tablets
DESCRIPTION
Each scored biconvex, engraved blue DITROPAN (oxybutynin chloride) Tablet
contains 5 mg of oxybutynin chloride. Chemically, oxybutynin chloride is d,l
(racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The
empirical formula of oxybutynin chloride is C22H31NO3HCl. The structural formula
appears below: structural formula
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It
is readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN Tablets also contain calcium stearate, FD&C Blue #1 Lake, lactose, and
microcrystalline cellulose.
DITROPAN Tablets are for oral administration.
Therapeutic Category: Antispasmodic, anticholinergic.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and
inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin
chloride exhibits only one fifth of the anticholinergic activity of atropine on the rabbit
detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects
occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin chloride increases bladder (vesical) capacity,
diminishes the frequency of uninhibited contractions of the detrusor muscle, and
delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the
frequency of both incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominately in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in
vitro studies.
Reference ID: 2996984
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Absorption
Following oral administration of DITROPAN, oxybutynin is rapidly absorbed
achieving Cmax within an hour, following which plasma concentration decreases with
an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of
oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for the tablets. Wide
interindividual variation in pharmacokinetic parameters is evident following oral
administration of oxybutynin.
The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in
Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar
in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Three Doses of
DITROPAN 5 mg Administered every 8 Hours (n=23)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
3.6 (2.2)
7.8 (4.1)
Tmax (h)
0.89 (0.34)
0.65 (0.32)
AUCt (ngh/mL)
22.6 (11.3)
35.0 (17.3)
AUCinf (ngh/mL)
24.3 (12.3)
37.3 (18.7)
Me
an P
la
sma
R-
Oxyb
ut
ynin
C
once
nt
ration (ng/mL)
0
4
8
12
16
20
24
Time (h)
Figure 1.
Mean R-oxybutynin plasma concentrations following three doses of DITROPAN 5 mg
administered every 8 hours for 1 day in 23 healthy adult volunteers
DITROPAN steady-state pharmacokinetics were also studied in 11 pediatric patients
with detrusor overactivity associated with a neurological condition (e.g., spina bifida).
These pediatric patients were on DITROPAN tablets with total daily dose ranging
from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg). Overall, most patients (86.9%) were
taking a total daily DITROPAN dose between 10 mg and 15 mg. Sparse sampling
Reference ID: 2996984
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
technique was used to obtain serum samples. When all available data are normalized
to an equivalent of 5 mg twice daily DITROPAN, the mean pharmacokinetic
parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are
summarized in Table 2. The plasma-time concentration profiles for R- and S
oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin when
all available data are normalized to an equivalent of 5 mg twice daily.
Table 2
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
Parameters In Children Aged 5-15 Following Administration of 7.5 mg to 15 mg Total
Daily Dose of DITROPAN Tablets (N=11)
All Available Data Normalized to an Equivalent of DITROPAN Tablets 5 mg BID or TID at Steady
State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax* (ng/mL)
6.1± 3.2
10.1 ± 7.5
55.4 ± 17.9
28.2 ± 10.0
Tmax (hr)
1.0
1.0
2.0
2.0
AUC**
19.8 ± 7.4
28.4 ± 12.7
238.8 ± 77.6
119.5 ± 50.7
(ng.hr/mL)
*Reflects Cmax for pooled data
**AUC0-end of dosing interval Mean R-Oxybutynin Plasma Concentration (ng/mL)
Figure 2.
Mean
steady-state
(±SD)
R-oxybutynin
plasma
concentrations
following
administration of total daily DITROPAN Tablet dose of 7.5 mg to 15 mg (0.22
mg/kg to 0.53 mg/kg) in children 5-15 years of age. – Plot represents all available
data normalized to the equivalent of DITROPAN 5 mg BID or TID at steady state
Reference ID: 2996984
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Food Effects
Data in the literature suggests that oxybutynin solution co-administered with food
resulted in a slight delay in absorption and an increase in its bioavailability by
25% (n=18)1.
Distribution
Plasma concentrations of oxybutynin decline biexponentially following intravenous
or oral administration. The volume of distribution is 193 L after intravenous
administration of 5 mg oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
CLINICAL STUDIES
DITROPAN was well tolerated in patients administered the drug in controlled studies
of 30 days’ duration and in uncontrolled studies in which some of the patients
received the drug for 2 years.
INDICATIONS AND USAGE
DITROPAN (oxybutynin chloride) is indicated for the relief of symptoms of bladder
instability associated with voiding in patients with uninhibited neurogenic or reflex
neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence,
dysuria).
CONTRAINDICATIONS
DITROPAN (oxybutynin chloride) is contraindicated in patients with urinary
retention, gastric retention and other severe decreased gastrointestinal motility
conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for
these conditions.
DITROPAN is also contraindicated in patients who have demonstrated
hypersensitivity to the drug substance or other components of the product.
Reference ID: 2996984
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Angioedema of the face, lips, tongue and/or larynx has been reported with
oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema
associated with upper airway swelling may be life-threatening. If involvement of the
tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued
and appropriate therapy and/or measures necessary to ensure a patent airway should
be promptly provided.
PRECAUTIONS
Central Nervous System Effects
Oxybutynin is associated with anticholinergic central nervous system (CNS) effects
(See ADVERSE REACTIONS). A variety of CNS anticholinergic effects have been
reported, including hallucinations, agitation, confusion and somnolence. Patients
should be monitored for signs of anticholinergic CNS effects, particularly in the first
few months after beginning treatment or increasing the dose. If a patient experiences
anticholinergic CNS effects, dose reduction or drug discontinuation should be
considered.
DITROPAN should be used with caution in patients with preexisting dementia treated
with cholinesterase inhibitors due to the risk of aggravation of symptoms.
General
DITROPAN (oxybutynin chloride) should be used with caution in the frail elderly,
in patients with hepatic or renal impairment, and in patients with myasthenia gravis.
DITROPAN may aggravate the symptoms of hyperthyroidism, coronary heart
disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia,
hypertension, myasthenia gravis, and prostatic hypertrophy.
Urinary Retention
DITROPAN should be administered with caution to patients with clinically
significant bladder outflow obstruction because of the risk of urinary retention
(see CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN should be administered with caution to patients with gastrointestinal
obstructive
disorders
because
of
the
risk
of
gastric
retention
(see CONTRAINDICATIONS).
Reference ID: 2996984
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Administration of DITROPAN to patients with ulcerative colitis may suppress
intestinal motility to the point of producing a paralytic ileus and precipitate or
aggravate toxic megacolon, a serious complication of the disease.
DITROPAN, like other anticholinergic drugs, may decrease gastrointestinal motility
and should be used with caution in patients with conditions such as ulcerative colitis,
and intestinal atony.
DITROPAN should be used with caution in patients who have gastroesophageal
reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can
cause or exacerbate esophagitis.
Information for Patients
Patients should be informed that oxybutynin may produce angioedema that could
result in life-threatening airway obstruction. Patients should be advised to promptly
discontinue oxybutynin therapy and seek immediate medical attention if they
experience edema of the tongue, edema of the laryngopharynx, or difficulty
breathing.
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence), or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other
agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such
effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This
may be of concern for drugs with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 3-4 fold higher
when DITROPAN was administered with ketoconazole, a potent CYP3A4 inhibitor.
Reference ID: 2996984
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic
agents
(e.g.,
itraconazole
and
miconazole)
or
macrolide
antibiotics
(e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic
parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions
is not known. Caution should be used when such drugs are co-administered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and
160 mg/kg/day showed no evidence of carcinogenicity. These doses are
approximately 6, 25, and 50 times the maximum human exposure, based on surface
area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella
typhimurium test systems.
Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse
have shown no definite evidence of impaired fertility.
Pregnancy
Category B. Reproduction studies using oxybutynin chloride in the hamster, rabbit,
rat, and mouse have shown no definite evidence of impaired fertility or harm to the
animal fetus. The safety of DITROPAN administered to women who are or who may
become pregnant has not been established. Therefore, DITROPAN should not be
given to pregnant women unless, in the judgment of the physician, the probable
clinical benefits outweigh the possible hazards.
Nursing Mothers
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 DITROPAN is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN administration have been demonstrated for
pediatric
patients
5
years
of
age
and
older
(see
DOSAGE
AND
ADMINISTRATION).
The safety and efficacy of DITROPAN Tablets were studied in 30 children in a 24
week, open-label trial. Patients were aged 5-15 years, all had symptoms of detrusor
overactivity in association with a neurological condition (e.g., spina bifida), all used
clean intermittent catheterization, and all were current users of oxybutynin chloride.
Reference ID: 2996984
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Study results demonstrated that the administration of DITROPAN was associated
with improvement in clinical and urodynamic parameters.
At total daily doses ranging from 5 mg to 15 mg, treatment with DITROPAN Tablets
was associated with an increase from baseline in mean urine volume per
catheterization from 122 mL to 145 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 168 mL, and an increase from
baseline in the mean percentage of catheterizations without a leaking episode from
43% to 61%. Urodynamic results in these patients were consistent with the clinical
results. Treatment with DITROPAN Tablets was associated with an increase from
baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from
baseline in mean detrusor pressure at maximum cystometric capacity from 36 cm
H20 to 33 cm H20, and a reduction in the percentage of patients demonstrating
uninhibited detrusor contractions (of at least 15 cm H20) from 39% to 20%.
As
there
is
insufficient
clinical
data
for
pediatric
populations
under
age 5, DITROPAN is not recommended for this age group.
Geriatric Use
Clinical studies of DITROPAN did not include sufficient numbers of subjects
age 65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses between
healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg
given 2 or 3 times a day has been recommended for the frail elderly due to a
prolongation of the elimination half-life from 2-3 hours to 5 hours.2,3,4 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
The safety and efficacy of DITROPAN (oxybutynin chloride) was evaluated in a
total of 199 patients in three clinical trials. These participants were treated with
DITROPAN 5-20 mg/day for up to 6 weeks. Table 3 shows the incidence of adverse
events judged by investigators to be at least possibly related to treatment and reported
by at least 5% of patients.
Reference ID: 2996984
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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
Table 3
Incidence (%) of Adverse Events Reported by 5% of Patients Using DITROPAN (5-20
mg/day)
Incidence (%
) of Adverse E
vents Rep
orted by ³ 5% of Patients Using DITROPAN (5-20 mg/day)
Infections and Infestations
Urinary tract infection
6.5%
Psychiatric Disorders
Insomnia
5.5%
Nervousness
6.5%
Nervous System Disorders
Dizziness
16.6%
Somnolence
14.0%
Headache
7.5%
Eye Disorders
Blurred vision
9.6%
Gastrointestinal Disorders
Dry mouth
71.4%
Constipation
15.1%
Nausea
11.6%
Dyspepsia
6.0%
Renal and Urinary Disorders
Urinary Hesitation
8.5%
Urinary Retention
6.0%
The most common adverse events reported by patients receiving DITROPAN
5-20 mg/day were the expected side effects of anticholinergic agents. The incidence
of dry mouth was dose-related.
In addition, the following adverse events were reported by 1 to <5% of patients using
DITROPAN
(5-20
mg/day)
in
all
studies.
Infections
and
Infestations:
nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection;
Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders:
confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye
Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations,
sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and
Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat,
sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders:
diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper,
dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue
Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back
pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria,
pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema
peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased,
blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural
Complications: fall.
Postmarketing Surveillance
Because postmarketing adverse events 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 following additional adverse
events have been reported from worldwide postmarketing experience with
Reference ID: 2996984
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DITROPAN: Psychiatric Disorders: psychotic disorder, agitation, hallucination,
memory impairment; Nervous System Disorders: convulsions; Eye Disorders:
cycloplegia, mydriasis; Cardiac Disorders: tachycardia, QT interval prolongation;
Gastrointestinal
Disorders:
decreased
gastrointestinal
motility;
Skin
and
Subcutaneous Tissue Disorders: rash, decreased sweating; Renal and Urinary
Disorders: impotence; Reproductive System and Breast Disorders: Suppression of
lactation; General Disorders and Administration Site Conditions: hypersensitivity
reactions, including angioedema with airway obstruction, urticaria, and face edema;
rare anaphylactic reactions requiring hospitalization for emergency treatment.
OVERDOSAGE
Treatment should be symptomatic and supportive. Activated charcoal as well as a
cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation (e.g., restlessness, tremor, irritability,
convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac
arrhythmia, vomiting, and urinary retention. Other symptoms may include
hypotension or hypertension, respiratory failure, paralysis, and coma.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been
reported in a 13-year-old boy who experienced memory loss, and a 34 year old
woman who developed stupor, followed by disorientation and agitation on
awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both
patients fully recovered with symptomatic treatment.
DOSAGE AND ADMINISTRATION
Adults: The usual dose is one 5-mg tablet two to three times a day. The maximum
recommended dose is one 5-mg tablet four times a day. A lower starting dose of
2.5 mg two or three times a day is recommended for the frail elderly.
Pediatric patients over 5 years of age: The usual dose is one 5-mg tablet two times a
day. The maximum recommended dose is one 5-mg tablet three times a day.
HOW SUPPLIED
DITROPAN (oxybutynin chloride) Tablets are supplied in bottles of 100 tablets
(NDC 17314-9200-1). Blue scored tablets (5 mg) are engraved with DITROPAN on
one side with 92 and 00, separated by a horizontal score, on the other side.
Pharmacist: Dispense in tight, light-resistant container as defined in the USP.
Store at controlled room temperature 59-86°F (15-30°C).
Reference ID: 2996984
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
REFERENCES
1. Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal
subjects. Pharm Res. 1991; 8 (Suppl.): S-320.
2. Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in
plasma, and its application to pharmacokinetic studies in young, elderly and frail
elderly volunteers. Xenobiotica. 1992; 22 (7): 859-869.
3. Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in
Geriatric Patients. J. Urol. 1988; 140: 47-50.
4. Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and
Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Instability.
Drugs & Aging. 1995; 6(3): 243-262.
Manufactured by sanofi-aventis U.S. LLC, Kansas City, MO 64137.
Marketed by Ortho Women’s Health & Urology, Division of Ortho-McNeil-Janssen
Pharmaceuticals, Inc., Raritan, NJ 08869
(OMP Logo)
Revised XXX 2011
Reference ID: 2996984
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:17.678835
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017577s036lbl.pdf', 'application_number': 17577, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
11,033
|
DITROPAN
(oxybutynin chloride)
Tablets
DESCRIPTION
Each scored biconvex, engraved blue DITROPAN (oxybutynin chloride) Tablet
contains 5 mg of oxybutynin chloride. Chemically, oxybutynin chloride is d,l
(racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The
empirical formula of oxybutynin chloride is C22H31NO3HCl. The structural formula
appears below: structural formula
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It
is readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN Tablets also contain calcium stearate, FD&C Blue #1 Lake, lactose, and
microcrystalline cellulose.
DITROPAN Tablets are for oral administration.
Therapeutic Category: Antispasmodic, anticholinergic.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and
inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin
chloride exhibits only one fifth of the anticholinergic activity of atropine on the rabbit
detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects
occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin chloride increases bladder (vesical) capacity,
diminishes the frequency of uninhibited contractions of the detrusor muscle, and
delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the
frequency of both incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominately in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in
vitro studies.
Reference ID: 3059351
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Absorption
Following oral administration of DITROPAN, oxybutynin is rapidly absorbed
achieving Cmax within an hour, following which plasma concentration decreases with
an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of
oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for the tablets. Wide
interindividual variation in pharmacokinetic parameters is evident following oral
administration of oxybutynin.
The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in
Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar
in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Three Doses of
DITROPAN 5 mg Administered every 8 Hours (n=23)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
3.6 (2.2)
7.8 (4.1)
Tmax (h)
0.89 (0.34)
0.65 (0.32)
AUCt (ngh/mL)
22.6 (11.3)
35.0 (17.3)
AUCinf (ngh/mL)
24.3 (12.3)
37.3 (18.7)
Figure 1.
Mean R-oxybutynin plasma concentrations following three doses of DITROPAN 5 mg
administered every 8 hours for 1 day in 23 healthy adult volunteers
gr
aph
0
4
8
12
16
20
24
Time (h)
DITROPAN steady-state pharmacokinetics were also studied in 11 pediatric patients
with detrusor overactivity associated with a neurological condition (e.g., spina bifida).
These pediatric patients were on DITROPAN tablets with total daily dose ranging
from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg). Overall, most patients (86.9%) were
taking a total daily DITROPAN dose between 10 mg and 15 mg. Sparse sampling
technique was used to obtain serum samples. When all available data are normalized
to an equivalent of 5 mg twice daily DITROPAN, the mean pharmacokinetic
Reference ID: 3059351
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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
parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are
summarized in Table 2. The plasma-time concentration profiles for R- and S
oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin when
all available data are normalized to an equivalent of 5 mg twice daily.
Table 2
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
Parameters In Children Aged 5-15 Following Administration of 7.5 mg to 15 mg Total
Daily Dose of DITROPAN Tablets (N=11)
All Available Data Normalized to an Equivalent of DITROPAN Tablets 5 mg BID or TID at Steady
State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax* (ng/mL)
6.1± 3.2
10.1 ± 7.5
55.4 ± 17.9
28.2 ± 10.0
Tmax (hr)
AUC†
1.0
19.8 ± 7.4
1.0
28.4 ± 12.7
2.0
238.8 ± 77.6
2.0
119.5 ± 50.7
(ng.hr/mL)
*Reflects Cmax for pooled data
†AUC0-end of dosing interval
Figure 2.
Mean
steady-state
(±SD)
R-oxybutynin
plasma
concentrations
following
administration of total daily DITROPAN Tablet dose of 7.5 mg to 15 mg (0.22
mg/kg to 0.53 mg/kg) in children 5-15 years of age. – Plot represents all available
data normalized to the equivalent of DITROPAN 5 mg BID or TID at steady state graph
Food Effects
Data in the literature suggests that oxybutynin solution co-administered with food
resulted in a slight delay in absorption and an increase in its bioavailability by
25% (n=18).1
Reference ID: 3059351
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Distribution
Oxybutynin is widely distributed in body tissues following systemic absorption. The
volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin
chloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma
proteins. Both enantiomers of desethyloxybutynin are also highly bound (>97%) to
plasma proteins. The major binding protein is alpha-1 acid glycoprotein.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
CLINICAL STUDIES
DITROPAN was well tolerated in patients administered the drug in controlled studies
of 30 days’ duration and in uncontrolled studies in which some of the patients
received the drug for 2 years.
INDICATIONS AND USAGE
DITROPAN (oxybutynin chloride) is indicated for the relief of symptoms of bladder
instability associated with voiding in patients with uninhibited neurogenic or reflex
neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence,
dysuria).
CONTRAINDICATIONS
DITROPAN (oxybutynin chloride) is contraindicated in patients with urinary
retention, gastric retention and other severe decreased gastrointestinal motility
conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for
these conditions.
DITROPAN is also contraindicated in patients who have demonstrated
hypersensitivity to the drug substance or other components of the product.
WARNINGS
Angioedema of the face, lips, tongue and/or larynx has been reported with
oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema
Reference ID: 3059351
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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
associated with upper airway swelling may be life-threatening. If involvement of the
tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued
and appropriate therapy and/or measures necessary to ensure a patent airway should
be promptly provided.
PRECAUTIONS
Central Nervous System Effects
Oxybutynin is associated with anticholinergic central nervous system (CNS) effects
(See ADVERSE REACTIONS). A variety of CNS anticholinergic effects have been
reported, including hallucinations, agitation, confusion and somnolence. Patients
should be monitored for signs of anticholinergic CNS effects, particularly in the first
few months after beginning treatment or increasing the dose. If a patient experiences
anticholinergic CNS effects, dose reduction or drug discontinuation should be
considered.
DITROPAN should be used with caution in patients with preexisting dementia treated
with cholinesterase inhibitors due to the risk of aggravation of symptoms.
General
DITROPAN (oxybutynin chloride) should be used with caution in the frail elderly,
in patients with hepatic or renal impairment, and in patients with myasthenia gravis.
DITROPAN may aggravate the symptoms of hyperthyroidism, coronary heart
disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia,
hypertension, myasthenia gravis, and prostatic hypertrophy.
Urinary Retention
DITROPAN should be administered with caution to patients with clinically
significant bladder outflow obstruction because of the risk of urinary retention
(see CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN should be administered with caution to patients with gastrointestinal
obstructive
disorders
because
of
the
risk
of
gastric
retention
(see CONTRAINDICATIONS).
Administration of DITROPAN to patients with ulcerative colitis may suppress
intestinal motility to the point of producing a paralytic ileus and precipitate or
aggravate toxic megacolon, a serious complication of the disease.
5
Reference ID: 3059351
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DITROPAN, like other anticholinergic drugs, may decrease gastrointestinal motility
and should be used with caution in patients with conditions such as ulcerative colitis,
and intestinal atony.
DITROPAN should be used with caution in patients who have gastroesophageal
reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can
cause or exacerbate esophagitis.
Information for Patients
Patients should be informed that oxybutynin may produce angioedema that could
result in life-threatening airway obstruction. Patients should be advised to promptly
discontinue oxybutynin therapy and seek immediate medical attention if they
experience edema of the tongue, edema of the laryngopharynx, or difficulty
breathing.
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence), or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other
agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such
effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This
may be of concern for drugs with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 3-4 fold higher
when DITROPAN was administered with ketoconazole, a potent CYP3A4 inhibitor.
Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic
agents
(e.g.,
itraconazole
and
miconazole)
or
macrolide
antibiotics
(e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic
parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions
is not known. Caution should be used when such drugs are co-administered.
6
Reference ID: 3059351
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and
160 mg/kg/day showed no evidence of carcinogenicity. These doses are
approximately 6, 25, and 50 times the maximum human exposure, based on surface
area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella
typhimurium test systems.
Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse
have shown no definite evidence of impaired fertility.
Pregnancy
Category B. Reproduction studies using oxybutynin chloride in the hamster, rabbit,
rat, and mouse have shown no definite evidence of impaired fertility or harm to the
animal fetus. The safety of DITROPAN administered to women who are or who may
become pregnant has not been established. Therefore, DITROPAN should not be
given to pregnant women unless, in the judgment of the physician, the probable
clinical benefits outweigh the possible hazards.
Nursing Mothers
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 DITROPAN is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN administration have been demonstrated for
pediatric
patients
5
years
of
age
and
older
(see
DOSAGE
AND
ADMINISTRATION).
The safety and efficacy of DITROPAN Tablets were studied in 30 children in a 24
week, open-label trial. Patients were aged 5-15 years, all had symptoms of detrusor
overactivity in association with a neurological condition (e.g., spina bifida), all used
clean intermittent catheterization, and all were current users of oxybutynin chloride.
Study results demonstrated that the administration of DITROPAN was associated
with improvement in clinical and urodynamic parameters.
At total daily doses ranging from 5 mg to 15 mg, treatment with DITROPAN Tablets
was associated with an increase from baseline in mean urine volume per
catheterization from 122 mL to 145 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 168 mL, and an increase from
Reference ID: 3059351
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
baseline in the mean percentage of catheterizations without a leaking episode from
43% to 61%. Urodynamic results in these patients were consistent with the clinical
results. Treatment with DITROPAN Tablets was associated with an increase from
baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from
baseline in mean detrusor pressure at maximum cystometric capacity from 36 cm
H20 to 33 cm H20, and a reduction in the percentage of patients demonstrating
uninhibited detrusor contractions (of at least 15 cm H20) from 39% to 20%.
As
there
is
insufficient
clinical
data
for
pediatric
populations
under
age 5, DITROPAN is not recommended for this age group.
Geriatric Use
Clinical studies of DITROPAN did not include sufficient numbers of subjects
age 65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses between
healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg
given 2 or 3 times a day has been recommended for the frail elderly due to a
prolongation of the elimination half-life from 2-3 hours to 5 hours.2,3,4 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
The safety and efficacy of DITROPAN (oxybutynin chloride) was evaluated in a
total of 199 patients in three clinical trials. These participants were treated with
DITROPAN 5-20 mg/day for up to 6 weeks. Table 3 shows the incidence of adverse
events judged by investigators to be at least possibly related to treatment and reported
by at least 5% of patients.
8
Reference ID: 3059351
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3
Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using DITROPAN (5-20
mg/day)
Body System
Adverse Event
DITROPAN
(5-20 mg/day) (n=199)
Infections and Infestations
Urinary tract infection
6.5%
Psychiatric Disorders
Insomnia
5.5%
Nervousness
6.5%
Nervous System Disorders
Dizziness
16.6%
Somnolence
14.0%
Headache
7.5%
Eye Disorders
Blurred vision
9.6%
Gastrointestinal Disorders
Dry mouth
71.4%
Constipation
15.1%
Nausea
11.6%
Dyspepsia
6.0%
Renal and Urinary Disorders
Urinary Hesitation
8.5%
Urinary Retention
6.0%
The most common adverse events reported by patients receiving DITROPAN
5-20 mg/day were the expected side effects of anticholinergic agents. The incidence
of dry mouth was dose-related.
In addition, the following adverse events were reported by 1 to <5% of patients using
DITROPAN
(5-20
mg/day)
in
all
studies.
Infections
and
Infestations:
nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection;
Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders:
confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye
Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations,
sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and
Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat,
sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders:
diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper,
dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue
Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back
pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria,
pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema
peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased,
blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural
Complications: fall.
Postmarketing Surveillance
Because postmarketing adverse events 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 following additional adverse
events have been reported from worldwide postmarketing experience with
Reference ID: 3059351
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DITROPAN: Psychiatric Disorders: psychotic disorder, agitation, hallucination,
memory impairment; Nervous System Disorders: convulsions; Eye Disorders:
cycloplegia, mydriasis; Cardiac Disorders: tachycardia, QT interval prolongation;
Gastrointestinal
Disorders:
decreased
gastrointestinal
motility;
Skin
and
Subcutaneous Tissue Disorders: rash, decreased sweating; Renal and Urinary
Disorders: impotence; Reproductive System and Breast Disorders: Suppression of
lactation; General Disorders and Administration Site Conditions: hypersensitivity
reactions, including angioedema with airway obstruction, urticaria, and face edema;
rare anaphylactic reactions requiring hospitalization for emergency treatment.
OVERDOSAGE
Treatment should be symptomatic and supportive. Activated charcoal as well as a
cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation (e.g., restlessness, tremor, irritability,
convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac
arrhythmia, vomiting, and urinary retention. Other symptoms may include
hypotension or hypertension, respiratory failure, paralysis, and coma.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been
reported in a 13-year-old boy who experienced memory loss, and a 34-year-old
woman who developed stupor, followed by disorientation and agitation on
awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both
patients fully recovered with symptomatic treatment.
DOSAGE AND ADMINISTRATION
Adults
The usual dose is one 5-mg tablet two to three times a day. The maximum
recommended dose is one 5-mg tablet four times a day. A lower starting dose of
2.5 mg two or three times a day is recommended for the frail elderly.
Pediatric patients over 5 years of age
The usual dose is one 5-mg tablet two times a day. The maximum recommended dose
is one 5-mg tablet three times a day.
HOW SUPPLIED
DITROPAN (oxybutynin chloride) Tablets are supplied in bottles of 100 tablets
(NDC 17314-9200-1). Blue scored tablets (5 mg) are engraved with DITROPAN on
one side with 92 and 00, separated by a horizontal score, on the other side.
Pharmacist: Dispense in tight, light-resistant container as defined in the USP.
Reference ID: 3059351
10
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 59-86°F (15-30°C).
REFERENCES
1. Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal
subjects. Pharm Res. 1991; 8 (Suppl.): S-320.
2. Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in
plasma, and its application to pharmacokinetic studies in young, elderly and frail
elderly volunteers. Xenobiotica. 1992; 22 (7): 859-869.
3. Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in
Geriatric Patients. J. Urol. 1988; 140: 47-50.
4. Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and
Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Instability.
Drugs & Aging. 1995; 6(3): 243-262.
Manufactured by sanofi-aventis U.S. LLC, Kansas City, MO 64137.
Marketed by Ortho Women’s Health & Urology, Division of Ortho-McNeil-Janssen
Pharmaceuticals, Inc., Raritan, NJ 08869
(OMP Logo)
Revised December 2011
Reference ID: 3059351
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:17.749414
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017577s037lbl.pdf', 'application_number': 17577, 'submission_type': 'SUPPL ', 'submission_number': 37}
|
11,034
|
DITROPAN
(oxybutynin chloride)
Tablets
DESCRIPTION
Each scored biconvex, engraved blue DITROPAN (oxybutynin chloride) Tablet
contains 5 mg of oxybutynin chloride. Chemically, oxybutynin chloride is d,l
(racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The
empirical formula of oxybutynin chloride is C22H31NO3HCl. The structural formula
appears below: structural formula
Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It
is readily soluble in water and acids, but relatively insoluble in alkalis.
DITROPAN Tablets also contain calcium stearate, FD&C Blue #1 Lake, lactose, and
microcrystalline cellulose.
DITROPAN Tablets are for oral administration.
Therapeutic Category: Antispasmodic, anticholinergic.
CLINICAL PHARMACOLOGY
Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and
inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin
chloride exhibits only one fifth of the anticholinergic activity of atropine on the rabbit
detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects
occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions
characterized by involuntary bladder contractions, cystometric studies have
demonstrated that oxybutynin chloride increases bladder (vesical) capacity,
diminishes the frequency of uninhibited contractions of the detrusor muscle, and
delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the
frequency of both incontinent episodes and voluntary urination.
Antimuscarinic activity resides predominately in the R-isomer. A metabolite,
desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in
vitro studies.
1
Reference ID: 3105471
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Absorption
Following oral administration of DITROPAN, oxybutynin is rapidly absorbed
achieving Cmax within an hour, following which plasma concentration decreases with
an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of
oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for the tablets. Wide
interindividual variation in pharmacokinetic parameters is evident following oral
administration of oxybutynin.
The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in
Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar
in shape; Figure 1 shows the profile for R-oxybutynin.
Table 1
Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Three Doses of
DITROPAN 5 mg Administered every 8 Hours (n=23)
Parameters (units)
R-Oxybutynin
S-Oxybutynin
Cmax (ng/mL)
3.6 (2.2)
7.8 (4.1)
Tmax (h)
0.89 (0.34)
0.65 (0.32)
AUCt (ngh/mL)
22.6 (11.3)
35.0 (17.3)
AUCinf (ngh/mL)
24.3 (12.3)
37.3 (18.7)
Figure 1.
Mean R-oxybutynin plasma concentrations following three doses of DITROPAN 5 mg
administered every 8 hours for 1 day in 23 healthy adult volunteers
gr
aph
0
4
8
12
16
20
24
Time (h)
DITROPAN steady-state pharmacokinetics were also studied in 11 pediatric patients
with detrusor overactivity associated with a neurological condition (e.g., spina bifida).
These pediatric patients were on DITROPAN tablets with total daily dose ranging
from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg). Overall, most patients (86.9%) were
taking a total daily DITROPAN dose between 10 mg and 15 mg. Sparse sampling
technique was used to obtain serum samples. When all available data are normalized
to an equivalent of 5 mg twice daily DITROPAN, the mean pharmacokinetic
Reference ID: 3105471
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are
summarized in Table 2. The plasma-time concentration profiles for R- and S
oxybutynin are similar in shape; Figure 2 shows the profile for R-oxybutynin when
all available data are normalized to an equivalent of 5 mg twice daily.
Table 2
Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic
Parameters In Children Aged 5-15 Following Administration of 7.5 mg to 15 mg Total
Daily Dose of DITROPAN Tablets (N=11)
All Available Data Normalized to an Equivalent of DITROPAN Tablets 5 mg BID or TID at Steady
State
R-Oxybutynin
S-Oxybutynin
R- Desethyloxybutynin
S- Desethyloxybutynin
Cmax* (ng/mL)
6.1± 3.2
10.1 ± 7.5
55.4 ± 17.9
28.2 ± 10.0
Tmax (hr)
AUC†
1.0
19.8 ± 7.4
1.0
28.4 ± 12.7
2.0
238.8 ± 77.6
2.0
119.5 ± 50.7
(ng.hr/mL)
*Reflects Cmax for pooled data
†AUC0-end of dosing interval
Figure 2.
Mean
steady-state
(±SD)
R-oxybutynin
plasma
concentrations
following
administration of total daily DITROPAN Tablet dose of 7.5 mg to 15 mg (0.22
mg/kg to 0.53 mg/kg) in children 5-15 years of age. – Plot represents all available
data normalized to the equivalent of DITROPAN 5 mg BID or TID at steady state graph
Food Effects
Data in the literature suggests that oxybutynin solution co-administered with food
resulted in a slight delay in absorption and an increase in its bioavailability by
25% (n=18).1
Reference ID: 3105471
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Distribution
Oxybutynin is widely distributed in body tissues following systemic absorption. The
volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin
chloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma
proteins. Both enantiomers of desethyloxybutynin are also highly bound (>97%) to
plasma proteins. The major binding protein is alpha-1 acid glycoprotein.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems,
particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products
include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and
desethyloxybutynin, which is pharmacologically active.
Excretion
Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the
administered dose excreted unchanged in the urine. Also, less than 0.1% of the
administered dose is excreted as the metabolite desethyloxybutynin.
CLINICAL STUDIES
DITROPAN was well tolerated in patients administered the drug in controlled studies
of 30 days’ duration and in uncontrolled studies in which some of the patients
received the drug for 2 years.
INDICATIONS AND USAGE
DITROPAN (oxybutynin chloride) is indicated for the relief of symptoms of bladder
instability associated with voiding in patients with uninhibited neurogenic or reflex
neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence,
dysuria).
CONTRAINDICATIONS
DITROPAN (oxybutynin chloride) is contraindicated in patients with urinary
retention, gastric retention and other severe decreased gastrointestinal motility
conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for
these conditions.
DITROPAN is also contraindicated in patients who have demonstrated
hypersensitivity to the drug substance or other components of the product.
WARNINGS
Angioedema of the face, lips, tongue and/or larynx has been reported with
oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema
Reference ID: 3105471
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
associated with upper airway swelling may be life-threatening. If involvement of the
tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued
and appropriate therapy and/or measures necessary to ensure a patent airway should
be promptly provided.
PRECAUTIONS
Central Nervous System Effects
Oxybutynin is associated with anticholinergic central nervous system (CNS) effects
(See ADVERSE REACTIONS). A variety of CNS anticholinergic effects have been
reported, including hallucinations, agitation, confusion and somnolence. Patients
should be monitored for signs of anticholinergic CNS effects, particularly in the first
few months after beginning treatment or increasing the dose. If a patient experiences
anticholinergic CNS effects, dose reduction or drug discontinuation should be
considered.
DITROPAN should be used with caution in patients with preexisting dementia treated
with cholinesterase inhibitors due to the risk of aggravation of symptoms.
General
DITROPAN (oxybutynin chloride) should be used with caution in the frail elderly,
in patients with hepatic or renal impairment, and in patients with myasthenia gravis.
DITROPAN may aggravate the symptoms of hyperthyroidism, coronary heart
disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia,
hypertension, myasthenia gravis, and prostatic hypertrophy.
Urinary Retention
DITROPAN should be administered with caution to patients with clinically
significant bladder outflow obstruction because of the risk of urinary retention
(see CONTRAINDICATIONS).
Gastrointestinal Disorders
DITROPAN should be administered with caution to patients with gastrointestinal
obstructive
disorders
because
of
the
risk
of
gastric
retention
(see CONTRAINDICATIONS).
Administration of DITROPAN to patients with ulcerative colitis may suppress
intestinal motility to the point of producing a paralytic ileus and precipitate or
aggravate toxic megacolon, a serious complication of the disease.
5
Reference ID: 3105471
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DITROPAN, like other anticholinergic drugs, may decrease gastrointestinal motility
and should be used with caution in patients with conditions such as ulcerative colitis,
and intestinal atony.
DITROPAN should be used with caution in patients who have gastroesophageal
reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can
cause or exacerbate esophagitis.
Information for Patients
Patients should be informed that oxybutynin may produce angioedema that could
result in life-threatening airway obstruction. Patients should be advised to promptly
discontinue oxybutynin therapy and seek immediate medical attention if they
experience edema of the tongue, edema of the laryngopharynx, or difficulty
breathing.
Patients should be informed that heat prostration (fever and heat stroke due to
decreased sweating) can occur when anticholinergics such as oxybutynin chloride are
administered in the presence of high environmental temperature.
Because anticholinergic agents such as oxybutynin may produce drowsiness
(somnolence), or blurred vision, patients should be advised to exercise caution.
Patients should be informed that alcohol may enhance the drowsiness caused by
anticholinergic agents such as oxybutynin.
Drug Interactions
The concomitant use of oxybutynin with other anticholinergic drugs or with other
agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other
anticholinergic-like effects may increase the frequency and/or severity of such
effects.
Anticholinergic agents may potentially alter the absorption of some concomitantly
administered drugs due to anticholinergic effects on gastrointestinal motility. This
may be of concern for drugs with a narrow therapeutic index.
Mean oxybutynin chloride plasma concentrations were approximately 3-4 fold higher
when DITROPAN was administered with ketoconazole, a potent CYP3A4 inhibitor.
Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic
agents
(e.g.,
itraconazole
and
miconazole)
or
macrolide
antibiotics
(e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic
parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions
is not known. Caution should be used when such drugs are co-administered.
6
Reference ID: 3105471
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and
160 mg/kg/day showed no evidence of carcinogenicity. These doses are
approximately 6, 25, and 50 times the maximum human exposure, based on surface
area.
Oxybutynin chloride showed no increase of mutagenic activity when tested in
Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae and Salmonella
typhimurium test systems.
Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse
have shown no definite evidence of impaired fertility.
Pregnancy
Category B. Reproduction studies using oxybutynin chloride in the hamster, rabbit,
rat, and mouse have shown no definite evidence of impaired fertility or harm to the
animal fetus. The safety of DITROPAN administered to women who are or who may
become pregnant has not been established. Therefore, DITROPAN should not be
given to pregnant women unless, in the judgment of the physician, the probable
clinical benefits outweigh the possible hazards.
Nursing Mothers
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 DITROPAN is
administered to a nursing woman.
Pediatric Use
The safety and efficacy of DITROPAN administration have been demonstrated for
pediatric
patients
5
years
of
age
and
older
(see
DOSAGE
AND
ADMINISTRATION).
The safety and efficacy of DITROPAN Tablets were studied in 30 children in a 24
week, open-label trial. Patients were aged 5-15 years, all had symptoms of detrusor
overactivity in association with a neurological condition (e.g., spina bifida), all used
clean intermittent catheterization, and all were current users of oxybutynin chloride.
Study results demonstrated that the administration of DITROPAN was associated
with improvement in clinical and urodynamic parameters.
At total daily doses ranging from 5 mg to 15 mg, treatment with DITROPAN Tablets
was associated with an increase from baseline in mean urine volume per
catheterization from 122 mL to 145 mL, an increase from baseline in mean urine
volume after morning awakening from 148 mL to 168 mL, and an increase from
Reference ID: 3105471
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
baseline in the mean percentage of catheterizations without a leaking episode from
43% to 61%. Urodynamic results in these patients were consistent with the clinical
results. Treatment with DITROPAN Tablets was associated with an increase from
baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from
baseline in mean detrusor pressure at maximum cystometric capacity from 36 cm
H2O to 33 cm H2O, and a reduction in the percentage of patients demonstrating
uninhibited detrusor contractions (of at least 15 cm H2O) from 39% to 20%.
As
there
is
insufficient
clinical
data
for
pediatric
populations
under
age 5, DITROPAN is not recommended for this age group.
Geriatric Use
Clinical studies of DITROPAN did not include sufficient numbers of subjects
age 65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses between
healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg
given 2 or 3 times a day has been recommended for the frail elderly due to a
prolongation of the elimination half-life from 2-3 hours to 5 hours.2,3,4 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
The safety and efficacy of DITROPAN (oxybutynin chloride) was evaluated in a
total of 199 patients in three clinical trials. These participants were treated with
DITROPAN 5-20 mg/day for up to 6 weeks. Table 3 shows the incidence of adverse
events judged by investigators to be at least possibly related to treatment and reported
by at least 5% of patients.
8
Reference ID: 3105471
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mg/day)
Body System
Adverse Event
DITROPAN
(5-20 mg/day) (n=199)
Infections and Infestations
Urinary tract infection
6.5%
Psychiatric Disorders
Insomnia
5.5%
Nervousness
6.5%
Nervous System Disorders
Dizziness
16.6%
Somnolence
14.0%
Headache
7.5%
Eye Disorders
Blurred vision
9.6%
Gastrointestinal Disorders
Dry mouth
71.4%
Constipation
15.1%
Nausea
11.6%
Dyspepsia
6.0%
Renal and Urinary Disorders
Urinary Hesitation
8.5%
Urinary Retention
6.0%
Table 3
Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using DITROPAN (5-20
The most common adverse events reported by patients receiving DITROPAN
5-20 mg/day were the expected side effects of anticholinergic agents. The incidence
of dry mouth was dose-related.
In addition, the following adverse events were reported by 1 to <5% of patients using
DITROPAN
(5-20
mg/day)
in
all
studies.
Infections
and
Infestations:
nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection;
Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders:
confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye
Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations,
sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and
Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat,
sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders:
diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper,
dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue
Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back
pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria,
pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema
peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased,
blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural
Complications: fall.
Postmarketing Surveillance
Because postmarketing adverse events 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 following additional adverse
events have been reported from worldwide postmarketing experience with
Reference ID: 3105471
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DITROPAN: Psychiatric Disorders: psychotic disorder, agitation, hallucination,
memory impairment; Nervous System Disorders: convulsions; Eye Disorders:
cycloplegia, mydriasis, glaucoma; Cardiac Disorders: tachycardia, QT interval
prolongation; Gastrointestinal Disorders: decreased gastrointestinal motility; Skin
and Subcutaneous Tissue Disorders: rash, decreased sweating; Renal and Urinary
Disorders: impotence; Reproductive System and Breast Disorders: Suppression of
lactation; General Disorders and Administration Site Conditions: hypersensitivity
reactions, including angioedema with airway obstruction, urticaria, and face edema;
rare anaphylactic reactions requiring hospitalization for emergency treatment.
OVERDOSAGE
Treatment should be symptomatic and supportive. Activated charcoal as well as a
cathartic may be administered.
Overdosage with oxybutynin chloride has been associated with anticholinergic effects
including central nervous system excitation (e.g., restlessness, tremor, irritability,
convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac
arrhythmia, vomiting, and urinary retention. Other symptoms may include
hypotension or hypertension, respiratory failure, paralysis, and coma.
Ingestion of 100 mg oxybutynin chloride in association with alcohol has been
reported in a 13-year-old boy who experienced memory loss, and a 34-year-old
woman who developed stupor, followed by disorientation and agitation on
awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both
patients fully recovered with symptomatic treatment.
DOSAGE AND ADMINISTRATION
Adults
The usual dose is one 5-mg tablet two to three times a day. The maximum
recommended dose is one 5-mg tablet four times a day. A lower starting dose of
2.5 mg two or three times a day is recommended for the frail elderly.
Pediatric patients over 5 years of age
The usual dose is one 5-mg tablet two times a day. The maximum recommended dose
is one 5-mg tablet three times a day.
HOW SUPPLIED
DITROPAN (oxybutynin chloride) Tablets are supplied in bottles of 100 tablets
(NDC 17314-9200-1). Blue scored tablets (5 mg) are engraved with DITROPAN on
one side with 92 and 00, separated by a horizontal score, on the other side.
Pharmacist: Dispense in tight, light-resistant container as defined in the USP.
Reference ID: 3105471
10
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 59-86°F (15-30°C).
REFERENCES
1. Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal
subjects. Pharm Res. 1991; 8 (Suppl.): S-320.
2. Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in
plasma, and its application to pharmacokinetic studies in young, elderly and frail
elderly volunteers. Xenobiotica. 1992; 22 (7): 859-869.
3. Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in
Geriatric Patients. J. Urol. 1988; 140: 47-50.
4. Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and
Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Instability.
Drugs & Aging. 1995; 6(3): 243-262.
Manufactured by sanofi-aventis U.S. LLC, Kansas City, MO 64137.
Marketed by Ortho Women’s Health & Urology, Division of Ortho-McNeil-Janssen
Pharmaceuticals, Inc., Raritan, NJ 08869
(OMP Logo)
Revised March 2012
Reference ID: 3105471
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:17.794438
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017577s038lbl.pdf', 'application_number': 17577, 'submission_type': 'SUPPL ', 'submission_number': 38}
|
11,035
|
1
1
EC-NAPROSYN® (naproxen delayed-release tablets)
2
NAPROSYN® (naproxen tablets)
3
ANAPROX®/ANAPROX®DS (naproxen sodium tablets)
4
NAPROSYN®(naproxen suspension)
5
Rx only
6
7
8
9
DESCRIPTION
10
Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory
11
drugs.
12
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2-
13
naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium
14
salt, respectively. Naproxen and naproxen sodium have the following structures,
15
respectively:
16
17
Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3.
18
Naproxen sodium has a molecular weight of 252.23 and a molecular formula of
19
C14H13NaO3.
20
Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble,
21
practically insoluble in water at low pH and freely soluble in water at high pH. The
22
octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium
23
is a white to creamy white, crystalline solid, freely soluble in water at neutral pH.
24
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of
25
naproxen, peach tablets containing 375 mg of naproxen and yellow tablets containing 500
26
mg of naproxen for oral administration. The inactive ingredients are croscarmellose
27
sodium, iron oxides, povidone and magnesium stearate.
28
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-coated white
29
tablets containing 375 mg of naproxen and 500 mg of naproxen for oral administration.
30
The inactive ingredients are croscarmellose sodium, povidone and magnesium stearate.
31
The enteric coating dispersion contains methacrylic acid copolymer, talc, triethyl citrate,
32
sodium hydroxide and purified water. The dispersion may also contain simethicone
33
emulsion. The dissolution of this enteric-coated naproxen tablet is pH dependent with
34
rapid dissolution above pH 6. There is no dissolution below pH 4.
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
2
ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of
36
naproxen sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue
37
tablets containing 550 mg of naproxen sodium for oral administration. The inactive
38
ingredients are magnesium stearate, microcrystalline cellulose, povidone and talc. The
39
coating suspension for the ANAPROX 275 mg tablet may contain hydroxypropyl
40
methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-
41
4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain
42
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or
43
Opadry YS-1-4216.
44
NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral
45
suspension containing 125 mg/5 mL of naproxen in a vehicle containing sucrose,
46
magnesium aluminum silicate, sorbitol solution and sodium chloride (30 mg/5 mL, 1.5
47
mEq), methylparaben, fumaric acid, FD&C Yellow No. 6, imitation pineapple flavor,
48
imitation orange flavor and purified water. The pH of the suspension ranges from 2.2 to
49
3.7.
50
CLINICAL PHARMACOLOGY
51
Pharmacodynamics: Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with
52
analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a
53
more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism
54
of action of the naproxen anion, like that of other NSAIDs, is not completely understood
55
but may be related to prostaglandin synthetase inhibition.
56
Pharmacokinetics: Naproxen itself is rapidly and completely absorbed from the
57
gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms
58
of NAPROSYN are bioequivalent in terms of extent of absorption (AUC) and peak
59
concentration (Cmax); however, the products do differ in their pattern of absorption. These
60
differences between naproxen products are related to both the chemical form of naproxen
61
used and its formulation. Even with the observed differences in pattern of absorption, the
62
elimination half-life of naproxen is unchanged across products ranging from 12 to 17
63
hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of
64
naproxen accumulation is consistent with this half-life. This suggests that the differences
65
in pattern of release play only a negligible role in the attainment of steady-state plasma
66
levels.
67
Absorption:
68
Immediate Release: After administration of NAPROSYN tablets, peak plasma levels are
69
attained in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels are
70
attained in 1 to 2 hours. The difference in rates between the two products is due to the
71
increased aqueous solubility of the sodium salt of naproxen used in ANAPROX. Peak
72
plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours.
73
Delayed Release: EC-NAPROSYN is designed with a pH-sensitive coating to provide a
74
barrier to disintegration in the acidic environment of the stomach and to lose integrity in
75
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
3
the more neutral environment of the small intestine. The enteric polymer coating selected
76
for EC-NAPROSYN dissolves above pH 6. When EC-NAPROSYN was given to fasted
77
subjects, peak plasma levels were attained about 4 to 6 hours following the first dose
78
(range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-NAPROSYN
79
tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine
80
rather than the stomach, so the absorption of the drug is delayed until the stomach is
81
emptied.
82
When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a
83
crossover study following 1 week of dosing, differences in time to peak plasma levels
84
(Tmax) were observed, but there were no differences in total absorption as measured by
85
Cmax and AUC:
86
EC-NAPROSYN*
500 mg bid
NAPROSYN*
500 mg bid
Cmax (µg/mL)
94.9 (18%)
97.4 (13%)
Tmax (hours)
4 (39%)
1.9 (61%)
AUC0–12 hr (µg·hr/mL)
845 (20%)
767 (15%)
*Mean value (coefficient of variation)
87
Antacid Effects: When EC-NAPROSYN was given as a single dose with antacid (54 mEq
88
buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to
89
peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although
90
not significantly.
91
Food Effects: When EC-NAPROSYN was given as a single dose with food, peak plasma
92
levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence
93
time in the small intestine until disintegration was independent of food intake. The
94
presence of food prolonged the time the tablets remained in the stomach, time to first
95
detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did
96
not affect peak naproxen levels (Cmax).
97
Distribution:
98
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is
99
greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is
100
less than proportional increase in plasma levels due to an increase in clearance caused by
101
saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and
102
56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen). The naproxen anion
103
has been found in the milk of lactating women at a concentrations equivalent to
104
approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS:
105
Nursing Mothers).
106
Metabolism:
107
Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and
108
metabolites do not induce metabolizing enzymes.
109
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
4
Excretion:
110
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from
111
any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl
112
naproxen (less than 1%) or their conjugates (66% to 92%). The plasma half-life of the
113
naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of
114
both naproxen’s metabolites and conjugates are shorter than 12 hours, and their rates of
115
excretion have been found to coincide closely with the rate of naproxen disappearance
116
from the plasma. In patients with renal failure metabolites may accumulate (see
117
PRECAUTIONS: Renal Effects).
118
Special Populations:
119
Pediatric Patients: In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen
120
levels following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND
121
ADMINISTRATION) were found to be similar to those found in normal adults following
122
a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients.
123
Pharmacokinetic studies of naproxen were not performed in pediatric patients younger
124
than 5 years of age. Pharmacokinetic parameters appear to be similar following
125
administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN
126
has not been studied in subjects under the age of 18.
127
Geriatric Patients: Studies indicate that although total plasma concentration of naproxen
128
is unchanged, the unbound plasma fraction of naproxen is increased in the elderly,
129
although the unbound fraction is less than 1% of the total naproxen concentration.
130
Unbound trough naproxen concentrations in elderly subjects have been reported to range
131
from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075%
132
in younger subjects. The clinical significance of this finding is unclear, although it is
133
possible that the increase in free naproxen concentration could be associated with an
134
increase in the rate of adverse events per a given dosage in some elderly patients.
135
Race: Pharmacokinetic differences due to race have not been studied.
136
Hepatic Insufficiency: Naproxen pharmacokinetics has not been determined in subjects
137
with hepatic insufficiency.
138
Renal Insufficiency: Naproxen pharmacokinetics has not been determined in subjects
139
with renal insufficiency. Given that naproxen, its metabolites and conjugates are
140
primarily excreted by the kidney, the potential exists for naproxen metabolites to
141
accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased
142
in patients with severe renal impairment. Naproxen-containing products are not
143
recommended for use in patients with moderate to severe and severe renal impairment
144
(creatinine < 30 ml/min) (see PRECAUTIONS: Renal Effects).
145
CLINICAL STUDIES
146
General Information: Naproxen has been studied in patients with rheumatoid arthritis,
147
osteoarthritis, juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute
148
gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a
149
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
5
reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in
150
disease activity as assessed by both the investigator and patient, and by increased
151
mobility as demonstrated by a reduction in walking time. Generally, response to
152
naproxen has not been found to be dependent on age, sex, severity or duration of
153
rheumatoid arthritis.
154
In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a
155
reduction in joint pain or tenderness, an increase in range of motion in knee joints,
156
increased mobility as demonstrated by a reduction in walking time, and improvement in
157
capacity to perform activities of daily living impaired by the disease.
158
In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a
159
day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group terminated
160
prematurely because of adverse events. Nineteen patients in the 1500 mg group
161
terminated prematurely because of adverse events. Most of these adverse events were
162
gastrointestinal events.
163
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile
164
arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in
165
controlling the aforementioned measures of disease activity, but the frequency and
166
severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and
167
nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in
168
naproxen-treated patients than in those treated with aspirin or indomethacin.
169
In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain,
170
morning stiffness and pain at rest. In double-blind studies the drug was shown to be as
171
effective as aspirin, but with fewer side effects.
172
In patients with acute gout, a favorable response to naproxen was shown by significant
173
clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours,
174
as well as by relief of pain and tenderness.
175
Naproxen has been studied in patients with mild to moderate pain secondary to
176
postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and
177
dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen
178
and within 30 minutes in patients taking naproxen sodium. Analgesic effect was shown
179
by such measures as reduction of pain intensity scores, increase in pain relief scores,
180
decrease in numbers of patients requiring additional analgesic medication, and delay in
181
time to remedication. The analgesic effect has been found to last for up to 12 hours.
182
Naproxen may be used safely in combination with gold salts and/or corticosteroids;
183
however, in controlled clinical trials, when added to the regimen of patients receiving
184
corticosteroids, it did not appear to cause greater improvement over that seen with
185
corticosteroids alone. Whether naproxen has a “steroid-sparing” effect has not been
186
adequately studied. When added to the regimen of patients receiving gold salts, naproxen
187
did result in greater improvement. Its use in combination with salicylates is not
188
recommended because there is evidence that aspirin increases the rate of excretion of
189
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
6
naproxen and data are inadequate to demonstrate that naproxen and aspirin produce
190
greater improvement over that achieved with aspirin alone. In addition, as with other
191
NSAIDs, the combination may result in higher frequency of adverse events than
192
demonstrated for either product alone.
193
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of
194
1000 mg of naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX
195
(naproxen sodium) has been demonstrated to cause statistically significantly less gastric
196
bleeding and erosion than 3250 mg of aspirin.
197
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375
198
or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted
199
comparing EC-NAPROSYN with NAPROSYN, including 355 rheumatoid arthritis and
200
osteoarthritis patients who had a recent history of NSAID-related GI symptoms. These
201
studies indicated that EC-NAPROSYN and NAPROSYN showed no significant
202
differences in efficacy or safety and had similar prevalence of minor GI complaints.
203
Individual patients, however, may find one formulation preferable to the other.
204
Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-
205
label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed
206
peptic ulcers and GI bleeds were similar to what has been historically reported for long-
207
term NSAID use.
208
Geriatric Patients: The hepatic and renal tolerability of long-term naproxen
209
administration was studied in two double blind clinical trials involving 586 patients. Of
210
the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age
211
75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice
212
daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and
213
renal function were noted in some patients, although there were no differences noted in
214
the occurrence of abnormal values among different age groups.
215
INDIVIDUALIZATION OF DOSAGE
216
Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and
217
ANAPROX DS all circulate in the plasma as naproxen, they have pharmacokinetic
218
differences that may affect onset of action. Onset of pain relief can begin within 30
219
minutes in patients taking naproxen sodium and within 1 hour in patients taking
220
naproxen. Because EC-NAPROSYN dissolves in the small intestine rather than in the
221
stomach, the absorption of the drug is delayed compared to the other naproxen
222
formulations (see CLINICAL PHARMACOLOGY).
223
The recommended strategy for initiating therapy is to choose a formulation and a starting
224
dose likely to be effective for the patient and then adjust the dosage based on observation
225
of benefit and/or adverse events. A lower dose should be considered in patients with renal
226
or hepatic impairment or in elderly patients (see PRECAUTIONS).
227
Analgesia/Dysmenorrhea/Bursitis and Tendinitis: Because the sodium salt of naproxen
228
is more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the
229
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
7
management of acute painful conditions when prompt onset of pain relief is desired. The
230
recommended starting dose is 550 mg followed by 550 mg every 12 hours or 275 mg
231
every 6 to 8 hours, as required. The initial total daily dose should not exceed 1375 mg of
232
naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen
233
sodium. NAPROSYN may also be used for treatment of acute pain and dysmenorrhea.
234
EC-NAPROSYN is not recommended for initial treatment of acute pain because
235
absorption of naproxen is delayed compared to other naproxen-containing products (see
236
CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE).
237
Acute Gout: The recommended starting dose is 750 mg of NAPROSYN followed by 250
238
mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting
239
dose of 825 mg followed by 275 mg every 8 hours as needed. EC-NAPROSYN is not
240
recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY).
241
Osteoarthritis/Rheumatoid Arthritis/Ankylosing Spondylitis: The recommended dose of
242
naproxen is NAPROSYN or NAPROSYN Suspension 250 mg, 375 mg or 500 mg taken
243
twice daily (morning and evening) or EC-NAPROSYN 375 mg or 500 mg taken twice
244
daily. Naproxen sodium may also be used (see DOSAGE AND ADMINISTRATION).
245
During long-term administration the dose of naproxen may be adjusted up or down
246
depending on the clinical response of the patient. A lower daily dose may suffice for
247
long-term administration. In patients who tolerate lower doses well, the dose may be
248
increased to 1500 mg per day for up to 6 months when a higher level of anti-
249
inflammatory/analgesic activity is required. When treating patients with naproxen 1500
250
mg/day (as NAPROSYN or 1650 mg of ANAPROX), the physician should observe
251
sufficient increased clinical benefit to offset the potential increased risk. The morning and
252
evening doses do not have to be equal in size and administration of the drug more
253
frequently than twice daily does not generally make a difference in response (see
254
CLINICAL PHARMACOLOGY).
255
Juvenile Arthritis: The use of NAPROSYN Suspension allows for more flexible dose
256
titration. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen
257
similar to those seen in adults taking 500 mg of naproxen (see CLINICAL
258
PHARMACOLOGY).
259
The recommended total daily dose is approximately 10 mg/kg given in two divided doses
260
(ie, 5 mg/kg given twice a day) (see DOSAGE AND ADMINISTRATION).
261
INDICATIONS AND USAGE
262
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
263
NAPROSYN Suspension is indicated:
264
• For the relief of the signs and symptoms of rheumatoid arthritis
265
• For the relief of the signs and symptoms of osteoarthritis
266
• For the relief of the signs and symptoms of ankylosing spondylitis
267
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
8
• For the relief of the signs and symptoms of juvenile arthritis
268
Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis
269
in order to obtain the maximum dosage flexibility based on the patient’s weight.
270
Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is
271
also indicated:
272
• For relief of the signs and symptoms of tendinitis
273
• For relief of the signs and symptoms of bursitis
274
• For relief of the signs and symptoms of acute gout
275
• For the management of pain
276
• For the management of primary dysmenorrhea
277
EC-NAPROSYN is not recommended for initial treatment of acute pain because the
278
absorption of naproxen is delayed compared to absorption from other naproxen-
279
containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND
280
ADMINISTRATION).
281
CONTRAINDICATIONS
282
All naproxen products are contraindicated in patients who have had allergic reactions to
283
prescription as well as to over-the-counter products containing naproxen. It is also
284
contraindicated
in
patients
in
whom
aspirin
or
other
nonsteroidal
anti-
285
inflammatory/analgesic drugs induce the syndrome of asthma, rhinitis, and nasal polyps.
286
Both types of reactions have the potential of being fatal. Anaphylactoid reactions to
287
naproxen, whether of the true allergic type or the pharmacologic idiosyncratic (eg, aspirin
288
hypersensitivity syndrome) type, usually but not always occur in patients with a known
289
history of such reactions. Therefore, careful questioning of patients for such things as
290
asthma, nasal polyps, urticaria, and hypotension associated with nonsteroidal anti-
291
inflammatory drugs before starting therapy is important. In addition, if such symptoms
292
occur during therapy, treatment should be discontinued (see WARNINGS: Anaphylactoid
293
Reactions and PRECAUTIONS: Preexisting Asthma).
294
WARNINGS
295
Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation:
296
Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the
297
stomach, small intestine or large intestine, can occur at any time, with or without warning
298
symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs).
299
Minor upper gastrointestinal problems, such as dyspepsia, are common and may also
300
occur at any time during NSAID therapy. Therefore, physicians and patients should
301
remain alert for ulceration and bleeding, even in the absence of previous GI tract
302
symptoms (see PRECAUTIONS: Hematological Effects). Patients should be informed
303
about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur.
304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
9
The utility of periodic laboratory monitoring has not been demonstrated, nor has it been
305
adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event
306
on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross
307
bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of
308
patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year.
309
These trends continue, thus increasing the likelihood of developing a serious GI event at
310
some time during the course of therapy. However, even short-term therapy is not without
311
risk.
312
NSAIDs should be prescribed with extreme caution in patients with a prior history of
313
ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are
314
in elderly or debilitated patients and therefore special care should be taken in treating this
315
population. To minimize the potential risk for an adverse GI event, the lowest
316
effective dose should be used for the shortest possible duration. For high-risk patients,
317
alternate therapies that do not involve NSAIDs should be considered.
318
Studies have shown that patients with a prior history of peptic ulcer disease and/or
319
gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for
320
developing a GI bleed than patients with neither of these risk factors. In addition to a past
321
history of ulcer disease, pharmacoepidemiological studies have identified several other
322
co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as:
323
treatment with oral corticosteroids, treatment with anticoagulants, longer duration of
324
NSAID therapy, smoking, alcoholism, older age, and poor general health status.
325
Anaphylactoid Reactions: As with other NSAIDs, anaphylactoid reactions may occur in
326
patients without known prior exposure to naproxen. Naproxen should not be given to
327
patients with the aspirin triad. This symptom complex typically occurs in asthmatic
328
patients who experience rhinitis with or without nasal polyps, or who exhibit severe,
329
potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
330
CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help
331
should be sought in cases where an anaphylactoid reaction occurs.
332
Advanced Renal Disease: In cases with advanced kidney disease, treatment with
333
naproxen is not recommended. If NSAID therapy, however, must be initiated, close
334
monitoring of the patient’s kidney function is advisable (see PRECAUTIONS: Renal
335
Effects).
336
Pregnancy: In late pregnancy, as with other NSAIDs, naproxen should be avoided
337
because it may cause premature closure of the ductus arteriosus.
338
PRECAUTIONS
339
General: NAPROXEN-CONTAINING PRODUCTS SUCH AS NAPROSYN, EC-
340
NAPROSYN, ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®*,
341
AND
OTHER
NAPROXEN
PRODUCTS
SHOULD
NOT
BE
USED
342
CONCOMITANTLY SINCE THEY ALL CIRCULATE IN THE PLASMA AS
343
THE NAPROXEN ANION.
344
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
10
Naproxen cannot be expected to substitute for corticosteroids or to treat corticosteroid
345
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
346
Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a
347
decision is made to discontinue corticosteroids and the patient should be observed closely
348
for any evidence of adverse effects, including adrenal insufficiency and exacerbation of
349
symptoms of arthritis.
350
Patients with initial hemoglobin values of 10 g or less who are to receive long-term
351
therapy should have hemoglobin values determined periodically.
352
The antipyretic and anti-inflammatory activities of the drug may reduce fever and
353
inflammation, thus diminishing their utility as diagnostic signs in detecting complications
354
of presumed noninfectious, noninflammatory painful conditions.
355
Because of adverse eye findings in animal studies with drugs of this class, it is
356
recommended that ophthalmic studies be carried out if any change or disturbance in
357
vision occurs.
358
Hepatic Effects: As with other nonsteroidal anti-inflammatory drugs, borderline
359
elevations of one or more liver tests may occur in up to 15% of patients. These
360
abnormalities may progress, may remain essentially unchanged, or may be transient with
361
continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver
362
dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or
363
SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. A patient
364
with symptoms and/or signs suggesting liver dysfunction or in whom an abnormal liver
365
test has occurred, should be evaluated for evidence of the development of more severe
366
hepatic reaction while on therapy with naproxen. Severe hepatic reactions, including
367
jaundice and cases of fatal hepatitis, have been reported with naproxen as with other
368
nonsteroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver
369
tests persist or worsen, if clinical signs and symptoms consistent with liver disease
370
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), naproxen
371
should be discontinued.
372
Renal Effects: Caution should be used when initiating treatment with naproxen in
373
patients with considerable dehydration. It is advisable to rehydrate patients first and then
374
start therapy with naproxen. Caution is also recommended in patients with pre-existing
375
kidney disease (see WARNINGS: Advanced Renal Disease).
376
As with other nonsteroidal anti-inflammatory drugs, long-term administration of
377
naproxen to animals has resulted in renal papillary necrosis and other abnormal renal
378
pathology. In humans, there have been reports of impaired renal function, renal failure,
379
acute interstitial nephritis, hematuria, proteinuria, renal papillary necrosis, and
380
occasionally nephrotic syndrome associated with naproxen-containing products and other
381
NSAIDs since they have been marketed.
382
A second form of renal toxicity has been seen in patients taking naproxen as well as other
383
nonsteroidal anti-inflammatory drugs. In patients with prerenal conditions leading to a
384
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
11
reduction in renal blood flow or blood volume, where the renal prostaglandins have a
385
supportive role in the maintenance of renal perfusion, caution should be observed since
386
administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent
387
reduction in prostaglandin formation and may precipitate overt renal decompensation or
388
failure. Patients at greatest risk of this reaction are those with impaired renal function,
389
hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and
390
ACE inhibitors, and the elderly. Discontinuation of nonsteroidal anti-inflammatory
391
therapy is typically followed by recovery to the pretreatment state.
392
Naproxen and its metabolites are eliminated primarily by the kidneys; therefore, the drug
393
should be used with caution in such patients and the monitoring of serum creatinine
394
and/or creatinine clearance is advised. A reduction in daily dosage should be considered
395
to avoid the possibility of excessive accumulation of naproxen metabolites in these
396
patients. Naproxen-containing products are not recommended for use in patients with
397
moderate to severe and severe renal impairment (creatinine < 30 ml/min).
398
Chronic alcoholic liver disease and probably other diseases with decreased or abnormal
399
plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the
400
plasma concentration of unbound naproxen is increased. Caution is advised when high
401
doses are required and some adjustment of dosage may be required in these patients. It is
402
prudent to use the lowest effective dose.
403
Studies indicate that although total plasma concentration of naproxen is unchanged, the
404
unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when
405
high doses are required and some adjustment of dosage may be required in elderly
406
patients. As with other drugs used in the elderly, it is prudent to use the lowest effective
407
dose.
408
Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs,
409
including naproxen. This may be due to fluid retention, GI loss, or an incompletely
410
described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs,
411
including naproxen, should have their hemoglobin or hematocrit checked if they exhibit
412
any signs or symptoms of anemia.
413
All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent
414
with platelet function and vascular responses to bleeding.
415
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in
416
some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of
417
shorter duration, and reversible. Naproxen does not generally affect platelet counts,
418
prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving naproxen
419
who may be adversely affected by alterations in platelet function, such as those with
420
coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
421
Fluid Retention and Edema: Peripheral edema has been observed in some patients
422
receiving naproxen. Since each ANAPROX or ANAPROX DS tablet contains 25 mg or
423
50 mg of sodium (about 1 mEq per each 250 mg of naproxen), and each teaspoonful of
424
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
12
NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of naproxen)
425
of sodium, this should be considered in patients whose overall intake of sodium must be
426
severely restricted. For these reasons, ANAPROX, ANAPROX DS and NAPROSYN
427
Suspension should be used with caution in patients with fluid retention, hypertension or
428
heart failure.
429
Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of
430
aspirin in patients with aspirin-sensitive asthma has been associated with severe
431
bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm,
432
between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such
433
aspirin-sensitive patients, naproxen should not be administered to patients with this form
434
of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
435
Information for Patients: Naproxen, in NAPROSYN, EC-NAPROSYN, ANAPROX,
436
ANAPROX DS and NAPROSYN Suspension can cause discomfort and, rarely, more
437
serious side effects, such as gastrointestinal bleeding, which may result in hospitalization
438
and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur
439
without warning symptoms, patients should be alert for the signs and symptoms of
440
ulcerations and bleeding, and should ask for medical advice when observing any
441
indicative signs or symptoms. Patients should be apprised of the importance of this
442
follow-up (see WARNINGS: Gastrointestinal (GI) Effects-Risk of GI Ulceration,
443
Bleeding, and Perforation).
444
Patients should promptly report signs or symptoms of gastrointestinal ulceration or
445
bleeding, skin rash, unexplained weight gain or edema to their physicians.
446
Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg,
447
nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-
448
like” symptoms). If these occur, patients should be instructed to stop therapy and seek
449
immediate medical therapy.
450
Patients should also be instructed to seek immediate emergency help in the case of an
451
anaphylactoid reaction (see WARNINGS).
452
In late pregnancy, naproxen, in NAPROSYN, EC-NAPROSYN, ANAPROX,
453
ANAPROX DS, and NAPROSYN SUSPENSION, should be avoided because it may
454
cause premature closure of the ductus arteriosus.
455
Caution should be exercised by patients whose activities require alertness if they
456
experience drowsiness, dizziness, vertigo or depression during therapy with naproxen.
457
Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without
458
warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. If
459
clinical signs and symptoms consistent with liver or renal disease develop, systemic
460
manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or
461
worsen, naproxen should be discontinued.
462
Drug Interactions:
463
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
13
Aspirin: Concomitant administration of naproxen and aspirin is not recommended
464
because naproxen is displaced from its binding sites during the concomitant
465
administration of aspirin, resulting in lower plasma concentrations and peak plasma
466
levels.
467
Methotrexate: Caution should be used if naproxen is administered concomitantly with
468
methotrexate. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory
469
drugs have been reported to reduce the tubular secretion of methotrexate in an animal
470
model, possibly increasing the toxicity of methotrexate.
471
ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect
472
of ACE-inhibitors. The use of NSAIDs in patients who are receiving ACE inhibitors may
473
potentiate renal disease states (see PRECAUTIONS: Renal Effects).
474
Furosemide: Clinical studies, as well as postmarketing observations, have shown that
475
NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients.
476
This response has been attributed to inhibition of renal prostaglandin synthesis.
477
Lithium: Inhibition of renal lithium clearance leading to increases in plasma lithium
478
concentrations has also been reported. The mean minimum lithium concentration
479
increased 15% and the renal clearance was decreased by approximately 20%. These
480
effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID.
481
Thus, when NSAIDs and lithium are administered concurrently, patients should be
482
observed carefully for signs of lithium toxicity.
483
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
484
patients taking both drugs have a risk of serious GI bleeding that is higher than patients
485
taking either drug alone. No significant interactions have been observed in clinical
486
studies with naproxen and coumarin-type anticoagulants. However, caution is advised
487
since interactions have been seen with other nonsteroidal agents of this class. The free
488
fraction of warfarin may increase substantially in some subjects and naproxen interferes
489
with platelet function.
490
Other Information Concerning Drug Interactions:
491
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for
492
interaction with other albumin-bound drugs such as coumarin-type anticoagulants,
493
sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously
494
receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed
495
for adjustment of dose if required.
496
Naproxen
and
other
nonsteroidal
anti-inflammatory
drugs
can
reduce
the
497
antihypertensive effect of propranolol and other beta-blockers.
498
Probenecid given concurrently increases naproxen anion plasma levels and extends its
499
plasma half-life significantly.
500
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid
501
therapy, concomitant administration of EC-NAPROSYN is not recommended.
502
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
14
Drug/Laboratory Test Interactions: Naproxen may decrease platelet aggregation and
503
prolong bleeding time. This effect should be kept in mind when bleeding times are
504
determined.
505
The administration of naproxen may result in increased urinary values for 17-ketogenic
506
steroids because of an interaction between the drug and/or its metabolites with m-di-
507
nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements
508
(Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy
509
with naproxen be temporarily discontinued 72 hours before adrenal function tests are
510
performed if the Porter-Silber test is to be used.
511
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid
512
(5HIAA).
513
Carcinogenesis: A 2-year study was performed in rats to evaluate the carcinogenic
514
potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2).
515
The maximum dose used was 0.28 times the systemic exposure to humans at the
516
recommended dose. No evidence of tumorigenicity was found.
517
Pregnancy: Teratogenic Effects: Pregnancy Category C. Reproduction studies have been
518
performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic
519
exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic
520
exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic
521
exposure) with no evidence of impaired fertility or harm to the fetus due to the drug.
522
There are no adequate and well-controlled studies in pregnant women. Because animal
523
reproduction studies are not always predictive of human response, naproxen should not
524
be used during pregnancy unless clearly needed.
525
Nonteratogenic Effects: There is some evidence to suggest that when inhibitors of
526
prostaglandin synthesis are used to delay preterm labor there is an increased risk of
527
neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and
528
intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition
529
has been associated with persistent pulmonary hypertension, renal dysfunction and
530
abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs
531
of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use
532
during third trimester should be avoided.
533
Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit
534
prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and
535
decreased pup survival occurred. Naproxen-containing products are not recommended in
536
labor and delivery because, through its prostaglandin synthesis inhibitory effect,
537
naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus
538
increasing the risk of uterine hemorrhage.
539
Nursing Mothers: The naproxen anion has been found in the milk of lactating women at
540
a concentrations equivalent to approximately 1% of maximum naproxen concentration in
541
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
15
plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on
542
neonates, use in nursing mothers should be avoided.
543
Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 years
544
have not been established. Pediatric dosing recommendations for juvenile arthritis are
545
based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are
546
no adequate effectiveness or dose-response data for other pediatric conditions, but the
547
experience in juvenile arthritis and other use experience have established that single
548
doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND
549
ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well
550
tolerated in pediatric patients over 2 years of age.
551
Geriatric Use: Studies indicate that although total plasma concentration of naproxen is
552
unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution
553
is advised when high doses are required and some adjustment of dosage may be required
554
in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest
555
effective dose.
556
Experience indicates that geriatric patients may be particularly sensitive to certain
557
adverse effects of nonsteroidal anti-inflammatory drugs. While age does not appear to be
558
an independent risk factor for the development of peptic ulceration and bleeding with
559
naproxen administration, elderly or debilitated patients seem to tolerate peptic ulceration
560
or bleeding less well when these events do occur. Most spontaneous reports of fatal GI
561
events are in the geriatric population (see WARNINGS).
562
Naproxen is known to be substantially excreted by the kidney, and the risk of toxic
563
reactions to this drug may be greater in patients with impaired renal function. Because
564
elderly patients are more likely to have decreased renal function, care should be taken in
565
dose selection, and it may be useful to monitor renal function. Geriatric patients may be
566
at a greater risk for the development of a form of renal toxicity precipitated by reduced
567
prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs
568
(see PRECAUTIONS: Renal Effects).
569
ADVERSE REACTIONS
570
Adverse reactions reported in controlled clinical trials in 960 patients treated for
571
rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients
572
treated chronically were reported 2 to 10 times more frequently than they were in short-
573
term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea.
574
The most frequent complaints reported related to the gastrointestinal tract.
575
A clinical study found gastrointestinal reactions to be more frequent and more severe in
576
rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those
577
taking 750 mg naproxen (see CLINICAL PHARMACOLOGY).
578
In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-
579
label studies with about 400 pediatric patients with juvenile arthritis treated with
580
naproxen, the incidence of rash and prolonged bleeding times were increased, the
581
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
16
incidence of gastrointestinal and central nervous system reactions were about the same,
582
and the incidence of other reactions were lower in pediatric patients than in adults.
583
In patients taking naproxen in clinical trials, the most frequently reported adverse
584
experiences in approximately 1 to 10% of patients are:
585
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*,
586
constipation*, diarrhea, dyspepsia, stomatitis
587
Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo
588
Dermatologic: pruritus (itching) *, skin eruptions*, ecchymoses*, sweating, purpura
589
Special Senses: tinnitus*, visual disturbances, hearing disturbances
590
Cardiovascular: edema*, palpitations
591
General: dyspnea*, thirst
592
* Incidence of reported reaction between 3% and 9%. Those reactions occurring in less
593
than 3% of the patients are unmarked.
594
In patients taking NSAIDs, the following adverse experiences have also been reported in
595
approximately 1 to 10% of patients.
596
Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI
597
ulcers (gastric/duodenal), vomiting
598
General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding
599
time, rashes
600
The following are additional adverse experiences reported in <1% of patients taking
601
naproxen during clinical trials and through post-marketing reports. Those adverse
602
reactions observed through post-marketing reports are italicized.
603
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders,
604
pyrexia (chills and fever)
605
Cardiovascular: congestive heart failure, vasculitis
606
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice,
607
pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal
608
ulceration, ulcerative stomatitis
609
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia,
610
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
611
Metabolic and Nutritional: hyperglycemia, hypoglycemia
612
Nervous System: inability to concentrate, depression, dream abnormalities, insomnia,
613
malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction
614
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
17
Respiratory: eosinophilic pneumonitis
615
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema
616
multiforme, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity
617
reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria)
618
or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of
619
pseudoporphyria occur, treatment should be discontinued and the patient monitored.
620
Special Senses: hearing impairment
621
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis,
622
nephrotic syndrome, renal disease, renal failure, renal papillary necrosis
623
In patients taking NSAIDs, the following adverse experiences have also been reported in
624
<1% of patients.
625
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death
626
Cardiovascular:
hypertension,
tachycardia,
syncope,
arrhythmia,
hypotension,
627
myocardial infarction
628
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis,
629
hepatitis, eructation, liver failure
630
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
631
Metabolic and Nutritional: weight changes
632
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence,
633
tremors, convulsions, coma, hallucinations
634
Respiratory: asthma, respiratory depression, pneumonia
635
Dermatologic: exfoliative dermatitis
636
Special Senses: blurred vision, conjunctivitis
637
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
638
OVERDOSAGE
639
Significant naproxen overdosage may be characterized by lethargy, dizziness,
640
drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea,
641
transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic
642
acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur.
643
Hypertension, acute renal failure, respiratory depression, and coma may occur, but are
644
rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs,
645
and may occur following an overdose. Because naproxen sodium may be rapidly
646
absorbed, high and early blood levels should be anticipated. A few patients have
647
experienced convulsions, but it is not clear whether or not these were drug-related. It is
648
not known what dose of the drug would be life threatening. The oral LD50 of the drug is
649
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
18
543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000
650
mg/kg in dogs.
651
Patients should be managed by symptomatic and supportive care following a NSAID
652
overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma
653
concentration of naproxen because of the high degree of its protein binding. Emesis
654
and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic
655
cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or
656
following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may
657
not be useful due to high protein binding.
658
DOSAGE AND ADMINISTRATION
659
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis:
660
NAPROSYN
250 mg
or 375 mg
or 500 mg
twice daily
twice daily
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
NAPROSYN
Suspension
250 mg (10 mL/2 tsp)
or 375 mg (15 mL/3 tsp)
or 500 mg (20 mL/4 tsp)
twice daily
twice daily
twice daily
EC-NAPROSYN
375 mg
or 500 mg
twice daily
twice daily
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be
661
broken, crushed or chewed during ingestion.
662
During long-term administration, the dose of naproxen may be adjusted up or down
663
depending on the clinical response of the patient. A lower daily dose may suffice for
664
long-term administration. The morning and evening doses do not have to be equal in size
665
and the administration of the drug more frequently than twice daily is not necessary.
666
In patients who tolerate lower doses well, the dose may be increased to naproxen 1500
667
mg per day for limited periods of up to 6 months when a higher level of anti-
668
inflammatory/analgesic activity is required. When treating such patients with naproxen
669
1500 mg/day, the physician should observe sufficient increased clinical benefits to offset
670
the
potential
increased
risk
(see
CLINICAL
PHARMACOLOGY
and
671
INDIVIDUALIZATION OF DOSAGE).
672
Geriatric Patients: Studies indicate that although total plasma concentration of naproxen
673
is unchanged, the unbound plasma fraction of naproxen is increased in the elderly.
674
Caution is advised when high doses are required and some adjustment of dosage may be
675
required in elderly patients. As with other drugs used in the elderly, it is prudent to use
676
the lowest effective dose.
677
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
19
Juvenile Arthritis: The recommended total daily dose of naproxen is approximately 10
678
mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup marked
679
in 1/2 teaspoon and 2.5 milliliter increments is provided with the NAPROSYN
680
Suspension. The following table may be used as a guide for dosing of NAPROSYN
681
Suspension:
682
Patient’s Weight
Dose
Administered as
683
13 kg (29 lb)
62.5 mg bid
2.5 mL (1/2 tsp) twice daily
684
25 kg (55 lb)
125 mg bid
5.0 mL (1 tsp) twice daily
685
38 kg (84 lb)
187.5 mg bid
7.5 mL (1 1/2 tsp) twice daily
686
Management of Pain, Primary Dysmenorrhea and Acute Tendonitis and Bursitis: The
687
recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX
688
DS followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The
689
initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the
690
total daily dose should not exceed 1100 mg of naproxen sodium. NAPROSYN may also
691
be used but EC-NAPROSYN is not recommended for initial treatment of acute pain
692
because absorption of naproxen is delayed compared to other naproxen-containing
693
products (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE and
694
INDIVIDUALIZATION OF DOSAGE).
695
Acute Gout: The recommended starting dose is 750 mg of NAPROSYN followed by 250
696
mg every 8 hours until the attack has subsided. ANAPROX may also be used at a starting
697
dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not
698
recommended because of the delay in absorption (see CLINICAL PHARMACOLOGY).
699
HOW SUPPLIED
700
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on
701
one side and scored on the other. Packaged in light-resistant bottles of 100.
702
100’s (bottle): NDC 0004-6313-01.
703
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-
704
resistant bottles of 100 and 500.
705
100’s (bottle): NDC 0004-6314-01; 500’s (bottle): NDC 0004-6314-14.
706
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on
707
the other. Packaged in light-resistant bottles of 100 and 500.
708
100’s (bottle): NDC 0004-6316-01; 500’s (bottle): NDC 0004-6316-14.
709
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant
710
containers.
711
NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5
712
mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28).
713
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen tablets),
ANAPROX®/ANAPROX® DS (naproxen sodium tablets), NAPROSYN® (naproxen
suspension)
20
Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense
714
in light-resistant containers.
715
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped, imprinted
716
with EC-NAPROSYN on one side and 375 on the other. Packaged in light-resistant
717
bottles of 100.
718
100’s (bottle): NDC 0004-6415-01.
719
500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side and 500 on
720
the other. Packaged in light-resistant bottles of 100.
721
100’s (bottle): NDC 0004-6416-01.
722
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant
723
containers.
724
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with
725
NPS-275 on one side. Packaged in bottles of 100.
726
100’s (bottle): NDC 0004-6202-01.
727
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
728
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-shaped, engraved
729
with NPS 550 on one side and scored on both sides. Packaged in bottles of 100 and 500.
730
100’s (bottle): NDC 0004-6203-01; 500’s (bottle): NDC 0004-6203-14.
731
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
732
* ALEVE is a registered trademark of Bayer-Roche L.L.C.
733
734
Distributed by:
735
736
XXXXXXXX
737
Revised: Month/Year
738
Copyright © 1999-2004 by Roche Laboratories Inc. All rights reserved.
739
740
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:18.248135
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17581s99,100,18164s50,51,18965s9,10,20067s4,6lbl.pdf', 'application_number': 17581, 'submission_type': 'SUPPL ', 'submission_number': 99}
|
11,037
|
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 3
EC-NAPROSYN® (naproxen delayed-release tablets)
NAPROSYN® (naproxen tablets)
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
NAPROSYN® (naproxen suspension)
Rx only
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk
may increase with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is contraindicated for the treatment of
peri-operative pain in the setting of coronary artery bypass graft (CABG)
surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or
intestines, which can be fatal. These events can occur at any time during
use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs.
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2-
naphthaleneacetic
acid
and
(S)-6-methoxy-α-methyl-2-naphthaleneacetic
acid,
sodium
salt,
respectively. Naproxen and naproxen sodium have the following structures, respectively:
Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium
has a molecular weight of 252.23 and a molecular formula of C14H13NaO3.
Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically
insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition
coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline
solid, freely soluble in water at neutral pH.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 4
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250 mg of naproxen, peach
tablets containing 375 mg of naproxen and yellow tablets containing 500 mg of naproxen for oral
administration. The inactive ingredients are croscarmellose sodium, iron oxides, povidone and
magnesium stearate.
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-coated white tablets
containing 375 mg of naproxen and 500 mg of naproxen for oral administration. The inactive
ingredients are croscarmellose sodium, povidone and magnesium stearate. The enteric coating
dispersion contains methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and purified
water. The dispersion may also contain simethicone emulsion. The dissolution of this enteric-coated
naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH
4.
ANAPROX (naproxen sodium tablets) is available as blue tablets containing 275 mg of naproxen
sodium and ANAPROX DS (naproxen sodium tablets) is available as dark blue tablets containing 550
mg of naproxen sodium for oral administration. The inactive ingredients are magnesium stearate,
microcrystalline cellulose, povidone and talc. The coating suspension for the ANAPROX 275 mg
tablet may contain hydroxypropyl methylcellulose 2910, Opaspray K-1-4210A, polyethylene glycol
8000 or Opadry YS-1-4215. The coating suspension for the ANAPROX DS 550 mg tablet may contain
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene glycol 8000 or Opadry YS-1-
4216.
NAPROSYN (naproxen suspension) is available as a light orange-colored opaque oral suspension
containing 125 mg/5 mL of naproxen in a vehicle containing sucrose, magnesium aluminum silicate,
sorbitol solution and sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C
Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified water. The pH of the
suspension ranges from 2.2 to 3.7.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties.
The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen
for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is
not completely understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics
Naproxen itself is rapidly and completely absorbed from the gastrointestinal tract with an in vivo
bioavailability of 95%. The different dosage forms of NAPROSYN are bioequivalent in terms of
extent of absorption (AUC) and peak concentration (Cmax); however, the products do differ in their
pattern of absorption. These differences between naproxen products are related to both the chemical
form of naproxen used and its formulation. Even with the observed differences in pattern of
absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17
hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen
accumulation is consistent with this half-life. This suggests that the differences in pattern of release
play only a negligible role in the attainment of steady-state plasma levels.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 5
Absorption
Immediate Release
After administration of NAPROSYN tablets, peak plasma levels are attained in 2 to 4 hours. After oral
administration of ANAPROX, peak plasma levels are attained in 1 to 2 hours. The difference in rates
between the two products is due to the increased aqueous solubility of the sodium salt of naproxen
used in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in
1 to 4 hours.
Delayed Release
EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier to disintegration in the
acidic environment of the stomach and to lose integrity in the more neutral environment of the small
intestine. The enteric polymer coating selected for EC-NAPROSYN dissolves above pH 6. When EC-
NAPROSYN was given to fasted subjects, peak plasma levels were attained about 4 to 6 hours
following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled EC-
NAPROSYN tablets demonstrated that EC-NAPROSYN dissolves primarily in the small intestine
rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied.
When EC-NAPROSYN and NAPROSYN were given to fasted subjects (n=24) in a crossover study
following 1 week of dosing, differences in time to peak plasma levels (Tmax) were observed, but there
were no differences in total absorption as measured by Cmax and AUC:
EC-NAPROSYN*
500 mg bid
NAPROSYN*
500 mg bid
Cmax (µg/mL)
94.9 (18%)
97.4 (13%)
Tmax (hours)
4 (39%)
1.9 (61%)
AUC0–12 hr (µg·hr/mL)
845 (20%)
767 (15%)
*Mean value (coefficient of variation)
Antacid Effects
When EC-NAPROSYN was given as a single dose with antacid (54 mEq buffering capacity), the peak
plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6
hours, mean Tmax with antacid 5 hours), although not significantly.
Food Effects
When EC-NAPROSYN was given as a single dose with food, peak plasma levels in most subjects
were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until
disintegration was independent of food intake. The presence of food prolonged the time the tablets
remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen
levels (Tmax), but did not affect peak naproxen levels (Cmax).
Distribution
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99%
albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase
in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at
higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of
naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 6
concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see
PRECAUTIONS, Nursing Mothers).
Metabolism
Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and metabolites do
not induce metabolizing enzymes.
Excretion
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is
excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates
(66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The
corresponding half-lives of both naproxen’s metabolites and conjugates are shorter than 12 hours, and
their rates of excretion have been found to coincide closely with the rate of naproxen disappearance
from the plasma. In patients with renal failure metabolites may accumulate (see WARNINGS, Renal
Effects).
Special Populations
Pediatric Patients
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg
single dose of naproxen suspension (see DOSAGE AND ADMINISTRATION) were found to be
similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be
similar in pediatric and adult patients. Pharmacokinetic studies of naproxen were not performed in
pediatric patients younger than 5 years of age. Pharmacokinetic parameters appear to be similar
following administration of naproxen suspension or tablets in pediatric patients. EC-NAPROSYN has
not been studied in subjects under the age of 18.
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound
plasma fraction of naproxen is increased in the elderly, although the unbound fraction is < 1% of the
total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been
reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to
0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible
that the increase in free naproxen concentration could be associated with an increase in the rate of
adverse events per a given dosage in some elderly patients.
Race
Pharmacokinetic differences due to race have not been studied.
Hepatic Insufficiency
Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency.
Renal Insufficiency
Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that
naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for
naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is
decreased in patients with severe renal impairment. Naproxen-containing products are not
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 7
recommended for use in patients with moderate to severe and severe renal impairment (creatinine
clearance <30 mL/min) (see WARNINGS, Renal Effects).
CLINICAL STUDIES
General Information
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis,
ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for
rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of
morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and
by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen
has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis.
In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in
joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as
demonstrated by a reduction in walking time, and improvement in capacity to perform activities of
daily living impaired by the disease.
In a clinical trial comparing standard formulations of naproxen 375 mg bid (750 mg a day) vs 750 mg
bid (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events.
Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of
these adverse events were gastrointestinal events.
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and juvenile arthritis, naproxen
has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned
measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse
effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness,
lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or
indomethacin.
In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning
stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but
with fewer side effects.
In patients with acute gout, a favorable response to naproxen was shown by significant clearing of
inflammatory changes (eg, decrease in swelling, heat) within 24 to 48 hours, as well as by relief of
pain and tenderness.
Naproxen has been studied in patients with mild to moderate pain secondary to postoperative,
orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief
can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen
sodium. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in
pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay
in time to remedication. The analgesic effect has been found to last for up to 12 hours.
Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in
controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not
appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a
“steroid-sparing” effect has not been adequately studied. When added to the regimen of patients
receiving gold salts, naproxen did result in greater improvement. Its use in combination with
salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 8
naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater
improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the
combination may result in higher frequency of adverse events than demonstrated for either product
alone.
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of
naproxen as 1000 mg of NAPROSYN (naproxen) or 1100 mg of ANAPROX (naproxen sodium) has
been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of
aspirin.
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN (naproxen) (375 or 500 mg bid,
n=385) and NAPROSYN (375 or 500 mg bid, n=279) were conducted comparing EC-NAPROSYN
with NAPROSYN, including 355 rheumatoid arthritis and osteoarthritis patients who had a recent
history of NSAID-related GI symptoms. These studies indicated that EC-NAPROSYN and
NAPROSYN showed no significant differences in efficacy or safety and had similar prevalence of
minor GI complaints. Individual patients, however, may find one formulation preferable to the other.
Five hundred and fifty-three patients received EC-NAPROSYN during long-term open-label trials
(mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI
bleeds were similar to what has been historically reported for long-term NSAID use.
Geriatric Patients
The hepatic and renal tolerability of long-term naproxen administration was studied in two double-
blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older
and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice
daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing
hepatic and renal function were noted in some patients, although there were no differences noted in the
occurrence of abnormal values among different age groups.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS or NAPROSYN Suspension and other treatment options before deciding to use
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use the
lowest effective dose for the shortest duration consistent with individual patient treatment goals (see
WARNINGS).
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN
Suspension is indicated:
• For the relief of the signs and symptoms of rheumatoid arthritis
• For the relief of the signs and symptoms of osteoarthritis
• For the relief of the signs and symptoms of ankylosing spondylitis
• For the relief of the signs and symptoms of juvenile arthritis
Naproxen as NAPROSYN Suspension is recommended for juvenile rheumatoid arthritis in order to
obtain the maximum dosage flexibility based on the patient’s weight.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 9
Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension is also
indicated:
• For relief of the signs and symptoms of tendonitis
• For relief of the signs and symptoms of bursitis
• For relief of the signs and symptoms of acute gout
• For the management of pain
• For the management of primary dysmenorrhea
EC-NAPROSYN is not recommended for initial treatment of acute pain because the absorption of
naproxen is delayed compared to absorption from other naproxen-containing products (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are
contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium.
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should
not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking
aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been
reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS,
Preexisting Asthma).
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension are
contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft
(CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDS, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 10
Hypertension
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
Suspension, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of
which may contribute to the increased incidence of CV events. Patients taking thiazides or loop
diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, should
be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely
during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs.
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should be
used with caution in patients with fluid retention, hypertension, or heart failure. Since each
ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250
mg of naproxen), and each teaspoonful of NAPROSYN Suspension contains 39 mg (about 1.5 mEq
per each 125 mg of naproxen) of sodium, this should be considered in patients whose overall intake of
sodium must be severely restricted.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
Suspension, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal.
These serious adverse events can occur at any time, with or without warning symptoms, in patients
treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on
NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs
occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for
one year. These trends continue with longer duration of use, increasing the likelihood of developing a
serious GI event at some time during the course of therapy. However, even short-term therapy is not
without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been
adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk for GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and therefore, special care should be taken in treating this population. To minimize the potential risk
for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for
the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of
GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and
treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID
until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not
involve NSAIDs should be considered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 11
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal
anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver
dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation
of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment
state (see WARNINGS, Advanced Renal Disease).
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension in patients with advanced
renal disease. Therefore, treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS
and NAPROSYN Suspension is not recommended in these patients with advanced renal disease. If
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension therapy
must be initiated, close monitoring of the patient's renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension.
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension should
not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic
patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal
bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
PRECAUTIONS, Preexisting Asthma). Emergency help should be sought in cases where an
anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
Suspension, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson
Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may
occur without warning. Patients should be informed about the signs and symptoms of serious skin
manifestations and use of the drug should be discontinued at the first appearance of skin rash or any
other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS and NAPROSYN Suspension should be avoided because it may cause premature closure of the
ductus arteriosus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
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PRECAUTIONS
General
Naproxen-containing products such as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS, NAPROSYN SUSPENSION, ALEVE®, and other naproxen products should not be used
concomitantly since they all circulate in the plasma as the naproxen anion.
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension cannot be
expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation
of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy
should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the
patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency
and exacerbation of symptoms of arthritis.
Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should
have hemoglobin values determined periodically.
The pharmacological activity of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension in reducing fever and inflammation may diminish the utility of these
diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful
conditions.
Because of adverse eye findings in animal studies with drugs of this class, it is recommended that
ophthalmic studies be carried out if any change or disturbance in vision occurs.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs
including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
Suspension. These laboratory abnormalities may progress, may remain essentially unchanged, or may
be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of
liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper
limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In
addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver
necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more severe hepatic reaction
while on therapy with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN
Suspension.
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations
occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension should be discontinued.
Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma
proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of
unbound naproxen is increased. Caution is advised when high doses are required and some adjustment
of dosage may be required in these patients. It is prudent to use the lowest effective dose.
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Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension. This may be due to fluid retention, occult
or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term
treatment with NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension, should have their hemoglobin or hematocrit checked if they exhibit any
signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving either NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs
has been reported in such aspirin-sensitive patients, NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension should not be administered to patients with this form of
aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like
other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in
hospitalization and even death. Although serious CV events can occur without warning symptoms,
patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness,
slurring of speech, and should ask for medical advice when observing any indicative sign or
symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS,
Cardiovascular Effects).
2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like
other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and
bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations
and bleeding can occur without warning symptoms, patients should be alert for the signs and
symptoms of ulcerations and bleeding, and should ask for medical advice when observing any
indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
Patients should be apprised of the importance of this follow-up (see WARNINGS,
Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation).
3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension, like
other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN,
which may result in hospitalizations and even death. Although serious skin reactions may occur
without warning, patients should be alert for the signs and symptoms of skin rash and blisters,
fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 14
observing any indicative signs or symptoms. Patients should be advised to stop the drug
immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (eg, difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension should be avoided because it may cause premature
closure of the ductus arteriosus.
8. Caution should be exercised by patients whose activities require alertness if they experience
drowsiness, dizziness, vertigo or depression during therapy with naproxen.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This
interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-
inhibitors.
Aspirin
When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN
Suspension is administered with aspirin, its protein binding is reduced, although the clearance of free
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is not
altered. The clinical significance of this interaction is not known; however, as with other NSAIDs,
concomitant administration of naproxen and naproxen sodium and aspirin is not generally
recommended because of the potential of increased adverse effects.
Diuretics
Clinical studies, as well as postmarketing observations, have shown that NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension can reduce the natriuretic
effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be
observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as to assure
diuretic efficacy.
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Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.
Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory drugs have been reported to
reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could
enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered
concomitantly with methotrexate.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs
together have a risk of serious GI bleeding higher than users of either drug alone. No significant
interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants.
However, caution is advised since interactions have been seen with other nonsteroidal agents of this
class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes
with platelet function.
Other Information Concerning Drug Interactions
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with
other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other
NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or
sulphonylurea should be observed for adjustment of dose if required.
Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of
propranolol and other beta-blockers.
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life
significantly.
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy,
concomitant administration of EC-NAPROSYN is not recommended.
Drug/Laboratory Test Interaction
Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in
mind when bleeding times are determined.
The administration of naproxen may result in increased urinary values for 17-ketogenic steroids
because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this
assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be
artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours
before adrenal function tests are performed if the Porter-Silber test is to be used.
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Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Carcinogenesis
A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of
8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2). The maximum dose used was 0.28 times the
systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the
human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic
exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with
no evidence of impaired fertility or harm to the fetus due to the drug. However, animal reproduction
studies are not always predictive of human response. There are no adequate and well-controlled studies
in pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
Suspension should be used in pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nonteratogenic Effects
There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay
preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis,
patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to
delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and
abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-
inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during
pregnancy (particularly late pregnancy) should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing
products are not recommended in labor and delivery because, through its prostaglandin synthesis
inhibitory effect, naproxen may adversely affect fetal circulation and inhibit uterine contractions, thus
increasing the risk of uterine hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension on labor and delivery in pregnant women are unknown.
Nursing Mothers
The naproxen anion has been found in the milk of lactating women at a concentration equivalent to
approximately 1% of maximum naproxen concentration in plasma. Because of the possible adverse
effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.
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Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years have not been established.
Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see
DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data
for other pediatric conditions, but the experience in juvenile arthritis and other use experience have
established that single doses of 2.5 to 5 mg/kg (as naproxen suspension, see DOSAGE AND
ADMINISTRATION), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in
pediatric patients over 2 years of age.
Geriatric Use
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound
plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are
required and some adjustment of dosage may be required in elderly patients. As with other drugs used
in the elderly, it is prudent to use the lowest effective dose.
Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of
nonsteroidal anti-inflammatory drugs. While age does not appear to be an independent risk factor for
the development of peptic ulceration and bleeding with naproxen administration, eElderly or
debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur.
Most spontaneous reports of fatal GI events are in the geriatric population (see WARNINGS).
Naproxen 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. Geriatric patients may be at a greater risk for the development of a form of
renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal
anti-inflammatory drugs (see WARNINGS, Renal Effects).
ADVERSE REACTIONS
Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or
osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10
times more frequently than they were in short-term studies in the 962 patients treated for mild to
moderate pain or for dysmenorrhea. The most frequent complaints reported related to the
gastrointestinal tract.
A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid
arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen
(see CLINICAL PHARMACOLOGY).
In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies
with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash
and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous
system reactions were about the same, and the incidence of other reactions were lower in pediatric
patients than in adults.
In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in
approximately 1% to 10% of patients are:
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*, constipation*,
diarrhea, dyspepsia, stomatitis
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Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating, purpura
Special Senses: tinnitus*, visual disturbances, hearing disturbances
Cardiovascular: edema*, palpitations
General: dyspnea*, thirst
*Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the
patients are unmarked.
In patients taking NSAIDs, the following adverse experiences have also been reported in
approximately 1% to 10% of patients.
Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers
(gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes
The following are additional adverse experiences reported in <1% of patients taking naproxen during
clinical trials and through postmarketing reports. Those adverse reactions observed through
postmarketing reports are italicized.
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills
and fever)
Cardiovascular: congestive heart failure, vasculitis
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, pancreatitis,
vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal ulceration, ulcerative
stomatitis
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis,
granulocytopenia, hemolytic anemia, aplastic anemia
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise,
myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction
Respiratory: eosinophilic pneumonitis
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme,
Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases
resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility,
blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued
and the patient monitored.
Special Senses: hearing impairment
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome,
renal disease, renal failure, renal papillary necrosis
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In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of
patients.
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death
Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, hepatitis, eructation,
liver failure
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors,
convulsions, coma, hallucinations
Respiratory: asthma, respiratory depression, pneumonia
Dermatologic: exfoliative dermatitis
Special Senses: blurred vision, conjunctivitis
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
OVERDOSAGE
Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric
pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function,
hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting.
Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and
coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion
of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly
absorbed, high and early blood levels should be anticipated. A few patients have experienced
convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the
drug would be life threatening. The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice,
4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
Patients should be managed by symptomatic and supportive care following a NSAID overdose. There
are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen
because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in
adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4
hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of
urine or hemoperfusion may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension and other treatment options before deciding to use
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension. Use the
lowest effective dose for the shortest duration consistent with individual patient treatment goals (see
WARNINGS).
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After observing the response to initial therapy with NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS or NAPROSYN Suspension, the dose and frequency should be adjusted to suit an
individual patient's needs.
Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily
bioequivalent. This difference should be taken into consideration when changing formulation.
Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN, ANAPROX and ANAPROX DS
all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of
action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within
1 hour in patients taking naproxen. Because EC-NAPROSYN dissolves in the small intestine rather
than in the stomach, the absorption of the drug is delayed compared to the other naproxen formulations
(see CLINICAL PHARMACOLOGY).
The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to
be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse
events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly
patients (see WARNINGS and PRECAUTIONS).
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound
plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are
required and some adjustment of dosage may be required in elderly patients. As with other drugs used
in the elderly, it is prudent to use the lowest effective dose.
Patients With Moderate to Severe Renal Impairment
Naproxen-containing products are not recommended for use in patients with moderate to severe and
severe renal impairment (creatinine clearance <30 mL/min) (see WARNINGS: Renal Effects).
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
NAPROSYN
250 mg
or 375 mg
or 500 mg
twice daily
twice daily
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
NAPROSYN
Suspension
250 mg (10 mL/2 tsp)
or 375 mg (15 mL/3 tsp)
or 500 mg (20 mL/4 tsp)
twice daily
twice daily
twice daily
EC-NAPROSYN
375 mg
or 500 mg
twice daily
twice daily
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken,
crushed or chewed during ingestion.
During long-term administration, the dose of naproxen may be adjusted up or down depending on the
clinical response of the patient. A lower daily dose may suffice for long-term administration. The
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morning and evening doses do not have to be equal in size and the administration of the drug more
frequently than twice daily is not necessary.
In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for
limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is
required. When treating such patients with naproxen 1500 mg/day, the physician should observe
sufficient increased clinical benefits to offset the potential increased risk. The morning and evening
doses do not have to be equal in size and administration of the drug more frequently than twice daily
does not generally make a difference in response (see CLINICAL PHARMACOLOGY).
Juvenile Arthritis
The use of NAPROSYN Suspension allows for more flexible dose titration. In pediatric patients, doses
of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of
naproxen (see CLINICAL PHARMACOLOGY).
The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses
(ie, 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2.5 milliliter increments
is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing
of NAPROSYN Suspension:
Patient’s Weight
Dose
Administered as
13 kg (29 lb)
62.5 mg bid 2.5 mL (1/2 tsp) twice daily
25 kg (55 lb)
125 mg bid 5.0 mL (1 tsp) twice daily
38 kg (84 lb)
187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily
Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis
The recommended starting dose is 550 mg of naproxen sodium as ANAPROX/ANAPROX DS
followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily
dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not
exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed,
ANAPROX/ANAPROX DS is recommended for the management of acute painful conditions when
prompt onset of pain relief is desired. NAPROSYN may also be used but EC-NAPROSYN is not
recommended for initial treatment of acute pain because absorption of naproxen is delayed compared
to other naproxen-containing products (see CLINICAL PHARMACOLOGY, INDICATIONS AND
USAGE).
Acute Gout
The recommended starting dose is 750 mg of NAPROSYN followed by 250 mg every 8 hours until the
attack has subsided. ANAPROX may also be used at a starting dose of 825 mg followed by 275 mg
every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption (see
CLINICAL PHARMACOLOGY).
HOW SUPPLIED
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR LE 250 on one side and
scored on the other. Packaged in light-resistant bottles of 100.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 22
100’s (bottle): NDC 0004-6313-01.
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side. Packaged in light-resistant
bottles of 100.
100’s (bottle): NDC 0004-6314-01.
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on the other.
Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 0004-6316-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers.
NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5 mEq/teaspoon):
Available in 1 pint (473 mL) light-resistant bottles (NDC 0004-0028-28).
Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F). Dispense in light-
resistant containers.
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped, imprinted with EC-
NAPROSYN on one side and 375 on the other. Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 0004-6415-01.
500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side and 500 on the other.
Packaged in light-resistant bottles of 100.
100’s (bottle): NDC 0004-6416-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers.
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped, engraved with NPS-275 on
one side. Packaged in bottles of 100.
100’s (bottle): NDC 0004-6202-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-shaped, engraved with NPS
550 on one side and scored on both sides. Packaged in bottles of 100.
100’s (bottle): NDC 0004-6203-01.
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
ALEVE is a registered trademark of Bayer Healthcare LLC.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 23
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 24
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-581/S-106, 18-164/S-056, 18-965/S-014, 20-067/S-011
Page 25
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:18.545468
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017581s106,018164s056,018965s014,020067s011lbl.pdf', 'application_number': 17581, 'submission_type': 'SUPPL ', 'submission_number': 106}
|
11,036
|
1
1
EC-NAPROSYN® (naproxen delayed-release tablets)
2
NAPROSYN® (naproxen tablets)
3
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
4
NAPROSYN® (naproxen suspension)
5
Rx only
6
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk
may increase with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is contraindicated for the treatment of
peri-operative pain in the setting of coronary artery bypass graft (CABG)
surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or
intestines, which can be fatal. These events can occur at any time during
use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
7
Naproxen is a proprionic acid derivative related to the arylacetic acid group of
8
nonsteroidal anti-inflammatory drugs.
9
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-
10
methyl-2-naphthaleneacetic
acid
and
(S)-6-methoxy-α-methyl-2-
11
naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen
12
sodium have the following structures, respectively:
13
14
Naproxen has a molecular weight of 230.26 and a molecular formula of
15
C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a
16
molecular formula of C14H13NaO3.
17
Naproxen is an odorless, white to off-white crystalline substance. It is lipid-
18
soluble, practically insoluble in water at low pH and freely soluble in water at
19
high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
2
to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely
21
soluble in water at neutral pH.
22
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250
23
mg of naproxen, pink tablets containing 375 mg of naproxen and yellow
24
tablets containing 500 mg of naproxen for oral administration. The inactive
25
ingredients are croscarmellose sodium, iron oxides, povidone and magnesium
26
stearate.
27
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-
28
coated white tablets containing 375 mg of naproxen and 500 mg of naproxen
29
for oral administration. The inactive ingredients are croscarmellose sodium,
30
povidone and magnesium stearate. The enteric coating dispersion contains
31
methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and
32
purified water. The dispersion may also contain simethicone emulsion. The
33
dissolution of this enteric-coated naproxen tablet is pH dependent with rapid
34
dissolution above pH 6. There is no dissolution below pH 4.
35
ANAPROX (naproxen sodium tablets) is available as blue tablets containing
36
275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is
37
available as dark blue tablets containing 550 mg of naproxen sodium for oral
38
administration.
The
inactive
ingredients
are
magnesium
stearate,
39
microcrystalline cellulose, povidone and talc. The coating suspension for the
40
ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910,
41
Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The
42
coating suspension for the ANAPROX DS 550 mg tablet may contain
43
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene
44
glycol 8000 or Opadry YS-1-4216.
45
NAPROSYN (naproxen suspension) is available as a light orange-colored
46
opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle
47
containing sucrose, magnesium aluminum silicate, sorbitol solution and
48
sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C
49
Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified
50
water. The pH of the suspension ranges from 2.2 to 3.7.
51
CLINICAL PHARMACOLOGY
52
Pharmacodynamics
53
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic
54
and antipyretic properties. The sodium salt of naproxen has been developed as
55
a more rapidly absorbed formulation of naproxen for use as an analgesic. The
56
mechanism of action of the naproxen anion, like that of other NSAIDs, is not
57
completely understood but may be related to prostaglandin synthetase
58
inhibition.
59
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
3
Pharmacokinetics
60
Naproxen and naproxen sodium are rapidly and completely absorbed from the
61
gastrointestinal tract with an in vivo bioavailability of 95%. The different
62
dosage forms of NAPROSYN are bioequivalent in terms of extent of
63
absorption (AUC) and peak concentration (Cmax); however, the products do
64
differ in their pattern of absorption. These differences between naproxen
65
products are related to both the chemical form of naproxen used and its
66
formulation. Even with the observed differences in pattern of absorption, the
67
elimination half-life of naproxen is unchanged across products ranging from
68
12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and
69
the degree of naproxen accumulation is consistent with this half-life. This
70
suggests that the differences in pattern of release play only a negligible role in
71
the attainment of steady-state plasma levels.
72
Absorption
73
Immediate Release
74
After administration of NAPROSYN tablets, peak plasma levels are attained
75
in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels
76
are attained in 1 to 2 hours. The difference in rates between the two products
77
is due to the increased aqueous solubility of the sodium salt of naproxen used
78
in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN
79
Suspension are attained in 1 to 4 hours.
80
Delayed Release
81
EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier
82
to disintegration in the acidic environment of the stomach and to lose integrity
83
in the more neutral environment of the small intestine. The enteric polymer
84
coating selected for EC-NAPROSYN dissolves above pH 6. When EC-
85
NAPROSYN was given to fasted subjects, peak plasma levels were attained
86
about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo
87
study in man using radiolabeled EC-NAPROSYN tablets demonstrated that
88
EC-NAPROSYN dissolves primarily in the small intestine rather than in the
89
stomach, so the absorption of the drug is delayed until the stomach is emptied.
90
When EC-NAPROSYN and NAPROSYN were given to fasted subjects
91
(n=24) in a crossover study following 1 week of dosing, differences in time to
92
peak plasma levels (Tmax) were observed, but there were no differences in total
93
absorption as measured by Cmax and AUC:
94
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
4
EC-NAPROSYN*
500 mg bid
NAPROSYN*
500 mg bid
Cmax (µg/mL)
94.9 (18%)
97.4 (13%)
Tmax (hours)
4 (39%)
1.9 (61%)
AUC0–12 hr (µg·hr/mL)
845 (20%)
767 (15%)
*Mean value (coefficient of variation)
95
Antacid Effects
96
When EC-NAPROSYN was given as a single dose with antacid (54 mEq
97
buffering capacity), the peak plasma levels of naproxen were unchanged, but
98
the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with
99
antacid 5 hours), although not significantly.
100
Food Effects
101
When EC-NAPROSYN was given as a single dose with food, peak plasma
102
levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours).
103
Residence time in the small intestine until disintegration was independent of
104
food intake. The presence of food prolonged the time the tablets remained in
105
the stomach, time to first detectable serum naproxen levels, and time to
106
maximal naproxen levels (Tmax), but did not affect peak naproxen levels
107
(Cmax).
108
Distribution
109
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels
110
naproxen is greater than 99% albumin-bound. At doses of naproxen greater
111
than 500 mg/day there is less than proportional increase in plasma levels due
112
to an increase in clearance caused by saturation of plasma protein binding at
113
higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and
114
1500 mg daily doses of naproxen, respectively). The naproxen anion has been
115
found in the milk of lactating women at a concentration equivalent to
116
approximately 1% of maximum naproxen concentration in plasma (see
117
PRECAUTIONS: Nursing Mothers).
118
Metabolism
119
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen,
120
and both parent and metabolites do not induce metabolizing enzymes. Both
121
naproxen and 6-0-desmethyl naproxen are further metabolized to their
122
respective acylglucuronide conjugated metabolites.
123
Excretion
124
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the
125
naproxen from any dose is excreted in the urine, primarily as naproxen (<1%),
126
6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma
127
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
5
half-life of the naproxen anion in humans ranges from 12 to 17 hours. The
128
corresponding half-lives of both naproxen’s metabolites and conjugates are
129
shorter than 12 hours, and their rates of excretion have been found to coincide
130
closely with the rate of naproxen disappearance from the plasma. Small
131
amounts, 3% or less of the administered dose, are excreted in the feces. In
132
patients with renal failure metabolites may accumulate (see WARNINGS:
133
Renal Effects).
134
Special Populations
135
Pediatric Patients
136
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels
137
following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND
138
ADMINISTRATION) were found to be similar to those found in normal
139
adults following a 500 mg dose. The terminal half-life appears to be similar in
140
pediatric and adult patients. Pharmacokinetic studies of naproxen were not
141
performed in pediatric patients younger than 5 years of age. Pharmacokinetic
142
parameters appear to be similar following administration of naproxen
143
suspension or tablets in pediatric patients. EC-NAPROSYN has not been
144
studied in subjects under the age of 18.
145
Geriatric Patients
146
Studies indicate that although total plasma concentration of naproxen is
147
unchanged, the unbound plasma fraction of naproxen is increased in the
148
elderly, although the unbound fraction is < 1% of the total naproxen
149
concentration. Unbound trough naproxen concentrations in elderly subjects
150
have been reported to range from 0.12% to 0.19% of total naproxen
151
concentration, compared with 0.05% to 0.075% in younger subjects. The
152
clinical significance of this finding is unclear, although it is possible that the
153
increase in free naproxen concentration could be associated with an increase
154
in the rate of adverse events per a given dosage in some elderly patients.
155
Race
156
Pharmacokinetic differences due to race have not been studied.
157
Hepatic Insufficiency
158
Naproxen pharmacokinetics has not been determined in subjects with hepatic
159
insufficiency.
160
Renal Insufficiency
161
Naproxen pharmacokinetics has not been determined in subjects with renal
162
insufficiency. Given that naproxen, its metabolites and conjugates are
163
primarily excreted by the kidney, the potential exists for naproxen metabolites
164
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
6
to accumulate in the presence of renal insufficiency. Elimination of naproxen
165
is decreased in patients with severe renal impairment. Naproxen-containing
166
products are not recommended for use in patients with moderate to severe and
167
severe
renal
impairment
(creatinine
clearance
<30
mL/min)
(see
168
WARNINGS: Renal Effects).
169
CLINICAL STUDIES
170
General Information
171
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis,
172
juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute
173
gout. Improvement in patients treated for rheumatoid arthritis was
174
demonstrated by a reduction in joint swelling, a reduction in duration of
175
morning stiffness, a reduction in disease activity as assessed by both the
176
investigator and patient, and by increased mobility as demonstrated by a
177
reduction in walking time. Generally, response to naproxen has not been
178
found to be dependent on age, sex, severity or duration of rheumatoid arthritis.
179
In patients with osteoarthritis, the therapeutic action of naproxen has been
180
shown by a reduction in joint pain or tenderness, an increase in range of
181
motion in knee joints, increased mobility as demonstrated by a reduction in
182
walking time, and improvement in capacity to perform activities of daily
183
living impaired by the disease.
184
In a clinical trial comparing standard formulations of naproxen 375 mg bid
185
(750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group
186
terminated prematurely because of adverse events. Nineteen patients in the
187
1500 mg group terminated prematurely because of adverse events. Most of
188
these adverse events were gastrointestinal events.
189
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and
190
juvenile arthritis, naproxen has been shown to be comparable to aspirin and
191
indomethacin in controlling the aforementioned measures of disease activity,
192
but the frequency and severity of the milder gastrointestinal adverse effects
193
(nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus,
194
dizziness, lightheadedness) were less in naproxen-treated patients than in
195
those treated with aspirin or indomethacin.
196
In patients with ankylosing spondylitis, naproxen has been shown to decrease
197
night pain, morning stiffness and pain at rest. In double-blind studies the drug
198
was shown to be as effective as aspirin, but with fewer side effects.
199
In patients with acute gout, a favorable response to naproxen was shown by
200
significant clearing of inflammatory changes (eg, decrease in swelling, heat)
201
within 24 to 48 hours, as well as by relief of pain and tenderness.
202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
7
Naproxen has been studied in patients with mild to moderate pain secondary
203
to postoperative, orthopedic, postpartum episiotomy and uterine contraction
204
pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in
205
patients taking naproxen and within 30 minutes in patients taking naproxen
206
sodium. Analgesic effect was shown by such measures as reduction of pain
207
intensity scores, increase in pain relief scores, decrease in numbers of patients
208
requiring additional analgesic medication, and delay in time to remedication.
209
The analgesic effect has been found to last for up to 12 hours.
210
Naproxen may be used safely in combination with gold salts and/or
211
corticosteroids; however, in controlled clinical trials, when added to the
212
regimen of patients receiving corticosteroids, it did not appear to cause greater
213
improvement over that seen with corticosteroids alone. Whether naproxen has
214
a “steroid-sparing” effect has not been adequately studied. When added to the
215
regimen of patients receiving gold salts, naproxen did result in greater
216
improvement. Its use in combination with salicylates is not recommended
217
because there is evidence that aspirin increases the rate of excretion of
218
naproxen and data are inadequate to demonstrate that naproxen and aspirin
219
produce greater improvement over that achieved with aspirin alone. In
220
addition, as with other NSAIDs, the combination may result in higher
221
frequency of adverse events than demonstrated for either product alone.
222
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily
223
administration of 1000 mg of naproxen as 1000 mg of NAPROSYN
224
(naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been
225
demonstrated to cause statistically significantly less gastric bleeding and
226
erosion than 3250 mg of aspirin.
227
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN
228
(naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid,
229
n=279) were conducted comparing EC-NAPROSYN with NAPROSYN,
230
including 355 rheumatoid arthritis and osteoarthritis patients who had a recent
231
history of NSAID-related GI symptoms. These studies indicated that EC-
232
NAPROSYN and NAPROSYN showed no significant differences in efficacy
233
or safety and had similar prevalence of minor GI complaints. Individual
234
patients, however, may find one formulation preferable to the other.
235
Five hundred and fifty-three patients received EC-NAPROSYN during long-
236
term open-label trials (mean length of treatment was 159 days). The rates for
237
clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been
238
historically reported for long-term NSAID use.
239
Geriatric Patients
240
The hepatic and renal tolerability of long-term naproxen administration was
241
studied in two double-blind clinical trials involving 586 patients. Of the
242
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
8
patients studied, 98 patients were age 65 and older and 10 of the 98 patients
243
were age 75 and older. Naproxen was administered at doses of 375 mg twice
244
daily or 750 mg twice daily for up to 6 months. Transient abnormalities of
245
laboratory tests assessing hepatic and renal function were noted in some
246
patients, although there were no differences noted in the occurrence of
247
abnormal values among different age groups.
248
INDICATIONS AND USAGE
249
Carefully consider the potential benefits and risks of NAPROSYN, EC-
250
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and
251
other treatment options before deciding to use NAPROSYN, EC-
252
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use
253
the lowest effective dose for the shortest duration consistent with individual
254
patient treatment goals (see WARNINGS).
255
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
256
NAPROSYN Suspension is indicated:
257
• For the relief of the signs and symptoms of rheumatoid arthritis
258
• For the relief of the signs and symptoms of osteoarthritis
259
• For the relief of the signs and symptoms of ankylosing spondylitis
260
• For the relief of the signs and symptoms of juvenile arthritis
261
Naproxen as NAPROSYN Suspension is recommended for juvenile
262
rheumatoid arthritis in order to obtain the maximum dosage flexibility based
263
on the patient’s weight.
264
Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
265
Suspension is also indicated:
266
• For relief of the signs and symptoms of tendonitis
267
• For relief of the signs and symptoms of bursitis
268
• For relief of the signs and symptoms of acute gout
269
• For the management of pain
270
• For the management of primary dysmenorrhea
271
EC-NAPROSYN is not recommended for initial treatment of acute pain
272
because the absorption of naproxen is delayed compared to absorption from
273
other naproxen-containing products (see CLINICAL PHARMACOLOGY
274
and DOSAGE AND ADMINISTRATION).
275
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
9
CONTRAINDICATIONS
276
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
277
NAPROSYN Suspension are contraindicated in patients with known
278
hypersensitivity to naproxen and naproxen sodium.
279
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
280
NAPROSYN Suspension should not be given to patients who have
281
experienced asthma, urticaria, or allergic-type reactions after taking aspirin or
282
other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs
283
have been reported in such patients (see WARNINGS: Anaphylactoid
284
Reactions and PRECAUTIONS: Preexisting Asthma).
285
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
286
NAPROSYN Suspension are contraindicated for the treatment of peri-
287
operative pain in the setting of coronary artery bypass graft (CABG) surgery
288
(see WARNINGS).
289
WARNINGS
290
CARDIOVASCULAR EFFECTS
291
Cardiovascular Thrombotic Events
292
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to
293
three years duration have shown an increased risk of serious cardiovascular
294
(CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.
295
All NSAIDS, both COX-2 selective and nonselective, may have a similar risk.
296
Patients with known CV disease or risk factors for CV disease may be at
297
greater risk. To minimize the potential risk for an adverse CV event in patients
298
treated with an NSAID, the lowest effective dose should be used for the
299
shortest duration possible. Physicians and patients should remain alert for the
300
development of such events, even in the absence of previous CV symptoms.
301
Patients should be informed about the signs and/or symptoms of serious CV
302
events and the steps to take if they occur.
303
There is no consistent evidence that concurrent use of aspirin mitigates the
304
increased risk of serious CV thrombotic events associated with NSAID use.
305
The concurrent use of aspirin and an NSAID does increase the risk of serious
306
GI events (see Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
307
Perforation).
308
Two large, controlled, clinical trials of a COX-2 selective NSAID for the
309
treatment of pain in the first 10-14 days following CABG surgery found an
310
increased
incidence
of
myocardial
infarction
and
stroke
(see
311
CONTRAINDICATIONS).
312
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
10
Hypertension
313
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
314
ANAPROX DS and NAPROSYN Suspension, can lead to onset of new
315
hypertension or worsening of pre-existing hypertension, either of which may
316
contribute to the increased incidence of CV events. Patients taking thiazides or
317
loop diuretics may have impaired response to these therapies when taking
318
NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
319
ANAPROX DS and NAPROSYN Suspension, should be used with caution in
320
patients with hypertension. Blood pressure (BP) should be monitored closely
321
during the initiation of NSAID treatment and throughout the course of
322
therapy.
323
Congestive Heart Failure and Edema
324
Fluid retention, edema, and peripheral edema have been observed in some
325
patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX,
326
ANAPROX DS and NAPROSYN Suspension should be used with caution in
327
patients with fluid retention, hypertension, or heart failure. Since each
328
ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium
329
(about 1 mEq per each 250 mg of naproxen), and each teaspoonful of
330
NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of
331
naproxen) of sodium, this should be considered in patients whose overall
332
intake of sodium must be severely restricted.
333
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
334
Perforation
335
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
336
ANAPROX DS and NAPROSYN Suspension, can cause serious
337
gastrointestinal (GI) adverse events including inflammation, bleeding,
338
ulceration, and perforation of the stomach, small intestine, or large intestine,
339
which can be fatal.
340
These serious adverse events can occur at any time, with or without warning
341
symptoms, in patients treated with NSAIDs. Only one in five patients, who
342
develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
343
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in
344
approximately 1% of patients treated for 3-6 months, and in about 2-4% of
345
patients treated for one year. These trends continue with longer duration of
346
use, increasing the likelihood of developing a serious GI event at some time
347
during the course of therapy. However, even short-term therapy is not without
348
risk. The utility of periodic laboratory monitoring has not been demonstrated,
349
nor has it been adequately assessed. Only 1 in 5 patients who develop a
350
serious upper GI adverse event on NSAID therapy is symptomatic.
351
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
11
NSAIDs should be prescribed with extreme caution in those with a prior
352
history of ulcer disease or gastrointestinal bleeding. Patients with a prior
353
history of peptic ulcer disease and/or gastrointestinal bleeding who use
354
NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
355
compared to patients with neither of these risk factors. Other factors that
356
increase the risk for GI bleeding in patients treated with NSAIDs include
357
concomitant use of oral corticosteroids or anticoagulants, longer duration of
358
NSAID therapy, smoking, use of alcohol, older age, and poor general health
359
status. Most spontaneous reports of fatal GI events are in elderly or debilitated
360
patients and therefore, special care should be taken in treating this population.
361
To minimize the potential risk for an adverse GI event in patients treated with
362
an NSAID, the lowest effective dose should be used for the shortest possible
363
duration. Patients and physicians should remain alert for signs and symptoms
364
of GI ulceration and bleeding during NSAID therapy and promptly initiate
365
additional evaluation and treatment if a serious GI adverse event is suspected.
366
This should include discontinuation of the NSAID until a serious GI adverse
367
event is ruled out. For high risk patients, alternate therapies that do not
368
involve NSAIDs should be considered.
369
Renal Effects
370
Long-term administration of NSAIDs has resulted in renal papillary necrosis
371
and other renal injury. Renal toxicity has also been seen in patients in whom
372
renal prostaglandins have a compensatory role in the maintenance of renal
373
perfusion.
In
these
patients,
administration
of
a
nonsteroidal
374
anti-inflammatory drug may cause a dose-dependent reduction in
375
prostaglandin formation and, secondarily, in renal blood flow, which may
376
precipitate overt renal decompensation. Patients at greatest risk of this
377
reaction are those with impaired renal function, hypovolemia, heart failure,
378
liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors,
379
and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug
380
therapy is usually followed by recovery to the pretreatment state (see
381
WARNINGS: Advanced Renal Disease).
382
Advanced Renal Disease
383
No information is available from controlled clinical studies regarding the use
384
of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
385
NAPROSYN Suspension in patients with advanced renal disease. Therefore,
386
treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS
387
and NAPROSYN Suspension is not recommended in these patients with
388
advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX,
389
ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close
390
monitoring of the patient’s renal function is advisable.
391
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
12
Anaphylactoid Reactions
392
As with other NSAIDs, anaphylactoid reactions may occur in patients without
393
known prior exposure to either NAPROSYN, EC-NAPROSYN, ANAPROX,
394
ANAPROX
DS
or
NAPROSYN
Suspension.
NAPROSYN,
EC-
395
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
396
should not be given to patients with the aspirin triad. This symptom complex
397
typically occurs in asthmatic patients who experience rhinitis with or without
398
nasal polyps, or who exhibit severe, potentially fatal bronchospasm after
399
taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
400
PRECAUTIONS: Preexisting Asthma). Emergency help should be sought
401
in cases where an anaphylactoid reaction occurs.
402
Skin Reactions
403
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
404
ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse
405
events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
406
toxic epidermal necrolysis (TEN), which can be fatal. These serious events
407
may occur without warning. Patients should be informed about the signs and
408
symptoms of serious skin manifestations and use of the drug should be
409
discontinued at the first appearance of skin rash or any other sign of
410
hypersensitivity.
411
Pregnancy
412
In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
413
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided
414
because it may cause premature closure of the ductus arteriosus.
415
PRECAUTIONS
416
General
417
Naproxen-containing products such as NAPROSYN, EC-NAPROSYN,
418
ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and
419
other naproxen products should not be used concomitantly since they all
420
circulate in the plasma as the naproxen anion.
421
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
422
NAPROSYN Suspension cannot be expected to substitute for corticosteroids
423
or to treat corticosteroid insufficiency. Abrupt discontinuation of
424
corticosteroids may lead to disease exacerbation. Patients on prolonged
425
corticosteroid therapy should have their therapy tapered slowly if a decision is
426
made to discontinue corticosteroids and the patient should be observed closely
427
for any evidence of adverse effects, including adrenal insufficiency and
428
exacerbation of symptoms of arthritis.
429
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
13
Patients with initial hemoglobin values of 10 g or less who are to receive long-
430
term therapy should have hemoglobin values determined periodically.
431
The
pharmacological
activity
of
NAPROSYN,
EC-NAPROSYN,
432
ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever
433
and inflammation may diminish the utility of these diagnostic signs in
434
detecting complications of presumed noninfectious, noninflammatory painful
435
conditions.
436
Because of adverse eye findings in animal studies with drugs of this class, it is
437
recommended that ophthalmic studies be carried out if any change or
438
disturbance in vision occurs.
439
Hepatic Effects
440
Borderline elevations of one or more liver tests may occur in up to 15% of
441
patients
taking
NSAIDs
including
NAPROSYN,
EC-NAPROSYN,
442
ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic
443
abnormalities may be the result of hypersensitivity rather than direct toxicity.
444
These laboratory abnormalities may progress, may remain essentially
445
unchanged, or may be transient with continued therapy. The SGPT (ALT) test
446
is probably the most sensitive indicator of liver dysfunction. Notable
447
elevations of ALT or AST (approximately three or more times the upper limit
448
of normal) have been reported in approximately 1% of patients in clinical
449
trials with NSAIDs. In addition, rare cases of severe hepatic reactions,
450
including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
451
failure, some of them with fatal outcomes have been reported.
452
A patient with symptoms and/or signs suggesting liver dysfunction, or in
453
whom an abnormal liver test has occurred, should be evaluated for evidence
454
of the development of more severe hepatic reaction while on therapy with
455
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
456
NAPROSYN Suspension.
457
If clinical signs and symptoms consistent with liver disease develop, or if
458
systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC-
459
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension
460
should be discontinued.
461
Chronic alcoholic liver disease and probably other diseases with decreased or
462
abnormal plasma proteins (albumin) reduce the total plasma concentration of
463
naproxen, but the plasma concentration of unbound naproxen is increased.
464
Caution is advised when high doses are required and some adjustment of
465
dosage may be required in these patients. It is prudent to use the lowest
466
effective dose.
467
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
14
Hematological Effects
468
Anemia is sometimes seen in patients receiving NSAIDs, including
469
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
470
NAPROSYN Suspension. This may be due to fluid retention, occult or gross
471
GI blood loss, or an incompletely described effect upon erythropoiesis.
472
Patients on long-term treatment with NSAIDs, including NAPROSYN, EC-
473
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension,
474
should have their hemoglobin or hematocrit checked if they exhibit any signs
475
or symptoms of anemia.
476
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding
477
time in some patients. Unlike aspirin, their effect on platelet function is
478
quantitatively less, of shorter duration, and reversible. Patients receiving either
479
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
480
NAPROSYN Suspension who may be adversely affected by alterations in
481
platelet function, such as those with coagulation disorders or patients
482
receiving anticoagulants, should be carefully monitored.
483
Preexisting Asthma
484
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in
485
patients with aspirin-sensitive asthma has been associated with severe
486
bronchospasm, which can be fatal. Since cross reactivity, including
487
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
488
drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC-
489
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
490
should not be administered to patients with this form of aspirin sensitivity and
491
should be used with caution in patients with preexisting asthma.
492
Information for Patients
493
Patients should be informed of the following information before initiating
494
therapy with an NSAID and periodically during the course of ongoing
495
therapy. Patients should also be encouraged to read the NSAID
496
Medication Guide that accompanies each prescription dispensed.
497
1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
498
NAPROSYN Suspension, like other NSAIDs, may cause serious CV side
499
effects, such as MI or stroke, which may result in hospitalization and even
500
death. Although serious CV events can occur without warning symptoms,
501
patients should be alert for the signs and symptoms of chest pain,
502
shortness of breath, weakness, slurring of speech, and should ask for
503
medical advice when observing any indicative sign or symptoms. Patients
504
should be apprised of the importance of this follow-up (see WARNINGS:
505
Cardiovascular Effects).
506
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
15
2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
507
NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort
508
and, rarely, serious GI side effects, such as ulcers and bleeding, which
509
may result in hospitalization and even death. Although serious GI tract
510
ulcerations and bleeding can occur without warning symptoms, patients
511
should be alert for the signs and symptoms of ulcerations and bleeding,
512
and should ask for medical advice when observing any indicative sign or
513
symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
514
Patients should be apprised of the importance of this follow-up (see
515
WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding,
516
and Perforation).
517
3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
518
NAPROSYN Suspension, like other NSAIDs, can cause serious skin side
519
effects such as exfoliative dermatitis, SJS, and TEN, which may result in
520
hospitalizations and even death. Although serious skin reactions may
521
occur without warning, patients should be alert for the signs and
522
symptoms of skin rash and blisters, fever, or other signs of
523
hypersensitivity such as itching, and should ask for medical advice when
524
observing any indicative signs or symptoms. Patients should be advised to
525
stop the drug immediately if they develop any type of rash and contact
526
their physicians as soon as possible.
527
4. Patients should promptly report signs or symptoms of unexplained weight
528
gain or edema to their physicians.
529
5. Patients should be informed of the warning signs and symptoms of
530
hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper
531
quadrant tenderness, and “flu-like” symptoms). If these occur, patients
532
should be instructed to stop therapy and seek immediate medical therapy.
533
6. Patients should be informed of the signs of an anaphylactoid reaction (eg,
534
difficulty breathing, swelling of the face or throat). If these occur, patients
535
should be instructed to seek immediate emergency help (see
536
WARNINGS).
537
7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
538
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be
539
avoided because it may cause premature closure of the ductus arteriosus.
540
8. Caution should be exercised by patients whose activities require alertness
541
if they experience drowsiness, dizziness, vertigo or depression during
542
therapy with naproxen.
543
Laboratory Tests
544
Because serious GI tract ulcerations and bleeding can occur without warning
545
symptoms, physicians should monitor for signs or symptoms of GI bleeding.
546
Patients on long-term treatment with NSAIDs should have their CBC and a
547
chemistry profile checked periodically. If clinical signs and symptoms
548
consistent with liver or renal disease develop, systemic manifestations occur
549
(eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
550
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
16
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
551
NAPROSYN Suspension should be discontinued.
552
Drug Interactions
553
ACE-inhibitors
554
Reports suggest that NSAIDs may diminish the antihypertensive effect of
555
ACE-inhibitors. This interaction should be given consideration in patients
556
taking NSAIDs concomitantly with ACE-inhibitors.
557
Antacids and Sucralfate
558
Concomitant administration of some antacids (magnesium oxide or aluminum
559
hydroxide) and sucralfate can delay the absorption of naproxen.
560
Aspirin
561
When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
562
DS or NAPROSYN Suspension is administered with aspirin, its protein
563
binding is reduced, although the clearance of free NAPROSYN, EC-
564
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is
565
not altered. The clinical significance of this interaction is not known;
566
however, as with other NSAIDs, concomitant administration of naproxen and
567
naproxen sodium and aspirin is not generally recommended because of the
568
potential of increased adverse effects.
569
Cholestyramine
570
As with other NSAIDs, Cconcomitant administration of cholestyramine can
571
delay the absorption of naproxen.
572
Diuretics
573
Clinical studies, as well as postmarketing observations, have shown that
574
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
575
NAPROSYN Suspension can reduce the natriuretic effect of furosemide and
576
thiazides in some patients. This response has been attributed to inhibition of
577
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
578
patient should be observed closely for signs of renal failure (see
579
WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
580
Lithium
581
NSAIDs have produced an elevation of plasma lithium levels and a reduction
582
in renal lithium clearance. The mean minimum lithium concentration
583
increased 15% and the renal clearance was decreased by approximately 20%.
584
These effects have been attributed to inhibition of renal prostaglandin
585
synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
586
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
17
concurrently, subjects should be observed carefully for signs of lithium
587
toxicity.
588
Methotrexate
589
NSAIDs have been reported to competitively inhibit methotrexate
590
accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other
591
nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular
592
secretion of methotrexate in an animal model. This may indicate that they
593
could enhance the toxicity of methotrexate. Caution should be used when
594
NSAIDs are administered concomitantly with methotrexate.
595
Warfarin
596
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
597
users of both drugs together have a risk of serious GI bleeding higher than
598
users of either drug alone. No significant interactions have been observed in
599
clinical studies with naproxen and coumarin-type anticoagulants. However,
600
caution is advised since interactions have been seen with other nonsteroidal
601
agents of this class. The free fraction of warfarin may increase substantially in
602
some subjects and naproxen interferes with platelet function.
603
Other Information Concerning Drug Interactions
604
Naproxen is highly bound to plasma albumin; it thus has a theoretical
605
potential for interaction with other albumin-bound drugs such as coumarin-
606
type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
607
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or
608
sulphonylurea should be observed for adjustment of dose if required.
609
Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the
610
antihypertensive effect of propranolol and other beta-blockers.
611
Probenecid given concurrently increases naproxen anion plasma levels and
612
extends its plasma half-life significantly.
613
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive
614
antacid therapy, concomitant administration of EC-NAPROSYN is not
615
recommended.
616
Drug/Laboratory Test Interaction
617
Naproxen may decrease platelet aggregation and prolong bleeding time. This
618
effect should be kept in mind when bleeding times are determined.
619
The administration of naproxen may result in increased urinary values for 17-
620
ketogenic steroids because of an interaction between the drug and/or its
621
metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-
622
corticosteroid measurements (Porter-Silber test) do not appear to be
623
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
18
artifactually altered, it is suggested that therapy with naproxen be temporarily
624
discontinued 72 hours before adrenal function tests are performed if the
625
Porter-Silber test is to be used.
626
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic
627
acid (5HIAA).
628
Carcinogenesis
629
A 2-year study was performed in rats to evaluate the carcinogenic potential of
630
naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2).
631
The maximum dose used was 0.28 times the systemic exposure to humans at
632
the recommended dose. No evidence of tumorigenicity was found.
633
Pregnancy
634
Teratogenic Effects
635
Pregnancy Category C
636
Reproduction studies have been performed in rats at 20 mg/kg/day
637
(125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20
638
mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and
639
mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic
640
exposure) with no evidence of impaired fertility or harm to the fetus due to the
641
drug. However, animal reproduction studies are not always predictive of
642
human response. There are no adequate and well-controlled studies in
643
pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
644
DS and NAPROSYN Suspension should be used in pregnancy only if the
645
potential benefit justifies the potential risk to the fetus.
646
Nonteratogenic Effects
647
There is some evidence to suggest that when inhibitors of prostaglandin
648
synthesis are used to delay preterm labor there is an increased risk of neonatal
649
complications such as necrotizing enterocolitis, patent ductus arteriosus and
650
intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay
651
parturition has been associated with persistent pulmonary hypertension, renal
652
dysfunction and abnormal prostaglandin E levels in preterm infants. Because
653
of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
654
cardiovascular system (closure of ductus arteriosus), use during pregnancy
655
(particularly late pregnancy) should be avoided.
656
Labor and Delivery
657
In rat studies with NSAIDs, as with other drugs known to inhibit
658
prostaglandin synthesis, an increased incidence of dystocia, delayed
659
parturition, and decreased pup survival occurred. Naproxen-containing
660
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
19
products are not recommended in labor and delivery because, through its
661
prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal
662
circulation and inhibit uterine contractions, thus increasing the risk of uterine
663
hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX,
664
ANAPROX DS and NAPROSYN Suspension on labor and delivery in
665
pregnant women are unknown.
666
Nursing Mothers
667
The naproxen anion has been found in the milk of lactating women at a
668
concentration equivalent to approximately 1% of maximum naproxen
669
concentration in plasma. Because of the possible adverse effects of
670
prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be
671
avoided.
672
Pediatric Use
673
Safety and effectiveness in pediatric patients below the age of 2 years have
674
not been established. Pediatric dosing recommendations for juvenile arthritis
675
are
based
on
well-controlled
studies
(see
DOSAGE
AND
676
ADMINISTRATION). There are no adequate effectiveness or dose-response
677
data for other pediatric conditions, but the experience in juvenile arthritis and
678
other use experience have established that single doses of 2.5 to 5 mg/kg (as
679
naproxen suspension, see DOSAGE AND ADMINISTRATION), with total
680
daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients
681
over 2 years of age.
682
Geriatric Use
683
Studies indicate that although total plasma concentration of naproxen is
684
unchanged, the unbound plasma fraction of naproxen is increased in the
685
elderly. Caution is advised when high doses are required and some adjustment
686
of dosage may be required in elderly patients. As with other drugs used in the
687
elderly, it is prudent to use the lowest effective dose.
688
Experience indicates that geriatric patients may be particularly sensitive to
689
certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or
690
debilitated patients seem to tolerate peptic ulceration or bleeding less well
691
when these events do occur. Most spontaneous reports of fatal GI events are in
692
the geriatric population (see WARNINGS).
693
Naproxen is known to be substantially excreted by the kidney, and the risk of
694
toxic reactions to this drug may be greater in patients with impaired renal
695
function. Because elderly patients are more likely to have decreased renal
696
function, care should be taken in dose selection, and it may be useful to
697
monitor renal function. Geriatric patients may be at a greater risk for the
698
development of a form of renal toxicity precipitated by reduced prostaglandin
699
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
20
formation during administration of nonsteroidal anti-inflammatory drugs (see
700
WARNINGS: Renal Effects).
701
ADVERSE REACTIONS
702
Adverse reactions reported in controlled clinical trials in 960 patients treated
703
for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions
704
in patients treated chronically were reported 2 to 10 times more frequently
705
than they were in short-term studies in the 962 patients treated for mild to
706
moderate pain or for dysmenorrhea. The most frequent complaints reported
707
related to the gastrointestinal tract.
708
A clinical study found gastrointestinal reactions to be more frequent and more
709
severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen
710
compared
to
those
taking
750
mg
naproxen
(see
CLINICAL
711
PHARMACOLOGY).
712
In controlled clinical trials with about 80 pediatric patients and in well-
713
monitored, open-label studies with about 400 pediatric patients with juvenile
714
arthritis treated with naproxen, the incidence of rash and prolonged bleeding
715
times were increased, the incidence of gastrointestinal and central nervous
716
system reactions were about the same, and the incidence of other reactions
717
were lower in pediatric patients than in adults.
718
In patients taking naproxen in clinical trials, the most frequently reported
719
adverse experiences in approximately 1% to 10% of patients are:
720
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*,
721
nausea*, constipation*, diarrhea, dyspepsia, stomatitis
722
Central
Nervous
System:
headache*,
dizziness*,
drowsiness*,
723
lightheadedness, vertigo
724
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating,
725
purpura
726
Special Senses: tinnitus*, visual disturbances, hearing disturbances
727
Cardiovascular: edema*, palpitations
728
General: dyspnea*, thirst
729
*Incidence of reported reaction between 3% and 9%. Those reactions
730
occurring in less than 3% of the patients are unmarked.
731
In patients taking NSAIDs, the following adverse experiences have also been
732
reported in approximately 1% to 10% of patients.
733
Gastrointestinal
(GI)
Experiences,
including:
flatulence,
gross
734
bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
735
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
21
General: abnormal renal function, anemia, elevated liver enzymes, increased
736
bleeding time, rashes
737
The following are additional adverse experiences reported in <1% of patients
738
taking naproxen during clinical trials and through postmarketing reports.
739
Those adverse reactions observed through postmarketing reports are italicized.
740
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual
741
disorders, pyrexia (chills and fever)
742
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary
743
edema
744
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis,
745
jaundice, pancreatitis, vomiting, colitis, abnormal liver function tests,
746
nonpeptic gastrointestinal ulceration, ulcerative stomatitis, esophagitis, peptic
747
ulceration, hepatitis (some cases have been fatal)
748
Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases
749
have been fatal)
750
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia,
751
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
752
Metabolic and Nutritional: hyperglycemia, hypoglycemia
753
Nervous System: inability to concentrate, depression, dream abnormalities,
754
insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive
755
dysfunction, convulsions
756
Respiratory: eosinophilic pneumonitis, asthma
757
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis,
758
erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus,
759
pustular reaction, systemic lupus erythematoses, Stevens-Johnson syndrome,
760
photosensitive dermatitis, photosensitivity reactions, including rare cases
761
resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis
762
bullosa. If skin fragility, blistering or other symptoms suggestive of
763
pseudoporphyria occur, treatment should be discontinued and the patient
764
monitored.
765
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar
766
optic neuritis, papilledema
767
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial
768
nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary
769
necrosis, raised serum creatinine
770
Reproduction (female): infertility
771
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
22
In patients taking NSAIDs, the following adverse experiences have also been
772
reported in <1% of patients.
773
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite
774
changes, death
775
Cardiovascular:
hypertension,
tachycardia,
syncope,
arrhythmia,
776
hypotension, myocardial infarction
777
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis,
778
glossitis, hepatitis, eructation, liver failure
779
Hepatobiliary: hepatitis, liver failure
780
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
781
Metabolic and Nutritional: weight changes
782
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia,
783
somnolence, tremors, convulsions, coma, hallucinations
784
Respiratory: asthma, respiratory depression, pneumonia
785
Dermatologic: exfoliative dermatitis
786
Special Senses: blurred vision, conjunctivitis
787
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
788
OVERDOSAGE
789
Significant naproxen overdosage may be characterized by lethargy, dizziness,
790
drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion,
791
nausea, transient alterations in liver function, hypoprothrombinemia, renal
792
dysfunction,
metabolic
acidosis,
apnea,
disorientation
or
vomiting.
793
Gastrointestinal bleeding can occur. Hypertension, acute renal failure,
794
respiratory depression, and coma may occur, but are rare. Anaphylactoid
795
reactions have been reported with therapeutic ingestion of NSAIDs, and may
796
occur following an overdose. Because naproxen sodium may be rapidly
797
absorbed, high and early blood levels should be anticipated. A few patients
798
have experienced convulsions, but it is not clear whether or not these were
799
drug-related. It is not known what dose of the drug would be life threatening.
800
The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110
801
mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
802
Patients should be managed by symptomatic and supportive care following a
803
NSAID overdose. There are no specific antidotes. Hemodialysis does not
804
decrease the plasma concentration of naproxen because of the high degree of
805
its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1
806
to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients
807
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
23
seen within 4 hours of ingestion with symptoms or following a large overdose.
808
Forced diuresis, alkalinization of urine or hemoperfusion may not be useful
809
due to high protein binding.
810
DOSAGE AND ADMINISTRATION
811
Carefully consider the potential benefits and risks of NAPROSYN, EC-
812
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and
813
other treatment options before deciding to use NAPROSYN, EC-
814
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension.
815
Use the lowest effective dose for the shortest duration consistent with
816
individual patient treatment goals (see WARNINGS).
817
After observing the response to initial therapy with NAPROSYN, EC-
818
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the
819
dose and frequency should be adjusted to suit an individual patient’s needs.
820
Different dose strengths and formulations (ie, tablets, suspension) of the
821
drug are not necessarily bioequivalent. This difference should be taken
822
into consideration when changing formulation.
823
Although
NAPROSYN,
NAPROSYN
Suspension,
EC-NAPROSYN,
824
ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they
825
have pharmacokinetic differences that may affect onset of action. Onset of
826
pain relief can begin within 30 minutes in patients taking naproxen sodium
827
and within 1 hour in patients taking naproxen. Because EC-NAPROSYN
828
dissolves in the small intestine rather than in the stomach, the absorption of
829
the drug is delayed compared to the other naproxen formulations (see
830
CLINICAL PHARMACOLOGY).
831
The recommended strategy for initiating therapy is to choose a formulation
832
and a starting dose likely to be effective for the patient and then adjust the
833
dosage based on observation of benefit and/or adverse events. A lower dose
834
should be considered in patients with renal or hepatic impairment or in elderly
835
patients (see WARNINGS and PRECAUTIONS).
836
Geriatric Patients
837
Studies indicate that although total plasma concentration of naproxen is
838
unchanged, the unbound plasma fraction of naproxen is increased in the
839
elderly. Caution is advised when high doses are required and some adjustment
840
of dosage may be required in elderly patients. As with other drugs used in the
841
elderly, it is prudent to use the lowest effective dose.
842
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
24
Patients With Moderate to Severe Renal Impairment
843
Naproxen-containing products are not recommended for use in patients with
844
moderate to severe and severe renal impairment (creatinine clearance <30
845
mL/min) (see WARNINGS: Renal Effects).
846
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
847
NAPROSYN
250 mg
or 375 mg
or 500 mg
twice daily
twice daily
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
NAPROSYN
Suspension
250 mg (10 mL/2 tsp)
or 375 mg (15 mL/3 tsp)
or 500 mg (20 mL/4 tsp)
twice daily
twice daily
twice daily
EC-NAPROSYN
375 mg
or 500 mg
twice daily
twice daily
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet
848
should not be broken, crushed or chewed during ingestion. NAPROSYN
849
Suspension should be shaken gently before use.
850
During long-term administration, the dose of naproxen may be adjusted up or
851
down depending on the clinical response of the patient. A lower daily dose
852
may suffice for long-term administration. The morning and evening doses do
853
not have to be equal in size and the administration of the drug more frequently
854
than twice daily is not necessary.
855
In patients who tolerate lower doses well, the dose may be increased to
856
naproxen 1500 mg/day for limited periods of up to 6 months when a higher
857
level of anti-inflammatory/analgesic activity is required. When treating such
858
patients with naproxen 1500 mg/day, the physician should observe sufficient
859
increased clinical benefits to offset the potential increased risk. The morning
860
and evening doses do not have to be equal in size and administration of the
861
drug more frequently than twice daily does not generally make a difference in
862
response (see CLINICAL PHARMACOLOGY).
863
Juvenile Arthritis
864
The use of NAPROSYN Suspension is recommended for juvenile arthritis in
865
children 2 years or older because it allows for more flexible dose titration
866
based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day
867
produced plasma levels of naproxen similar to those seen in adults taking 500
868
mg of naproxen (see CLINICAL PHARMACOLOGY).
869
The recommended total daily dose of naproxen is approximately 10 mg/kg
870
given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup
871
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
25
marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the
872
NAPROSYN Suspension. The following table may be used as a guide for
873
dosing of NAPROSYN Suspension:
874
Patient’s Weight
Dose
Administered as
875
13 kg (29 lb)
62.5 mg bid 2.5 mL (1/2 tsp) twice daily
876
25 kg (55 lb)
125 mg bid 5.0 mL (1 tsp) twice daily
877
38 kg (84 lb)
187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily
878
Management of Pain, Primary Dysmenorrhea, and Acute
879
Tendonitis and Bursitis
880
The recommended starting dose is 550 mg of naproxen sodium as
881
ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg
882
every 6 to 8 hours as required. The initial total daily dose should not exceed
883
1375 mg of naproxen sodium. Thereafter, the total daily dose should not
884
exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is
885
more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the
886
management of acute painful conditions when prompt onset of pain relief is
887
desired. NAPROSYN may also be used but EC-NAPROSYN is not
888
recommended for initial treatment of acute pain because absorption of
889
naproxen is delayed compared to other naproxen-containing products (see
890
CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE).
891
Acute Gout
892
The recommended starting dose is 750 mg of NAPROSYN followed by 250
893
mg every 8 hours until the attack has subsided. ANAPROX may also be used
894
at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-
895
NAPROSYN is not recommended because of the delay in absorption (see
896
CLINICAL PHARMACOLOGY).
897
HOW SUPPLIED
898
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR
899
LE 250 on one side and scored on the other. Packaged in light-resistant bottles
900
of 100.
901
100’s (bottle): NDC 0004-6313-01.
902
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side.
903
Packaged in light-resistant bottles of 100.
904
100’s (bottle): NDC 0004-6314-01.
905
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and
906
scored on the other. Packaged in light-resistant bottles of 100.
907
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
26
100’s (bottle): NDC 0004-6316-01.
908
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-
909
resistant containers.
910
NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5
911
mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC
912
0004-0028-28).
913
Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F).
914
Dispense in light-resistant containers. Shake gently before use.
915
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, capsule-shaped,
916
imprinted with EC-NAPROSYN on one side and 375 on the other. Packaged
917
in light-resistant bottles of 100.
918
100’s (bottle): NDC 0004-6415-01.
919
500 mg: white, capsule-shaped, imprinted with EC-NAPROSYN on one side
920
and 500 on the other. Packaged in light-resistant bottles of 100.
921
100’s (bottle): NDC 0004-6416-01.
922
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-
923
resistant containers.
924
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped,
925
engraved with NPS-275 on one side. Packaged in bottles of 100.
926
100’s (bottle): NDC 0004-6202-01.
927
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
928
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong-
929
shaped, engraved with NPS 550 on one side and scored on both sides.
930
Packaged in bottles of 100.
931
100’s (bottle): NDC 0004-6203-01.
932
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
933
Revised: January 2006Month Year
934
935
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
27
Medication Guide
936
for
937
Non-steroidal Anti-Inflammatory Drugs (NSAIDs)
938
(See the end of this Medication Guide for a list of prescription NSAID
939
medicines.)
940
941
What is the most important information I should know about medicines
942
called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
943
NSAID medicines may increase the chance of a heart attack or
944
stroke that can lead to death. This chance increases:
945
• with longer use of NSAID medicines
946
• in people who have heart disease
947
948
NSAID medicines should never be used right before or after a
949
heart surgery called a “coronary artery bypass graft (CABG).”
950
NSAID medicines can cause ulcers and bleeding in the stomach
951
and intestines at any time during treatment. Ulcers and bleeding:
952
• can happen without warning symptoms
953
• may cause death
954
955
The chance of a person getting an ulcer or bleeding increases
956
with:
957
• taking medicines called “corticosteroids” and
958
“anticoagulants”
959
• longer use
960
• smoking
961
• drinking alcohol
962
• older age
963
• having poor health
964
965
NSAID medicines should only be used:
966
• exactly as prescribed
967
• at the lowest dose possible for your treatment
968
• for the shortest time needed
969
970
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
971
NSAID medicines are used to treat pain and redness, swelling, and heat
972
(inflammation) from medical conditions such as:
973
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
28
• different types of arthritis
974
• menstrual cramps and other types of short-term pain
975
976
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
977
Do not take an NSAID medicine:
978
• if you had an asthma attack, hives, or other allergic reaction with
979
aspirin or any other NSAID medicine
980
• for pain right before or after heart bypass surgery
981
982
Tell your healthcare provider:
983
• about all of your medical conditions.
984
• about all of the medicines you take. NSAIDs and some other
985
medicines can interact with each other and cause serious side
986
effects. Keep a list of your medicines to show to your
987
healthcare provider and pharmacist.
988
• if you are pregnant. NSAID medicines should not be used by
989
pregnant women late in their pregnancy.
990
• if you are breastfeeding. Talk to your doctor.
991
992
What are the possible side effects of Non-Steroidal Anti-Inflammatory
993
Drugs (NSAIDs)?
994
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling
(fluid retention)
•
kidney problems including kidney
failure
•
bleeding and ulcers in the stomach
and intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver
failure
•
asthma attacks in people who have
asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
995
Get emergency help right away if you have any of the following
996
symptoms:
997
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
29
•
shortness of breath or trouble
breathing
•
chest pain
•
weakness in one part or side of your
body
•
slurred speech
•
swelling of the face or
throat
998
Stop your NSAID medicine and call your healthcare provider right away
999
if you have any of the following symptoms:
1000
•
nausea
•
more tired or weaker than usual
•
itching
•
your skin or eyes look yellow
•
stomach pain
•
flu-like symptoms
•
vomit blood
•
there is blood in your
bowel movement or it is
black and sticky like tar
•
unusual weight gain
•
skin rash or blisters with
fever
•
swelling of the arms and
legs, hands and feet
1001
These are not all the side effects with NSAID medicines. Talk to your
1002
healthcare provider or pharmacist for more information about NSAID
1003
medicines.
1004
Other information about Non-Steroidal Anti-Inflammatory Drugs
1005
(NSAIDs):
1006
• Aspirin is an NSAID medicine but it does not increase the chance of a
1007
heart attack. Aspirin can cause bleeding in the brain, stomach, and
1008
intestines. Aspirin can also cause ulcers in the stomach and intestines.
1009
• Some of these NSAID medicines are sold in lower doses without a
1010
prescription (over-the-counter). Talk to your healthcare provider before
1011
using over-the-counter NSAIDs for more than 10 days.
1012
1013
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
30
NSAID medicines that need a prescription
1014
Generic Name
Tradename
Celecoxib
Celebrex®
Diclofenac
Cataflam®, Voltaren®, Arthrotec™ (combined with
misoprostol)
Diflunisal
Dolobid®
Etodolac
Lodine®, Lodine®XL
Fenoprofen
Nalfon®, Nalfon®200
Flurbirofen
Ansaid®
Ibuprofen
Motrin®, Tab-Profen®, Vicoprofen® (combined with
hydrocodone), Combunox™ (combined with
oxycodone)
Indomethacin
Indocin®, Indocin®SR, Indo-Lemmon™,
Indomethagan™
Ketoprofen
Oruvail®
Ketorolac
Toradol®
Mefenamic Acid
Ponstel®
Meloxicam
Mobic®
Nabumetone
Relafen®
Naproxen
Naprosyn®, Anaprox®, Anaprox®DS, EC-Naprosyn®,
Naprelan®, Naprapac® (copackaged with
lansoprazole)
Oxaprozin
Daypro®
Piroxicam
Feldene®
Sulindac
Clinoril®
Tolmetin
Tolectin®, Tolectin DS®, Tolectin®600
1015
Issued: January 2006
1016
This Medication Guide has been approved by the U.S. Food and Drug
1017
Administration.
1018
1019
All registered trademarks in this document are the property of their respective
1020
owners.
1021
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
31
Distributed by:
1022
1023
27899102xxxxxxxx
1024
Copyright © 1999-2006 by Roche Laboratories Inc. All rights reserved.
1025
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/
---------------------
Sharon Hertz
3/10/2006 03:59:36 PM
Signing for Bob Rappaport, M.D.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:18.556546
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020067s010,018965s013,018164s055, 017581s105lbl.pdf', 'application_number': 17581, 'submission_type': 'SUPPL ', 'submission_number': 105}
|
11,038
|
(RoChe)
EC-NAPROSYN~ (naproxen delayed-release tablets)
NAPROSYN~ (naproxen tablets)
ANAPROX~/ANAPROX~ DS (naproxen sodium tablets)
NAPROSYN~ (naproxen suspension)
Rx only
Cardiovascular Risk
. NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fataL. This risk
may increase with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
. Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is contraindicated for the treatment of
peri-operative pain in the setting of coronary artery bypass graft (CAB
G)
surgery (see WARNINGS).
Gastrointestinal Risk
. NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or
intestines, which can be fataL. These events can occur at any time during
use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
DESCRIPTION
Naproxen is a proprionic acid derivative related to the arylacetic acid group of
nonsteroidal anti-inflammatory drugs.
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-a-
methyl-2-naphthaleneacetic acid and (S)-6-methoxy-a-methyl-2-
naphthaJeneacetic acid, sodium salt, respectively. Naproxen and naproxen
sodium have the following stiyctures, respectively:
;Oo R..." napro'en (R..COOH) C14HI.o, mol
wi 230.26
CH;¡
napro,.n ,odium (R.-COONa) C14H "NaO, mol wl 252.23
CH:iÜ
Naproxen has a molecular weight of 230.26 and a molecular formula of
C14H1403. Naproxen sodium has a molecular weight of 252.23 and a
molecular formula of CI4H13Na03.
Naproxen is an odorless, white to off-white crystallne substance. It is lipid-
soluble, practically insoluble in water at low pH and freely soluble in water at
high pH. The octanol/water partition coeffcient of naproxen at pH 7.4 is 1.6
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely
soluble in water at neutral pH.
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250
mg of naproxen, pink tablets containing 375 mg of naproxen and yellow
tablets containing 500 mg of naproxen for oral administration. The inactive
ingredients are croscarmellose sodium, iron oxides, povidone and magnesium .
stearate.
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric-
coated :white tablets containing 375 mg of naproxen and 500 mg of naproxen
for oral administration. The inactive ingredients are croscarmellose sodium,
povidone and magnesium stearate. The enteric coating dispersion contains
methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and
purified water. The dissolution of this enteric-coated naproxen tablet is pH
dependent with rapid dissolution above pH 6. There is no dissolution below
pH4.
ANAPROX (naproxen sodium tablets) is available as blue tablets containing
275 mg ofnaproxen sodium and ANAPROX DS (naproxen sodium tablets) is
available as dark blue tablets containing 550 mg of naproxen sodium for oral
administration. The inactive ingredients are magnesium stearate,
microcrystalline cellulose, povidone and talc. The coating suspension for the
ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910,
Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The
coating suspension for the ANAPROX DS 550 mg tablet may contain
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene
glycol 8000 or Opadry YS-1-4216.
NAPROSYN (naproxen suspension) is available as a light orange-colored
opaque oral suspension containing 125 mg/5 mL of naproxen in a
vehicle
containing, sucrose, magnesium aluminum silcate, sorbitol solution and
sodium chloride (30 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C
Yellow No.6, imitation pineapple flavor, imitation orange flavor and purified
water. The pH ofthe suspension ranges from 2.2 to 3.7.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic
and antipyretic properties. The sodium salt of naproxen has been developed as
a more rapidly absorbed formulation of naproxen for use as an analgesic. The
mechanism of action of the naproxen anion, like that of other NSAIDs, is not
completely understood but may be related to prostaglandin synthetase
inhibition.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
Pharmacokinetics
Naproxen and naproxen sodium are rapidly and completely absorbed from the
gastrointestinal tract with an in vivo bioavailability of 95%. The different
dosage forms of NAPROSYN are bioequivalent in terms of extent of
absorption (AUC) and peak concentration (Cmax); however, the products do
differ in their pattern of absorption. These differences between naproxen
products are related to both the chemical form of naproxen used and its
formulation. Even with the observed differences in pattern of absorption, the
elimination half-life of naproxen is unchanged across products ranging from
12 to 17 hours. Steady-state levels ofnaproxen are reached in 4 to 5 days, and
the degree of naproxen accumulation is consistent with this half-life. This
suggests that the differences in pattern of release play only a negligible role in
the attainment of steady-state plasma levels.
Absorption
Immediate Release
After administration of NAPROSYN tablets, peak plasma levels are attained
in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels
are attained in 1 to 2 hours. The difference in rates between the two products
is due to the increased aqueous solubility of the sodium salt of naproxen used
in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN
Suspension arc attained in 1 to 4 hours.
Delayed Release
EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier
to disintegration in the acidic environment of the stomach and to lose integrity
in the more neutral environment of the small intestine. The enteric polymer
coating selected for EC-NAPROSYN dissolves above pH 6. When EC-
NAPROSYN was given to fasted subjects, peak plasma levels were attained
about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo
study in man using radio
labeled EC-NAPROSYN tablets demonstrated that
EC-NAPROSYN dissolves primarily in the small intestine rather than in the
stomach, so the absorption of the drug is delayed until the stomach is emptied.
When EC-NAPROSYN and NAPROSYN were given to fasted subjects
(n=24) in a crossover study following 1 week of dosing, differences in time to
peak plasma levels (T max) were observed, but there were no differences in total
absorption as measured by Cmax and AUC:
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
EC-NAPROSYN*
NAPROSYN*
500 mg bid
500 mg bid
Cmax (f.g/mL)
94.9 (18%)
97.4 (13%)
Tmax (hours)
4 (39%)
1.9 (61 %)
AUCo-12 hr (f.g'hr/mL)
845 (20%)
767 (15%)
*Mean value (coefficient of
variation)
Antacid Effects
When EC-NAPROSYN was given as a single dose with antacid (54 mEq
buffering capacity), the peak plasma levels of naproxen were unchanged, but
the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with
antacid 5 hours), although not significantly.
Food Effects
When EC-NAPROSYN was given as a single dose with food, peak plasma
levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours).
Residence time in the small intestine until disintegration was independent of
food intake. The presence of food prolonged the time the tablets remained in
the stomach, time to first detectable serum naproxen levels, and time to
maximal naproxen levels (T max), but did not affect peak naproxen levels
(Cmax).
Distribution
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels
naproxen is greater than 99% albumin-bound. At doses of naproxen greater
than 500 mg/day there is less than proportional increase in plasma levels due
to an increase in clearance caused by saturation of plasma protein binding at
higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and
1500 mg daily doses of naproxen, respectively). The naproxen anion has been
found in the milk of lactating women at a concentration equivalent to
approximately 1% of maximum naproxen concentration in plasma (see
PRECAUTIONS: Nursing Mothers).
Metabolism
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen,
and both parent and metabolites do not induce metabolizing enzymes. Both
naproxen and 6-0-desmethyl naproxen are further metabolized to their
respective acyl
glucuronide conjugated metabolites.
Excretion
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the
naproxen from any dose is excreted in the urine, primarily as naproxen (":1 %),
6-0-desmethyl naproxen (":1 %) or their conjugates (66% to 92%). The plasma
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPRO~/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
half-life of the naproxen anion in humans ranges from 12 to 17 hours. The
corresponding half-lives of both naproxen's metabolites and conjugates are
shorter than 12 hours, and their rates of excretion have been found to coincide
closely with the rate of naproxen disappearance from the plasma. Small
amounts, 3% or less of the administered dose, are excreted in the feces. In
patients with renal failure metabolites may accumulate (see WARNINGS:
Renal Effects).
Special Populations
Pediatric Patients
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels
following a 5 mg/kg single dose ofnaproxen suspension (see DOSAGE AND
ADMINISTRATION) were found to be similar to those found in normal
adults following a 500 mg dose. The terminal half-life appears to be similar in
pediatric and adult patients. Pharmacokinetic studies of naproxen were not
pcrformed in pediatric patients younger than 5 years of age. Pharmacokinetic
parameters appear to be similar following administration of naproxen
suspension or tablets in pediatric patients. EC-NAPROSYN has not been
studied in subjects under the age of 18.
Geriatric Patients
Studies indicate that although total plasma concentration of nàproxen is
unchanged, the unbound plasma fraction of naproxen is increased in the
elderly, although the unbound fraction is ..1% of the total naproxen
concentration. Unbound trough naproxen concentrations in elderly subjects
have been reported to range from 0.12% to 0.19% of total naproxen
concentration, compared with 0.05% to 0.075% in younger subjects. The
clinical significance of this finding is unclear, although it is possible that the
increase in free naproxen concentration could be associated with an increase
in the rate of adverse events per a given dosage in some elderly patients.
Race
Pharmacokinetic differences due to race have not been studied.
Hepatic Insufficiency
Naproxen pharmacokinetics has not been determined in subjects with hepatic
insuffciency.
Renal
Insufficiency
Naproxen pharmacokinetics has not been determined in subjects with renal
insuffciency. Given that naproxen, its metabolites and conjugates are
primarily excreted by the kidney, the potential exists for naproxen metabolites
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
to accumulate in the presence of renal insufficiency. Elimination of naproxen
is decreased in patients with severe renal impairment. Naproxen-containing
products are not recommended for use in patients with moderate to severe and
severe renal impairment (creatinine clearance ..30 mL/min) (see
WARNINGS: Renal Effects).
CLINICAL STUDIES
General
Information
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis,
juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute
gout. Improvement in patients treated for rheumatoid arthritis was
demonstrated by a reduction in joint swellng, a reduction in duration of
morning stiffness, a reduction in disease activity as assessed by both the
investigator and patient, and by increased mobility as demonstrated by a
reduction in walking time. Generally, response to naproxen has not been
found to be dependent on age, sex, severity or duration of rheumatoid arthritis.
In patients with osteoarthritis, the therapeutic action of naproxen has been
shown by a reduction in joint pain or tenderness, an increase in range of
motion in knee joints, increased mobility as demonstrated by a reduction in
walking time, and improvement in capacity to perform activities of daily
living impaired by the disease.
In a clinical trial comparing standard formulations of naproxen 375 mg bid
(750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group
terminated prematurely because of adverse events. Nineteen patients in the
1500 mg group terminated prematurely because of adverse events. Most of
these adverse events were gastrointestinal events.
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and
juvenile arthritis, naproxen has been shown to be comparable to aspirin and
indomethacin in controlling the aforementioned measures of disease activity,
but the frequency and severity of the milder gastrointestinal adverse effects
(nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus,
dizziness, lightheadcdness) were less in naproxen-treated patients than in
those treated with aspirin or indomethacin.
In patients with ankylosing spondylitis, naproxen has been shown to decrease
night pain, morning stiffness and pain at rest. In double-blind studics the drug
was shown to be as effective as aspirin, but with fewer side effects.
In patients with acute gout, a favorable response to naproxen was shown by
significant clearing of inflammatory changes (eg, decrease in swellng, heat)
within 24 to 48 hours, as well as by relief of pain and tenderness.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
Naproxen has been studied in patients with mild to moderate pain secondary
to postoperative, orthopedic, postpartum episiotomy and uterine contraction
pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in
patients taking naproxen and within 30 minutes in patients taking naproxen
sodium. Analgesic effect was shown by such measures as reduction of pain
intensity scores, increase in pain relief scores, decrease in numbers of patients
requiring additional analgesic medication, and delay in time to remedication.
The analgesic effect has been found to last for up to 12 hours.
Naproxen may be used safely in combination with gold salts and/or
corticosteroids; however, in controlled clinical trials, when added to the
regimen of patients receiving corticosteroids, it did not appear to cause greater
improvement over that seen with corticosteroids alone. Whether naproxcn has
a "steroid-sparing" effect has not been adequately studied. When added to the
regimen of patients receiving gold salts, naproxen did result in greater
improvement. Its use in combination with salicylates is not recommended
because there is evidence that aspirin increases the rate of excretion of
naproxen and data are inadequate to demonstrate that naproxen and aspirin
produce greater improvement over that achieved with aspirin alonc. In
addition, as with other NSAIDs, the combination may result in higher
frequency of adverse events than demonstrated for either product alone.
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily
administration of 1000 mg of naproxen as 1000 mg of NAPROSYN
(naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been
demonstrated to cause statistically significantly less gastric bleeding and
erosion than 3250 mg of aspirin.
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN
(naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid,
n=279) were conducted comparing EC-NAPROSYN with NAPROSYN,
including 355 rheumatoid arthritis and osteoarthritis patients who had a recent
history of NSAID-related GI symptoms. These studies indicated that EC-
NAPROSYN and NAPROSYN showed no significant differences in effcacy
or safety and had similar prevalence of minor GI complaints. Individual
patients, however, may find one formulation preferable to the other.
Five hundred and fifty-three patients received EC-NAPROSYN during long-
term open-label trials (mean length of treatment was 159 days). The rates for
clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been
historically reported for long-term NSAID use.
Geriatric Patients
The hepatic and renal tolerability of long-term naproxen administration was
studied in two double-blind clinical trials involving 586 patients. Of the
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
patients studied, 98 patients were age 65 and older and 10 of the 98 patients
were age 75 and older. Naproxen was administered at doses of 375 mg twice
daily or 750 mg twice daily for up to 6 months. Transient abnormalities of
laboratory tests assessing hepatic and renal function were noted in some
patients, although there were no differences noted in the occurrence of
abnormal values among different age groups.
INDICATIONS AND USAGE
Carcfully consider the potential benefits and risks of NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and
other treatment options before deciding to use NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use
the lowest effective dose for the shortest duration consistent with individual
patient treatment goals (see WARNINGS).
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension is indicated:
. For the relief of
the signs and symptoms of
rheumatoid arthritis
. For the relief ofthe signs and symptoms of osteoarthritis
. For the relief of
the signs and symptoms of ankylosing spondylitis
. For the relief of
the signs and symptoms of
juvenile arthritis
Naproxen as NAPROSYN Suspension is recommended for juvenile
rheumatoid arthritis in order to obtain the maximum dosage flexibility based
on the patient's weight.
Naproxen as NAPROSYN~ ANAPROX, ANAPROX DS and NAPROSYN
Suspension is also indicated:
. For relief of
the signs and symptoms of
tendonitis
. For relief of
the signs and symptoms of
bursitis
. For relief of the signs and symptoms of acute gout
. For the management of
pain
. For the management of primary dysmenorrhea
EC-NAPROSYN is not recommended for initial treatment of acute pain
because the absorption of naproxen is delayed compared to absorption from
other naproxen-containing products (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION).
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
CONTRAINDICA TIONS
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension are contraindicated in patients with known
hypersensitivity to naproxen and naproxen sodium.
NAPROSYN, EC-NAPROSYN,' ANAPROX, ANAPROX DS and
NAPROSYN Suspension should not be given to patients who have
experienced asthma, urticaria, or allergic-type reactions after taking aspirin or
other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs
have been reported in such patients (see WARNINGS: Anaphylactoid
Reactions and PRECAUTIONS: Preexisting Asthma).
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension are contraindicated for the treatment of peri-
operative pain in the setting of coronary artery bypass graft (CAB
G) surgery
(see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to
three years duration have shown an increased risk of serious cardiovascular
(CV) thrombotic events, myocardial infarction, and stroke, which can be fataL.
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
Patients with known CV disease or risk factors for CV disease may be at
greater risk. To minimize the potential risk for an adverse CV event in patients
treated with an NSAID, the lowest effective dose should be used for the
shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms.
Patients should be informed about the signs and/or symptoms of serious CV
events and the steps to take if
they occur.
There is no consistent evidence that concurrent use of aspirin mitigatcs the
increased risk of serious CV thrombotic events associated with NSAID use.
The concurrent use of aspirin and an NSAID does increase the risk of serious
GI events (see Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
Perforation).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the
treatment of pain in the first 10-14 days following CABG surgery found an
increased incidence of myocardial infarction and stroke. (see
CONTRAINDICA TIONS).
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
Hypertension
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension, can lead to onset of new
hypertension or worsening of pre-existing hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking thiazid~s or
loop diuretics may have impaired response to these therapies when taking
NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension, should be used with caution in
patients with hypertension. Blood pressure (BP) should be monitored closely
during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema
Fluid retention, edema, and peripheral edema have been observed in some
patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension should be used with caution in
patients with fluid retention, hypertension, or hear failure. Since each
ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium
(about 1 mEq per each 250 mg of naproxen), and each teaspoonful of
NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of
naproxen) of sodium, this should be considered in patients whose overall
intakc of sodium must be severely restricted.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
Perforation
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension, can cause seflOUS
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fataL.
These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who
develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs OCCU! in
approximately 1 % of patients treated for 3-6 months, and in about 2-4% of
patients treated for one year. These trends continue with longer duration of
use, increasing the likelihood of developing a serious GI event at some time
during the course of
therapy. However, even short-term therapy is not without
risk. The utility of periodic laboratory monitoring has not been demonstrated,
nor has it been adequately assessed. Only 1 in 5 patients who develop a
serious upper GI adverse event on NSAID therapy is symptomatic.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
NSAIDs should be prescribed with extreme caution in those with a prior
history of ulcer disease or gastrointestinal bleeding. Patients with a prior
history of peptic ulcer disease and/or gastrointestinal bleeding who use
NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that
increase the risk for GI bleeding in patients treated with NSAIDs include
concomitant use of oral corticosteroids or anticoagulants, longer duration of
NSAID therapy, smoking, use of alcohol, older age, and poor general health
status. Most spontaneous reports of fatal GI events are in elderly or debilitated
patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with
an NSAID, the lowest effective dose should be used for the shortest possible
duration. Patients and physicians should remain alert for signs and symptoms
of GI ulceration and bleeding during NSAID therapy and promptly initiate
additional evaluation and treatment if a serious GI adverse event is suspected.
This should include discontinuation of the NSAID until a serious GI adverse
event is ruled out. For high risk patients, alternate therapies that do not
involve NSAIDs should be considered.
Epidemiological studies, both of the case-control and cohort design, have
demonstrated an association between use of psychotropic drugs that interfere
with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
In two studies, concurrent use of an NSAID or aspirin potcntiated the risk of
bleeding (see PRECAUTIONS - Drug Interactions). Although these studies
focused on upper gastrointestinal bleeding, there is reason to belicve that
bleeding at other sites may be similarly potentiated.
NSAIDs should be given with care to patients with a history of inflammatory
bowel disease (ulcerative colitis, Crohn's disease) as their condition may be
exacerbated.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papilary necrosis
and other renal injury. Renal toxicity has also been seen in patients in whom
renal prostaglandins have a compensatory role in the maintenance of renal
perfusion. In these patients, administration of a nonsteroidal
anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, hypovolemia, heart failure,
liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors,
and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug
therapy is usually followcd by recovery to the pretreatment state (see
WARNINGS: Advanced Renal Disease).
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use
of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension in patients with advanced renal disease. Therefore,
treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS
and NAPROSYN Suspension is not recommended in these patients with
advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close
monitoring of the patient's renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without
known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS or NAPROSYN Suspension. NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
should not be given to patients with the aspirin triad. This symptom complex
typically occurs in asthmatic patients who experience rhinitis with or without
nasal polyps, or who exhibit severe, potentially fatal bronchospasm after
taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
PRECAUTIONS: Preexisting Asthma). Emergency help should be sought
in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like
anaphylaxis, may have a fatal outcome.
Skin Reactions
NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse
events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
toxic epidermal necrolysis (TEN), which can be fataL. These serious events
may occur without warning. Patients should be inforied about the signs and
symptoms of serious skin manifestations and use of the drug should be
discontinued at the first appearance of skin rash or any other sign of
hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided
because it may cause premature closure of the ductus areriosus.
PRECAUTIONS
General
Naproxen-containing products such as NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE~, and
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
other naproxen products should not
be used concomitantly since they all
circulate in the plasma as the naproxen anion.
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspcnsion cannot be expected to substitute for corticosteroids
or to treat corticosteroid insufficiency. Abrupt discontinuation of
corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is
made to discontinue corticosteroids and the patient should be observed closely
for any evidence of adverse effects, including adrenal insufficiency and
exacerbation of symptoms of arthritis.
Patients with initial hemoglobin values of 109 or less who are to receive long-
term therapy should have hemoglobin values determined periodically.
The pharmacological activity of NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever
and inflammation may diminish the utility of these diagnostic signs in
detecting complications of presumed noninfectious, noninflammatory painful
conditions.
Because of adverse eye findings in animal studies with drugs of this class, it is
recommended that ophthalmic studies be carried out if any change or
disturbance in vision occurs.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of
patients taking NSAIDs including NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic
abnormalities may be the result of hypersensitivity rather than direct toxicity.
These laboratory abnormalities may progress, may remain essentially
unchanged, or may be transient with continued therapy. The SGPT (AL T) test
is probably the most sensitive indicator of liver dysfunction. Notable
elevations of AL T or AST (approximately three or more times the upper limit
of normal) have been reported in approximately 1 % of patients in clinical
trials with NSAIDs. In addition, rare cases of severe hepatic reactions,
including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
failure, some of them with fatal outcomes have been reported.
A patient with .symptoms and/or signs suggesting liver dysfunction, or in
whom an abnormal liver test has occurred, should be evaluated for evidence
of the development of more severe hepatic reaction while on therapy with
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSY~ (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension
should be discontinued.
Chronic alcoholic liver disease and probably other diseases with decreased or
abnormal plasma proteins (albumin) reduce the total plasma concentration of
naproxen, but the plasma concentration of unbound naproxen is increased.
Caution is advised when high doses are required and some adjustmcnt of
dosage may be required in these patients. It is prudent to use the lowest
effective dose.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension. This may be due to fluid retention, occult or gross
GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension,
should have their hemoglobin or hematocrit checked if they exhibit any signs
or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding
time in some patients. Unlike aspirin, their effect on platelet fuction is
quantitatively less, of shorter duration, and reversible. Patients receiving either
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
NAPROSYN Suspension who may be adversely affected by alterations in
platelct function, such as those with coagulation disorders or patients
receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in
patients with aspirin-sensitive asthma has been associated with severe
bronchospasm, which can be fataL. Since cross reactivity, including
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
should not be administered to patients with this form of aspirin sensitivity and
should be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
N.APROSYN (naproxen suspension)
therapy. Patients should also
be encouraged to read the NSAID
Medication Guide that accompanies each prescription dispensed.
1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension, like other NSAIDs, may causc serious CV side
effects, such as MI or stroke, which may result in hospitalization and even
death. Although serious CV events can occur without warning symptoms,
patients should be alert for the signs and symptoms of chest pain,
shortness of breath, weakness, slurring of speech, and should ask for
medical advice when obsei:ving any indicative sign or symptoms. Patients
should be apprised ofthe importance of
this follow-up (see WARNINGS:
Cardiovascular Effects).
2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension, like other ;N"SAIDs, can cause GI discomfort
and, rarely, serious GI side cffccts, such as ulcers and bleeding, which
may result in hospitalization and even death. Although serious GI tract
ulcerations and bleeding can occur without warning symptoms, patients
should be alert for the signs and symptoms of ulcerations and bleeding,
and should ask for medical advice when observing any indicative sign or
symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
Patients should be apprised ofthe importance of
this follow-up (see
WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding,
and Perforation).
3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension, like other NSAIDs, can cause serious skin side
effects such as exfoliative dermatitis, SJS, and TEN, which may result in
hospitalizations and even death. Although serious skin reactions may
occur without warning, patients should be alert for the signs and
symptoms of skin rash and blisters, fever, or other signs of
hypersensitivity such as itching, and should ask for medical advice when
observing any indicative signs or symptoms. Patients should be advised to
stop the drug immediately if they develop any type of rash and contact
their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of
unexplained weight
gain or edema to their physicians.
5. Patients should be informed of
the warning signs and symptoms of
hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper
quadrant tenderness, and "flu-like" symptoms). If
these occur, patients
should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (eg,
diffculty breathing, swelling of
the face or throat). If
these occur, patients
should be instructed to seek in'mediate emergency help (see
WARNINGS).
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be
avoided because it may cause premature closure of the ductus arteriosus.
8. Caution should be exercised by
patients whose activities require alertness
if they experience drowsiness, dizziness, vertigo or depression during
therapy with naproxen.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding.
Patients on long-term treatment with NSAIDs should have their CBC and a
chemistry profie checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur
(eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspcnsion should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of
ACE-inhibitors. This interaction should be given consideration in patients
taking NSAIDs concomitantly with ACE-inhibitors.
Antacids and Sucralfate
Concomitant administration of some antacids (magnesium oxide or aluminum
hydroxide) and sucralfate can delay the absorption of naproxen.
Aspirin
When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is administered with aspirin, its protein
binding is reduced, although the clearance of free NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is
not altered. The clinical significance of this interaction is not known;
however, as with other NSAIDs, concomitant administration of naproxen and
naproxen sodium and aspirin is not generally recommended because of the
potential of increased adverse effects.
Ch
o/es
tyramine
As with other NSAIDs, concomitant administration of cholestyramine can
delay the absorption of naproxen.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
Diuretics
Clinical studies, as well as postmarketing observations, have shown that
NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
NAPROSYN Suspension can reduce the natriuretic effect of furosemide and
thiazides in some patients. This response has been attributed to inhibition of
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see
WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction
in renal lithium clearance. The mean minimum lithium concentration
increased 15% and the rcnal clearance was decreased by approximately 20%.
These effects have been attributed to inhibition of renal prostaglandin
synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium
toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate
accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other
nonsteroidal anti-inflammatory drugs have been rcported to reduce the tubular
secretion of methotrexate in an animal modeL. This may indicate that they
could enhance the toxicity of methotrexate. Caution should be used when
NSAIDs are administered concomitantly with methotrexate.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
users of both drugs together have a risk of serious GI bleeding higher than
users of either drug alone. No significant interactions have been observed in
clinical studies with naproxen and coumarin-type anticoagulants. However,
caution is advised since interactions have been seen with other nonsteroidal
agents of
this class. The free fraction of
warfarin may increase substantially in
some subjects and naproxen interferes with platelet function.
Selective Serotonin Reuptake Inhibitors (SSRls)
There is an increased risk of gastrointestinal bleeding when selective serotonin
reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be
used when NSAIDs are administed concomintantly with SSRIs.
Other Information Concerning Drug Interactions
Naproxen is highly bound to plasma albumin; it thus has a theoretical
potential for interaction with other albumin-bound drugs such as coumarin-
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
type anticoagulants, sulphonylureas, hydantoins, othcr NSAIDs, and aspirin.
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or
sulphonylurea should be observed for adjustment of dose if required.
Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the
antihypertensive effect of propranolol and other beta-blockers.
Probenecid given concurrently increases naproxen anion plasma levels and
extends its plasma half-life significantly.
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive
antacid therapy, concomitant administration of EC-NAPROSYN is not
recommended.
Drug/Laboratory Test Interaction
Naproxen may decrease platelet aggregation and prolong bleeding time. This
effect should be kept in mind when bleeding times are determined.
The administration of naproxen may result in increased urinary values for 17-
ketogenic steroids because of an interaction between the drug and/or its
metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-
corticosteroid measurements (Porter-Silber test) do not appear to be
artifactually altered, it is suggested that therapy with naproxen be temporarily
discontinued 72 hours before adrenal function tests are performed if the
Porter-Silber test is to be used.
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic
acid (5HIAA).
Carcinogenesis
A 2-year study was performed in rats to evaluate the carcinogenic potential of
naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2).
The maximum dose used was 0.28 times the, systemic exposure to humans at
the recommended dose. No evidence oftumorigenicity was found.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Reproduction studies have been performed in rats at 20 mg/kg/day
(125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20
mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and
mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic
exposure) with no evidence of impaired fertility or harm to the fetus due to the
drug. However, animal reproduction studies are not always predictive of
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
human response. There are no adequate and well-controlled studies in
pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS and NAPROSYN Suspension should be used in pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
There is some evidence to suggest that when inhibitors of prostaglandin
synthesis are us
cd to delay preterm labor there is an increased risk of neonatal
complications such as necrotizing enterocolitis, patent ductus arteriosus and
intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay
parturition has been associated with persistent pulmonary hypertension, renal
dysfunction and abnormal prostaglandin E levels in preterm infants. Because
of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
cardiovascular system (closure of ductus arteriosus), use during pregnancy
(paricularly late pregnancy) should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit
prostaglandin synthesis, an increased incidence of dystocia, delayed
parturition, and decreased pup survival occurred. Naproxen-containing
products are not recommended in labor and delivery because, through its
prostaglandin synthesis inhibitory effect, naproxen may advcrsely affect fetal
circulation and inhibit uterine contractions, thus increasing the risk of uterine
hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX,
ANAPROX DS and NAPROSYN Suspension on labor and delivery in
pregnant women are unknown.
Nursing Mothers
The naproxen anion has been found in the milk of lactating women at a
concentration equivalent to approximately 1 % of maximum naproxen
concentration in plasma. Because of the possible adverse effects of
prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be
avoided.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 years have
not been established. Pediatric dosing recommendations for juvenile arthritis
are based on well-controlled studies (see DOSAGE- AND
ADMINISTRATION). There are no adequate effectiveness or dose-response
data for other pediatric conditions, but the experience in juvenile arthritis and
other use experience have established that single doses of 2.5 to 5 mg/kg (as
naproxen suspension, see DOSAGE AND ADMINISTRATION), with total
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients
over 2 years of age.
Geriatric Use
Studies indicate that although total plasma concentration of naproxen is
unchanged, the unbound plasma fraction of naproxen is increased in the
elderly. Caution is advised when high doses are required and some adjustment
of dosage may be required in elderly patients. As with other drugs used in the
elderly, it is prudent to use the lowest effective dose.
Experience indicates that geriatric paticnts may be particularly sensitive to
certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or
debilitated patients seem to tolerate peptic ulceration or bleeding less well
when these events do occur. Most spontaneous reports of fatal GI events are in
the geriatric population (see WARNINGS).
Naproxen 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
fuction, care should be taken in dose selection, and it may be useful to
monitor renal function. Geriatric patients may be at a greater risk for the
development of a form of renal toxicity precipitated by reduced prostaglandin
formation during administration of nonsteroidal anti-inflammatory drugs (see
WARNINGS: Renal Effects).
ADVERSE REACTIONS
Adverse reactions reported in controlled clinical trials in 960 patients treated
for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions
in patients treated chronically were reported 2 to 10 times more frequently
than they were in short-term studies in the 962 patients treated for mild to
moderate pain or for dysmenorrhea. The most frequent complaints reported
related to the gastrointestinal tract.
A clinical study found gastrointestinal reactions to be more frequent and more
severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen
compared to those taking 750 mg naproxen (see CLINICAL
PHARMACOLOGY).
In controlled clinical trials with about 80 pediatric patients and in well-
monitored, open-label studies with about 400 pediatric patients with juvenile
arthritis treated with naproxen, the incidence of rash and prolonged bleeding
times were increased, the incidence of gastrointestinal and central nervous
system reactions were about the same, and the incidence of other reactions
were lower in pediatric patients than in adults.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
In patients taking naproxen in clinical trials, the most frequently reported
adverse experiences in approximately 1 % to 10% of patients are:
Gastrointestinal (GI) Experiences, including: heartburn
* , abdominal pain*,
nausea*, constipation*, diarrhea, dyspepsia, stomatitis
Central Nervous System: headache
* , dizziness
* , drowsiness
* ,
lightheadedness, vertigo
Dermatologic: pruritus (itching)
* , skin eruptions
* , ecchymoses*, sweating,
purpura
Special Senses: tinnitus*, visual disturbances, hearing disturbances
Cardiovascular: edema*, palpitations
General: dyspnea*, thirst
*Incidence of reported reaction between 3% and 9%. Those reactions
occurring in less than 3% of
the patients are unmarked.
In patients taking NSAIDs, the following adverse experiences have also been
reported in approximately 1 % to 10% of patients.
Gastrointestinal (GI) Experiences, including: flatulence, gross
bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased
bleeding time, rashes
The following are additional adverse experiences reported in ..1 % of patients
taking naproxen during clinical trials and through postmarketing reports.
Those adverse reactions observed through postmarketing reports are italicized.
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual
disorders, pyrexia (chils andfever)
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary
edema
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis,
pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease
(ulcerative colitis, Crohn's disease), nonpeptic gastrointestinal ulceration,
ulcerative stomatitis, esophagitis, peptic ulceration
Hepatobilary: jaundice, abnormal
liver function tests, hepatits (some cases
have been fatal)
Hemic and Lymphatic: eosinophila, leucopenia, melena, thrombocytopenia,
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: inability to concentrate, depression, dream abnormalities,
insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive
dysfunction, convulsions
Respiratory: eosinophilc pneumonits, asthma
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis,
. erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus,
pustular reaction, systemic lupus erythematoses, bullous reactions, including
Stevens-Johnson syndrome, photosensitve dermatitis, photosensitvity
reactions, including rare cases resembling porphyria cutanea tarda
(pseudoporphyria) or epidermolysis bullosa. If skin fragilty, blistering or
other symptoms suggestive of pseudoporphyria occur, treatment should be
discontinued and the patient monitored
Special Senses: hearing impairment, corneal opacity, papilitis, retrobulbar
optic neuritis, papiledema
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial
nephritis, nephrotic syndrome, renal disease, renal failure, renal papilary
necrosis, raised serum creatinine
Reproduction (female): infertility
In patients taking NSAIDs, the following adverse experiences have also been
reported in":l % of
patients.
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite
changes, death
Cardiovascular: hypertension, tachycardia,
hypotension, myocardial infarction
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulccrs, gastritis,
glossitis, eructation
syncope,
arrhythmia,
Hepatobilary: hepatitis, liver failure
Hemic and Lymphatic: rectal blecding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia,
somnolence, tremors, convulsions, coma, hallucinations
Respiratory: asthma, respiratory
depression, pneumonia
Dermatologic: exfoliative dermatitis
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
Special Senses: blured vision, conjunctivitis
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
OVERDOSAGE
Symptoms and Signs
Significant naproxen overdosage may be characterized by lethargy, dizziness,
drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion,
nausea, transient alterations in liver fuction, hypoprothrombinemia, renal
dysfunction, metabolic acidosis, apnea, disorientation or vomiting.
Gastrointestinal bleeding can occur. Hypertension, acute renal failure,
respiratory depression, and coma may occur, but are rare. Anaphylactoid
reactions have been reported with therapeutic ingestion of NSAIDs, and may
occur following an overdose. Because naproxen sodium may be rapidly
absorbed, high and early blood levels should be anticipated. A few patients
have experienced convulsions, but it is not clear whether or not these were
drug-related. It is not known what dose of the drug would be life threatening.
The oral LDso of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110
mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
Treatment
Patients should be managed by symptomatic and supportive care following a
NSAID overdose. There are no specific antidotes. Hemodialysis does not
decrease the plasma concentration of naproxen because of the high degree of
its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1
to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients
seen within 4 hours of ingestion with symptoms or following a large overdose.
Forced diuresis, alkalinization of urine or hemoperfusion may not be useful
due to high protein binding.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and
other treatment options before dcciding to use NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension.
Use the lowest effectivc dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with NAPROSYN, EC-
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the
dose and frequency should be adjusted to suit an individual patient's needs,
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
Different dose strengths and formulations (ie, tablets, suspension) of the
drug are not necessarily bioequivalent. This difference should be taken
into consideration when changing formulation.
Although NAPROSYN, NAPROSYN Suspension, EC-NAPROSYN,
ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they
have pharmacokinetic differences that may affect onset of action. Onset of
pain relief can begin within 30 minutes in patients taking naproxen sodium
and within 1 hour in patients taking naproxen. Because EC-NAPROSYN
dissolves in the small intestine rather than in the stomach, the absorption of
the drug is delayed compared to the other naproxen formulations (see
CLINICAL PHARMACOLOGY).
The recommended strategy for initiating therapy is to choose a formulation
and a staring dose likely to be effective for the patient and then adjust the
dosage based on observation of benefit and/or adverse events. A lower dose
should be considered in patients with renal or hepatic impairment or in elderly
patients (see WARNINGS and PRECAUTIONS).
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is
unchanged, . the unbound plasma fraction of naproxen is increased in the
eldcrly. Caution is advised when high doses are required and some adjustment
of dosage may be required in elderly patients. As with other drugs used in the
elderly, it is prudent to use the lowest cffective dose.
Patients With Moderate to Severe Renal
Impairment
Naproxen-containing products are not recommended for use in patients with
moderate to severe and severe renal impairment (creatinine clearance ..30
mL/min) (see WARNINGS: Renal Effects).
Rheumatoid Arthritis, Osteoarthritis and Ankylosin9 Spondylitis
NAPROSYN
250 mg
twice daily
or 375 mg
twice daily
or 500 mg
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
NAPROSYN
250 mg (10 mL/2 tsp)
twice daily
Suspension
or 375 mg (15 mL/3 tsp)
twice daily
or 500 mg (20 mL/4 tsp)
twice daily
EC-NAPROSYN
375 mg
twice daily
or 500 mg
twice daily
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
. To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet
should not be broken, crushed or chewed during ingestion. NAPROSYN
Suspension should be shaken gently before use.
During long-term administration, the dose of naproxen may be adjusted up or
down depending on the clinical response of the patient. A lower daily dose
may suffce for long-term administration. The morning and evening doses do
not have to be equal in size and the administration of the drug more frequently
than twice daily is not necessary.
In patients who tolerate lower doses well, the dose may be increased to
naproxen 1500 mg/day for limited periods of up to 6 months when a higher
level of anti-inflammatory/analgesic activity is required. When treating such
patients with naproxen 1500 mg/day, the physician should observe sufficient
increased clinical benefits to offset the potential increased risk. The morning
and evening doses do not have to be equal in size and administration of the
drug more frequently than twice daily does not generally make a difference in
response (see CLINICAL PHARMACOLOGY).
Juvenile Arthritis
The use of NAPROSYN Suspension is recommended for juvenile arthritis in
children 2 years or older because it allows for more flexible dose titration
based on the child's weight. In pediatric patients, doses of 5 mg/kg/day
produced plasma levels of naproxen similar to those seen in adults taking 500
mg of naproxen (see CLINICAL PHARMACOLOGY).
The recommended total daily dose of naproxen is approximately 10 mg/kg
given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup
marked in 1/2 teaspoon and 2.5 mililiter increments is provided with the
NAPROSYN Suspension. The following table may be used as a guide for
dosing ofNAPROSYN Suspension:
Patient's Weight
Dose
Administered as
13 kg (29 lb)
62.5 mg bid
2.5 mL (1/2 tsp) twice daily
25 kg (55 lb)
125 mg bid
5.0 mL (1 tsp) twice daily
38 kg (84 lb)
187.5 mg bid
7.5 mL (1 1/2 tsp) twice daily
Management of Pain, Primary Dysmenorrhea, and Acute
Tendonitis and Bursitis
The recommended starting dose is 550 mg of naproxen sodium as
ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg
every 6 to 8 hours as required. The initial total daily dose should not exceed
1375 mg of naproxen sodium. Thereafter, the total daily dose should not
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is
more rapidly àbsorbed, ANAPROXIANAPROX DS is recommended for the
management of acute painful conditions when prompt onset of pain relief is
desired. NAPROSYN may also be used but EC-NAPROSYN is not
recommended for initial treatment of acute pain because absorption of
naproxen is delayed compared to other naproxen-containing products (see
CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE).
Acute Gout
The recommended starting dose is 750 mg of NAPROSYN followed by 250
mg every 8 hours until the attack has subsided. ANAPROX may also be used
at a starting dose of 825 mg followed by 275 mg cvery 8 hours. EC-
NAPROSYN is not recommended because of the delay in absorption (see
CLINICAL PHARMACOLOGY).
HOW SUPPLIED
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR
LE 250 on one side and scored on the other. Packaged in light-resistant bottles
of100. .
100's (bottle): NDC 0004-6313-01.
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side.
Packaged in light-resistant bottles of 100.
100' s (bottle): NDC 0004-6314-01.
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and
scored on the other. Packaged in light-resistant bottles of 100.
100's (bottle): NDC 0004-6316-01.
Store at 150 to 30°C (590 to 86°F) in well-closed containers; dispensc in light-
resistant containers.
NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5
mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC
0004-0028-28).
Store at 150 to 30°C (590 to 86°F); avoid excessive heat, above 40°C (104°F).
Dispense in light-resistant containers. Shake gently before use.
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex
coated tablets imprinted with NPR EC 375 on one side. Packaged in light-
resistant bottles of 100.
100's (bottle): NDC 0004-6415-01.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
500 mg: white, oblong coated tablets imprintcd with NPR EC 500 on one side.
Packaged in light-resistant bottles of 100.
100' s (bottle): NDC 0004-6416-01.
Store at 150 to 30°C (590 to 86°F) in well-closed containers; dispense in light-
resistant containers.
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped,
engraved with NPS-275 on one side. Packaged in bottles of 100.
100's (bottle): NDC 0004-6202-01.
Store at 15°to 30°C (590 to 86°F) in well-closed containers.
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong.:
shaped, engraved with NPS 550 on one side and scored on both sides.
Packaged in bottles of 100.
100' s (bottle): NDC 0004-6203 -0 1.
Store at 150 to 30°C (590 to 86°F) in well-closed containers.
Revised: September 2007
Medication Guide
for
Non-steroidal Anti-Inflammatorv Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID
medicines.)
What is the most important information I should know about medicines
called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or
stroke that can lead to death. This chance increases:
. with longer use of NSAID medicines
. in people who have heart disease
NSAID medicines should never be used right before or after a
heart surgery called a "coronary artery bypass graft (CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach
and intestines at any time during treatment. Ulcers and bleeding:
. can happen without warning symptoms
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSY~ (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
. may cause death
The chance of a person getting an ulcer or bleeding increases
with:
. taking medicines called "corticosteroids" and
"anticoagulants"
. longer use
. smoking
. drinking alcohol
. older age
. having poor health
NSAID medicines should only be used:
. exactly as prescribed
. at the lowest dose possible for your treatment
. for the shortest time needed
!
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swellng, and heat
(inflammation) from medical conditions such as:
. different types of arthritis
. menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
. if you had an asthma attack, hives, or other allergic reaction with
aspirin or any other NSAID medicine
. for pain right before or after heart bypass surgery
Tell your healthcare provider:
. about all of your medical conditions.
. about all of the medicines you take. NSAIDs and some other
medicines can interact with each other and cause serious side
effects. Keep a list of your medicines to show to your
health
care provider and pharmacist.
. if you are pregnant. NSAID medicines should not be used by
pregnant women late in their pregnancy.
. if
you are breastfeeding. Talk to your doctor.
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN(j (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN(j (naproxen suspension)
What are the possible side effects of Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)?
Serious side effects include:
. heart attack
. stroke
. high blood pressure
. heart failure from body swelling
(fluid retention)
. kidney problems including kidney
failure
. bleeding and ulcers in the stomach
and intestine
. low red blood cells (anemia)
. life-threatcning skin reactions
. life-threatening allergic reactions
. liver problems including liver
failure
. asthma attacks in peoplc who have
asthma
Other side effects include:
.
stomach pain
.
constipation
.
diarrhea
.
gas
.
heartburn
.
nausea
.
vomiting
.
dizziness
Get emergency help right away if you have any of the following
symptoms:
. shortness of breath or trouble
breathing
. chest pain
. weakness in one part or side of your
body
. slurred speech
. swellng of the face or
throat
Stop your NSAID medicine and call your healthcare provider right away
if you have any of the following symptoms:
. nausea
. more tired or weaker than usual
. itching
. your skin or eyes look yellow
. stomach pain
. flu-like symptoms
. vomit blood
. there is blood in your
bowel movement or it is
black and sticky like tar
. unusual weight gain
. skin rash or blisters with
fever
. swellng of the arms and
legs, hands and feet
These are not all the side effects with NSAID _me.dicines._Talk_ to_your - -
healthcare provider or pharmacist for more information about NSAID
medicines.
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN (naproxen delayed-release tablets), NAPROSYNW (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYNW (naproxen suspension)
Other information about Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs):
. Aspirin is an NSAID medicine but it does not increase the chance of a
heart attack. Aspirin can cause bleeding in the brain, stomach, and
intestines. Aspirin can also cause ulcers in the stomach and intestines.
. Some of these NSAID medicines are sold in lower doses without a
prescription (over-the-counter). Talk to your healthcareprovider before
using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradenaiie
Celecoxib
Celebrex~
Diclofcnac
Cataflam~, VoltarenCB, Arthrotec™ (combined with
misoprostol)
Diflunisal
Dolobid~
Etodolac
Lodine CB, Lodine CBXL
Fenoprofen
Nalfon~, Nalfon~200
Flurbirofen
Ansaid~
Ibuprofen
Motrin~, Tab-Profen~, VicoprofenCB* (combined with
hydrocodone), Combunox ™ (combined with
oxycodone)
Indomethacin
IndocinCB, Indocin~SR, Indo-Lemmon™,
Indomethagan ™
Ketoprofen
Oruvail~
Ketorolac
Toradol~
Mefenamic Acid
Ponstel~
Meloxicam
Mobic~
N abumetone
Relafen ~
Naproxen
NaprosynCB, AnaproxCB, Anaprox~DS, EC-NaprosynCB,
Naprelan~, Naprapac~ (copackagcd with
lansoprazole)
Oxaprozin
DayproCB
Piroxicam
Feldene~
Sulindac
ClinorilCB
Tolmetin
Tolectin~, Tolectin DS~, TolectinCB600
*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC)
NSAID, and is usually used for less than 10 days to treat pain. The OTC
NSAID label warns that long term continuous use may increase the risk of
heart attack or stroke.
Revised: January 2007
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYNW (naproxen delayed-release tablets), NAPROSYN(j (naproxen
tablets), ANAPROX(j/ANAPROX(j DS (naproxen sodium tablets),
NAPROSYN (naproxen suspension)
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
All registered trademarks in this document are the property of their respective
owners.
Distributed by:
(Roche) Pharmaceuticals
Roche Laboratories Inc.
340 Kingsland Street
Nutley, New Jersey 07110- 1199
xxxxxxxx
XXXXXXXX
Copyright (9 1999-2001 by Roche Laboratories Inc. All rights reserved.
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:18.662381
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017581s108,18164s58,18965s16,20067s14lbl.pdf', 'application_number': 17581, 'submission_type': 'SUPPL ', 'submission_number': 108}
|
11,041
|
LOMUSTINE - lomustine capsule, gelatin coated
NextSource Biotechnology, LLC
Lomustine
Capsules
WARNINGS
Lomustine should be administered under the supervision of a qualified physician experienced in the use of cancer
chemotherapeutic agents.
Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming
infections in an already compromised patient, is the most common and severe of the toxic effects of Lomustine (see
WARNINGS and ADVERSE REACTIONS).
Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks
after a dose (see ADVERSE REACTIONS). At the recommended dosage, courses of Lomustine should not be given more
frequently than every 6 weeks.
The bone marrow toxicity of Lomustine is cumulative and therefore dosage adjustment must be considered on the basis of
nadir blood counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).
DESCRIPTION
Lomustine (CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1-(2-chloro-ethyl)-3
cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71.
Lomustine is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Lomustine is relatively insoluble in
water (<0.05 mg per mL).
It is relatively un-ionized at a physiological pH.
Inactive ingredients in Lomustine Capsules are magnesium stearate and mannitol.
The structural formula is:
Lomustine is available in 10 mg, 40 mg, and 100 mg capsules for oral administration.
CLINICAL PHARMACOLOGY
Although it is generally agreed that lomustine alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other
nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.
Lomustine may be given orally. Following oral administration of radioactive lomustine at doses ranging from 30 mg/m2 to 100 mg/
m2, about half of the radioactivity given was excreted in the urine in the form of degradation products within 24 hours.
The serum half-life of the metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma levels at 15 minutes
after intravenous administration.
Because of the high lipid solubility and the relative lack of ionization at physiological pH, lomustine crosses the blood-brain barrier
quite effectively. Levels of radioactivity in the CSF are 50% or greater than those measured concurrently in plasma.
INDICATIONS AND USAGE
Lomustine has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination
therapy with other approved chemotherapeutic agents in the following:
Brain tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic
procedures.
Hodgkin's disease—secondary therapy in combination with other approved drugs in patients who relapse while being treated with
primary therapy, or who fail to respond to primary therapy.
CONTRAINDICATIONS
Lomustine should not be given to individuals who have demonstrated a previous hypersensitivity to it.
WARNINGS
Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a
dose (see ADVERSE REACTIONS). At the recommended dosage, courses of Lomustine should not be given more frequently than
every 6 weeks.
The bone marrow toxicity of Lomustine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood
counts from prior dose (see dosage adjustment table under DOSAGE AND ADMINISTRATION).
Pulmonary toxicity from Lomustine appears to be dose related (see ADVERSE REACTIONS).
Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.
Liver and renal function tests should be monitored periodically (see ADVERSE REACTIONS).
page 1 of 5
Reference ID: 3357967
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy Category D
Lomustine can cause fetal harm when administered to a pregnant woman. Lomustine is embryotoxic and teratogenic in rats and
embryotoxic in rabbits at dose levels equivalent to the human dose. There are no adequate and well controlled studies in pregnant
women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should
be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
PRECAUTIONS
General
In all instances where the use of Lomustine is considered for chemotherapy, the physician must evaluate the need and usefulness of
the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such
effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be
taken according to the clinical judgment of the physician. Reinstitution of Lomustine therapy should be carried out with caution and
with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.
Information for Patients
Provide patients with the following information and instructions:
1. In order to provide the proper dose of Lomustine, the dose may be made up of 2 or more different strengths and colors of capsules.
Each strength must be dispensed separately by the pharmacist.
2. Lomustine is given as a single oral dose and will not be repeated for at least 6 weeks. Daily use of the recommended dose may lead
to toxicities and fatal outcomes.
3. Patients may experience nausea and vomiting that usually last less than 24 hours. Patients may also experience loss of appetite that
may last for several days.
4. Instruct patients to contact their physician if they develop any of the following reactions: fever, chills, sore throat, unusual bleeding
or bruising, shortness of breath, dry cough, swelling of feet or lower legs, mental confusion, or yellowing of eyes and skin.
5. Instruct patients to wear impervious (rubber or latex) gloves when handling Lomustine Capsules.
Laboratory Tests
Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose.
Baseline pulmonary function studies should be conducted along with frequent pulmonary function tests during treatment. Patients with
a baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) are particularly
at risk.
Since Lomustine may cause liver dysfunction, it is recommended that liver function tests be monitored periodically.
Renal function tests should also be monitored periodically.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed
clinically. Nitrosourea therapy does have carcinogenic potential in humans (see ADVERSE REACTIONS). Lomustine also affects
fertility in male rats at doses somewhat higher than the human dose.
Pregnancy
Pregnancy Category D
See WARNINGS.
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 Lomustine, 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
See ADVERSE REACTIONS: Pulmonary Toxicity and DOSAGE AND ADMINISTRATION.
Geriatric Use
No data from clinical studies of Lomustine are available for patients 65 years of age and over to determine whether they respond
differently than younger patients. Other reported clinical experience has not identified differences in responses between 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.
page 2 of 5
Reference ID: 3357967
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lomustine and its metabolites are 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 renal function should be monitored.
ADVERSE REACTIONS
Hematologic Toxicity
The most frequent and most serious toxicity of Lomustine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug
administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks.
Leukopenia occurs at 5 to 6 weeks after a dose of Lomustine and persists for 1 to 2 weeks. Approximately 65% of patients receiving
130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six percent developed white blood counts below 3000 wbc/
mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.
Lomustine may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of
suppression after repeated doses.
The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea
therapy.
Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.
Pulmonary Toxicity
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with Lomustine. Onset of toxicity
has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of Lomustine usually greater than
1100 mg/m2. There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.
Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related
nitrosoureas in childhood and early adolescence (1–16 years) combined with cranial radiotherapy for intracranial tumors. There
appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly
progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years
of age died of delayed pulmonary fibrosis.
Gastrointestinal Toxicity
Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics
is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if Lomustine is
administered to fasting patients.
Hepatotoxicity
A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has been
reported in a small percentage of patients receiving Lomustine.
Nephrotoxicity
Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who
received large cumulative doses after prolonged therapy with Lomustine. Kidney damage has also been reported occasionally in
patients receiving lower total doses.
Other Toxicities
Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently.
Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving Lomustine.
However, the relationship to medication in these patients is unclear.
OVERDOSAGE
Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone
marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and
shortness of breath.
No proven antidotes have been established for Lomustine overdosage. In case of overdose, appropriate supportive measures should be
taken.
DOSAGE AND ADMINISTRATION
The recommended dose of Lomustine in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2
as a single oral dose every 6 weeks (see PRECAUTIONS: Information for Patients and HOW SUPPLIED: Directions to the
Pharmacist). In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks.
When Lomustine is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly. All doses of
Lomustine must be rounded to the nearest 10 mg by the prescriber (see HOW SUPPLIED).
page 3 of 5
Reference ID: 3357967
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The
following schedule is suggested as a guide to dosage adjustment:
Nadir After Prior Dose
Percentage of Prior Dose
to be Given
Leukocytes (/mm3)
Platelets (/mm3)
≥4000
3000–3999
2000–2999
<2000
≥100,000
75,000–99,999
25,000–74,999
<25,000
100%
100%
70%
50%
A repeat course of Lomustine should not be given until circulating blood elements have returned to acceptable levels (platelets
above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be
present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before
6 weeks because the hematologic toxicity is delayed and cumulative.
HOW SUPPLIED
Lomustine Capsules are available in individual bottles of 5 capsules each.
NDC 58181-3032-5
100 mg capsules (Green/Green)
NDC 58181-3031-5
40 mg capsules (White/Green)
NDC 58181-3030-5
10 mg capsules (White/White)
Stability
Lomustine Capsules are stable for the lot life indicated on package labeling when stored in well-closed containers at 25°C (77°F);
excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature]. Avoid excessive heat (over 40°C, 104°F).
Directions to the Pharmacist
Confirm the total dose prescribed by the physician can be obtained by determining the appropriate combination of capsule strengths.
Only the appropriate number of Lomustine capsules required for the administration of a single dose should be dispensed.
In order to provide the proper dose of Lomustine, patients should be aware that the prescribed dose may be made up of 2 or more
different strengths and colors of capsules and that each strength must be dispensed separately. Inform patients that Lomustine is taken
as a single oral dose and will not be repeated for at least 6 weeks. Daily use of the recommended dose may lead to toxicities and fatal
outcomes.
Caution should be exercised when handling Lomustine Capsules. Procedures for proper handling and disposal of anticancer drugs
should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear
impervious gloves when handling bottles containing Lomustine Capsules. Lomustine Capsules should not be broken. Personnel
should avoid exposure to broken capsules. If contact occurs, wash immediately and thoroughly. More information is available in the
references listed below.
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 JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd
ed. Pittsburgh, PA: Oncology Nursing Society.
NEXTSOURCE
Biotechnology
Manufactured by Corden Pharma Latina S.p.A., Sermoneta (LT), Italy for:
NextSource Biotechnolgy, LLC
Miami, FL 33155 USA
To report SUSPECTED ADVERSE REACTIONS, contact NextSource Biotechnology at 855-NSB-2468 (855-672-2468) or FDA at
1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch.
page 4 of 5
Reference ID: 3357967
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rev May 2013
Principal Display Panel - 10 mg Carton Label
NDC 58181-3030-5 5 capsules
Lomustine
Capsules
10 mg per capsule
Rx only
Caution: DO NOT DISPENSE
ENTIRE CONTAINER.
Dispense only enough
capsules for one dose.
NEXTSOURCE
Biotechnology
Principal Display Panel - 40 mg Carton Label
NDC 58181-3031-5 5 capsules
Lomustine
Capsules
40 mg per capsule
Rx only
Caution: DO NOT DISPENSE
ENTIRE CONTAINER.
Dispense only enough
capsules for one dose.
NEXTSOURCE
Biotechnology
Principal Display Panel - 100 mg Carton Label
NDC 58181-3032-5 5 capsules
Lomustine
Capsules
100 mg per capsule
Rx only
Caution: DO NOT DISPENSE
ENTIRE CONTAINER.
Dispense only enough
capsules for one dose.
NEXTSOURCE
Biotechnology
page 5 of 5
Reference ID: 3357967
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:18.859654
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017588s039lbl.pdf', 'application_number': 17588, 'submission_type': 'SUPPL ', 'submission_number': 39}
|
11,039
|
1
2
EC-NAPROSYN® (naproxen delayed-release tablets)
3
NAPROSYN® (naproxen tablets)
4
ANAPROX®/ANAPROX® DS (naproxen sodium tablets)
5
NAPROSYN® (naproxen suspension) Roche Logo
6
Rx only
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk
may increase with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk (see
WARNINGS).
• Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
DS or NAPROSYN Suspension is contraindicated for the treatment of
peri-operative pain in the setting of coronary artery bypass graft (CABG)
surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or
intestines, which can be fatal. These events can occur at any time during
use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
7
DESCRIPTION
8
Naproxen is a proprionic acid derivative related to the arylacetic acid group of
9
nonsteroidal anti-inflammatory drugs.
10
The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α
11
methyl-2-naphthaleneacetic
acid
and
(S)-6-methoxy-α-methyl-2
12
naphthaleneacetic acid, sodium salt, respectively. Naproxen and naproxen
13
sodium have the following structures, respectively:
Chemical Structure
15
Naproxen has a molecular weight of 230.26 and a molecular formula of
16
C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a
17
molecular formula of C14H13NaO3.
18
Naproxen is an odorless, white to off-white crystalline substance. It is lipid
19
soluble, practically insoluble in water at low pH and freely soluble in water at
20
high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
21
to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely
22
soluble in water at neutral pH.
23
NAPROSYN (naproxen tablets) is available as yellow tablets containing 250
24
mg of naproxen, pink tablets containing 375 mg of naproxen and yellow
25
tablets containing 500 mg of naproxen for oral administration. The inactive
26
ingredients are croscarmellose sodium, iron oxides, povidone and magnesium
27
stearate.
28
EC-NAPROSYN (naproxen delayed-release tablets) is available as enteric
29
coated white tablets containing 375 mg of naproxen and 500 mg of naproxen
30
for oral administration. The inactive ingredients are croscarmellose sodium,
31
povidone and magnesium stearate. The enteric coating dispersion contains
32
methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide and
33
purified water. The dissolution of this enteric-coated naproxen tablet is pH
34
dependent with rapid dissolution above pH 6. There is no dissolution below
35
pH 4.
36
ANAPROX (naproxen sodium tablets) is available as blue tablets containing
37
275 mg of naproxen sodium and ANAPROX DS (naproxen sodium tablets) is
38
available as dark blue tablets containing 550 mg of naproxen sodium for oral
39
administration.
The
inactive
ingredients
are
magnesium
stearate,
40
microcrystalline cellulose, povidone and talc. The coating suspension for the
41
ANAPROX 275 mg tablet may contain hydroxypropyl methylcellulose 2910,
42
Opaspray K-1-4210A, polyethylene glycol 8000 or Opadry YS-1-4215. The
43
coating suspension for the ANAPROX DS 550 mg tablet may contain
44
hydroxypropyl methylcellulose 2910, Opaspray K-1-4227, polyethylene
45
glycol 8000 or Opadry YS-1-4216.
46
NAPROSYN (naproxen suspension) is available as a light orange-colored
47
opaque oral suspension containing 125 mg/5 mL of naproxen in a vehicle
48
containing sucrose, magnesium aluminum silicate, sorbitol solution and
49
sodium chloride (39 mg/5 mL, 1.5 mEq), methylparaben, fumaric acid, FD&C
50
Yellow No. 6, imitation pineapple flavor, imitation orange flavor and purified
51
water. The pH of the suspension ranges from 2.2 to 3.7.
52
CLINICAL PHARMACOLOGY
53
Pharmacodynamics
54
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic
55
and antipyretic properties. The sodium salt of naproxen has been developed as
56
a more rapidly absorbed formulation of naproxen for use as an analgesic. The
57
mechanism of action of the naproxen anion, like that of other NSAIDs, is not
58
completely understood but may be related to prostaglandin synthetase
59
inhibition.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
60
Pharmacokinetics
61
Naproxen and naproxen sodium are rapidly and completely absorbed from the
62
gastrointestinal tract with an in vivo bioavailability of 95%. The different
63
dosage forms of NAPROSYN are bioequivalent in terms of extent of
64
absorption (AUC) and peak concentration (Cmax); however, the products do
65
differ in their pattern of absorption. These differences between naproxen
66
products are related to both the chemical form of naproxen used and its
67
formulation. Even with the observed differences in pattern of absorption, the
68
elimination half-life of naproxen is unchanged across products ranging from
69
12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and
70
the degree of naproxen accumulation is consistent with this half-life. This
71
suggests that the differences in pattern of release play only a negligible role in
72
the attainment of steady-state plasma levels.
73
Absorption
74
Immediate Release
75
After administration of NAPROSYN tablets, peak plasma levels are attained
76
in 2 to 4 hours. After oral administration of ANAPROX, peak plasma levels
77
are attained in 1 to 2 hours. The difference in rates between the two products
78
is due to the increased aqueous solubility of the sodium salt of naproxen used
79
in ANAPROX. Peak plasma levels of naproxen given as NAPROSYN
80
Suspension are attained in 1 to 4 hours.
81
Delayed Release
82
EC-NAPROSYN is designed with a pH-sensitive coating to provide a barrier
83
to disintegration in the acidic environment of the stomach and to lose integrity
84
in the more neutral environment of the small intestine. The enteric polymer
85
coating selected for EC-NAPROSYN dissolves above pH 6. When EC
86
NAPROSYN was given to fasted subjects, peak plasma levels were attained
87
about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo
88
study in man using radiolabeled EC-NAPROSYN tablets demonstrated that
89
EC-NAPROSYN dissolves primarily in the small intestine rather than in the
90
stomach, so the absorption of the drug is delayed until the stomach is emptied.
91
When EC-NAPROSYN and NAPROSYN were given to fasted subjects
92
(n=24) in a crossover study following 1 week of dosing, differences in time to
93
peak plasma levels (Tmax) were observed, but there were no differences in total
94
absorption as measured by Cmax and AUC:
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
EC-NAPROSYN*
500 mg bid
NAPROSYN*
500 mg bid
Cmax (µg/mL)
Tmax (hours)
AUC0–12 hr (µg·hr/mL)
94.9 (18%)
4 (39%)
845 (20%)
97.4 (13%)
1.9 (61%)
767 (15%)
95
*Mean value (coefficient of variation)
96
Antacid Effects
97
When EC-NAPROSYN was given as a single dose with antacid (54 mEq
98
buffering capacity), the peak plasma levels of naproxen were unchanged, but
99
the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with
100
antacid 5 hours), although not significantly.
101
Food Effects
102
When EC-NAPROSYN was given as a single dose with food, peak plasma
103
levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours).
104
Residence time in the small intestine until disintegration was independent of
105
food intake. The presence of food prolonged the time the tablets remained in
106
the stomach, time to first detectable serum naproxen levels, and time to
107
maximal naproxen levels (Tmax), but did not affect peak naproxen levels
108
(Cmax).
109
Distribution
110
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels
111
naproxen is greater than 99% albumin-bound. At doses of naproxen greater
112
than 500 mg/day there is less than proportional increase in plasma levels due
113
to an increase in clearance caused by saturation of plasma protein binding at
114
higher doses (average trough Css 36.5, 49.2 and 56.4 mg/L with 500, 1000 and
115
1500 mg daily doses of naproxen, respectively). The naproxen anion has been
116
found in the milk of lactating women at a concentration equivalent to
117
approximately 1% of maximum naproxen concentration in plasma (see
118
PRECAUTIONS: Nursing Mothers).
119
Metabolism
120
Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen,
121
and both parent and metabolites do not induce metabolizing enzymes. Both
122
naproxen and 6-0-desmethyl naproxen are further metabolized to their
123
respective acylglucuronide conjugated metabolites.
124
Excretion
125
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the
126
naproxen from any dose is excreted in the urine, primarily as naproxen (<1%),
127
6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
128
half-life of the naproxen anion in humans ranges from 12 to 17 hours. The
129
corresponding half-lives of both naproxen’s metabolites and conjugates are
130
shorter than 12 hours, and their rates of excretion have been found to coincide
131
closely with the rate of naproxen disappearance from the plasma. Small
132
amounts, 3% or less of the administered dose, are excreted in the feces. In
133
patients with renal failure metabolites may accumulate (see WARNINGS:
134
Renal Effects).
135
Special Populations
136
Pediatric Patients
137
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels
138
following a 5 mg/kg single dose of naproxen suspension (see DOSAGE AND
139
ADMINISTRATION) were found to be similar to those found in normal
140
adults following a 500 mg dose. The terminal half-life appears to be similar in
141
pediatric and adult patients. Pharmacokinetic studies of naproxen were not
142
performed in pediatric patients younger than 5 years of age. Pharmacokinetic
143
parameters appear to be similar following administration of naproxen
144
suspension or tablets in pediatric patients. EC-NAPROSYN has not been
145
studied in subjects under the age of 18.
146
Geriatric Patients
147
Studies indicate that although total plasma concentration of naproxen is
148
unchanged, the unbound plasma fraction of naproxen is increased in the
149
elderly, although the unbound fraction is <1% of the total naproxen
150
concentration. Unbound trough naproxen concentrations in elderly subjects
151
have been reported to range from 0.12% to 0.19% of total naproxen
152
concentration, compared with 0.05% to 0.075% in younger subjects. The
153
clinical significance of this finding is unclear, although it is possible that the
154
increase in free naproxen concentration could be associated with an increase
155
in the rate of adverse events per a given dosage in some elderly patients.
156
Race
157
Pharmacokinetic differences due to race have not been studied.
158
Hepatic Insufficiency
159
Naproxen pharmacokinetics has not been determined in subjects with hepatic
160
insufficiency.
161
Renal Insufficiency
162
Naproxen pharmacokinetics has not been determined in subjects with renal
163
insufficiency. Given that naproxen, its metabolites and conjugates are
164
primarily excreted by the kidney, the potential exists for naproxen metabolites
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
165
to accumulate in the presence of renal insufficiency. Elimination of naproxen
166
is decreased in patients with severe renal impairment. Naproxen-containing
167
products are not recommended for use in patients with moderate to severe and
168
severe
renal
impairment
(creatinine
clearance
<30
mL/min)
(see
169
WARNINGS: Renal Effects).
170
CLINICAL STUDIES
171
General Information
172
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis,
173
juvenile arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute
174
gout. Improvement in patients treated for rheumatoid arthritis was
175
demonstrated by a reduction in joint swelling, a reduction in duration of
176
morning stiffness, a reduction in disease activity as assessed by both the
177
investigator and patient, and by increased mobility as demonstrated by a
178
reduction in walking time. Generally, response to naproxen has not been
179
found to be dependent on age, sex, severity or duration of rheumatoid arthritis.
180
In patients with osteoarthritis, the therapeutic action of naproxen has been
181
shown by a reduction in joint pain or tenderness, an increase in range of
182
motion in knee joints, increased mobility as demonstrated by a reduction in
183
walking time, and improvement in capacity to perform activities of daily
184
living impaired by the disease.
185
In a clinical trial comparing standard formulations of naproxen 375 mg bid
186
(750 mg a day) vs 750 mg bid (1500 mg/day), 9 patients in the 750 mg group
187
terminated prematurely because of adverse events. Nineteen patients in the
188
1500 mg group terminated prematurely because of adverse events. Most of
189
these adverse events were gastrointestinal events.
190
In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and
191
juvenile arthritis, naproxen has been shown to be comparable to aspirin and
192
indomethacin in controlling the aforementioned measures of disease activity,
193
but the frequency and severity of the milder gastrointestinal adverse effects
194
(nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus,
195
dizziness, lightheadedness) were less in naproxen-treated patients than in
196
those treated with aspirin or indomethacin.
197
In patients with ankylosing spondylitis, naproxen has been shown to decrease
198
night pain, morning stiffness and pain at rest. In double-blind studies the drug
199
was shown to be as effective as aspirin, but with fewer side effects.
200
In patients with acute gout, a favorable response to naproxen was shown by
201
significant clearing of inflammatory changes (eg, decrease in swelling, heat)
202
within 24 to 48 hours, as well as by relief of pain and tenderness.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
203
Naproxen has been studied in patients with mild to moderate pain secondary
204
to postoperative, orthopedic, postpartum episiotomy and uterine contraction
205
pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in
206
patients taking naproxen and within 30 minutes in patients taking naproxen
207
sodium. Analgesic effect was shown by such measures as reduction of pain
208
intensity scores, increase in pain relief scores, decrease in numbers of patients
209
requiring additional analgesic medication, and delay in time to remedication.
210
The analgesic effect has been found to last for up to 12 hours.
211
Naproxen may be used safely in combination with gold salts and/or
212
corticosteroids; however, in controlled clinical trials, when added to the
213
regimen of patients receiving corticosteroids, it did not appear to cause greater
214
improvement over that seen with corticosteroids alone. Whether naproxen has
215
a “steroid-sparing” effect has not been adequately studied. When added to the
216
regimen of patients receiving gold salts, naproxen did result in greater
217
improvement. Its use in combination with salicylates is not recommended
218
because there is evidence that aspirin increases the rate of excretion of
219
naproxen and data are inadequate to demonstrate that naproxen and aspirin
220
produce greater improvement over that achieved with aspirin alone. In
221
addition, as with other NSAIDs, the combination may result in higher
222
frequency of adverse events than demonstrated for either product alone.
223
In 51Cr blood loss and gastroscopy studies with normal volunteers, daily
224
administration of 1000 mg of naproxen as 1000 mg of NAPROSYN
225
(naproxen) or 1100 mg of ANAPROX (naproxen sodium) has been
226
demonstrated to cause statistically significantly less gastric bleeding and
227
erosion than 3250 mg of aspirin.
228
Three 6-week, double-blind, multicenter studies with EC-NAPROSYN
229
(naproxen) (375 or 500 mg bid, n=385) and NAPROSYN (375 or 500 mg bid,
230
n=279) were conducted comparing EC-NAPROSYN with NAPROSYN,
231
including 355 rheumatoid arthritis and osteoarthritis patients who had a recent
232
history of NSAID-related GI symptoms. These studies indicated that EC
233
NAPROSYN and NAPROSYN showed no significant differences in efficacy
234
or safety and had similar prevalence of minor GI complaints. Individual
235
patients, however, may find one formulation preferable to the other.
236
Five hundred and fifty-three patients received EC-NAPROSYN during long
237
term open-label trials (mean length of treatment was 159 days). The rates for
238
clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been
239
historically reported for long-term NSAID use.
240
Geriatric Patients
241
The hepatic and renal tolerability of long-term naproxen administration was
242
studied in two double-blind clinical trials involving 586 patients. Of the
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
243
patients studied, 98 patients were age 65 and older and 10 of the 98 patients
244
were age 75 and older. Naproxen was administered at doses of 375 mg twice
245
daily or 750 mg twice daily for up to 6 months. Transient abnormalities of
246
laboratory tests assessing hepatic and renal function were noted in some
247
patients, although there were no differences noted in the occurrence of
248
abnormal values among different age groups.
249
INDICATIONS AND USAGE
250
Carefully consider the potential benefits and risks of NAPROSYN, EC
251
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension and
252
other treatment options before deciding to use NAPROSYN, EC
253
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension. Use
254
the lowest effective dose for the shortest duration consistent with individual
255
patient treatment goals (see WARNINGS).
256
Naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
257
NAPROSYN Suspension is indicated:
258
• For the relief of the signs and symptoms of rheumatoid arthritis
259
• For the relief of the signs and symptoms of osteoarthritis
260
• For the relief of the signs and symptoms of ankylosing spondylitis
261
• For the relief of the signs and symptoms of juvenile arthritis
262
Naproxen as NAPROSYN Suspension is recommended for juvenile
263
rheumatoid arthritis in order to obtain the maximum dosage flexibility based
264
on the patient’s weight.
265
Naproxen as NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN
266
Suspension is also indicated:
267
• For relief of the signs and symptoms of tendonitis
268
• For relief of the signs and symptoms of bursitis
269
• For relief of the signs and symptoms of acute gout
270
• For the management of pain
271
• For the management of primary dysmenorrhea
272
EC-NAPROSYN is not recommended for initial treatment of acute pain
273
because the absorption of naproxen is delayed compared to absorption from
274
other naproxen-containing products (see CLINICAL PHARMACOLOGY
275
and DOSAGE AND ADMINISTRATION).
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
276
CONTRAINDICATIONS
277
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
278
NAPROSYN Suspension are contraindicated in patients with known
279
hypersensitivity to naproxen and naproxen sodium.
280
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
281
NAPROSYN Suspension should not be given to patients who have
282
experienced asthma, urticaria, or allergic-type reactions after taking aspirin or
283
other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs
284
have been reported in such patients (see WARNINGS: Anaphylactoid
285
Reactions and PRECAUTIONS: Preexisting Asthma).
286
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
287
NAPROSYN Suspension are contraindicated for the treatment of peri
288
operative pain in the setting of coronary artery bypass graft (CABG) surgery
289
(see WARNINGS).
290
WARNINGS
291
CARDIOVASCULAR EFFECTS
292
Cardiovascular Thrombotic Events
293
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to
294
three years duration have shown an increased risk of serious cardiovascular
295
(CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.
296
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
297
Patients with known CV disease or risk factors for CV disease may be at
298
greater risk. To minimize the potential risk for an adverse CV event in patients
299
treated with an NSAID, the lowest effective dose should be used for the
300
shortest duration possible. Physicians and patients should remain alert for the
301
development of such events, even in the absence of previous CV symptoms.
302
Patients should be informed about the signs and/or symptoms of serious CV
303
events and the steps to take if they occur.
304
There is no consistent evidence that concurrent use of aspirin mitigates the
305
increased risk of serious CV thrombotic events associated with NSAID use.
306
The concurrent use of aspirin and an NSAID does increase the risk of serious
307
GI events (see Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
308
Perforation).
309
Two large, controlled, clinical trials of a COX-2 selective NSAID for the
310
treatment of pain in the first 10-14 days following CABG surgery found an
311
increased
incidence
of
myocardial
infarction
and
stroke
(see
312
CONTRAINDICATIONS).
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
313
Hypertension
314
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
315
ANAPROX DS and NAPROSYN Suspension, can lead to onset of new
316
hypertension or worsening of pre-existing hypertension, either of which may
317
contribute to the increased incidence of CV events. Patients taking thiazides or
318
loop diuretics may have impaired response to these therapies when taking
319
NSAIDs. NSAIDs, including NAPROSYN, EC-NAPROSYN, ANAPROX,
320
ANAPROX DS and NAPROSYN Suspension, should be used with caution in
321
patients with hypertension. Blood pressure (BP) should be monitored closely
322
during the initiation of NSAID treatment and throughout the course of
323
therapy.
324
Congestive Heart Failure and Edema
325
Fluid retention, edema, and peripheral edema have been observed in some
326
patients taking NSAIDs. NAPROSYN, EC-NAPROSYN, ANAPROX,
327
ANAPROX DS and NAPROSYN Suspension should be used with caution in
328
patients with fluid retention, hypertension, or heart failure. Since each
329
ANAPROX or ANAPROX DS tablet contains 25 mg or 50 mg of sodium
330
(about 1 mEq per each 250 mg of naproxen), and each teaspoonful of
331
NAPROSYN Suspension contains 39 mg (about 1.5 mEq per each 125 mg of
332
naproxen) of sodium, this should be considered in patients whose overall
333
intake of sodium must be severely restricted.
334
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
335
Perforation
336
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
337
ANAPROX DS and NAPROSYN Suspension, can cause serious
338
gastrointestinal (GI) adverse events including inflammation, bleeding,
339
ulceration, and perforation of the stomach, small intestine, or large intestine,
340
which can be fatal.
341
These serious adverse events can occur at any time, with or without warning
342
symptoms, in patients treated with NSAIDs. Only one in five patients, who
343
develop a serious upper GI adverse event on NSAID therapy, is symptomatic.
344
Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in
345
approximately 1% of patients treated for 3-6 months, and in about 2-4% of
346
patients treated for one year. These trends continue with longer duration of
347
use, increasing the likelihood of developing a serious GI event at some time
348
during the course of therapy. However, even short-term therapy is not without
349
risk. The utility of periodic laboratory monitoring has not been demonstrated,
350
nor has it been adequately assessed. Only 1 in 5 patients who develop a
351
serious upper GI adverse event on NSAID therapy is symptomatic.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
352
NSAIDs should be prescribed with extreme caution in those with a prior
353
history of ulcer disease or gastrointestinal bleeding. Patients with a prior
354
history of peptic ulcer disease and/or gastrointestinal bleeding who use
355
NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
356
compared to patients with neither of these risk factors. Other factors that
357
increase the risk for GI bleeding in patients treated with NSAIDs include
358
concomitant use of oral corticosteroids or anticoagulants, longer duration of
359
NSAID therapy, smoking, use of alcohol, older age, and poor general health
360
status. Most spontaneous reports of fatal GI events are in elderly or debilitated
361
patients and therefore, special care should be taken in treating this population.
362
To minimize the potential risk for an adverse GI event in patients treated with
363
an NSAID, the lowest effective dose should be used for the shortest possible
364
duration. Patients and physicians should remain alert for signs and symptoms
365
of GI ulceration and bleeding during NSAID therapy and promptly initiate
366
additional evaluation and treatment if a serious GI adverse event is suspected.
367
This should include discontinuation of the NSAID until a serious GI adverse
368
event is ruled out. For high risk patients, alternate therapies that do not
369
involve NSAIDs should be considered.
370
Epidemiological studies, both of the case-control and cohort design, have
371
demonstrated an association between use of psychotropic drugs that interfere
372
with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
373
In two studies, concurrent use of an NSAID or aspirin potentiated the risk of
374
bleeding (see PRECAUTIONS: Drug Interactions). Although these studies
375
focused on upper gastrointestinal bleeding, there is reason to believe that
376
bleeding at other sites may be similarly potentiated.
377
NSAIDs should be given with care to patients with a history of inflammatory
378
bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be
379
exacerbated.
380
Renal Effects
381
Long-term administration of NSAIDs has resulted in renal papillary necrosis
382
and other renal injury. Renal toxicity has also been seen in patients in whom
383
renal prostaglandins have a compensatory role in the maintenance of renal
384
perfusion.
In
these
patients,
administration
of
a
nonsteroidal
385
anti-inflammatory drug may cause a dose-dependent reduction in
386
prostaglandin formation and, secondarily, in renal blood flow, which may
387
precipitate overt renal decompensation. Patients at greatest risk of this
388
reaction are those with impaired renal function, hypovolemia, heart failure,
389
liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors,
390
and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug
391
therapy is usually followed by recovery to the pretreatment state (see
392
WARNINGS: Advanced Renal Disease).
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
393
Advanced Renal Disease
394
No information is available from controlled clinical studies regarding the use
395
of NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS or
396
NAPROSYN Suspension in patients with advanced renal disease. Therefore,
397
treatment with NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS
398
and NAPROSYN Suspension is not recommended in these patients with
399
advanced renal disease. If NAPROSYN, EC-NAPROSYN, ANAPROX,
400
ANAPROX DS or NAPROSYN Suspension therapy must be initiated, close
401
monitoring of the patient’s renal function is advisable.
402
Anaphylactoid Reactions
403
As with other NSAIDs, anaphylactoid reactions may occur in patients without
404
known prior exposure to NAPROSYN, EC-NAPROSYN, ANAPROX,
405
ANAPROX
DS
or
NAPROSYN
Suspension.
NAPROSYN,
EC
406
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
407
should not be given to patients with the aspirin triad. This symptom complex
408
typically occurs in asthmatic patients who experience rhinitis with or without
409
nasal polyps, or who exhibit severe, potentially fatal bronchospasm after
410
taking aspirin or other NSAIDs (see CONTRAINDICATIONS and
411
PRECAUTIONS: Preexisting Asthma). Emergency help should be sought
412
in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like
413
anaphylaxis, may have a fatal outcome.
414
Skin Reactions
415
NSAIDs,
including
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
416
ANAPROX DS and NAPROSYN Suspension, can cause serious skin adverse
417
events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and
418
toxic epidermal necrolysis (TEN), which can be fatal. These serious events
419
may occur without warning. Patients should be informed about the signs and
420
symptoms of serious skin manifestations and use of the drug should be
421
discontinued at the first appearance of skin rash or any other sign of
422
hypersensitivity.
423
Pregnancy
424
In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
425
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be avoided
426
because it may cause premature closure of the ductus arteriosus.
427
PRECAUTIONS
428
General
429
Naproxen-containing products such as NAPROSYN, EC-NAPROSYN,
430
ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE®, and
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
431
other naproxen products should not be used concomitantly since they all
432
circulate in the plasma as the naproxen anion.
433
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
434
NAPROSYN Suspension cannot be expected to substitute for corticosteroids
435
or to treat corticosteroid insufficiency. Abrupt discontinuation of
436
corticosteroids may lead to disease exacerbation. Patients on prolonged
437
corticosteroid therapy should have their therapy tapered slowly if a decision is
438
made to discontinue corticosteroids and the patient should be observed closely
439
for any evidence of adverse effects, including adrenal insufficiency and
440
exacerbation of symptoms of arthritis.
441
Patients with initial hemoglobin values of 10 g or less who are to receive long
442
term therapy should have hemoglobin values determined periodically.
443
The
pharmacological
activity
of
NAPROSYN,
EC-NAPROSYN,
444
ANAPROX, ANAPROX DS and NAPROSYN Suspension in reducing fever
445
and inflammation may diminish the utility of these diagnostic signs in
446
detecting complications of presumed noninfectious, noninflammatory painful
447
conditions.
448
Because of adverse eye findings in animal studies with drugs of this class, it is
449
recommended that ophthalmic studies be carried out if any change or
450
disturbance in vision occurs.
451
Hepatic Effects
452
Borderline elevations of one or more liver tests may occur in up to 15% of
453
patients
taking
NSAIDs
including
NAPROSYN,
EC-NAPROSYN,
454
ANAPROX, ANAPROX DS and NAPROSYN Suspension. Hepatic
455
abnormalities may be the result of hypersensitivity rather than direct toxicity.
456
These laboratory abnormalities may progress, may remain essentially
457
unchanged, or may be transient with continued therapy. The SGPT (ALT) test
458
is probably the most sensitive indicator of liver dysfunction. Notable
459
elevations of ALT or AST (approximately three or more times the upper limit
460
of normal) have been reported in approximately 1% of patients in clinical
461
trials with NSAIDs. In addition, rare cases of severe hepatic reactions,
462
including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
463
failure, some of them with fatal outcomes have been reported.
464
A patient with symptoms and/or signs suggesting liver dysfunction, or in
465
whom an abnormal liver test has occurred, should be evaluated for evidence
466
of the development of more severe hepatic reaction while on therapy with
467
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
468
NAPROSYN Suspension.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
469
If clinical signs and symptoms consistent with liver disease develop, or if
470
systemic manifestations occur (eg, eosinophilia, rash, etc.), NAPROSYN, EC
471
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension
472
should be discontinued.
473
Chronic alcoholic liver disease and probably other diseases with decreased or
474
abnormal plasma proteins (albumin) reduce the total plasma concentration of
475
naproxen, but the plasma concentration of unbound naproxen is increased.
476
Caution is advised when high doses are required and some adjustment of
477
dosage may be required in these patients. It is prudent to use the lowest
478
effective dose.
479
Hematological Effects
480
Anemia is sometimes seen in patients receiving NSAIDs, including
481
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
482
NAPROSYN Suspension. This may be due to fluid retention, occult or gross
483
GI blood loss, or an incompletely described effect upon erythropoiesis.
484
Patients on long-term treatment with NSAIDs, including NAPROSYN, EC
485
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension,
486
should have their hemoglobin or hematocrit checked if they exhibit any signs
487
or symptoms of anemia.
488
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding
489
time in some patients. Unlike aspirin, their effect on platelet function is
490
quantitatively less, of shorter duration, and reversible. Patients receiving either
491
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
or
492
NAPROSYN Suspension who may be adversely affected by alterations in
493
platelet function, such as those with coagulation disorders or patients
494
receiving anticoagulants, should be carefully monitored.
495
Preexisting Asthma
496
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in
497
patients with aspirin-sensitive asthma has been associated with severe
498
bronchospasm, which can be fatal. Since cross reactivity, including
499
bronchospasm, between aspirin and other nonsteroidal anti-inflammatory
500
drugs has been reported in such aspirin-sensitive patients, NAPROSYN, EC
501
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension
502
should not be administered to patients with this form of aspirin sensitivity and
503
should be used with caution in patients with preexisting asthma.
504
Information for Patients
505
Patients should be informed of the following information before initiating
506
therapy with an NSAID and periodically during the course of ongoing
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
507
therapy. Patients should also be encouraged to read the NSAID
508
Medication Guide that accompanies each prescription dispensed.
509
1. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
510
NAPROSYN Suspension, like other NSAIDs, may cause serious CV side
511
effects, such as MI or stroke, which may result in hospitalization and even
512
death. Although serious CV events can occur without warning symptoms,
513
patients should be alert for the signs and symptoms of chest pain,
514
shortness of breath, weakness, slurring of speech, and should ask for
515
medical advice when observing any indicative sign or symptoms. Patients
516
should be apprised of the importance of this follow-up (see WARNINGS:
517
Cardiovascular Effects).
518
2. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
519
NAPROSYN Suspension, like other NSAIDs, can cause GI discomfort
520
and, rarely, serious GI side effects, such as ulcers and bleeding, which
521
may result in hospitalization and even death. Although serious GI tract
522
ulcerations and bleeding can occur without warning symptoms, patients
523
should be alert for the signs and symptoms of ulcerations and bleeding,
524
and should ask for medical advice when observing any indicative sign or
525
symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
526
Patients should be apprised of the importance of this follow-up (see
527
WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding,
528
and Perforation).
529
3. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX DS and
530
NAPROSYN Suspension, like other NSAIDs, can cause serious skin side
531
effects such as exfoliative dermatitis, SJS, and TEN, which may result in
532
hospitalizations and even death. Although serious skin reactions may
533
occur without warning, patients should be alert for the signs and
534
symptoms of skin rash and blisters, fever, or other signs of
535
hypersensitivity such as itching, and should ask for medical advice when
536
observing any indicative signs or symptoms. Patients should be advised to
537
stop the drug immediately if they develop any type of rash and contact
538
their physicians as soon as possible.
539
4. Patients should promptly report signs or symptoms of unexplained weight
540
gain or edema to their physicians.
541
5. Patients should be informed of the warning signs and symptoms of
542
hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper
543
quadrant tenderness, and “flu-like” symptoms). If these occur, patients
544
should be instructed to stop therapy and seek immediate medical therapy.
545
6. Patients should be informed of the signs of an anaphylactoid reaction (eg,
546
difficulty breathing, swelling of the face or throat). If these occur, patients
547
should be instructed to seek immediate emergency help (see
548
WARNINGS).
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
549
7. In late pregnancy, as with other NSAIDs, NAPROSYN, EC-NAPROSYN,
550
ANAPROX, ANAPROX DS and NAPROSYN Suspension should be
551
avoided because it may cause premature closure of the ductus arteriosus.
552
8. Caution should be exercised by patients whose activities require alertness
553
if they experience drowsiness, dizziness, vertigo or depression during
554
therapy with naproxen.
555
Laboratory Tests
556
Because serious GI tract ulcerations and bleeding can occur without warning
557
symptoms, physicians should monitor for signs or symptoms of GI bleeding.
558
Patients on long-term treatment with NSAIDs should have their CBC and a
559
chemistry profile checked periodically. If clinical signs and symptoms
560
consistent with liver or renal disease develop, systemic manifestations occur
561
(eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
562
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
563
NAPROSYN Suspension should be discontinued.
564
Drug Interactions
565
ACE-inhibitors
566
Reports suggest that NSAIDs may diminish the antihypertensive effect of
567
ACE-inhibitors. This interaction should be given consideration in patients
568
taking NSAIDs concomitantly with ACE-inhibitors.
569
Antacids and Sucralfate
570
Concomitant administration of some antacids (magnesium oxide or aluminum
571
hydroxide) and sucralfate can delay the absorption of naproxen.
572
Aspirin
573
When naproxen as NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
574
DS or NAPROSYN Suspension is administered with aspirin, its protein
575
binding is reduced, although the clearance of free NAPROSYN, EC
576
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension is
577
not altered. The clinical significance of this interaction is not known;
578
however, as with other NSAIDs, concomitant administration of naproxen and
579
naproxen sodium and aspirin is not generally recommended because of the
580
potential of increased adverse effects.
581
Cholestyramine
582
As with other NSAIDs, concomitant administration of cholestyramine can
583
delay the absorption of naproxen.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
584
Diuretics
585
Clinical studies, as well as postmarketing observations, have shown that
586
NAPROSYN,
EC-NAPROSYN,
ANAPROX,
ANAPROX
DS
and
587
NAPROSYN Suspension can reduce the natriuretic effect of furosemide and
588
thiazides in some patients. This response has been attributed to inhibition of
589
renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the
590
patient should be observed closely for signs of renal failure (see
591
WARNINGS: Renal Effects), as well as to assure diuretic efficacy.
592
Lithium
593
NSAIDs have produced an elevation of plasma lithium levels and a reduction
594
in renal lithium clearance. The mean minimum lithium concentration
595
increased 15% and the renal clearance was decreased by approximately 20%.
596
These effects have been attributed to inhibition of renal prostaglandin
597
synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
598
concurrently, subjects should be observed carefully for signs of lithium
599
toxicity.
600
Methotrexate
601
NSAIDs have been reported to competitively inhibit methotrexate
602
accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other
603
nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular
604
secretion of methotrexate in an animal model. This may indicate that they
605
could enhance the toxicity of methotrexate. Caution should be used when
606
NSAIDs are administered concomitantly with methotrexate.
607
Warfarin
608
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
609
users of both drugs together have a risk of serious GI bleeding higher than
610
users of either drug alone. No significant interactions have been observed in
611
clinical studies with naproxen and coumarin-type anticoagulants. However,
612
caution is advised since interactions have been seen with other nonsteroidal
613
agents of this class. The free fraction of warfarin may increase substantially in
614
some subjects and naproxen interferes with platelet function.
615
Selective Serotonin Reuptake Inhibitors (SSRIs)
616
There is an increased risk of gastrointestinal bleeding when selective serotonin
617
reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be
618
used when NSAIDs are administered concomitantly with SSRIs.
619
Other Information Concerning Drug Interactions
620
Naproxen is highly bound to plasma albumin; it thus has a theoretical
621
potential for interaction with other albumin-bound drugs such as coumarin
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
622
type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
623
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or
624
sulphonylurea should be observed for adjustment of dose if required.
625
Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the
626
antihypertensive effect of propranolol and other beta-blockers.
627
Probenecid given concurrently increases naproxen anion plasma levels and
628
extends its plasma half-life significantly.
629
Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive
630
antacid therapy, concomitant administration of EC-NAPROSYN is not
631
recommended.
632
Drug/Laboratory Test Interaction
633
Naproxen may decrease platelet aggregation and prolong bleeding time. This
634
effect should be kept in mind when bleeding times are determined.
635
The administration of naproxen may result in increased urinary values for 17
636
ketogenic steroids because of an interaction between the drug and/or its
637
metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy
638
corticosteroid measurements (Porter-Silber test) do not appear to be
639
artifactually altered, it is suggested that therapy with naproxen be temporarily
640
discontinued 72 hours before adrenal function tests are performed if the
641
Porter-Silber test is to be used.
642
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic
643
acid (5HIAA).
644
Carcinogenesis
645
A 2-year study was performed in rats to evaluate the carcinogenic potential of
646
naproxen at rat doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m2).
647
The maximum dose used was 0.28 times the systemic exposure to humans at
648
the recommended dose. No evidence of tumorigenicity was found.
649
Pregnancy
650
Teratogenic Effects
651
Pregnancy Category C
652
Reproduction studies have been performed in rats at 20 mg/kg/day
653
(125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20
654
mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and
655
mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic
656
exposure) with no evidence of impaired fertility or harm to the fetus due to the
657
drug. However, animal reproduction studies are not always predictive of
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
658
human response. There are no adequate and well-controlled studies in
659
pregnant women. NAPROSYN, EC-NAPROSYN, ANAPROX, ANAPROX
660
DS and NAPROSYN Suspension should be used in pregnancy only if the
661
potential benefit justifies the potential risk to the fetus.
662
Nonteratogenic Effects
663
There is some evidence to suggest that when inhibitors of prostaglandin
664
synthesis are used to delay preterm labor there is an increased risk of neonatal
665
complications such as necrotizing enterocolitis, patent ductus arteriosus and
666
intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay
667
parturition has been associated with persistent pulmonary hypertension, renal
668
dysfunction and abnormal prostaglandin E levels in preterm infants. Because
669
of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
670
cardiovascular system (closure of ductus arteriosus), use during pregnancy
671
(particularly late pregnancy) should be avoided.
672
Labor and Delivery
673
In rat studies with NSAIDs, as with other drugs known to inhibit
674
prostaglandin synthesis, an increased incidence of dystocia, delayed
675
parturition, and decreased pup survival occurred. Naproxen-containing
676
products are not recommended in labor and delivery because, through its
677
prostaglandin synthesis inhibitory effect, naproxen may adversely affect fetal
678
circulation and inhibit uterine contractions, thus increasing the risk of uterine
679
hemorrhage. The effects of NAPROSYN, EC-NAPROSYN, ANAPROX,
680
ANAPROX DS and NAPROSYN Suspension on labor and delivery in
681
pregnant women are unknown.
682
Nursing Mothers
683
The naproxen anion has been found in the milk of lactating women at a
684
concentration equivalent to approximately 1% of maximum naproxen
685
concentration in plasma. Because of the possible adverse effects of
686
prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be
687
avoided.
688
Pediatric Use
689
Safety and effectiveness in pediatric patients below the age of 2 years have
690
not been established. Pediatric dosing recommendations for juvenile arthritis
691
are
based
on
well-controlled
studies
(see
DOSAGE
AND
692
ADMINISTRATION). There are no adequate effectiveness or dose-response
693
data for other pediatric conditions, but the experience in juvenile arthritis and
694
other use experience have established that single doses of 2.5 to 5 mg/kg (as
695
naproxen suspension, see DOSAGE AND ADMINISTRATION), with total
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
696
daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients
697
over 2 years of age.
698
Geriatric Use
699
Studies indicate that although total plasma concentration of naproxen is
700
unchanged, the unbound plasma fraction of naproxen is increased in the
701
elderly. Caution is advised when high doses are required and some adjustment
702
of dosage may be required in elderly patients. As with other drugs used in the
703
elderly, it is prudent to use the lowest effective dose.
704
Experience indicates that geriatric patients may be particularly sensitive to
705
certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or
706
debilitated patients seem to tolerate peptic ulceration or bleeding less well
707
when these events do occur. Most spontaneous reports of fatal GI events are in
708
the geriatric population (see WARNINGS).
709
Naproxen is known to be substantially excreted by the kidney, and the risk of
710
toxic reactions to this drug may be greater in patients with impaired renal
711
function. Because elderly patients are more likely to have decreased renal
712
function, care should be taken in dose selection, and it may be useful to
713
monitor renal function. Geriatric patients may be at a greater risk for the
714
development of a form of renal toxicity precipitated by reduced prostaglandin
715
formation during administration of nonsteroidal anti-inflammatory drugs (see
716
WARNINGS: Renal Effects).
717
ADVERSE REACTIONS
718
Adverse reactions reported in controlled clinical trials in 960 patients treated
719
for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions
720
in patients treated chronically were reported 2 to 10 times more frequently
721
than they were in short-term studies in the 962 patients treated for mild to
722
moderate pain or for dysmenorrhea. The most frequent complaints reported
723
related to the gastrointestinal tract.
724
A clinical study found gastrointestinal reactions to be more frequent and more
725
severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen
726
compared
to
those
taking
750
mg
naproxen
(see
CLINICAL
727
PHARMACOLOGY).
728
In controlled clinical trials with about 80 pediatric patients and in well
729
monitored, open-label studies with about 400 pediatric patients with juvenile
730
arthritis treated with naproxen, the incidence of rash and prolonged bleeding
731
times were increased, the incidence of gastrointestinal and central nervous
732
system reactions were about the same, and the incidence of other reactions
733
were lower in pediatric patients than in adults.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
734
In patients taking naproxen in clinical trials, the most frequently reported
735
adverse experiences in approximately 1% to 10% of patients are:
736
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*,
737
nausea*, constipation*, diarrhea, dyspepsia, stomatitis
738
Central
Nervous
System:
headache*,
dizziness*,
drowsiness*,
739
lightheadedness, vertigo
740
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating,
741
purpura
742
Special Senses: tinnitus*, visual disturbances, hearing disturbances
743
Cardiovascular: edema*, palpitations
744
General: dyspnea*, thirst
745
*Incidence of reported reaction between 3% and 9%. Those reactions
746
occurring in less than 3% of the patients are unmarked.
747
In patients taking NSAIDs, the following adverse experiences have also been
748
reported in approximately 1% to 10% of patients.
749
Gastrointestinal
(GI)
Experiences,
including:
flatulence,
gross
750
bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
751
General: abnormal renal function, anemia, elevated liver enzymes, increased
752
bleeding time, rashes
753
The following are additional adverse experiences reported in <1% of patients
754
taking naproxen during clinical trials and through postmarketing reports.
755
Those adverse reactions observed through postmarketing reports are italicized.
756
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual
757
disorders, pyrexia (chills and fever)
758
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary
759
edema
760
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis,
761
pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease
762
(ulcerative colitis, Crohn’s disease), nonpeptic gastrointestinal ulceration,
763
ulcerative stomatitis, esophagitis, peptic ulceration
764
Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases
765
have been fatal)
766
Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia,
767
agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
768
Metabolic and Nutritional: hyperglycemia, hypoglycemia
769
Nervous System: inability to concentrate, depression, dream abnormalities,
770
insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive
771
dysfunction, convulsions
772
Respiratory: eosinophilic pneumonitis, asthma
773
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis,
774
erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus,
775
pustular reaction, systemic lupus erythematoses, bullous reactions, including
776
Stevens-Johnson
syndrome,
photosensitive
dermatitis,
photosensitivity
777
reactions, including rare cases resembling porphyria cutanea tarda
778
(pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or
779
other symptoms suggestive of pseudoporphyria occur, treatment should be
780
discontinued and the patient monitored.
781
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar
782
optic neuritis, papilledema
783
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial
784
nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary
785
necrosis, raised serum creatinine
786
Reproduction (female): infertility
787
In patients taking NSAIDs, the following adverse experiences have also been
788
reported in <1% of patients.
789
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite
790
changes, death
791
Cardiovascular:
hypertension,
tachycardia,
syncope,
arrhythmia,
792
hypotension, myocardial infarction
793
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis,
794
glossitis, eructation
795
Hepatobiliary: hepatitis, liver failure
796
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
797
Metabolic and Nutritional: weight changes
798
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia,
799
somnolence, tremors, convulsions, coma, hallucinations
800
Respiratory: asthma, respiratory depression, pneumonia
801
Dermatologic: exfoliative dermatitis
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
802
Special Senses: blurred vision, conjunctivitis
803
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
804
OVERDOSAGE
805
Symptoms and Signs
806
Significant naproxen overdosage may be characterized by lethargy, dizziness,
807
drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion,
808
nausea, transient alterations in liver function, hypoprothrombinemia, renal
809
dysfunction,
metabolic
acidosis,
apnea,
disorientation
or
vomiting.
810
Gastrointestinal bleeding can occur. Hypertension, acute renal failure,
811
respiratory depression, and coma may occur, but are rare. Anaphylactoid
812
reactions have been reported with therapeutic ingestion of NSAIDs, and may
813
occur following an overdose. Because naproxen sodium may be rapidly
814
absorbed, high and early blood levels should be anticipated. A few patients
815
have experienced convulsions, but it is not clear whether or not these were
816
drug-related. It is not known what dose of the drug would be life threatening.
817
The oral LD50 of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110
818
mg/kg in hamsters, and greater than 1000 mg/kg in dogs.
819
Treatment
820
Patients should be managed by symptomatic and supportive care following a
821
NSAID overdose. There are no specific antidotes. Hemodialysis does not
822
decrease the plasma concentration of naproxen because of the high degree of
823
its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1
824
to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients
825
seen within 4 hours of ingestion with symptoms or following a large overdose.
826
Forced diuresis, alkalinization of urine or hemoperfusion may not be useful
827
due to high protein binding.
828
DOSAGE AND ADMINISTRATION
829
Carefully consider the potential benefits and risks of NAPROSYN, EC
830
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension and
831
other treatment options before deciding to use NAPROSYN, EC
832
NAPROSYN, ANAPROX, ANAPROX DS and NAPROSYN Suspension.
833
Use the lowest effective dose for the shortest duration consistent with
834
individual patient treatment goals (see WARNINGS).
835
After observing the response to initial therapy with NAPROSYN, EC
836
NAPROSYN, ANAPROX, ANAPROX DS or NAPROSYN Suspension, the
837
dose and frequency should be adjusted to suit an individual patient’s needs.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
838
Different dose strengths and formulations (ie, tablets, suspension) of the
839
drug are not necessarily bioequivalent. This difference should be taken
840
into consideration when changing formulation.
841
Although
NAPROSYN,
NAPROSYN
Suspension,
EC-NAPROSYN,
842
ANAPROX and ANAPROX DS all circulate in the plasma as naproxen, they
843
have pharmacokinetic differences that may affect onset of action. Onset of
844
pain relief can begin within 30 minutes in patients taking naproxen sodium
845
and within 1 hour in patients taking naproxen. Because EC-NAPROSYN
846
dissolves in the small intestine rather than in the stomach, the absorption of
847
the drug is delayed compared to the other naproxen formulations (see
848
CLINICAL PHARMACOLOGY).
849
The recommended strategy for initiating therapy is to choose a formulation
850
and a starting dose likely to be effective for the patient and then adjust the
851
dosage based on observation of benefit and/or adverse events. A lower dose
852
should be considered in patients with renal or hepatic impairment or in elderly
853
patients (see WARNINGS and PRECAUTIONS).
854
Geriatric Patients
855
Studies indicate that although total plasma concentration of naproxen is
856
unchanged, the unbound plasma fraction of naproxen is increased in the
857
elderly. Caution is advised when high doses are required and some adjustment
858
of dosage may be required in elderly patients. As with other drugs used in the
859
elderly, it is prudent to use the lowest effective dose.
860
Patients With Moderate to Severe Renal Impairment
861
Naproxen-containing products are not recommended for use in patients with
862
moderate to severe and severe renal impairment (creatinine clearance <30
863
mL/min) (see WARNINGS: Renal Effects).
864
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
NAPROSYN
250 mg
or 375 mg
or 500 mg
twice daily
twice daily
twice daily
ANAPROX
275 mg (naproxen 250 mg with 25 mg sodium)
twice daily
ANAPROX DS
550 mg (naproxen 500 mg with 50 mg sodium)
twice daily
NAPROSYN
Suspension
250 mg (10 mL/2 tsp)
or 375 mg (15 mL/3 tsp)
or 500 mg (20 mL/4 tsp)
twice daily
twice daily
twice daily
EC-NAPROSYN
375 mg
or 500 mg
twice daily
twice daily
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
865
To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet
866
should not be broken, crushed or chewed during ingestion. NAPROSYN
867
Suspension should be shaken gently before use.
868
During long-term administration, the dose of naproxen may be adjusted up or
869
down depending on the clinical response of the patient. A lower daily dose
870
may suffice for long-term administration. The morning and evening doses do
871
not have to be equal in size and the administration of the drug more frequently
872
than twice daily is not necessary.
873
In patients who tolerate lower doses well, the dose may be increased to
874
naproxen 1500 mg/day for limited periods of up to 6 months when a higher
875
level of anti-inflammatory/analgesic activity is required. When treating such
876
patients with naproxen 1500 mg/day, the physician should observe sufficient
877
increased clinical benefits to offset the potential increased risk. The morning
878
and evening doses do not have to be equal in size and administration of the
879
drug more frequently than twice daily does not generally make a difference in
880
response (see CLINICAL PHARMACOLOGY).
881
Juvenile Arthritis
882
The use of NAPROSYN Suspension is recommended for juvenile arthritis in
883
children 2 years or older because it allows for more flexible dose titration
884
based on the child’s weight. In pediatric patients, doses of 5 mg/kg/day
885
produced plasma levels of naproxen similar to those seen in adults taking 500
886
mg of naproxen (see CLINICAL PHARMACOLOGY).
887
The recommended total daily dose of naproxen is approximately 10 mg/kg
888
given in 2 divided doses (ie, 5 mg/kg given twice a day). A measuring cup
889
marked in 1/2 teaspoon and 2.5 milliliter increments is provided with the
890
NAPROSYN Suspension. The following table may be used as a guide for
891
dosing of NAPROSYN Suspension:
892
Patient’s Weight
Dose
Administered as
893
13 kg (29 lb)
62.5 mg bid 2.5 mL (1/2 tsp) twice daily
894
25 kg (55 lb)
125 mg bid 5.0 mL (1 tsp) twice daily
895
38 kg (84 lb)
187.5 mg bid 7.5 mL (1 1/2 tsp) twice daily
896
Management of Pain, Primary Dysmenorrhea, and Acute
897
Tendonitis and Bursitis
898
The recommended starting dose is 550 mg of naproxen sodium as
899
ANAPROX/ANAPROX DS followed by 550 mg every 12 hours or 275 mg
900
every 6 to 8 hours as required. The initial total daily dose should not exceed
901
1375 mg of naproxen sodium. Thereafter, the total daily dose should not
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
902
exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is
903
more rapidly absorbed, ANAPROX/ANAPROX DS is recommended for the
904
management of acute painful conditions when prompt onset of pain relief is
905
desired. NAPROSYN may also be used but EC-NAPROSYN is not
906
recommended for initial treatment of acute pain because absorption of
907
naproxen is delayed compared to other naproxen-containing products (see
908
CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE).
909
Acute Gout
910
The recommended starting dose is 750 mg of NAPROSYN followed by 250
911
mg every 8 hours until the attack has subsided. ANAPROX may also be used
912
at a starting dose of 825 mg followed by 275 mg every 8 hours. EC
913
NAPROSYN is not recommended because of the delay in absorption (see
914
CLINICAL PHARMACOLOGY).
915
HOW SUPPLIED
916
NAPROSYN Tablets: 250 mg: round, yellow, biconvex, engraved with NPR
917
LE 250 on one side and scored on the other. Packaged in light-resistant bottles
918
of 100.
919
100’s (bottle): NDC 0004-6313-01.
920
375 mg: pink, biconvex oval, engraved with NPR LE 375 on one side.
921
Packaged in light-resistant bottles of 100.
922
100’s (bottle): NDC 0004-6314-01.
923
500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and
924
scored on the other. Packaged in light-resistant bottles of 100.
925
100’s (bottle): NDC 0004-6316-01.
926
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light
927
resistant containers.
928
NAPROSYN Suspension: 125 mg/5 mL (contains 39 mg sodium, about 1.5
929
mEq/teaspoon): Available in 1 pint (473 mL) light-resistant bottles (NDC
930
0004-0028-28).
931
Store at 15° to 30°C (59° to 86°F); avoid excessive heat, above 40°C (104°F).
932
Dispense in light-resistant containers. Shake gently before use.
933
EC-NAPROSYN Delayed-Release Tablets: 375 mg: white, oval biconvex
934
coated tablets imprinted with NPR EC 375 on one side. Packaged in light
935
resistant bottles of 100.
936
100’s (bottle): NDC 0004-6415-01.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
937
500 mg: white, oblong coated tablets imprinted with NPR EC 500 on one side.
938
Packaged in light-resistant bottles of 100.
939
100’s (bottle): NDC 0004-6416-01.
940
Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light
941
resistant containers.
942
ANAPROX Tablets: Naproxen sodium 275 mg: light blue, oval-shaped,
943
engraved with NPS-275 on one side. Packaged in bottles of 100.
944
100’s (bottle): NDC 0004-6202-01.
945
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
946
ANAPROX DS Tablets: Naproxen sodium 550 mg: dark blue, oblong
947
shaped, engraved with NPS 550 on one side and scored on both sides.
948
Packaged in bottles of 100.
949
100’s (bottle): NDC 0004-6203-01.
950
Store at 15° to 30°C (59° to 86°F) in well-closed containers.
951
Revised: September 2007
952
953
Medication Guide
954
for
955
Non-steroidal Anti-Inflammatory Drugs (NSAIDs)
956
(See the end of this Medication Guide for a list of prescription NSAID
957
medicines.)
958
959
What is the most important information I should know about medicines
960
called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
961
NSAID medicines may increase the chance of a heart attack or
962
stroke that can lead to death. This chance increases:
963
• with longer use of NSAID medicines
964
• in people who have heart disease
965
966
NSAID medicines should never be used right before or after a
967
heart surgery called a “coronary artery bypass graft (CABG).”
968
NSAID medicines can cause ulcers and bleeding in the stomach
969
and intestines at any time during treatment. Ulcers and bleeding:
970
• can happen without warning symptoms
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
971
• may cause death
972
973
The chance of a person getting an ulcer or bleeding increases
974
with:
975
• taking medicines called “corticosteroids” and
976
“anticoagulants”
977
• longer use
978
• smoking
979
• drinking alcohol
980
• older age
981
• having poor health
982
983
NSAID medicines should only be used:
984
• exactly as prescribed
985
• at the lowest dose possible for your treatment
986
• for the shortest time needed
987
988
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
989
NSAID medicines are used to treat pain and redness, swelling, and heat
990
(inflammation) from medical conditions such as:
991
• different types of arthritis
992
• menstrual cramps and other types of short-term pain
993
994
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
995
Do not take an NSAID medicine:
996
• if you had an asthma attack, hives, or other allergic reaction with
997
aspirin or any other NSAID medicine
998
• for pain right before or after heart bypass surgery
999
1000
Tell your healthcare provider:
1001
• about all of your medical conditions.
1002
• about all of the medicines you take. NSAIDs and some other
1003
medicines can interact with each other and cause serious side
1004
effects. Keep a list of your medicines to show to your
1005
healthcare provider and pharmacist.
1006
• if you are pregnant. NSAID medicines should not be used by
1007
pregnant women late in their pregnancy.
1008
• if you are breastfeeding. Talk to your doctor.
1009
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
1010
What are the possible side effects of Non-Steroidal Anti-Inflammatory
1011
Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling
(fluid retention)
•
kidney problems including kidney
failure
•
bleeding and ulcers in the stomach
and intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver
failure
•
asthma attacks in people who have
asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
1012
1013
Get emergency help right away if you have any of the following
1014
symptoms:
• shortness of breath or trouble
•
slurred speech
breathing
•
swelling of the face or
• chest pain
throat
• weakness in one part or side of your
body
1015
1016
Stop your NSAID medicine and call your healthcare provider right away
1017
if you have any of the following symptoms:
• nausea
•
there is blood in your
• more tired or weaker than usual
bowel movement or it is
• itching
black and sticky like tar
• your skin or eyes look yellow
•
unusual weight gain
• stomach pain
•
skin rash or blisters with
• flu-like symptoms
fever
• vomit blood
•
swelling of the arms and
legs, hands and feet
1018
1019
These are not all the side effects with NSAID medicines. Talk to your
1020
healthcare provider or pharmacist for more information about NSAID
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
1021
medicines. Call your doctor for medical advice about side effects. You may
1022
report side effects to FDA at 1-800-FDA-1088 or Roche at 1-800-526-6367.
1023
Other information about Non-Steroidal Anti-Inflammatory Drugs
1024
(NSAIDs):
1025
• Aspirin is an NSAID medicine but it does not increase the chance of a
1026
heart attack. Aspirin can cause bleeding in the brain, stomach, and
1027
intestines. Aspirin can also cause ulcers in the stomach and intestines.
1028
• Some of these NSAID medicines are sold in lower doses without a
1029
prescription (over-the-counter). Talk to your healthcare provider before
1030
using over-the-counter NSAIDs for more than 10 days.
1031
1032
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex®
Diclofenac
Cataflam®, Voltaren®, Arthrotec™ (combined with
misoprostol)
Diflunisal
Dolobid®
Etodolac
Lodine®, Lodine®XL
Fenoprofen
Nalfon®, Nalfon®200
Flurbirofen
Ansaid®
Ibuprofen
Motrin®, Tab-Profen®, Vicoprofen®* (combined with
hydrocodone), Combunox™ (combined with
oxycodone)
Indomethacin
Indocin®, Indocin®SR, Indo-Lemmon™,
Indomethagan™
Ketoprofen
Oruvail®
Ketorolac
Toradol®
Mefenamic Acid
Ponstel®
Meloxicam
Mobic®
Nabumetone
Relafen®
Naproxen
Naprosyn®, Anaprox®, Anaprox®DS, EC-Naprosyn® ,
Naprelan®, Naprapac® (copackaged with
lansoprazole)
Oxaprozin
Daypro®
Piroxicam
Feldene®
Sulindac
Clinoril®
Tolmetin
Tolectin®, Tolectin DS®, Tolectin®600
1033
*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC)
1034
NSAID, and is usually used for less than 10 days to treat pain. The OTC
1035
NSAID label warns that long term continuous use may increase the risk of
1036
heart attack or stroke.
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
EC-NAPROSYN® (naproxen delayed-release tablets), NAPROSYN® (naproxen
tablets), ANAPROX®/ANAPROX® DS (naproxen sodium tablets),
NAPROSYN® (naproxen suspension)
1037
This Medication Guide has been approved by the U.S. Food and Drug
1038
Administration.
1039
Medication Guide Revised: Month Year
1040
1041
All registered trademarks in this document are the property of their respective
1042
owners.
1043
Distributed by:
Logo & Address
1045
1046
1047
XXXXXXXX
1048
Copyright © 1999-200X by Roche Laboratories Inc. All rights reserved.
31
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/2008/017581s110,18164s60,18965s18,20067s17lbl.pdf', 'application_number': 17581, 'submission_type': 'SUPPL ', 'submission_number': 110}
|
11,040
|
CeeNU
(lomustine)
Capsules
WARNINGS
CeeNU (lomustine) should be administered under the supervision of a qualified physician
experienced in the use of cancer chemotherapeutic agents.
Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to
bleeding and overwhelming infections in an already compromised patient, is the most common
and severe of the toxic effects of CeeNU (see WARNINGS and ADVERSE REACTIONS).
Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored
weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the recommended
dosage, courses of CeeNU should not be given more frequently than every 6 weeks.
The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be
considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under
DOSAGE AND ADMINISTRATION).
DESCRIPTION
CeeNU® (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain
neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder
with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. CeeNU is
soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). CeeNU is
relatively insoluble in water (<0.05 mg per mL).
It is relatively un-ionized at a physiological pH.
Inactive ingredients in CeeNU Capsules are magnesium stearate and mannitol.
1
Reference ID: 3220000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The structural formula is: structural formula
CeeNU is available in 10 mg, 40 mg, and 100 mg capsules for oral administration.
CLINICAL PHARMACOLOGY
Although it is generally agreed that CeeNU alkylates DNA and RNA, it is not cross resistant
with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic
processes by carbamoylation of amino acids in proteins.
CeeNU may be given orally. Following oral administration of radioactive CeeNU at doses
ranging from 30 mg/m2 to 100 mg/m2, about half of the radioactivity given was excreted in
the urine in the form of degradation products within 24 hours.
The serum half-life of the metabolites ranges from 16 hours to 2 days. Tissue levels are
comparable to plasma levels at 15 minutes after intravenous administration.
Because of the high lipid solubility and the relative lack of ionization at physiological pH,
CeeNU crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF
are 50% or greater than those measured concurrently in plasma.
INDICATIONS AND USAGE
CeeNU has been shown to be useful as a single agent in addition to other treatment
modalities, or in established combination therapy with other approved chemotherapeutic
agents in the following:
Brain tumors—both primary and metastatic, in patients who have already received
appropriate surgical and/or radiotherapeutic procedures.
Hodgkin’s disease—secondary therapy in combination with other approved drugs in patients
who relapse while being treated with primary therapy, or who fail to respond to primary
therapy.
2
Reference ID: 3220000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
CeeNU should not be given to individuals who have demonstrated a previous hypersensitivity
to it.
WARNINGS
Since the major toxicity is delayed bone marrow suppression, blood counts should be
monitored weekly for at least 6 weeks after a dose (see ADVERSE REACTIONS). At the
recommended dosage, courses of CeeNU should not be given more frequently than every
6 weeks.
The bone marrow toxicity of CeeNU is cumulative and therefore dosage adjustment must be
considered on the basis of nadir blood counts from prior dose (see dosage adjustment table
under DOSAGE AND ADMINISTRATION).
Pulmonary toxicity from CeeNU appears to be dose related (see ADVERSE REACTIONS).
Long-term use of nitrosoureas has been reported to be possibly associated with the
development of secondary malignancies.
Liver and renal function tests should be monitored periodically (see ADVERSE
REACTIONS).
Pregnancy Category D
CeeNU can cause fetal harm when administered to a pregnant woman. CeeNU is embryotoxic
and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose.
There are no adequate and well controlled studies in pregnant women. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the
patient should be apprised of the potential hazard to the fetus. Women of childbearing
potential should be advised to avoid becoming pregnant.
PRECAUTIONS
General
In all instances where the use of CeeNU is considered for chemotherapy, the physician must
evaluate the need and usefulness of the drug against the risks of toxic effects or adverse
reactions. Most such adverse reactions are reversible if detected early. When such effects or
reactions do occur, the drug should be reduced in dosage or discontinued and appropriate
corrective measures should be taken according to the clinical judgment of the physician.
Reinstitution of CeeNU therapy should be carried out with caution and with adequate
3
Reference ID: 3220000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
consideration of the further need for the drug and alertness as to possible recurrence of
toxicity.
Information for Patients
Provide patients with the following information and instructions:
1. In order to provide the proper dose of CeeNU, the dose may be made up of 2
or more different strengths and colors of capsules. Each strength must be
dispensed separately by the pharmacist.
2. CeeNU is given as a single oral dose and will not be repeated for at least 6
weeks. Daily use of the recommended dose may lead to toxicities and fatal
outcomes.
3. Patients may experience nausea and vomiting that usually last less than 24
hours. Patients may also experience loss of appetite that may last for several
days.
4. Instruct patients to contact their physician if they develop any of the
following reactions: fever, chills, sore throat, unusual bleeding or bruising,
shortness of breath, dry cough, swelling of feet or lower legs, mental
confusion, or yellowing of eyes and skin.
5. Instruct patients to wear impervious (rubber or latex) gloves when handling
CeeNU Capsules.
Laboratory Tests
Due to delayed bone marrow suppression, blood counts should be monitored weekly for at
least 6 weeks after a dose.
Baseline pulmonary function studies should be conducted along with frequent pulmonary
function tests during treatment. Patients with a baseline below 70% of the predicted Forced
Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) are particularly at
risk.
Since CeeNU may cause liver dysfunction, it is recommended that liver function tests be
monitored periodically.
Renal function tests should also be monitored periodically.
4
Reference ID: 3220000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, Impairment of Fertility
CeeNU is carcinogenic in rats and mice, producing a marked increase in tumor incidence in
doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic
potential in humans (see ADVERSE REACTIONS). CeeNU also affects fertility in male rats
at doses somewhat higher than the human dose.
Pregnancy
Pregnancy Category D
See WARNINGS.
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 CeeNU, 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
See
ADVERSE
REACTIONS:
Pulmonary
Toxicity
and
DOSAGE
AND
ADMINISTRATION.
Geriatric Use
No data from clinical studies of CeeNU are available for patients 65 years of age and over to
determine whether they respond differently than younger patients. Other reported clinical
experience has not identified differences in responses between 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.
Lomustine and its metabolites are 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 renal function should be monitored.
5
Reference ID: 3220000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Hematologic Toxicity
The most frequent and most serious toxicity of CeeNU is delayed myelosuppression. It usually
occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at
about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to
6 weeks after a dose of CeeNU and persists for 1 to 2 weeks. Approximately 65% of patients
receiving 130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six percent
developed white blood counts below 3000 wbc/mm3. Thrombocytopenia is generally more
severe than leukopenia. However, both may be dose-limiting toxicities.
CeeNU may produce cumulative myelosuppression, manifested by more depressed indices
or longer duration of suppression after repeated doses.
The occurrence of acute leukemia and bone marrow dysplasias have been reported in
patients following long-term nitrosourea therapy.
Anemia also occurs, but is less frequent and less severe than thrombocytopenia or
leukopenia.
Pulmonary Toxicity
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported
rarely with CeeNU. Onset of toxicity has occurred after an interval of 6 months or longer from
the start of therapy with cumulative doses of CeeNU usually greater than 1100 mg/m2. There is
1 report of pulmonary toxicity at a cumulative dose of only 600 mg.
Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in
patients who received related nitrosoureas in childhood and early adolescence (1–16 years)
combined with cranial radiotherapy for intracranial tumors. There appeared to be some late
reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be
slowly progressive and has resulted in death in some cases. In this long-term study of
carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary
fibrosis.
Gastrointestinal Toxicity
Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than
24 hours. Prior administration of antiemetics is effective in diminishing and sometimes
preventing this side effect. Nausea and vomiting can also be reduced if CeeNU is administered
to fasting patients.
6
Reference ID: 3220000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hepatotoxicity
A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline
phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving
CeeNU.
Nephrotoxicity
Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal
failure have been reported in patients who received large cumulative doses after prolonged
therapy with CeeNU. Kidney damage has also been reported occasionally in patients receiving
lower total doses.
Other Toxicities
Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been
reported infrequently.
Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted
in some patients receiving CeeNU. However, the relationship to medication in these patients is
unclear.
OVERDOSAGE
Accidental overdose with lomustine has been reported, including fatal cases. Accidental
overdose has been associated with bone marrow suppression, abdominal pain, diarrhea,
vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of
breath.
No proven antidotes have been established for CeeNU overdosage. In case of overdose,
appropriate supportive measures should be taken.
DOSAGE AND ADMINISTRATION
The recommended dose of CeeNU in adult and pediatric patients as a single agent in previously
untreated patients is 130 mg/m2 as a single oral dose every 6 weeks (see PRECAUTIONS:
Information for Patients and HOW SUPPLIED: Directions to the Pharmacist). In
individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2
every 6 weeks. When CeeNU is used in combination with other myelosuppressive drugs, the
doses should be adjusted accordingly. All doses of CeeNU must be rounded to the nearest
10 mg by the prescriber (see HOW SUPPLIED).
7
Reference ID: 3220000
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Doses subsequent to the initial dose should be adjusted according to the hematologic response
of the patient to the preceding dose. The following schedule is suggested as a guide to dosage
adjustment:
Nadir After Prior Dose
Percentage of Prior Dose
to be Given
Leukocytes (/mm3)
Platelets (/mm3)
4000
3000–3999
2000–2999
<2000
100,000
75,000–99,999
25,000–74,999
<25,000
100%
100%
70%
50%
A repeat course of CeeNU should not be given until circulating blood elements have
returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3),
and this is usually in 6 weeks. Adequate number of neutrophils should be present on a
peripheral blood smear. Blood counts should be monitored weekly and repeat courses
should not be given before 6 weeks because the hematologic toxicity is delayed and
cumulative.
HOW SUPPLIED
CeeNU® (lomustine) Capsules are available in individual bottles of 20 capsules each.
NDC 0015-3032-20
100 mg capsules (Green/Green)
NDC 0015-3031-20
40 mg capsules (White/Green)
NDC 0015-3030-20
10 mg capsules (White/White)
Stability
CeeNU Capsules are stable for the lot life indicated on package labeling when stored in well-
closed containers at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP
Controlled Room Temperature]. Avoid excessive heat (over 40°C, 104°F).
Directions to the Pharmacist
Confirm the total dose prescribed by the physician can be obtained by determining the
appropriate combination of capsule strengths. Only the appropriate number of CeeNU capsules
required for the administration of a single dose should be dispensed.
In order to provide the proper dose of CeeNU, patients should be aware that the prescribed dose
may be made up of 2 or more different strengths and colors of capsules and that each strength
must be dispensed separately. Inform patients that CeeNU is taken as a single oral dose and
will not be repeated for at least 6 weeks. Daily use of the recommended dose may lead to
toxicities and fatal outcomes.
Reference ID: 3220000
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Caution should be exercised when handling CeeNU Capsules. Procedures for proper handling
and disposal of anticancer drugs should be utilized. Several guidelines on this subject have
been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves
when handling bottles containing CeeNU Capsules. CeeNU Capsules should not be broken.
Personnel should avoid exposure to broken capsules. If contact occurs, wash immediately and
thoroughly. More information is available in the references listed below.
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 JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines
and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.
Manufactured for:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Made in Italy
Rev November 2012
9
Reference ID: 3220000
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/2012/017588s036lbl.pdf', 'application_number': 17588, 'submission_type': 'SUPPL ', 'submission_number': 36}
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11,042
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
GLEOSTINE safely and effectively. See full prescribing information for
GLEOSTINE.
GLEOSTINE® (lomustine) capsules, for oral use
Initial U.S. Approval: 1976
WARNING: DELAYED MYELOSUPPRESSION and RISK OF
OVERDOSAGE
See full prescribing information for complete boxed warning.
Delayed Myelosuppression
Gleostine causes myelosuppression including fatal myelosuppression.
Myelosuppression is delayed, dose-related, and cumulative.
Thrombocytopenia is generally more severe than leukopenia. Monitor
blood counts and do not give Gleostine more frequently than every 6
weeks. (2.2, 2.3, 5.1)
Risk of Overdosage
PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH
CAPSULES FOR ONE DOSE. Fatal toxicity occurs with overdosage of
Gleostine. Both physician and pharmacist should emphasize to patient
that only one dose of Gleostine is taken every 6 weeks. (2.1, 5.2, 10)
INDICATIONS AND USAGE
Gleostine is an alkylating drug indicated for the treatment of patients with:
• Brain tumors, primary and metastatic, following appropriate surgical and/or
radiotherapeutic procedures. (1)
• Hodgkin’s lymphoma in combination with other chemotherapies, following
disease progression with initial chemotherapy. (1)
DOSAGE AND ADMINISTRATION
• Recommended dose in adult and pediatric patients is 130 mg/m2 orally
every 6 weeks. (2.1)
• Round dose to nearest 5 mg.
• Give as a single oral dose and do not repeat for at least 6 weeks.
DOSAGE FORMS AND STRENGTHS
Capsules: 5mg, 10 mg, 40 mg, and 100 mg (3)
WARNINGS AND PRECAUTIONS
• Pulmonary toxicity: Pulmonary infiltrates and/or fibrosis occurs with
Gleostine. Perform pulmonary function tests prior to treatment and repeat
frequently. Permanently discontinue Gleostine in patients diagnosed with
pulmonary fibrosis. (5.3)
• Secondary malignancies: Acute leukemia and myelodysplasia can occur
with long-term use. (5.4)
• Hepatotoxicity: Increased levels of transaminases, alkaline phosphatase
and bilirubin can occur with Gleostine. Monitor liver function. (5.5)
• Nephrotoxicity: Can cause renal failure. Monitor renal function. (5.6)
• Embryo-fetal toxicity: Can cause fetal harm. Advise males and females of
reproductive potential of the potential risk to a fetus and to use effective
contraception. (5.7, 8.1, 8.3)
ADVERSE REACTIONS
Common adverse reactions include delayed myelosupression, nausea,
vomiting, stomatitis, and alopecia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact NextSource
Biotechnology at 855- 672-2468 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Lactation: Do not breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 1/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: DELAYED MYELOSUPPRESSION AND RISK OF
OVERDOSAGE
1
INDICATIONS AND USAGE
1.1 Brain Tumors
1.2 Hodgkin’s Lymphoma
2
DOSAGE AND ADMINISTRATION
2.1 Important Prescribing and Dispensing Information
2.2 Recommended Dose
2.3 Dose Modifications
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Delayed Myelosuppression
5.2 Risk of Overdosage
5.3 Pulmonary Toxicity
5.4 Secondary Malignancies
5.5 Hepatotoxicity
5.6 Nephrotoxicity
5.7 Embryo-Fetal Toxicity
6
ADVERSE REACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
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
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Page 1 of 10
Reference ID: 3869801
This label may not be the latest approved by FDA.
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FULL PRESCRIBING INFORMATION
WARNING: DELAYED MYELOSUPPRESSION and RISK OF OVERDOSAGE
DELAYED MYELOSUPPRESSION
Gleostine causes myelosuppression including fatal myelosuppression. Myelosuppression is delayed, dose-related, and
cumulative; occurring 4 to 6 weeks after drug administration and persisting for 1 to 2 weeks. Thrombocytopenia is generally
more severe than leukopenia. Cumulative myelosuppression from Gleostine is manifested by greater severity and longer
duration of cytopenias. Monitor blood counts for at least 6 weeks after each dose. Do not give Gleostine more frequently than
every 6 weeks [see Warnings and Precautions (5.1), Dosage and Administration (2.2, 2.3)].
RISK OF OVERDOSAGE
PRESCRIBE, DISPENSE, AND ADMINISTER ONLY ENOUGH CAPSULES FOR ONE DOSE. Fatal toxicity occurs with
overdosage of Gleostine. Both physician and pharmacist should emphasize to the patient that only one dose of Gleostine is
taken every 6 weeks [see Dosage and Administration (2.1), Warnings and Precautions (5.2), Overdosage (10)].
1
INDICATIONS AND USAGE
1.1
Brain Tumors
Gleostine is indicated for the treatment of patients with primary and metastatic brain tumors following
appropriate surgical and/or radiotherapeutic procedures.
1.2
Hodgkin’s Lymphoma
Gleostine is indicated as a component of combination chemotherapy for the treatment of patients with
Hodgkin’s lymphoma whose disease has progressed following initial chemotherapy.
2
DOSAGE AND ADMINISTRATION
2.1
Important Prescribing and Dispensing Information
PRESCRIBE ONLY ONE DOSE FOR EACH TREATMENT CYCLE. DO NOT DISPENSE ENTIRE
CONTAINER. Dispense only a sufficient number of capsules for one dose.
Confirm the total dose prescribed by the physician and the appropriate combination of capsule strengths.
Dispense only the appropriate number of Gleostine capsules required for the administration of a single dose.
The prescribed dose may consist of two or more different strengths and colors of capsules.
Instruct patients that Gleostine is taken as a single oral dose and will not be repeated for at least 6 weeks.
Taking more than the recommended dose causes toxicities, including fatal outcomes [see Warnings and
Precautions (5.2) and Overdosage (10)].
Gleostine is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1
To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing
Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact
occurs, wash areas of skin contact immediately and thoroughly.
Page 2 of 10
Reference ID: 3869801
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2
Recommended Dose
The recommended dose of Gleostine in adult and pediatric patients is 130 mg/m2 taken as a single oral dose
every 6 weeks. Round doses to the nearest 5 mg. Give as a single oral dose and do not repeat for at least 6
weeks. Reduce dose to 100 mg/m2 every 6 weeks in patients with compromised bone marrow function. Also
reduce dose accordingly when using with other myelosuppressive drugs.
2.3
Dose Modifications
Perform weekly complete blood counts and withhold each subsequent dose for more than 6 weeks if needed
until platelet counts recover to 100,000/mm3 or greater and leukocytes recover to 4000/mm3or greater [see
Warnings and Precautions (5.1)].
Modify each dose of Gleostine according to the hematologic response of the preceding dose as described in
Table 1:
Table 1. Dose Modifications for Gleostine
Nadir After Prior Dose
Dose Adjustment
Leukocytes (/mm3)
Platelets (/mm3)
≥ 4000
≥ 100,000
None
3000 – 3999
75,000 – 99,999
None
2000 – 2999
25,000 – 74,999
Reduce dose by 70%
< 2000
< 25,000
Reduce dose by 50%
3
DOSAGE FORMS AND STRENGTHS
Gleostine capsules are available in four strengths, distinguishable by the color of the capsules:
100 mg capsules (green/green)
40 mg capsules (white/green)
10 mg capsules (white/white)
5 mg capsules (yellow/yellow)
4
CONTRAINDICATIONS
None.
5
WARNINGS AND PRECAUTIONS
5.1
Delayed Myelosuppression
Gleostine causes myelosuppression that can result in fatal infections and bleeding. Myelosuppression from
Gleostine is delayed, dose-related, and cumulative. It usually occurs 4 to 6 weeks after drug administration and
persists for 1 to 2 weeks.
Thrombocytopenia is generally more severe than leukopenia. Cumulative
myelosuppression from Gleostine is manifested by greater severity and longer duration of cytopenias.
Page 3 of 10
Reference ID: 3869801
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Monitor blood counts for at least 6 weeks after each dose. Do not give Gleostine more frequently than every 6
weeks. Adjust dose based on nadir blood counts from prior dose [see Dosage and Administration (2.3)].
5.2
Risk of Overdosage
Fatal toxicity occurs with overdosage of Gleostine. Dispensing or administering more than one dose can lead to
fatal toxicity.
Prescribe only one dose at a time. Dispense only enough capsules for one dose. Both physician and pharmacist
should emphasize to the patient that only one dose of Gleostine is taken every 6 weeks [see Dosage and
Administration (2.1) and Overdosage (10)].
5.3
Pulmonary Toxicity
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurs with Gleostine. Patients with a
baseline below 70% of the predicted Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity
(DLCO) are at increased risk. The onset of pulmonary toxicity occurs after an interval of 6 months or longer
from the start of therapy, with cumulative doses of Gleostine usually greater than 1100 mg/m2.
Obtain baseline pulmonary function tests prior to initiating treatment and repeat frequently during treatment.
Permanently discontinue Gleostine in patients diagnosed with pulmonary fibrosis.
5.4
Secondary Malignancies
Secondary malignancies, including acute leukemia and myelodysplasia, occur with long term use.
5.5
Hepatotoxicity
Hepatic toxicity, manifested by increased levels of transaminases, alkaline phosphatase, and bilirubin occurs
with Gleostine.
Monitor liver function.
5.6
Nephrotoxicity
Progressive renal failure with a decrease in kidney size occurs with Gleostine.
Monitor renal function.
5.7
Embryo-Fetal Toxicity
Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a
pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats and rabbits receiving lomustine
daily during organogenesis at doses approximately two to four times the total human dose of 130 mg/m2 over 6
weeks (0.18 to 0.27 times the single human dose of 130 mg/m2) based on body surface area (BSA). Advise
pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective
contraception during treatment with Gleostine and for 2 weeks after the final dose. Advise males with female
partners of reproductive potential to use effective contraception during treatment with Gleostine and for 3.5
months after the final dose [see Use in Specific Populations (8.1, 8.3)].
Page 4 of 10
Reference ID: 3869801
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6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
Delayed myelosuppression [see Warnings and Precautions (5.1)]
Risks of overdosage [see Warnings and Precautions (5.2)]
Pulmonary toxicity [see Warnings and Precautions (5.3)]
Secondary malignancies [see Warnings and Precautions (5.4)]
Hepatotoxicity [see Warnings and Precautions (5.5)]
Nephrotoxicity [see Warnings and Precautions (5.6)]
The following adverse reactions associated with the use of Gleostine were identified in clinical trials or
postmarketing reports. Because these reactions were reported from a population of uncertain size, it is not
possible to estimate their frequency, reliability, or establishment a causal relationship to drug exposure.
Gastrointestinal disorders: nausea, vomiting, and stomatitis
Ocular disorders: optic atrophy, visual disturbances, and blindness
Neurologic disorders: disorientation, lethargy, ataxia, and dysarthria
Other: alopecia
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Based on animal data and its mechanism of action, Gleostine can cause fetal harm when administered to a
pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on Gleostine exposure in
pregnant women. Lomustine was teratogenic in rats and embryotoxic in rabbits at total dose levels
approximately two to four times the total human dose of 130 mg/m2 over 6 weeks (0.18 to 0.27 times the single
human dose of 130 mg/m2) based on BSA [see Data]. Advise pregnant women of the potential risk to a fetus.
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
Animal Data
Lomustine was administered by intraperitoneal injection daily to pregnant rats during the period of
organogenesis at dose levels of 0, 2, 4, 6, and 8 mg/kg. Resorption rates and post-implantation loss occurred at
doses greater than or equal to 4 mg/kg (approximately 0.18 times the clinical dose of 130 mg/m2 based on BSA
or approximately twice the total clinical dose of lomustine over 6 weeks). Malformations (omphalocele, ectepia
cordis, scoliosis, syndactyly, hydrocephalus, microphthalmia, anophthalmia, anomalies of aortic arch,
dextrocardia, malpositioning of the ovaries and testes, sternoschisis, and shortened/misshapen bone of the fore
or hind limbs) and decreased fetal body weight occurred at all dose levels. In pregnant rabbits treated with
Page 5 of 10
Reference ID: 3869801
This label may not be the latest approved by FDA.
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lomustine at 3 mg/kg (approximately 0.27 times the 130 mg/m2 clinical dose based on BSA or approximately
four times the total clinical dose of lomustine over 6 weeks) during organogenesis, there were increases in
abortions and decreases in surviving pup weight that persisted postnatally.
8.2
Lactation
Risk Summary
There is no information on the presence of lomustine or its metabolites in human milk, its effects on the
breastfed infant, or its effects on milk production. Because of the potential for serious adverse reactions in
breastfed infants from Gleostine, advise women not to breastfeed during treatment with Gleostine and for 2
weeks after the final dose.
8.3
Females and Males of Reproductive Potential
Contraception
Females
Based on animal data and its mechanism of action, Gleostine can cause fetal harm [see Use in Specific
Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment
and for 2 weeks after the final dose.
Males
Based on Gleostine’s mechanism of action, advise males with female partners of reproductive potential to use
effective contraception during treatment with Gleostine and for 3.5 months after the final dose [see Clinical
Pharmacology (12.1)].
Infertility
Based on animal findings and its mechanism of action, Gleostine may result in reduced fertility in males and
females of reproductive potential [see Nonclinical Toxicology (13.1)].
8.4
Pediatric Use
Pediatric use, including dose, is not based on adequate and well-controlled clinical studies.
8.5
Geriatric Use
No data in the clinical studies of Gleostine are available for patients 65 years of age and over to determine
whether they respond differently than younger patients. Other reported clinical experience has not identified
differences in responses between 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.
Lomustine and its metabolites are 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 renal function should be
monitored.
Page 6 of 10
Reference ID: 3869801
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10 OVERDOSAGE
Overdosage with Gleostine has occurred, including fatal cases [see Dosage and Administration (2.1), Warnings
and Precautions (5.2)]. Overdosage causes severe myelosuppression, as well as abdominal pain, diarrhea,
vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.
No antidotes exist for Gleostine overdosage.
11 DESCRIPTION
Gleostine (lomustine) is an alkylating drug for oral administration. The chemical name for lomustine is 1-(2
chloro-ethyl)-3-cyclohexyl-1-nitrosourea and the molecular formula is C9H16ClN3O2. The molecular weight is
233.71. Lomustine is a yellow powder, which is soluble in 10% ethanol (0.05 mg per mL) and in absolute
alcohol (70 mg per mL). Lomustine is insoluble in water (<0.05 mg per mL).
The chemical structure is:
Gleostine is supplied as 5 mg, 10 mg, 40 mg, and 100 mg capsules and contains the following inactive
ingredients: magnesium stearate NF and mannitol USP. The capsule shells are composed of gelatin and
coloring pigments, depending on the strength: titanium dioxide, and/or yellow iron oxide, and/or Indigotine –
FD&C Blue2.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Lomustine alkylates DNA and RNA. As with other nitrosoureas, it may also inhibit several key enzymatic
processes by carbamoylation of amino acids in proteins.
12.2
Pharmacodynamic
The pharmacodynamics of lomustine are unknown.
12.3
Pharmacokinetics
Distribution
Lomustine crosses the blood-brain barrier.
Elimination
The serum half-life of lomustine metabolites ranges from 16 hours to 48 hours.
Metabolism
Metabolic pathways involved in the elimination of lomustine have not been characterized.
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Reference ID: 3869801
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Excretion
Following oral administration of radioactive lomustine at doses ranging from 30 mg/m2 to 100 mg/m2,
approximately half of the radioactivity administered was excreted in the urine in the form of degradation
products within 24 hours.
Specific Populations
The impact of patient specific (e.g., age, sex, and race) or disease (e.g., renal or hepatic impairment)
characteristics on the pharmacokinetics of lomustine is unknown.
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses lower than
those employed clinically.
In female rats, daily intraperitoneal treatment with lomustine for 2 weeks prior to mating with untreated males
resulted in dose dependent decreases in number of corpora lutea and resorption rates with no live births at a
dose of 3 mg/kg (approximately 0.14 times the recommended clinical dose of 130 mg/m2 based on body surface
area (BSA), or approximately twice the total clinical dose of lomustine over 6 weeks) and decreased pup
survival during the first 4 postnatal days at doses greater than or equal to 1.5 mg/kg (a daily dose of
approximately 0.06 times the recommended clinical dose of 130 mg/m2 based on BSA or approximately equal
to the total clinical dose of lomustine over 6 weeks). Gleostine may also result in decreased male fertility.
Intraperitoneal injection of lomustine resulted in decreased fertility in male rats mated to untreated females
based on decreased implantations and decreased fetal body weight at weekly doses greater than or equal to 5
mg/kg (approximately 0.23 times the single clinical dose of 130 mg/m2 based on BSA, or approximately equal
to the total clinical dose of lomustine over 6 weeks), and increased resorptions at doses greater than or equal to
2.5 mg/kg/week.
15 REFERENCES
OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
Gleostine is available in four strengths, distinguishable by the color of the capsules, in individual bottles of 5
capsules each:
Strength
Capsule Description
NDC Code
100 mg
Moss green cap and body, imprinted in black ink, with "CPL" over "3032" on the
cap and "100 mg" on the body of the capsule.
58181-3042-5
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Reference ID: 3869801
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40 mg
White cap and a moss green body, imprinted in black ink, with "CPL" over "3031"
on the cap and "40 mg" on the body of the capsule.
58181-3041-5
10 mg
White cap and body, imprinted in black ink, with "CPL" over "3030" on the cap
and "10 mg" on the body of the capsule
58181-3040-5
5 mg
Yellow cap and body, imprinted in black ink, with "CPL" over "3033" on the cap
and "5 mg" on the body of the capsule.
58181-3043-5
16.2
Storage and Handling
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room
Temperature]. Avoid temperatures over 40°C (104°F).
Gleostine is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing
Gleostine capsules. Do not break Gleostine capsules; avoid exposure to broken capsules. If dermal contact
occurs, wash areas of skin contact immediately and thoroughly.
17 PATIENT COUNSELING INFORMATION
Myelosuppression
Advise patients that periodic assessment of their blood counts are required. Advise patients to contact their
healthcare provider for new onset of bleeding or fever or symptoms of infection [see Warnings and Precautions
(5.1)].
Overdosage
Advise patients that toxicity including fatal toxicity occurs with Gleostine overdosage [see Warnings and
Precautions (5.2), Overdosage (10), Dosage and Administration (2.1)].
Advise patients to take Gleostine as directed:
Gleostine is taken as a single oral dose that will not be repeated for at least 6 weeks.
Use of the recommended dose at less than 6 week intervals leads to toxicities including fatal toxicities.
Each dose may consist of 2 or more different strengths and colors of capsules.
Pulmonary Fibrosis
Advise patients to contact their healthcare provider for new or worsening cough, chest pain, or shortness of
breath [see Warnings and Precautions (5.3)].
Hepatotoxicity
Inform patients that Gleostine can cause hepatotoxicity and that liver function monitoring during treatment is
necessary [see Warnings and Precautions (5.5)].
Nephrotoxicity
Inform patients that Gleostine can cause nephrotoxicity and that renal function and electrolyte monitoring
during treatment is necessary [see Warnings and Precautions (5.6)].
Page 9 of 10
Reference ID: 3869801
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider
of a known or suspected pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].
Advise females of reproductive potential to use effective contraception during treatment with Gleostine and for
at least 2 weeks after the final dose [see Use in Specific Populations (8.3)].
Advise male patients with female partners of reproductive potential to use condoms during treatment with
Gleostine and for 4 months after the final dose [see Use in Specific Populations (8.3)].
Lactation
Advise women not to breastfeed during treatment with Gleostine and for 2 weeks after the final dose [see Use
in Specific Populations (8.2)].
Infertility
Advise females and males of reproductive potential of the potential for reduced fertility from Gleostine [see Use
in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
Manufactured by Corden Pharma Latina S.p.A., Sermoneta (LT), Italy for:
NextSource Biotechnology, LLC
Miami, FL 33155 USA
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Reference ID: 3869801
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|
custom-source
|
2025-02-12T13:44:19.070281
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s042lbl.pdf', 'application_number': 17588, 'submission_type': 'SUPPL ', 'submission_number': 42}
|
11,043
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1
SEPTRA
® Tablets
SEPTRA
® DS (Double Strength) Tablets
SEPTRA
® Suspension
SEPTRA
® Grape Suspension
(trimethoprim and sulfamethoxazole)
DESCRIPTION: SEPTRA (trimethoprim and sulfamethoxazole) is a
synthetic antibacterial combination product. Each SEPTRA
Tablet contains 80 mg trimethoprim and 400 mg sulfamethoxazole
and the inactive ingredients docusate sodium (0.4 mg per
tablet), FD&C Red No. 40, magnesium stearate, povidone, and
sodium starch glycolate.
Each SEPTRA DS (double strength) Tablet contains 160 mg
trimethoprim and 800 mg sulfamethoxazole and the inactive
ingredients docusate sodium (0.8 mg per tablet), FD&C Red No.
40, magnesium stearate, povidone, and sodium starch glycolate.
Each teaspoonful (5 mL) of SEPTRA Suspension contains 40 mg
trimethoprim and 200 mg sulfamethoxazole and the inactive
ingredients alcohol 0.26%, methylparaben 0.1% and sodium
benzoate 0.1% (added as preservatives), carboxymethylcellulose
sodium, citric acid, FD&C Red No. 40 and Yellow No. 6, flavor,
glycerin, microcrystalline cellulose, polysorbate 80,
saccharin sodium, and sorbitol. Each teaspoonful (5 mL) of
SEPTRA Grape Suspension contains 40 mg trimethoprim and 200 mg
sulfamethoxazole and the inactive ingredients alcohol 0.26%,
methylparaben 0.1%, and sodium benzoate 0.1% (added as
preservatives), carboxymethylcellulose sodium, citric acid,
FD&C Red No. 40 and Blue No. 1, flavor, glycerin,
microcrystalline cellulose, polysorbate 80, saccharin sodium,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
and sorbitol. Both tablet and suspension forms are for oral
administration.
Trimethoprim is 5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-
pyrimidinediamine. It is a white to light yellow,
odorless, bitter compound with a molecular weight of 290.32,
and the molecular formula C14H18N4O3. The structural formula is:
Sulfamethoxazole is 4-amino-N-(5-methyl-3-
isoxazolyl)benzenesulfonamide. It is an almost white,
odorless, tasteless compound with a molecular weight of
253.28, and the molecular formula C10H11N3O3S. The structural
formula is:
CLINICAL PHARMACOLOGY: SEPTRA is rapidly absorbed following
oral administration. Both sulfamethoxazole and trimethoprim
exist in the blood as unbound, protein-bound, and metabolized
forms; sulfamethoxazole also exists as the conjugated form.
The metabolism of sulfamethoxazole occurs predominately by N4-
acetylation, although the glucuronide conjugate has been
identified. The principal metabolites of trimethoprim are the
1- and 3-oxides and the 3’- and 4’-hydroxy derivatives. The
free forms of sulfamethoxazole and trimethoprim are considered
to be the therapeutically active forms. Approximately 44% of
trimethoprim and 70% of sulfamethoxazole are bound to plasma
proteins. The presence of 10 mg percent sulfamethoxazole in
plasma decreases the protein binding of trimethoprim by an
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
insignificant degree; trimethoprim does not influence the
protein binding of sulfamethoxazole.
Peak blood levels for the individual components occur 1 to 4
hours after oral administration. The mean serum half-lives of
sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours,
respectively. However, patients with severely impaired renal
function exhibit an increase in the half-lives of both
components, requiring dosage regimen adjustment (see DOSAGE
AND ADMINISTRATION). Detectable amounts of trimethoprim and
sulfamethoxazole are present in the blood 24 hours after drug
administration. During administration of 160 mg trimethoprim
and 800 mg sulfamethoxazole b.i.d., the mean steady-state
plasma concentration of trimethoprim was 1.72 mcg/mL. The
steady-state minimal plasma levels of free and total
sulfamethoxazole were 57.4 mcg/mL and 68.0 mcg/mL,
respectively. These steady-state levels were achieved after 3
days of drug administration.
1
Excretion of sulfamethoxazole and trimethoprim is primarily by
the kidneys through both glomerular filtration and tubular
secretion. Urine concentrations of both sulfamethoxazole and
trimethoprim are considerably higher than are the
concentrations in the blood. The average percentage of the
dose recovered in urine from 0 to 72 hours after a single oral
dose is 84.5% for total sulfonamide and 66.8% for free
trimethoprim. Thirty percent of the total sulfonamide is
excreted as free sulfamethoxazole, with the remaining as N4-
acetylated metabolite.
2 When administered together as SEPTRA,
neither sulfamethoxazole nor trimethoprim affects the urinary
excretion pattern of the other.
Both trimethoprim and sulfamethoxazole distribute to sputum,
vaginal fluid, and middle ear fluid; trimethoprim also
distributes to bronchial secretions, and both pass the
placental barrier and are excreted in human milk.
Microbiology: Sulfamethoxazole inhibits bacterial synthesis of
dihydrofolic acid by competing with para-aminobenzoic acid
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4
(PABA). Trimethoprim blocks the production of tetrahydrofolic
acid from dihydrofolic acid by binding to and reversibly
inhibiting the required enzyme, dihydrofolate reductase. Thus,
SEPTRA blocks two consecutive steps in the biosynthesis of
nucleic acids and proteins essential to many bacteria.
In vitro studies have shown that bacterial resistance develops
more slowly with SEPTRA than with either trimethoprim or
sulfamethoxazole alone.
In vitro serial dilution tests have shown that the spectrum of
antibacterial activity of SEPTRA includes the common urinary
tract pathogens with the exception of Pseudomonas aeruginosa.
The following organisms are usually susceptible: Escherichia
coli, Klebsiella species, Enterobacter species, Morganella
morganii, Proteus mirabilis, and indole-positive Proteus
species including Proteus vulgaris.
The usual spectrum of antimicrobial activity of SEPTRA
includes bacterial pathogens isolated from middle ear exudate
and from bronchial secretions (Haemophilus influenzae,
including ampicillin-resistant strains, and Streptococcus
pneumoniae), and enterotoxigenic strains of Escherichia coli
(ETEC) causing bacterial gastroenteritis. Shigella flexneri
and Shigella sonnei are also usually susceptible.
REPRESENTATIVE MINIMUM INHIBITORY CONCENTRATION VALUES FOR
ORGANISMS SUSCEPTIBLE TO SEPTRA (MICµg/mL)
TMP/SMX (1:19)
TMP
SMX
Bacteria
Alone
Alone
TMP
SMX
Escherichia coli
0.05-1.5
1.0-245
0.05-0.5 0.95-9.5
Escherichia coli
0.015-0.150.285->9500.005-0.150.095-2.85
(enterotoxigenic strains)
Proteus species
0.5-5.0
7.35-300 0.05-1.5 0.95-28.5
(indole positive)
TMP/SMX (1:19)
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TMP
SMX
Bacteria
Alone
Alone
TMP
SMX
Morganella morganii
0.5-5.0
7.35-300 0.05-1.5 0.95-28.5
Proteus mirabilis
0.5-1.5
7.35-30 0.05-0.15 0.95-2.85
Klebsiella species
0.15-5.0 2.45-245 0.05-1.5 0.95-28.5
Enterobacter species 0.15-5.0 2.45-245 0.05-1.5 0.95-28.5
Haemophilus
0.15-1.5
2.85-95 0.015-0.150.285-2.85
influenzae
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TMP/SMX (1:19)
TMP
SMX
Bacteria
Alone
Alone
TMP
SMX
Streptococcus
pneumoniae
0.15-1.5 7.35-24.5 0.05-0.15 0.95-2.85
Shigella flexneri* <0.01-0.04<0.16->320<0.002-0.030.04-0.625
Shigella sonnei*
0.02-0.08 0.625->3200.004-0.06 0.08-1.25
TMP=trimethoprim
SMX=sulfamethoxazole
*Rudoy RC, Nelson JD, Haltalin KC. Antimicrobial Agents and
Chemotherapy. 1974;5:439-443.
Susceptibility Testing: The recommended quantitative disc
susceptibility method may be used for estimating the
susceptibility of bacteria to SEPTRA.
3,4 With this procedure, a
report from the laboratory of ‘‘Susceptible to trimethoprim
and sulfamethoxazole’’ indicates that the infection is likely
to respond to therapy with SEPTRA. If the infection is
confined to the urine, a report of ‘‘Intermediate
susceptibility to trimethoprim and sulfamethoxazole’’ also
indicates that the infection is likely to respond. A report of
‘‘Resistant to trimethoprim and sulfamethoxazole’’ indicates
that the infection is unlikely to respond to therapy with
SEPTRA.
Geriatric Pharmacokinetics: The pharmacokinetics of
sulfamethoxazole 800 mg and trimethoprim 160 mg were studied
in 6 geriatric subjects (mean age: 78.6 years) and 6 young
healthy subjects (mean age: 29.3 years) using a non-US
approved formulation. Pharmacokinetic values for
sulfamethoxazole in geriatric subjects were similar to those
observed in young adult subjects. The mean renal clearance of
trimethoprim was significantly lower in geriatric subjects
compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg).
However, after normalizing by body weight, the apparent total
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7
body clearance of trimethoprim was an average 19% lower in
geriatric subjects compared with young adult subjects.
3
INDICATIONS AND USAGE:
Urinary Tract Infections: For the treatment of urinary tract
infections due to susceptible strains of the following
organisms: Escherichia coli, Klebsiella species, Enterobacter
species, Morganella morganii, Proteus mirabilis, and Proteus
vulgaris. It is recommended that initial episodes of
uncomplicated urinary tract infections be treated with a
single effective antibacterial agent rather than the
combination.
Acute Otitis Media: For the treatment of acute otitis media in
pediatric patients due to susceptible strains of Streptococcus
pneumoniae or Haemophilus influenzae when, in the judgment of
the physician, SEPTRA offers some advantage over the use of
other antimicrobial agents. To date, there is limited data on
the safety of repeated use of SEPTRA in pediatric patients
under two years of age. SEPTRA is not indicated for
prophylactic or prolonged administration in otitis media at
any age.
Acute Exacerbations of Chronic Bronchitis in Adults: For the
treatment of acute exacerbations of chronic bronchitis due to
susceptible strains of Streptococcus pneumoniae or Haemophilus
influenzae when, in the judgment of the physician, SEPTRA
offers some advantage over the use of a single antimicrobial
agent.
Travelers’ Diarrhea in Adults: For the treatment of travelers’
diarrhea due to susceptible strains of enterotoxigenic E.
coli.
Shigellosis: For the treatment of enteritis caused by
susceptible strains of Shigella flexneri and Shigella sonnei
when antibacterial therapy is indicated.
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Pneumocystis Carinii Pneumonia: For the treatment of
documented Pneumocystis carinii pneumonia. For prophylaxis
against Pneumocystis carinii pneumonia in individuals who are
immunosuppressed and considered to be at an increased risk of
developing Pneumocystis carinii pneumonia.
CONTRAINDICATIONS: SEPTRA is contraindicated in patients with
a known hypersensitivity to trimethoprim or sulfonamides and
in patients with documented megaloblastic anemia due to folate
deficiency. SEPTRA is also contraindicated in pregnant
patients at term and in nursing mothers, because sulfonamides
pass the placenta and are excreted in the milk and may cause
kernicterus. SEPTRA is contraindicated in pediatric patients
less than 2 months of age.
WARNINGS: FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF
SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE
REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL
NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS,
APLASTIC ANEMIA, AND OTHER BLOOD DYSCRASIAS.
SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH
AS TRIMETHOPRIM/SULFAMETHOXAZOLE, SHOULD BE DISCONTINUED AT
THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE
REACTION. In rare instances, a skin rash may be followed by a
more severe reaction, such as Stevens-Johnson syndrome, toxic
epidermal necrolysis, hepatic necrosis, and serious blood
disorder (see PRECAUTIONS).
Clinical signs, such as rash, sore throat, fever, arthralgia,
pallor, purpura, or jaundice may be early indications of
serious reactions.
Cough, shortness of breath, and pulmonary infiltrates are
hypersensitivity reactions of the respiratory tract that have
been reported in association with sulfonamide treatment.
The sulfonamides should not be used for the treatment of group
A beta-hemolytic streptococcal infections. In an established
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9
infection, they will not eradicate the streptococcus and,
therefore, will not prevent sequelae such as rheumatic fever.
Pseudomembranous colitis has been reported with nearly all
antibacterial agents, including trimethoprim/sulfamethoxazole,
and may range in severity from mild to life-threatening.
Therefore, it is important to consider this diagnosis in
patients who present with diarrhea subsequent to the
administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of
the colon and may permit overgrowth of clostridia. Studies
indicate that a toxin produced by Clostridium difficile is one
primary cause of ‘‘antibiotic-associated colitis.”
After the diagnosis of pseudo-membranous colitis has been
established, therapeutic measures should be initiated. Mild
cases of pseudomembranous colitis usually respond to drug
discontinuation alone. In moderate to severe cases,
consideration should be given to management with fluids
andelectrolytes, protein supplementation, and treatment with
an antibacterial drug effective against C. difficile.
PRECAUTIONS: General: SEPTRA should be given with caution to
patients with impaired renal or hepatic function, to those
with possible folate deficiency (e.g., the elderly, chronic
alcoholics, patients receiving anticonvulsant therapy,
patients with malabsorption syndrome, and patients in
malnutrition states), and to those with severe allergy or
bronchial asthma. In glucose-6-phosphate dehydrogenase-
deficient individuals, hemolysis may occur. This reaction is
frequently dose-related (see CLINICAL PHARMACOLOGY and DOSAGE
AND ADMINISTRATION).
Use in the Elderly: There may be an increased risk of severe
adverse reactions in elderly patients, particularly when
complicating conditions exist, e.g., impaired kidney and/or
liver function, or concomitant use of other drugs. Severe skin
reactions, or generalized bone marrow suppression (see
WARNINGS and ADVERSE REACTIONS), or a specific decrease in
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platelets (with or without purpura) are the most frequently
reported severe adverse reactions in elderly patients. In
those concurrently receiving certain diuretics, primarily
thiazides, an increased incidence of thrombocytopenia with
purpura has been reported. Appropriate dosage adjustments
should be made for patients with impaired kidney function (see
DOSAGE AND ADMINISTRATION).
Use in the Treatment of and Prophylaxis for Pneumocystis
carinii Pneumonia in Patients with Acquired Immunodeficiency
Syndrome (AIDS): The incidence of side effects, particularly
rash, fever, leukopenia, and elevated aminotransferase
(transaminase) values in AIDS patients who are being treated
with SEPTRA for Pneumocystis carinii pneumonia has been
reported to be greatly increased compared with the incidence
normally associated with the use of SEPTRA in non-AIDS
patients. The incidence of hyperkalemia and hyponatremia
appears to be increased in AIDS patients receiving SEPTRA.
Adverse effects are generally less severe in patients
receiving SEPTRA for prophylaxis. A history of mild
intolerance to SEPTRA in AIDS patients does not appear to
predict intolerance of subsequent secondary prophylaxis.
However, if a patient develops skin rash or any sign of
adverse reaction, therapy with SEPTRA should be re-evaluated
(see WARNINGS).
The concomitant use of leucovorin with trimethoprim-
sulfamethoxazole for the acute treatment of Pneumocystis
carinii pneumonia in patients with HIV infection was
associated with increased rates of treatment failure and
morbidity in a placebo-controlled study.
Information for Patients: Patients should be instructed to
maintain an adequate fluid intake in order to prevent
crystalluria and stone formation.
Laboratory Tests: Complete blood counts should be done
frequently in patients receiving SEPTRA; if a significant
reduction in the count of any formed blood element is noted,
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SEPTRA should be discontinued. Urinalyses with careful
microscopic examination and renal function tests should be
performed during therapy, particularly for those patients with
impaired renal function.
Drug Interactions: In elderly patients concurrently receiving
certain diuretics, primarily thiazides, an increased incidence
of thrombocytopenia with purpura has been reported. In the
literature, two cases of hyperkalemia in elderly patients have
been reported after concomitant intake of
trimethoprim/sulfamethoxazole and an angiotensin converting
enzyme inhibitor.
It has been reported that SEPTRA may prolong the prothrombin
time in patients who are receiving the anticoagulant warfarin.
This interaction should be kept in mind when SEPTRA is given
to patients already on anticoagulant therapy, and the
coagulation time should be reassessed.
SEPTRA may inhibit the hepatic metabolism of phenytoin.
SEPTRA, given at a common clinical dosage, increased the
phenytoin half-life by 39% and decreased the phenytoin
metabolic clearance rate by 27%. When administering these
drugs concurrently, one should be alert for possible excessive
phenytoin effect.
Sulfonamides can also displace methotrexate from plasma
protein binding sites, thus increasing free methotrexate
concentrations.
Drug/Laboratory Test Interactions: SEPTRA, specifically the
trimethoprim component, can interfere with a serum
methotrexate assay as determined by the competitive binding
protein technique (CBPA) when a bacterial dihydrofolate
reductase is used as the binding protein. No interference
occurs, however, if methotrexate is measured by a
radioimmunoassay (RIA).
The presence of trimethoprim and sulfamethoxazole may also
interfere with the Jaffé alkaline picrate reaction assay for
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12
creatinine, resulting in overestimations of about 10% in the
range of normal values.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Long-term studies in animals to evaluate
carcinogenic potential have not been conducted with SEPTRA.
Mutagenesis: Bacterial mutagenic studies have not been
performed with sulfamethoxazole and trimethoprim in
combination. Trimethoprim was demonstrated to be non-mutagenic
in the Ames assay. In studies at two laboratories, no
chromosomal damage was detected in cultured Chinese hamster
ovary cells at concentrations approximately 500 times human
plasma levels; at concentrations approximately 1,000 times
human plasma levels in these same cells, a low level of
chromosomal damage was induced at one of the laboratories. No
chromosomal abnormalities were observed in cultured human
leukocytes at concentrations of trimethoprim up to 20 times
human steady-state plasma levels. No chromosomal effects were
detected in peripheral lymphocytes of human subjects receiving
320 mg of trimethoprim in combination with up to 1,600 mg of
sulfamethoxazole per day for as long as 112 weeks.
Impairment of Fertility: No adverse effects on fertility or
general reproductive performance were observed in rats given
oral dosages as high as 70 mg/kg/day trimethoprim plus 350
mg/kg/day sulfamethoxazole.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In rats,
oral doses of 533 mg/kg sulfamethoxazole or 200 mg/kg
trimethoprim produced teratological effects manifested mainly
as cleft palates. The highest dose which did not cause cleft
palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg
trimethoprim when administered separately. In two studies in
rats, no teratogenicity was observed when 512 mg/kg of
sulfamethoxazole was used in combination with 128 mg/kg of
trimethoprim. In one study, however, cleft palates were
observed in one litter out of nine when 355 mg/kg of
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sulfamethoxazole was used in combination with 88 mg/kg of
trimethoprim.
In some rabbit studies, an overall increase in fetal loss
(dead and resorbed and malformed conceptuses) was associated
with doses of trimethoprim six times the human therapeutic
dose.
While there are no large, well-controlled studies on the use
of trimethoprim and sulfameth oxazole in pregnant women,
Brumfitt and Pursell,
5 in a retrospective study, reported the
outcome of 186 pregnancies during which the mother received
either placebo or trimethoprim and sulfamethoxazole. The
incidence of congenital abnormalities was 4.5% (3 of 66) in
those who received placebo and 3.3% (4 of 120) in those
receiving trimethoprim and sulfamethoxazole. There were no
abnormalities in the 10 children whose mothers received the
drug during the first trimester. In a separate survey,
Brumfitt and Pursell also found no congenital abnormalities in
35 children whose mothers had received oral trimethoprim and
sulfamethoxazole at the time of conception or shortly
thereafter.
Because trimethoprim and sulfamethoxazole may interfere with
folic acid metabolism, SEPTRA should be used during pregnancy
only if the potential benefit justifies the potential risk to
the fetus.
Nonteratogenic Effects: See CONTRAINDICATIONS section.
Nursing Mothers: See CONTRAINDICATIONS section.
Pediatric Use: SEPTRA is not recommended for pediatric
patients younger than 2 months of age (see INDICATIONS AND
USAGE and CONTRAINDICATIONS).
Geriatric Use: Clinical studies of SEPTRA did not include
sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects.
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There may be an increase risk of severe adverse reactions in
elderly patients, particularly when complicating conditions
exist, e.g., impaired kidney and/or liver function, possible
folate deficiency, or concomitant use of other drugs. Severe
skin reactions, generalized bone marrow suppression (see
WARNINGS and ADVERSE REACTIONS sections), a specific decrease
in platelets (with or without purpura), and hyperkalemia are
the most frequently reported severe adverse reactions in
elderly patients. In those concurrently receiving certain
diuretics, primarily thiazides, an increased incidence of
thrombocytopenia with purpura has been reported. Increased
digoxin blood levels can occur with concomitant Septra
therapy, especially in elderly patients. Serum digoxin levels
should be monitored. Hematological changes indicative of folic
acid deficiency may occur in elderly patients. These effects
are reversible by folinic acid therapy. Appropriate dosage
adjustments should be made for patients with impaired kidney
function and duration of use should be as short as possible to
minimize risks of undesired reactions (see DOSAGE AND
ADMINISTRATION section). The trimethoprim component of Septra
may cause hyperkalemia when administered to patients with
underlying disorders of potassium metabolism, with renal
insufficiency, or when given concomitantly with drugs known to
induce hyperkalemia, such as angiotensin converting enzyme
inhibitors. Close monitoring of serum potassium is warranted
in these patients. Discontinuation of Septra treatment is
recommended to help lower potassium serum levels. Septra
Tablets contain 1.8 mg (0.08 mEq) of sodium per tablet. Septra
DS Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet.
Pharmacokinetics parameters for sulfamethoxazole were similar
for geriatric subjects and younger adult subjects. The mean
maximum serum trimethoprim concentration was higher and mean
renal clearance of trimpethoprim was lower in geriatric
subjects compared with younger subjects
3 (see CLINICAL
PHARMACOLOGY: Geriatric Pharmacokinetcs).
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ADVERSE REACTIONS: The most common adverse effects are
gastrointestinal disturbances (nausea, vomiting, anorexia) and
allergic skin reactions (such as rash and urticaria).
FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES,
ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS,
INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL
NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS,
APLASTIC ANEMIA, OTHER BLOOD DYSCRASIAS, AND HYPERSENSITIVITY
OF THE RESPIRATORY TRACT (SEE WARNINGS).
Hematologic: Agranulocytosis, aplastic anemia,
thrombocytopenia, leukopenia, neutropenia, hemolytic anemia,
megaloblastic anemia, hypoprothrombinemia, methemoglobinemia,
eosinophilia.
Allergic: Stevens-Johnson syndrome, toxic epidermal
necrolysis, anaphylaxis, allergic myocarditis, erythema
multiforme, exfoliative dermatitis, angioedema, drug fever,
chills, Henoch-Schönlein purpura, serum sickness-like
syndrome, generalized allergic reactions, generalized skin
eruptions, photosensitivity, conjunctival and scleral
injection, pruritus, urticaria, and rash. In addition,
periarteritis nodosa and systemic lupus erythematosus have
been reported.
Gastrointestinal: Hepatitis, including cholestatic jaundice
and hepatic necrosis, elevation of serum transaminase and
bilirubin, pseudomembranous enterocolitis, pancreatitis,
stomatitis, glossitis, nausea, emesis, abdominal pain,
diarrhea, anorexia.
Genitourinary: Renal failure, interstitial nephritis, BUN and
serum creatinine elevation, toxic nephrosis with oliguria and
anuria, and crystalluria.
Metabolic: Hyperkalemia, hyponatremia.
Neurologic: Aseptic meningitis, convulsions, peripheral
neuritis, ataxia, vertigo, tinnitus, headache.
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Chronic: Use of SEPTRA at high doses and/or for extended
periods of time may cause bone marrow depression manifested as
thrombocytopenia, leukopenia, and/or megaloblastic anemia. If
signs of bone marrow depression occur, the patient should be
given leucovorin; 5 to 15 mg leucovorin daily has been
recommended by some investigators.
DOSAGE AND ADMINISTRATION: Contraindicated in pediatric
patients less than 2 months of age.
Urinary Tract Infections and Shigellosis in Adults and
Pediatric Patients and Acute Otitis Media in Pediatric
Patients: Adults: The usual adult dosage in the treatment of
urinary tract infections is one SEPTRA DS (double strength)
tablet, two SEPTRA tablets, or four teaspoonfuls (20 mL)
SEPTRA Suspension every 12 hours for 10 to 14 days. An
identical daily dosage is used for 5 days in the treatment of
shigellosis.
Pediatric Patients: The recommended dose for pediatric
patients with urinary tract infections or acute otitis media
is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole per 24
hours, given in two divided doses every 12 hours for 10 days.
An identical daily dosage is used for 5 days in the treatment
of shigellosis. The following table is a guideline for the
attainment of this dosage:
Pediatric Patients: Two Months of Age or Older
Weight
Dose -- Every 12 Hours
lb
kg
Teaspoonfuls
Tablets
22
10
1 ( 5 mL)
44
20
2 (10 mL)
1
66
30
3 (15 mL)
11⁄2
88
40
4 (20 mL)
2(or 1 DS Tablet)
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Psychiatric: Hallucinations, depression, apathy, nervousness.
Endocrine: The sulfonamides bear certain chemical similarities
to some goitrogens, diuretics (acetazolamide and the
thiazides), and oral hypoglycemic agents. Cross-sensitivity
may exist with these agents. Diuresis and hypoglycemia have
occurred rarely in patients receiving sulfonamides.
Musculoskeletal: Arthralgia and myalgia.
Respiratory System: Cough, shortness of breath, and pulmonary
infiltrates (see WARNINGS).
Miscellaneous: Weakness, fatigue, insomnia.
OVERDOSAGE:
Acute: The amount of a single dose of SEPTRA that is either
associated with symptoms of overdosage or is likely to be
life-threatening has not been reported. Signs and symptoms of
overdosage reported with sulfonamides include anorexia, colic,
nausea, vomiting, dizziness, headache, drowsiness, and
unconsciousness. Pyrexia, hematuria, and crystalluria may be
noted. Blood dyscrasias and jaundice are potential late
manifestations of overdosage. Signs of acute overdosage with
trimethoprim include nausea, vomiting, dizziness, headache,
mental depression, confusion, and bone marrow depression.
General principles of treatment include the institution of
gastric lavage or emesis; forcing oral fluids; and the
administration of intravenous fluids if urine output is low
and renal function is normal. Acidification of the urine will
increase renal elimination of trimethoprim. The patient should
be monitored with blood counts and appropriate blood
chemistries, including electrolytes. If a significant blood
dyscrasia or jaundice occurs, specific therapy should be
instituted for these complications. Peritoneal dialysis is not
effective and hemodialysis is only moderately effective in
eliminating trimethoprim and sulfamethoxazole.
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For Patients With Impaired Renal Function: When renal function
is impaired, a reduced dosage should be employed using the
following table:
Creatinine
Recommended
Clearance
Dosage
(mL/min)
Regimen
Above 30
Use Standard Regimen
15-30
1⁄2 the Usual Regimen
Below 15
Use Not Recommended
Acute Exacerbations of Chronic Bronchitis in Adults: The usual
adult dosage in the treatment of acute exacerbations of
chronic bronchitis is one SEPTRA DS (double strength) tablet,
two SEPTRA tablets, or four teaspoonfuls (20 mL) SEPTRA
Suspension every 12 hours for 14 days.
Travelers’ Diarrhea in Adults: For the treatment of travelers’
diarrhea, the usual adult dosage is one SEPTRA DS (double
strength) tablet, two SEPTRA tablets, or four teaspoonfuls (20
mL) of SEPTRA Suspension every 12 hours for 5 days.
Pneumocystis Carinii Pneumonia: Treatment:
Adults and Pediatric Patients:
The recommended dosage for treatment of patients with
documented Pneumocystis carinii pneumonia is 15 to 20 mg/kg
trimethoprim and 75 to 100 mg/kg sulfamethoxazole per 24 hours
given in equally divided doses every 6 hours for 14 to 21
days. The following table is a guideline for the upper limit
of this dosage:
WeightDose - Every 6 Hours
lb
kg
Teaspoonfuls
Tablets
18
8
1 ( 5 mL)
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35
16
2 (10 mL)
1
53
24
3 (15 mL)
1 1⁄2
70
32
4 (20 mL)
2 (or 1 DS Tablet)
88
40
5 (25 mL)
2 1⁄2
106
48
6 (30 mL)
3 (or 1 1⁄2 DS Tablets)
141
64
8 (40 mL)
4 (or 2 DS Tablets)
176
80
10 (50 mL)
5 (or 2 1⁄2 DS Tablets)
For the lower limit dose (15 mg/kg trimethoprim and 75 mg/kg
sulfamethoxazole per 24 hours) administer 75% of the dose in
the above table.
Prophylaxis:
Adults:
The recommended dosage for prophylaxis in adults is one SEPTRA
DS (double strength) tablet daily.
Pediatric Patients:
For pediatric patients, the recommended dose is 150 mg/m
2/day
trimethoprim with 750 mg/m
2/day sulfamethoxazole given orally
in equally divided doses twice a day, on 3 consecutive days
per week. The total daily dose should not exceed 320 mg
trimethoprim and 1,600 mg sulfamethoxazole. The following
table is a guideline for the attainment of this dosage in
pediatric patients:
Body Surface AreaDose-every 12 hours
(m
2)
Teaspoonfuls
Tablets
0.26
1⁄2 (2.5 mL)
0.53
1 (5 mL)
1⁄2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
1.06
2 (10 mL)
1
HOW SUPPLIED:
TABLETS (pink, scored, round-shaped) containing 80 mg
trimethoprim and 400 mg sulfamethoxazole: Bottles of 100 (NDC
61570-052-01). Imprint on tablets “ M052” .
DS (DOUBLE STRENGTH) TABLETS (pink, scored, oval-shaped)
containing 160 mg trimethoprim and 800 mg sulfamethoxazole:
Bottles of 20 (NDC 61570-053-20), 100 (NDC 61570-053-01), 250
(NDC 61570-053-52) and 500 (NDC 61570-053-05). Imprint on
tablets ‘‘M053’’.
ORAL SUSPENSIONS (pink, cherry-flavored) containing 40 mg
trimethoprim and 200 mg sulfamethoxazole in each teaspoonful
(5 mL): Bottle of 1 pint (473 mL) (NDC 61570-050-16) and 100
mL-package of 6 (NDC 61570-050-11); and (purple, grape-
flavored) containing 40 mg trimethoprim and 200 mg
sulfamethoxazole in each teaspoonful (5 mL): Bottle of 1 pint
(473 mL) (NDC 61570-051-16).
Tablets should be stored at 15° to 25°C (59° to 77°F) in a dry
place and protected from light.
Suspensions should be stored at 15° to 25°C (59° to 77°F) and
protected from light.
Also available:
SEPTRA I.V. Infusion: 5 mL vials, containing 80 mg
trimethoprim (16 mg/mL) and 400 mg sulfamethoxazole (80
mg/mL), tray of 10;
10 mL multiple dose vials containing 160 mg trimethoprim (16
mg/mL) and 800 mg sulfamethoxazole (80 mg/mL), tray of 10;
20 mL multiple dose vials containing 320 mg trimethoprim (16
mg/mL) and 1600 mg sulfamethoxazole (80 mg/mL), tray of 10.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
REFERENCES:
1.
Kremers P, Duvivier J, Heusghem C. Pharmacokinetic
studies of co-trimoxazole in man after single and
repeated doses. J Clin Pharmacol. 1974;14:112-117.
2.
Kaplan SA, Weinfeld RE, Abruzzo CW, McFaden K, Jack ML,
Weissman L. Pharmacokinetic profile of trimethoprim-
sulfamethoxazole in man. J Infect Dis.
1973;128(suppl):S547-S555.
3.
Antibiotic susceptibility discs; certification procedure.
Federal Register. 1972;37:20527-20529.
4.
Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic
susceptibility testing by standardized single disk
method. Am J Clin Pathol. 1966;45:493-496.
5.
Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in
the treatment of bacteriuria in women.
JInfectDis.1973;128 (suppl):S657-S663.
6.
Marinella MA. Trimethoprim - induced hyperkalemia: An
analysis of reported cases. Gerontology 45: 209-212,
1999.
Rx Only.
Prescribing Information as of January 2005.
Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN
37620
(A wholly owned subsidiary of King Pharmaceuticals, Inc.)
Manufactured by: King Pharmaceuticals, Inc., Bristol, TN 37620
3000259
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:19.139469
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017376s056,017598s039lbl.pdf', 'application_number': 17598, 'submission_type': 'SUPPL ', 'submission_number': 39}
|
11,045
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NDA 17-604/S-040
Page 3
NALFON®
(fenoprofen calcium capsules, USP)
200 mg & 300mg
Rx only
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with
cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See
WARNINGS).
•Nalfon® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur at any
time during use and without warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal events (see WARNINGS).
DESCRIPTION
Nalfon® (Fenoprofen Calcium Capsules, USP) is a nonsteroidal, anti-inflammatory, antiarthritic drug.
Nalfon capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826
mmol) or 300 mg (1.24 mmol) of fenoprofen. The capsules also contain cellulose, gelatin, iron oxides,
silicone, titanium dioxide, and other inactive ingredients. The 300 mg capsules also contain D & C
Yellow No. 10 and F D & C Yellow No. 6.
Chemically, Nalfon is an arylacetic acid derivative.
The structural formula is as follows:
Benzeneacetic acid, α-methyl-3-phenoxy-,
calcium salt dihydrate, (±)-
Nalfon is a white crystalline powder that has the structural formula C30H26CaO6•2H2O representing a
molecular weight of 558.65. At 25°C, it dissolves to a 15 mg/mL solution in alcohol (95%). It is
slightly soluble in water and insoluble in benzene.
The pKa of Nalfon is a 4.5 at 25°C.
CLINICAL PHARMACOLOGY
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NDA 17-604/S-040
Page 4
Nalfon is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and
antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin
synthetase inhibition is involved. Nalfon has been shown to inhibit prostaglandin synthetase isolated
from bovine seminal vesicles. Reproduction studies in rats have shown Nalfon to be associated with
prolonged labor and difficult parturition when given during late pregnancy. Evidence suggests that this
may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis.
Its action is not mediated through the adrenal gland.
Fenoprofen shows anti-inflammatory effects in rodents by inhibiting the development of redness and
edema in acute inflammatory conditions and by reducing soft-tissue swelling and bone damage
associated with chronic inflammation. It exhibits analgesic activity in rodents by inhibiting the
writhing response caused by the introduction of an irritant into the peritoneal cavities of mice and by
elevating pain thresholds that are related to pressure in edematous hindpaws of rats. In rats made
febrile by the subcutaneous administration of brewer’s yeast, fenoprofen produces antipyretic action.
These effects are characteristic of nonsteroidal, anti-inflammatory, antipyretic, analgesic drugs.
The results in humans confirmed the anti-inflammatory and analgesic actions found in animals. The
emergence and degree of erythemic response were measured in adult male volunteers exposed to
ultraviolet irradiation. The effects of Nalfon, aspirin, and indomethacin were each compared with those
of a placebo. All 3 drugs demonstrated antierythemic activity.
In all patients with rheumatoid arthritis, the anti-inflammatory action of Nalfon has been evidenced by
relief of pain, increase in grip strength, and reductions in joint swelling, duration of morning stiffness,
and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action
of Nalfon has also been evidenced by increased mobility (i.e., a decrease in the number of joints
having limited motion).
The use of Nalfon in combination with gold salts or corticosteroids has been studied in patients with
rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further
improvement is obtained by adding Nalfon to maintenance therapy with gold salts or steroids. Whether
or not Nalfon used in conjunction with partially effective doses of a corticosteroid has a “steroid-
sparing” effect is unknown.
In patients with osteoarthritis, the anti-inflammatory and analgesic effects of Nalfon have been
demonstrated by reduction in tenderness as a response to pressure and reductions in night pain,
stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator).
These effects have also been demonstrated by relief of pain with motion and at rest and increased
range of motion in involved joints.
In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown Nalfon to be
comparable to aspirin in controlling the aforementioned measures of disease activity, but mild
gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated
with Nalfon than in aspirin-treated patients. It is not known whether Nalfon causes less peptic
ulceration than does aspirin.
In patients with pain, the analgesic action of Nalfon has produced a reduction in pain intensity, an
increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect.
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NDA 17-604/S-040
Page 5
Under fasting conditions, Nalfon is rapidly absorbed, and peak plasma levels of 50 µg/mL are achieved
within 2 hours after oral administration of 600 mg doses. Good dose proportionality was observed
between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3
hours. About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-
hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly
bound (99%) to albumin.
The concomitant administration of antacid (containing both aluminum and magnesium hydroxide)
does not interfere with absorption of Nalfon.
There is less suppression of collagen-induced platelet aggregation with single doses of Nalfon than
there is with aspirin.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of Nalfon and other treatment options before
deciding to use Nalfon. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
Nalfon is indicated:
• For relief of mild to moderate pain in adults.
• For relief of the signs and symptoms of rheumatoid arthritis.
• For relief of the signs and symptoms of osteoarthritis.
CONTRAINDICATIONS
Nalfon is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium.
Nalfon should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and
PRECAUTIONS – Preexisting Asthma).
Nalfon is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Nalfon is contraindicated in patients with a history of significantly impaired renal function. (see
WARNINGS – Advanced Renal Disease).
WARNINGS
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NDA 17-604/S-040
Page 6
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical Trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may gave a similar
risk. Patients with know CV disease or risk factors for CV disease may be at greater risk. To minimize
the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose
should be used for the shortest duration possible. Physicians and patients should remain alert for the
development of such event, even in the absence of previous CV symptoms. Patients should be
informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent us of aspirin mitigates the increased risk of
serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an
NSAID does increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in
the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction
and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including Nalfon, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including Nalfon, should be used with caution in patients with hypertension. Blood pressure
(BP) should be monitored closely during the initiation of NSAID treatment and throughout the course
of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. Nalfon should be
used with caution in patients with fluid retention, compromised cardiac function or heart failure. The
possibility of renal involvement should be considered.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including Nalfon, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of
patients treated for one year. These trends continue with longer duration of use, increasing the
likelihood of developing a serious GI event at some time during the course of therapy. However, even
short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk for GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking use of alcohol, older age, and poor general
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NDA 17-604/S-040
Page 7
health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and
therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should
include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk
patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which my precipitate overt renal decomposition. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
Since Nalfon is primarily eliminated by the kidneys, patients with possibly compromised renal
function (such as the elderly) should be monitored periodically, especially during long-term therapy.
For such patients, it may be anticipated that a lower daily dosage will avoid excessive drug
accumulation.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of Nalfon in
patients with advanced renal disease. Therefore, treatment with Nalfon is not recommended in these
patients with advanced renal disease (see CONTRAINDICATIONS). If Nalfon therapy must be
initiated, close monitoring of the patient's renal function is advisable.
Genitourinary Tract
NSAIDs including Nalfon can lead to onset of genitourinary tract problems. The most frequently
reported problems have been episodes of dysuria, cystitis, hematuria, interstitial nephritis and
nephrotic syndrome. This syndrome may be preceded by the appearance of fever, rash, arthralgia,
oliguria, and azotemia and may progress to anuria. There may also be substantial proteinuria and, on
renal biopsy, electron microscopy has shown foot process fusion and T-lymphocyte infiltration in the
renal interstitium. Early recognition of the syndrome and withdrawal of the drug have been followed
by rapid recovery. Administration of steroids and the use of dialysis have also been included in the
treatment.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to
Nalfon. Nalfon should not be given to patients with the aspirin triad. This symptom complex typically
occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit
severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including Nalfon, can cause serious skin adverse events such as exfoliative
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NDA 17-604/S-040
Page 8
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be
fatal. These serious events may occur without warning. Patients should be informed about the signs
and symptoms of serious skin manifestations and use of the drug should be discontinued at the first
appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, Nalfon should be avoided because it may cause
premature closure of the ductus arteriosus.
Ocular
Studies to date have not shown changes in the eyes attributable to the administration of Nalfon.
However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye
examinations, therefore, should be performed if visual disturbances occur in patients taking Nalfon.
Central Nervous System
Caution should be exercised by patients whose activities require alertness if they experience CNS side
effects while taking Nalfon.
Hearing
Since the safety of Nalfon has not been established in patients with impaired hearing, these patients
should have periodic tests of auditory function during prolonged therapy with Nalfon.
PRECAUTIONS
General
Nalfon cannot be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to
discontinue corticosteroids.
The pharmacological activity of Nalfon in reducing inflammation may diminish the utility of these
diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs
including Nalfon. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials
with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal
fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been
reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction
while on therapy with Nalfon. If clinical signs and symptoms consistent with liver disease develop, or
if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Nalfon should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including Nalfon. This may be due to fluid
retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including Nalfon, should have their hemoglobin or
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NDA 17-604/S-040
Page 9
hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet
aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their
effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving
Nalfon who may be adversely affected by alterations in platelet function, such as those with
coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs
has been reported in such aspirin-sensitive patients, Nalfon should not be administered to patients with
this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating therapy with an NSAID and
periodically during the course of ongoing therapy. Patients should also be encouraged to read the
NSAID Medication Guide that accompanies each prescription dispensed.
1. Nalfon, like other NSAIDs, may cause serious CV side effects, such as MI or stroke,
which may result in hospitalization and even death. Although serious CV events can occur without
warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative
sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS,
Cardiovascular Effects).
2. Nalfon, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side
effects, such as ulcers and bleeding, which may result in hospitalization and even death.
Although serious GI tract ulcerations and bleeding can occur without warning symptoms,
patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for
medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia,
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
3. Nalfon, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although
serious skin reactions may occur without warning, patients should be alert for the signs and symptoms
of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for
medical advice when observing any indicative signs or symptoms. Patients should be advised to stop
the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these
occur, patients should be instructed to stop therapy and seek immediate medical therapy.
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NDA 17-604/S-040
Page 10
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, Nalfon should be avoided because it will may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs,
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, Nalfon should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This
interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-
inhibitors.
Aspirin
The coadministration of aspirin decreases the biologic half-life of fenoprofen because of an increase in
metabolic clearance that results in a greater amount of hydroxylated fenoprofen in the urine. Although
the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction
and displacement of fenoprofen from plasma albumin binding sites are possibilities. As with other
NSAIDs, concomitant administration of fenoprofen calcium and aspirin is not generally recommended
because of the potential of increased adverse effects.
Furosemide Diuretics
Clinical studies, as well as post marketing observations, have shown that Nalfon can reduce the
natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to
inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient
should be observed closely for signs of renal failure (see PRECAUTIONSWARNINGS, Renal
Effects), as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal
prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered
concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.
This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when
NSAIDs are administered concomitantly with methotrexate.
Warfarin
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NDA 17-604/S-040
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The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs
together have a risk of serious GI bleeding higher than users of either drug alone.
Phenobarbital
Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a decrease
in the plasma half-life of fenoprofen. When phenobarbital is added to or withdrawn from treatment,
dosage adjustment of Nalfon may be required.
Plasma Protein Binding
In vitro studies have shown that fenoprofen, because of it affinity for albumin, may displace from their
binding sites other drugs that are also albumin bound, and this may lead to drug interaction.
Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides, or
sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity
from these drugs.
Drug/Laboratory Test Interactions
Amerlex-M kit assay values of total and free triiodothyronine in patients receiving Nalfon have been
reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the
assay. Thyroid-stimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are
not affected.
Pregnancy
Teratogenic Effects. Pregnancy Category C.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental
abnormalities. However, animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies in pregnant women. Nalfon should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late
pregnancy) should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Nalfon
on labor and delivery in pregnant women are unknown.
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 Nalfon, 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 pediatric patients below the age of 18 havehas not been established.
Geriatric Use
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NDA 17-604/S-040
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As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
ADVERSE REACTIONS
During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of
pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the
following data emerged. These encompass observations in 6,786 patients, including 188 observed for
at least 52 weeks. For comparison, data are also presented from complaints received from the 266
patients who received placebo in these same trials. During short-term studies for analgesia, the
incidence of adverse reactions was markedly lower than that seen in longer-term studies.
INCIDENCE GREATER THAN 1%
Probable Causal Relationship
Digestive System—During clinical trials with Nalfon, the most common adverse reactions were
gastrointestinal in nature and occurred in 20.8% of patients receiving Nalfon as compared to 16.9% of
patients receiving placebo. In descending order of frequency, these reactions included dyspepsia
(10.3%, Nalfon, vs. 2.3%, placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting
(2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%).
The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of
patients during premarketing studies.
Nervous System —The most frequent adverse neurologic reactions were headache (8.7%
treated vs. 7.5% placebo) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2%
vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently.
Nalfon was discontinued in less than 0.5% of patients because of these side effects during
premarketing studies.
Skin and Appendages—Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%), and rash
(3.7% vs. 0.4%) were reported.
Nalfon was discontinued in about 1% of patients because of an adverse effect related to the skin
during premarketing studies.
Special Senses—Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased
hearing (1.6% vs. none) were reported.
Nalfon was discontinued in less than 0.5% of patients because of adverse effects related to the
special senses during premarketing studies.
Cardiovascular—Palpitations (2.5% vs. 0.4%).
Nalfon was discontinued in about 0.5% of patients because of adverse cardiovascular reactions
during premarketing studies.
Miscellaneous—Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema
(5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5%
vs. 5.6%), and nasopharyngitis (1.2% vs. none).
INCIDENCE LESS THAN 1%
Probable Causal Relationship
The following adverse reactions, occurring in less than 1% of patients, were reported in
controlled clinical trials and voluntary reports made since Nalfon was initially marketed. The
probability of a causal relationship exists between Nalfon and these adverse reactions:
Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage,
anorexia, flatulence, dry mouth, and blood in the stool. Increases in alkaline phosphatase, LDH, and
SGOT, jaundice, and cholestatic hepatitis were observed (see PRECAUTIONS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-604/S-040
Page 13
Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria,
interstitial nephritis, nephrosis, and papillary necrosis (see WARNINGS).
Hypersensitivity—Angioedema (angioneurotic edema).
Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic
anemia, agranulocytosis, and pancytopenia.
Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, and tachycardia.
INCIDENCE LESS THAN 1%
Causal Relationship Unknown
Other reactions reported either in clinical trials or spontaneously, occurred in circumstances in
which a causal relationship could not be established. However, with these rarely reported reactions, the
possibility of such a relationship cannot be excluded. Therefore, these observations are listed to alert
the physician.
Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson
syndrome, and alopecia.
Digestive System—Aphthous ulcerations of the buccal mucosa, metallic taste, and pancreatitis.
Cardiovascular—Atrial filbrillationfibrillation, pulmonary edema, electrocardiographic
changes, and supraventricular tachycardia.
Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia.
Special Senses—Burning tongue, diplopia, and optic neuritis.
Miscellaneous—Personality change, lymphadenopathy, mastodynia, and fever.
OVERDOSAGE
Signs and Symptoms—Symptoms of overdose appear within several hours and generally
involve the gastrointestinal and central nervous systems. They include dyspepsia, nausea, vomiting,
abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness, and confusion.
Hyperpyrexia, tachycardia, hypotension, and acute renal failure may occur rarely following overdose.
Respiratory depression and metabolic acidosis have also been reported following overdose with certain
NSAIDs.
Treatment—To obtain up-to-date information about the treatment of overdose, a good resource
is your certified Regional Poison Control Center. Telephone numbers of certified poison control
centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the
possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your
patient.
Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and
maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc.
Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal,
which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in
addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some
drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or
charcoal.
Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis, and charcoal
hemoperfusion do not enhance systemic drug elimination.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of Nalfon and other treatment options
before deciding to use Nalfon. Use the lowest effective dose for the shortest duration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-604/S-040
Page 14
consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted
to suit an individual patient's needs.
Analgesia
For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to
6 hours, as needed.
Rheumatoid Arthritis and Osteoarthritis
For the relief of rheumatoid arthritis or osteoarthritis the recommended dose is 300 to 600 mg given
orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased
or decreased depending on the severity of the symptoms. Dosage adjustments may be made after
initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed
3,200 mg.
Nalfon may be administered with meals or with milk. Although the total amount absorbed is not
affected, peak blood levels are delayed and diminished.
Patients with rheumatoid arthritis generally seem to require larger doses of Nalfon than do those with
osteoarthritis. The smallest dose that yields acceptable control should be employed.
Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be
required to gauge the full benefits of therapy.
HOW SUPPLIED
Nalfon® (Fenoprofen Calcium Capsules, USP) are available in:
The 200 mg* capsule is opaque yellow cap and opaque white body, imprinted with “RX681” on the
cap and body.
NDC 0884-6600-10
Bottles of 100
The 300 mg* capsule is opaque yellow cap and opaque yellow body, imprinted with “RX682” on the
cap and body.
NDC 0884-6700-10
Bottles of 100
* Equivalent to fenoprofen.
Preserve in well-closed containers.
Store at 20° - 25° C (68° - 77° F). (See USP Controlled Room Temperature).
Manufactured for:
Pedinol Pharmacal Inc.
Farmingdale, NY 11735 USA
By: Ohm Laboratories, Inc.
North Brunswick, NJ 08902 USA
July 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-604/S-040
Page 15
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-604/S-040
Page 16
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-604/S-040
Page 17
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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.
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/s/
---------------------
Bob Rappaport
1/18/2006 06:09:27 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:19.453616
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017604s040lbl.pdf', 'application_number': 17604, 'submission_type': 'SUPPL ', 'submission_number': 40}
|
11,044
|
Septra Tablets (trimethoprim and sulfamethoxazole tablets) Tablet
Septra Ds Tablets (trimethoprim and sulfamethoxazole ds tablets) Tablet
Septra Suspension (trimethoprim and sulfamethoxazole suspension) Suspension
Septra Grape Suspension (trimethoprim and sulfamethoxazole grape suspension) Suspension
To reduce the development of drug-resistant bacteria and maintain the effectiveness of SEPTRA and
other antibacterial drugs, SEPTRA should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by bacteria.
DESCRIPTION
SEPTRA (trimethoprim and sulfamethoxazole) is a synthetic antibacterial combination product. Each
SEPTRA Tablet contains 80 mg trimethoprim and 400 mg sulfamethoxazole and the inactive ingredients
docusate sodium (0.4 mg per tablet), FD&C Red No. 40, magnesium stearate, povidone, and sodium
starch glycolate.
Each SEPTRA DS (double strength) Tablet contains 160 mg trimethoprim and 800 mg
sulfamethoxazole and the inactive ingredients docusate sodium (0.8 mg per tablet), FD&C Red No. 40,
magnesium stearate, povidone, and sodium starch glycolate.
Each teaspoonful (5 mL) of SEPTRA Suspension contains 40 mg trimethoprim and 200 mg
sulfamethoxazole and the inactive ingredients alcohol 0.26%, methylparaben 0.1% and sodium benzoate
0.1% (added as preservatives), carboxymethylcellulose sodium, citric acid, FD&C Red No. 40 and
Yellow No. 6, flavor, glycerin, microcrystalline cellulose, polysorbate 80, saccharin sodium, and
sorbitol. Each teaspoonful (5 mL) of SEPTRA Grape Suspension contains 40 mg trimethoprim and 200
mg sulfamethoxazole and the inactive ingredients alcohol 0.26%, methylparaben 0.1%, and sodium
benzoate 0.1% (added as preservatives), carboxymethylcellulose sodium, citric acid, FD&C Red No. 40
and Blue No. 1, flavor, glycerin, microcrystalline cellulose, polysorbate 80, saccharin sodium, and
sorbitol. Both tablet and suspension forms are for oral administration.
Trimethoprim is 5-[(3,4,5-trimeth-oxyphenyl)methyl]-2,4- pyrimidinediamine. It is a white to light
yellow, odorless, bitter compound with a molecular weight of 290.32, and the molecular formula
C
H N O . The structural formula is:
Sulfamethoxazole is 4-amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide. It is an almost white,
odorless, tasteless compound with a molecular weight of 253.28, and the molecular formula
C
H N O S. The structural formula is:
CLINICAL PHARMACOLOGY
SEPTRA is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim
exist in the blood as unbound, protein-bound, and metabolized forms; sulfamethoxazole also exists as
the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N -acetylation,
although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are
Image from Drug Label Content
Image from Drug Label Content
14
18
4
3
10
11
3
3
4
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This label may not be the latest approved by FDA.
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the 1- and 3-oxides and the 3’- and 4’-hydroxy derivatives. The free forms of sulfamethoxazole and
trimethoprim are considered to be the therapeutically active forms. Approximately 44% of trimethoprim
and 70% of sulfamethoxazole are bound to plasma proteins. The presence of 10 mg percent
sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree;
trimethoprim does not influence the protein binding of sulfamethoxazole.
Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean
serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However,
patients with severely impaired renal function exhibit an increase in the half-lives of both components,
requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION). Detectable amounts
of trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration.
During administration of 160 mg trimethoprim and 800 mg sulfamethoxazole b.i.d., the mean steady-
state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state minimal plasma levels
of free and total sulfamethoxazole were 57.4 mcg/mL and 68.0 mcg/mL, respectively. These steady-
state levels were achieved after 3 days of drug administration.
Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular
filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are
considerably higher than are the concentrations in the blood. The average percentage of the dose
recovered in urine from 0 to 72 hours after a single oral dose is 84.5% for total sulfonamide and 66.8%
for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with
the remaining as N -acetylated metabolite. When administered together as SEPTRA, neither
sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.
Both trimethoprim and sulfamethoxazole distribute to sputum, vaginal fluid, and middle ear fluid;
trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted
in human milk.
Geriatric Pharmacokinetics:
The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric
subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-US
approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to
those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly
lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However,
after normalizing by body weight, the apparent total body clearance of trimethoprim was an average
19% lower in geriatric subjects compared with young adult subjects.
Microbiology:
Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic
acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by
binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, SEPTRA
blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.
In vitro studies have shown that bacterial resistance develops more slowly with SEPTRA than with
either trimethoprim or sulfamethoxazole alone.
In vitro serial dilution tests have shown that the spectrum of antibacterial activity of SEPTRA includes
the common urinary tract pathogens with the exception of Pseudomonas aeruginosa. The following
organisms are usually susceptible: Escherichia coli, Klebsiella species, Enterobacter species,
Morganella morganii, Proteus mirabilis, and indole-positive Proteus species including Proteus vulgaris.
The usual spectrum of antimicrobial activity of SEPTRA includes bacterial pathogens isolated from
1
4
2
3
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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
middle ear exudate and from bronchial secretions (Haemophilus influenzae, including ampicillin-
resistant strains, and Streptococcus pneumoniae), and enterotoxigenic strains of Escherichia coli
(ETEC) causing bacterial gastroenteritis. Shigella flexneri and Shigella sonnei are also usually
susceptible.
TMP=trimethoprim
SMX=sulfamethoxazole
*Rudoy RC, Nelson JD, Haltalin KC. Antimicrobial Agents and Chemotherapy. 1974;5:439-443.
Susceptibility Testing:
The recommended quantitative disc susceptibility method may be used for estimating the susceptibility
of bacteria to SEPTRA.
With this procedure, a report from the laboratory of “Susceptible to
trimethoprim and sulfamethoxazole” indicates that the infection is likely to respond to therapy with
SEPTRA. If the infection is confined to the urine, a report of “Intermediate susceptibility to
trimethoprim and sulfamethoxazole” also indicates that the infection is likely to respond. A report of
“Resistant to trimethoprim and sulfamethoxazole” indicates that the infection is unlikely to respond to
therapy with SEPTRA.
INDICATIONS AND USAGE
REPRESENTATIVE MINIMUM INHIBITORY CONCENTRATION VALUES FOR
ORGANISMS SUSCEPTIBLE TO SEPTRA (MICµg/mL)
TMP/SMX (1:19)
TMP
SMX
Bacteria
Alone
Alone
TMP
SMX
Escherichia coli
0.05-1.5
1.0-245
0.05-0.5
0.95-9.5
Escherichia coli
(enterotoxigenic strains)
0.015-0.15
0.285->950
0.005-0.15
0.095-2.85
Proteus species (indole
positive)
0.5-5.0
7.35-300
0.05-1.5
0.95-28.5
TMP/SMX (1:19)
TMP
SMX
Bacteria
Alone
Alone
TMP
SMX
Morganella morganii
0.5-5.0
7.35-300
0.05-1.5
0.95-28.5
Proteus mirabilis
0.5-1.5
7.35-30
0.05-0.15
0.95-2.85
Klebsiella species
0.15-5.0
2.45-245
0.05-1.5
0.95-28.5
Enterobacter species
0.15-5.0
2.45-245
0.05-1.5
0.95-28.5
Haemophilus influenzae
0.15-1.5
2.85-95
0.015-0.15
0.285-2.85
TMP/SMX (1:19)
TMP
SMX
Bacteria
Alone
Alone
TMP
SMX
Streptococcus
pneumoniae
0.15-1.5
7.35-24.5
0.05-0.15
0.95-2.85
Shigella flexneri*
<0.01-0.04
<0.16->320
<0.002-0.03
0.04-0.625
Shigella sonnei*
0.02-0.08
0.625->320
0.004-0.06
0.08-1.25
4,5
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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
To reduce the development of drug-resistant bacteria and maintain the effectiveness of SEPTRA and
other antibacterial drugs, SEPTRA 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.
Urinary Tract Infections:
For the treatment of urinary tract infections due to susceptible strains of the following organisms:
Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, and
Proteus vulgaris. It is recommended that initial episodes of uncomplicated urinary tract infections be
treated with a single effective antibacterial agent rather than the combination.
Acute Otitis Media:
For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus
pneumoniae or Haemophilus influenzae when, in the judgment of the physician, SEPTRA offers some
advantage over the use of other antimicrobial agents. To date, there is limited data on the safety of
repeated use of SEPTRA in pediatric patients under two years of age. SEPTRA is not indicated for
prophylactic or prolonged administration in otitis media at any age.
Acute Exacerbations of Chronic Bronchitis in Adults:
For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus
pneumoniae or Haemophilus influenzae when, in the judgment of the physician, SEPTRA offers some
advantage over the use of a single antimicrobial agent.
Travelers’ Diarrhea in Adults:
For the treatment of travelers’ diarrhea due to susceptible strains of enterotoxigenic E. coli.
Shigellosis:
For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when
antibacterial therapy is indicated.
Pneumocystis Carinii Pneumonia:
For the treatment of documented Pneumocystis carinii pneumonia. For prophylaxis against
Pneumocystis carinii pneumonia in individuals who are immunosuppressed and considered to be at an
increased risk of developing Pneumocystis carinii pneumonia.
CONTRAINDICATIONS
SEPTRA is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides
and in patients with documented megaloblastic anemia due to folate deficiency. SEPTRA is also
contraindicated in pregnant patients at term and in nursing mothers, because sulfonamides pass the
placenta and are excreted in the milk and may cause kernicterus. SEPTRA is contraindicated in pediatric
patients less than 2 months of age.
WARNINGS
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FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES,
ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING
STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT
HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA, AND OTHER BLOOD
DYSCRASIAS.
SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS
TRIMETHOPRIM/SULFAMETHOXAZOLE, SHOULD BE DISCONTINUED AT THE FIRST
APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION. In rare instances, a
skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic
epidermal necrolysis, hepatic necrosis, and serious blood disorder (see PRECAUTIONS).
Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice may be early
indications of serious reactions.
Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the
respiratory tract that have been reported in association with sulfonamide treatment.
The sulfonamides should not be used for the treatment of group A beta-hemolytic streptococcal
infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not
prevent sequelae such as rheumatic fever.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, including SEPTRA, and may range in severity from mild diarrhea to fatal colitis. Treatment with
antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients
who present with diarrhea following antibiotic use.
Careful medical history is necessary since CDAD has been reported to occur over two months after the
administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
PRECAUTIONS
General
Prescribing SEPTRA 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.
SEPTRA should be given with caution to patients with impaired renal or hepatic function, to those with
possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy,
patients with malabsorption syndrome, and patients in malnutrition states), and to those with severe
allergy or bronchial asthma. In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis
may occur. This reaction is frequently dose-related (see CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION).
Use in the Elderly:
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There may be an increased risk of severe adverse reactions in elderly patients, particularly when
complicating conditions exist, e.g., impaired kidney and/or liver function, or concomitant use of other
drugs. Severe skin reactions, or generalized bone marrow suppression (see WARNINGS and
ADVERSE REACTIONS), or a specific decrease in platelets (with or without purpura) are the most
frequently reported severe adverse reactions in elderly patients. In those concurrently receiving certain
diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been
reported. Appropriate dosage adjustments should be made for patients with impaired kidney function
(see DOSAGE AND ADMINISTRATION).
Use in the Treatment of and Prophylaxis for Pneumocystis carinii Pneumonia in Patients with
Acquired Immunodeficiency Syndrome (AIDS):
The incidence of side effects, particularly rash, fever, leukopenia, and elevated aminotransferase
(transaminase) values in AIDS patients who are being treated with SEPTRA for Pneumocystis carinii
pneumonia has been reported to be greatly increased compared with the incidence normally associated
with the use of SEPTRA in non-AIDS patients. The incidence of hyperkalemia and hyponatremia
appears to be increased in AIDS patients receiving SEPTRA. Adverse effects are generally less severe in
patients receiving SEPTRA for prophylaxis. A history of mild intolerance to SEPTRA in AIDS patients
does not appear to predict intolerance of subsequent secondary prophylaxis. However, if a patient
develops skin rash or any sign of adverse reaction, therapy with SEPTRA should be re-evaluated (see
WARNINGS).
The concomitant use of leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of
Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of
treatment failure and morbidity in a placebo-controlled study.
Information for Patients:
Patients should be counseled that antibacterial drugs including SEPTRA should only be used to treat
bacterial infections. They do not treat viral infections (e.g., the common cold). When SEPTRA 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 with SEPTRA
or other antibacterial drugs in the future.
Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and
stone formation.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and
bloody stools (with or without stomach cramps and fever) even as late as two or more months after
having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon
as possible.
Laboratory Tests:
Complete blood counts should be done frequently in patients receiving SEPTRA; if a significant
reduction in the count of any formed blood element is noted, SEPTRA should be discontinued.
Urinalyses with careful microscopic examination and renal function tests should be performed during
therapy, particularly for those patients with impaired renal function.
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Drug Interactions:
In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of
thrombocytopenia with purpura has been reported. In the literature, two cases of hyperkalemia in elderly
patients have been reported after concomitant intake of trimethoprim/sulfamethoxazole and an
angiotensin converting enzyme inhibitor.
It has been reported that SEPTRA may prolong the prothrombin time in patients who are receiving the
anticoagulant warfarin. This interaction should be kept in mind when SEPTRA is given to patients
already on anticoagulant therapy, and the coagulation time should be reassessed.
SEPTRA may inhibit the hepatic metabolism of phenytoin. SEPTRA, given at a common clinical
dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate
by 27%. When administering these drugs concurrently, one should be alert for possible excessive
phenytoin effect.
Sulfonamides can also displace methotrexate from plasma protein binding sites, thus increasing free
methotrexate concentrations.
Drug/Laboratory Test Interactions:
SEPTRA, specifically the trimethoprim component, can interfere with a serum methotrexate assay as
determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate
reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured
by a radioimmunoassay (RIA).
The presence of trimethoprim and sulfamethoxazole may also interfere with the Jaffé alkaline picrate
reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Long-term studies in animals to evaluate carcinogenic potential have not been
conducted with SEPTRA.
Mutagenesis: Bacterial mutagenic studies have not been performed with sulfamethoxazole and
trimethoprim in combination. Trimethoprim was demonstrated to be non-mutagenic in the Ames assay.
In studies at two laboratories, no chromosomal damage was detected in cultured Chinese hamster ovary
cells at concentrations approximately 500 times human plasma levels; at concentrations approximately
1,000 times human plasma levels in these same cells, a low level of chromosomal damage was induced
at one of the laboratories. No chromosomal abnormalities were observed in cultured human leukocytes
at concentrations of trimethoprim up to 20 times human steady-state plasma levels. No chromosomal
effects were detected in peripheral lymphocytes of human subjects receiving 320 mg of trimethoprim in
combination with up to 1,600 mg of sulfamethoxazole per day for as long as 112 weeks.
Impairment of Fertility: No adverse effects on fertility or general reproductive performance were
observed in rats given oral dosages as high as 70 mg/kg/day trimethoprim plus 350 mg/kg/day
sulfamethoxazole.
Pregnancy
Teratogenic Effects:
Pregnancy Category C. In rats, oral doses of 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim
produced teratological effects manifested mainly as cleft palates. The highest dose which did not cause
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cleft palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg trimethoprim when administered
separately. In two studies in rats, no teratogenicity was observed when 512 mg/kg of sulfamethoxazole
was used in combination with 128 mg/kg of trimethoprim. In one study, however, cleft palates were
observed in one litter out of nine when 355 mg/kg of sulfamethoxazole was used in combination with 88
mg/kg of trimethoprim.
In some rabbit studies, an overall increase in fetal loss (dead and resorbed and malformed conceptuses)
was associated with doses of trimethoprim six times the human therapeutic dose.
While there are no large, well-controlled studies on the use of trimethoprim and sulfamethoxazole in
pregnant women, Brumfitt and Pursell, in a retrospective study, reported the outcome of 186
pregnancies during which the mother received either placebo or trimethoprim and sulfamethoxazole.
The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3%
(4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10
children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and
Pursell also found no congenital abnormalities in 35 children whose mothers had received oral
trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.
Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, SEPTRA should
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects:
See CONTRAINDICATIONS section.
Nursing Mothers:
See CONTRAINDICATIONS section.
Pediatric Use:
SEPTRA is not recommended for pediatric patients younger than 2 months of age (see INDICATIONS
AND USAGE and CONTRAINDICATIONS).
Geriatric Use:
Clinical studies of SEPTRA did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects.
There may be an increased risk of severe adverse reactions in elderly patients, particularly when
complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or
concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression (see
WARNINGS and ADVERSE REACTIONS sections), a specific decrease in platelets (with or without
purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients.
In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of
thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with
concomitant Septra therapy, especially in elderly patients. Serum digoxin levels should be monitored.
Hematological changes indicative of folic acid deficiency may occur in elderly patients. These effects
are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with
impaired kidney function and duration of use should be as short as possible to minimize risks of
undesired reactions (see DOSAGE AND ADMINISTRATION section). The trimethoprim component
of Septra may cause hyperkalemia when administered to patients with underlying disorders of potassium
metabolism, with renal insufficiency, or when given concomitantly with drugs known to induce
hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium
6
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is warranted in these patients. Discontinuation of Septra treatment is recommended to help lower
potassium serum levels. Septra Tablets contain 1.8 mg (0.08 mEq) of sodium per tablet. Septra DS
Tablets contain 3.6 mg (0.16 mEq) of sodium per tablet.
Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult
subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of
trimpethoprim was lower in geriatric subjects compared with younger subjects (see CLINICAL
PHARMACOLOGY: Geriatric Pharmacokinetics).
ADVERSE REACTIONS
The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and
allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE
ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE
TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC
EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS,
APLASTIC ANEMIA, OTHER BLOOD DYSCRASIAS, AND HYPERSENSITIVITY OF THE
RESPIRATORY TRACT (SEE WARNINGS).
Hematologic:
Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia,
megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.
Allergic:
Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema
multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch- Schönlein purpura, serum
sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity,
conjunctival and scleral injection, pruritus, urticaria, and rash. In addition, periarteritis nodosa and
systemic lupus erythematosus have been reported.
Gastrointestinal:
Hepatitis, including cholestatic jaundice and hepatic necrosis, elevation of serum transaminase and
bilirubin, pseudo-membranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal
pain, diarrhea, anorexia.
Genitourinary:
Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria
and anuria, and crystalluria.
Metabolic:
Hyperkalemia, hyponatremia.
Neurologic:
Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.
Psychiatric:
Hallucinations, depression, apathy, nervousness.
3
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Endocrine:
The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the
thiazides), and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and
hypoglycemia have occurred rarely in patients receiving sulfonamides.
Musculoskeletal:
Arthralgia and myalgia.
Respiratory System:
Cough, shortness of breath, and pulmonary infiltrates (see WARNINGS).
Miscellaneous:
Weakness, fatigue, insomnia.
OVERDOSAGE
Acute:
The amount of a single dose of SEPTRA that is either associated with symptoms of overdosage or is
likely to be life-threatening has not been reported. Signs and symptoms of overdosage reported with
sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness, and
unconsciousness. Pyrexia, hematuria, and crystalluria may be noted. Blood dyscrasias and jaundice are
potential late manifestations of overdosage. Signs of acute overdosage with trimethoprim include
nausea, vomiting, dizziness, headache, mental depression, confusion, and bone marrow depression.
General principles of treatment include the institution of gastric lavage or emesis; forcing oral fluids;
and the administration of intravenous fluids if urine output is low and renal function is normal.
Acidification of the urine will increase renal elimination of trimethoprim. The patient should be
monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant
blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications.
Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating
trimethoprim and sulfamethoxazole.
Chronic:
Use of SEPTRA at high doses and/or for extended periods of time may cause bone marrow depression
manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow
depression occur, the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been
recommended by some investigators.
DOSAGE AND ADMINISTRATION
Contraindicated in pediatric patients less than 2 months of age.
Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients and Acute Otitis Media
in Pediatric Patients:
Adults: The usual adult dosage in the treatment of urinary tract infections is one SEPTRA DS (double
strength) tablet, two SEPTRA tablets, or four teaspoonfuls (20 mL) SEPTRA Suspension every 12 hours
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for 10 to 14 days. An identical daily dosage is used for 5 days in the treatment of shigellosis.
Pediatric Patients: The recommended dose for pediatric patients with urinary tract infections or acute
otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole per 24 hours, given in two divided
doses every 12 hours for 10 days. An identical daily dosage is used for 5 days in the treatment of
shigellosis. The following table is a guideline for the attainment of this dosage:
For Patients With Impaired Renal Function: When renal function is impaired, a reduced dosage
should be employed using the following table:
Acute Exacerbations of Chronic Bronchitis in Adults:
The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is one SEPTRA DS
(double strength) tablet, two SEPTRA tablets, or four teaspoonfuls (20 mL) SEPTRA Suspension every
12 hours for 14 days.
Travelers’ Diarrhea in Adults:
For the treatment of travelers’ diarrhea, the usual adult dosage is one SEPTRA DS (double strength)
tablet, two SEPTRA tablets, or four teaspoonfuls (20 mL) of SEPTRA Suspension every 12 hours for 5
days.
Pneumocystis Carinii Pneumonia:
Treatment:
Adults and Pediatric Patients: The recommended dosage for treatment of patients with documented
Pneumocystis cariniipneumonia is 15 to 20 mg/kg trimethoprim and 75 to 100 mg/kg sulfamethoxazole
per 24 hours given in equally divided doses every 6 hours for 14 to 21 days. The following table is a
guideline for the upper limit of this dosage:
Pediatric Patients: Two Months of
Age or Older
Weight
Dose – Every 12 Hours
lb kg Teaspoonfuls
Tablets
22 10
1 (5 mL)
44 20
2 (10 mL)
1
66 30
3 (15 mL)
11⁄2
88 40
4 (20 mL)
2 (or 1 DS Tablet)
Creatinine
Recommended
Clearance
Dosage
(mL/min)
Regimen
Above 30 Use Standard Regimen
15-30
1⁄2 the Usual Regimen
Below 15 Use Not Recommended
Weight Dose – Every 6 Hours
lb
kg
Teaspoonfuls
Tablets
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For the lower limit dose (15 mg/kg trimethoprim and 75 mg/kg sulfamethoxazole per 24 hours)
administer 75% of the dose in the above table.
Prophylaxis:
Adults: The recommended dosage for prophylaxis in adults is one SEPTRA DS (double strength) tablet
daily.
Pediatric Patients: For pediatric patients, the recommended dose is 150 mg/m /day trimethoprim with
750 mg/m /day sulfamethoxazole given orally in equally divided doses twice a day, on 3 consecutive
days per week. The total daily dose should not exceed 320 mg trimethoprim and 1,600 mg
sulfamethoxazole. The following table is a guideline for the attainment of this dosage in pediatric
patients:
HOW SUPPLIED
TABLETS (pink, scored, round-shaped) containing 80 mg trimethoprim and 400 mg sulfamethoxazole:
Bottles of 100 (NDC 61570-052-01). Imprint on tablets “M052”.
DS (DOUBLE STRENGTH) TABLETS (pink, scored, oval-shaped) containing 160 mg trimethoprim
and 800 mg sulfamethoxazole: Bottles of 20 (NDC 61570-053-20), 100 (NDC 61570-053-01), 250
(NDC 61570-053-52) and 500 (NDC 61570- 053-05). Imprint on tablets “M053”.
ORAL SUSPENSIONS (pink, cherry-flavored) containing 40 mg trimethoprim and 200 mg
sulfamethoxazole in each teaspoonful (5 mL): Bottle of 1 pint (473 mL) (NDC 61570-050-16) and 100
mL–package of 6 (NDC 61570-050-11); and (purple, grape-flavored) containing 40 mg trimethoprim
and 200 mg sulfamethoxazole in each teaspoonful (5 mL): Bottle of 1 pint (473 mL) (NDC 61570-051-
16).
Tablets should be stored at 15° to 25°C (59° to 77°F) in a dry place and protected from light.
Suspensions should be stored at 15° to 25°C (59° to 77°F) and protected from light.
REFERENCES
18
8
1 (5 mL)
35
16
2 (10 mL)
1
53
24
3 (15 mL)
1 1⁄2
70
32
4 (20 mL)
2 (or 1 DS Tablet)
88
40
5 (25 mL)
2 1⁄2
106
48
6 (30 mL)
3 (or 1 1⁄2 DS Tablets)
141
64
8 (40 mL)
4 (or 2 DS Tablets)
176
80
10 (50 mL)
5 (or 2 1⁄2 DS Tablets)
Body Surface Area Dose–every 12 hours
(m )
Teaspoonfuls
Tablets
0.26
1⁄2 (2.5 mL)
0.53
1 (5 mL)
1⁄2
1.06
2 (10 mL)
1
2
2
2
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1. Kremers P, Duvivier J, Heusghem C. Pharmacokinetic studies of co-trimoxazole in man after
single and repeated doses. J Clin Pharmacol. 1974;14:112-117.
2. Kaplan SA, Weinfeld RE, Abruzzo CW, McFaden K, Jack ML, Weissman L. Pharmacokinetic
profile of trimethoprim- sulfamethoxazole in man. J Infect Dis. 1973;128(suppl):S547-S555.
3. Varoqaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the
elderly. Br J Clin Pharmacol. 1985; 20: 575-581.
4. Antibiotic susceptibility discs; certification procedure. Federal Register. 1972;37:20527-20529.
5. Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic susceptibility testing by standardized
single disk method. Am J Clin Pathol. 1966;45:493-496.
6. Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women.
J Infect Dis. 1973;128 (suppl):S657-S663.
7. Marinella MA. Trimethoprim – induced hyperkalemia: An analysis of reported cases.
Gerontology 45: 209-212, 1999.
Rx Only.
Prescribing Information as of March 2007.
Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620
(A wholly owned subsidiary of King Pharmaceuticals, Inc.)
Manufactured by: King Pharmaceuticals, Inc., Bristol, TN 37620
Septra Tablets (trimethoprim and sulfamethoxazole tablets)
PRODUCT INFO
Product Code
61570-052
Dosage Form
TABLET
Route Of Administration
ORAL
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
trimethoprim (trimethoprim)
Active
80 MILLIGRAM In 1 TABLET
sulfamethoxazole (sulfamethoxazole)
Active
400 MILLIGRAM In 1 TABLET
docusate sodium
Inactive
FD&C Red No. 40
Inactive
magnesium stearate
Inactive
povidone
Inactive
sodium starch glycolate
Inactive
IMPRINT INFORMATION
Characteristic Appearance
Characteristic
Appearance
Color
PINK
Score
2
Shape
ROUND
Symbol
false
Imprint Code
SEPTRA; M052
Coating
false
Size
11mm
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PACKAGING
# NDC
Package Description
Multilevel Packaging
1 61570-052-01
100 TABLET In 1 BOTTLE (1 BOTTLE)
None
Septra DS Tablets (trimethoprim and sulfamethoxazole ds tablets)
PRODUCT INFO
Product Code
61570-053
Dosage Form
TABLET
Route Of Administration
ORAL
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
trimethoprim (trimethoprim)
Active
160 MILLIGRAM In 1 TABLET
sulfamethoxazole (sulfamethoxazole)
Active
800 MILLIGRAM In 1 TABLET
docusate sodium
Inactive
FD&C Red No. 40
Inactive
magnesium stearate
Inactive
povidone
Inactive
sodium starch glycolate
Inactive
IMPRINT INFORMATION
Characteristic Appearance
Characteristic
Appearance
Color
PINK
Score
2
Shape
OVAL
Symbol
false
Imprint Code
SEPTRA DS; M053
Coating
false
Size
20mm
PACKAGING
# NDC
Package Description
Multilevel Packaging
1 61570-053-01
100 TABLET In 1 BOTTLE (1 BOTTLE)
None
2 61570-053-20
20 TABLET In 1 BOTTLE (1 BOTTLE)
None
3 61570-053-52
250 TABLET In 1 BOTTLE (1 BOTTLE)
None
4 61570-053-05
500 TABLET In 1 BOTTLE (1 BOTTLE)
None
Septra Suspension (trimethoprim and sulfamethoxazole suspension)
PRODUCT INFO
Product Code
61570-050
Dosage Form
SUSPENSION
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Route Of Administration
ORAL
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
trimethoprim (trimethoprim)
Active
40 MILLIGRAM In 5 MILLILITER
sulfamethoxazole (sulfamethoxazole)
Active
200 MILLIGRAM In 5 MILLILITER
alcohol
Inactive
methylparaben
Inactive
sodium benzoate
Inactive
carboxymethulcullulose sodium
Inactive
citric acid
Inactive
FD&C Red No. 40
Inactive
Yellow No. 6
Inactive
flavor
Inactive
glycerin
Inactive
microcrystalline cellulose
Inactive
polysorbate 80
Inactive
saccharin sodium
Inactive
sorbitol
Inactive
IMPRINT INFORMATION
Characteristic Appearance
Characteristic
Appearance
Color
PINK (cherry flavored)
Score
Shape
Symbol
Imprint Code
Coating
Size
PACKAGING
# NDC
Package Description
Multilevel Packaging
1 61570-050-16
16 OUNCE In 1 BOTTLE (1 BOTTLE)
None
2 61570-050-11
100 MILLILITER In 1 BOTTLE (6 BOTTLE)
None
Septra Grape Suspension (trimethoprim and sulfamethoxazole grape suspension)
PRODUCT INFO
Product Code
61570-051
Dosage Form
SUSPENSION
Route Of Administration
ORAL
DEA Schedule
INGREDIENTS
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SEPTRA® Tablets SEPTRA® DS (Double Strength) Tablets SEPTRA® Suspension S...
9/5/2007
file://\\Cdsesub1\n17598\S_041\2007-03-23\labeling\spl\septra.xml
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Name (Active Moiety)
Type
Strength
trimethoprim (trimethoprim)
Active
40 MILLIGRAM In 5 MILLILITER
sulfamethoxazole (sulfamethoxazole)
Active
200 MILLIGRAM In 5 MILLILITER
alcohol
Inactive
methylparaben
Inactive
sodium benzoate
Inactive
carboxymethylcellulose sodium
Inactive
citric acid
Inactive
FD&C Red No. 40
Inactive
Blue No. 1
Inactive
flavor
Inactive
glycerin
Inactive
microcrystalline cellulose
Inactive
polysorbate 80
Inactive
saccharin sodium
Inactive
sorbitol
Inactive
IMPRINT INFORMATION
Characteristic Appearance
Characteristic
Appearance
Color
PURPLE (grape flavored)
Score
Shape
Symbol
Imprint Code
Coating
Size
PACKAGING
# NDC
Package Description
Multilevel Packaging
1 61570-051-16
16 OUNCE In 1 BOTTLE (1 BOTTLE)
None
Page 16 of 16
SEPTRA® Tablets SEPTRA® DS (Double Strength) Tablets SEPTRA® Suspension S...
9/5/2007
file://\\Cdsesub1\n17598\S_041\2007-03-23\labeling\spl\septra.xml
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:19.643705
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017376s059,017598s041lbl.pdf', 'application_number': 17598, 'submission_type': 'SUPPL ', 'submission_number': 41}
|
11,046
|
NALFONCI
(fenoprofen calcium capsules, USP)
200 mg
Rx onl y
Cardiovascular Risk
. NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk
may increase with duration of use. Patients with cardiovascular disease or
risk factors for cardiovascular disease may be at greater risk (See
WARINGS) .
. NalfonCI is contraindicated for the treatment of peri-operative pain in
the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS) .
Gastrointestinal Risk
. NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of stomach or intestines,
which can be fatal. These events can occur at any time during use and
wi thout warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal events (see WARINGS) .
DESCRIPTION
NalfonCI (fenoprofen calcium capsules, USP) is a nonsteroidal, anti-
inflammatory, antiarthritic drug. Nalfon capsules contain fenoprofen
calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) of
fenoprofen. The capsules also contain cellulose, gelatin, iron oxides,
silicone, titanium dioxide, and other inactive ingredients. Chemically,
Nalfon is an arylacetic acid derivative.
The structural formula is as follows:
t
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Benzeneacetic acid, a-methyl-3-phenoxy-,
calcium salt dihydrate, (t)-
Nalfon is a white crystalline powder that has the structural formula
C30H26Ca06e2H20 representing a molecular weight of 558.65. At 25°C, it
dissolves to a 15 mg/mL solution in alcohol (95%). It is slightly soluble
in water and insoluble in benzene.
The pKa of Nalfon is a 4.5 at 25°C.
CLINICAL PHACOLOGY
Nalfon is a nonsteroidal, anti-inflammatory, antiarthritic drug that
also possesses analgesic and antipyretic activities. Its exact mode of
action is unknown, but it is thought that prostaglandin synthetase
inhibi tion is involved. Nalfon has been shown to inhibit prostaglandin
synthetase isolated from bovine seminal vesicles. Reproduction studies in
rats have shown Nalfon to be associated with prolonged labor and difficult
parturition when given during late pregnancy. Evidence suggests that this
may be due to decreased uterine contractility resulting from the inhibition
of prostaglandin synthesis. Its action is not mediated through the adrenal
gland.
Fenoprofen shows anti-inflammatory effects in rodents by inhibiting the
development of redness and edema in acute inflammatory conditions and by
reducing soft-tissue swelling and bone damage associated with chronic
inflammation. It exhibits analgesic activity in rodents by inhibiting the
wri thing response caused by the introduction of an irri tant into the
peritoneal cavities of mice and by elevating pain thresholds that are
related to pressure in edematous hindpaws of rats. In rats made febrile by
the subcutaneous administration of brewer's yeast, fenoprofen produces
antipyretic action. These effects are characteristic of nonsteroidal, anti-
inflammatory, antipyretic, analgesic drugs.
The results in humans confirmed the anti-inflammatory and analgesic
actions found in animals. The emergence and degree of erythemic response
were measured in adult male volunteers exposed to ultraviolet irradiation.
The effects of Nalfon, aspirin, and indomethacin were each compared with
those of a placebo. All 3 drugs demonstrated antierythemic activity.
In all patients with rheumatoid arthritis, the anti-inflammatory action
of Nalfon has been evidenced by relief of pain, increase in grip strength,
and reductions in joint swelling, duration of morning stiffness, and
disease activity (as assessed by both the investigator and the patient).
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The anti-inflammatory action of Nalfon has also been evidenced by increased
mobility (i. e., a decrease in the number of joints having limited motion) .
The use of Nalfon in combination with gold salts or corticosteroids has
been studied in patients with rheumatoid arthritis. The studies, however,
were inadequate in demonstrating whether further improvement is obtained by
adding Nalfon to maintenance therapy with gold salts or steroids. Whether
or not Nalfon used in conjunction with partially effective doses of a
corticosteroid has a ~steroid-sparing" effect is unknown.
In patients with osteoarthritis, the anti-inflammatory and analgesic
effects of Nalfon have been demonstrated by reduction in tenderness as a
response to pressure and reductions in night pain, stiffness, swelling, and
overall disease activity (as assessed by both the patient and the
investigator). These effects have also been demonstrated by relief of pain
with motion and at rest and increased range of motion in involved joints.
In patients with rheumatoid arthritis and osteoarthritis, clinical
studies have shown Nalfon to be comparable to aspirin in controlling the
aforementioned measures of disease activity, but mild gastrointestinal
reactions (nausea, dyspepsia) and tinnitus occurred less frequently in
patients treated with Nalfon than in aspirin-treated patients. It is not
known whether Nalfon causes less peptic ulceration than does aspirin.
In patients with pain, the analgesic action of Nalfon has produced a
reduction in pain intensity, an increase in pain relief, improvement in
total analgesia scores, and a sustained analgesic effect.
Under fasting conditions, Nalfon is rapidly absorbed, and peak plasma
levels of 50 ~g/mL are achieved within 2 hours after oral administration of
600 mg doses. Good dose proportionality was observed between 200 mg and 600
mg doses in fasting male volunteers. The plasma half-life is approximately
3 hours. About 90% of a single oral dose is eliminated within 24 hours as
fenoprofen glucuronide and 4 i -hydroxyfenoprofen glucuronide, the major
urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to
albumin.
The concomitant administration of antacid (containing both aluminum and
magnesium hydroxide) does not interfere with absorption of Nalfon.
There is less suppression of collagen-induced platelet aggregation with
single doses of Nalfon than there is with aspirin.
l
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of Nalfon and other
treatment options before deciding to use Nalfon. Use the lowest effective
dose for the shortest duration consistent with individual patient treatment
goal s (see WARINGS) .
Nalfon is indicated:
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. For relief of mild to moderate pain in adults.
. For relief of the signs and symptoms of rheumatoid arthritis.
. For relief of the signs and symptoms of osteoarthritis.
CONTRAINDI
CAT
I ONS
Nalfon is contraindicated in patients who have shown hypersensitivity to
fenoprofen calcium.
Nalfon should not be given to patients who have experienced asthma,
urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been
reported in such patients (see WARINGS - Anaphylactoid Reactions, and
PRECAUTIONS - Preexisting Asthma) .
Nalfon is contraindicated for the treatment of peri-operative pain in
the setting of coronary artery bypass graft (CABG) surgery (see WARINGS) .
Nalfon is contraindicated in patients with a history of significantly
impaired renal function (see WARINGS - Advanced Renal Disease) .
WARINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up
to three years duration have shown an increased risk of serious
cardiovascular (CV) thrombotic events, myocardial infarction, and stroke,
which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may
give a similar risk. Patients with known CV disease or risk factors for CV
disease may be at greater risk. To minimize the potential risk for an
adverse CV event in patients treated with an NSAID, the lowest effective
dose should be used for the shortest duration possible. Physicians and
patients should remain alert for the development of such events, even in
the absence of previous CV symptoms. Patients should be informed about the
signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates
the increased risk of serious CV thrombotic events associated with NSAID
use. The concurrent use of aspirin and an NSAID does increase the risk of
serious GI events (see GI WARINGS) .
Two large, controlled, clinical trials of a COX-2 selective NSAID for
the treatment of pain in the first 10-14 days following CABG surgery found
an increased incidence of myocardial infarction and stroke (see
CONTRAINDICATIONS) .
Hypertension
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NSAIDs, including Nalfon, can lead to onset of new hypertension or
worsening of pre-existing hypertension, either of which may contribute to
the increased incidence of CV events. Patients taking thiazides or loop
diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including Nalfon, should be used with caution in patients with
hypertension. Blood pressure (BP) should be monitored closely during the
initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking
NSAIDs. Nalfon should be used with caution in patients with fluid
retention, compromised cardiac function or heart failure. The possibility
of renal involvement should be considered.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including Nalfon, can cause serious gastrointestinal (GI)
adverse events including inflammation, bleeding, ulceration, and
perforation of the stomach, small intestine, or large intestine, which can
be fatal. These serious adverse events can occur at any time, with or
without warning symptoms, in patients treated with NSAIDs. Only
one in five
patients, who develop a serious upper GI adverse event on NSAID therapy, is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by
NSAIDs occur in approximately 1% of patients treated for 3 -6 months, and in
about 2-4% of patients treated for one year. These trends continue with
longer duration of use, increasing the likelihood of developing a serious
GI event at some time during the course of therapy. However, even short-
term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior
history of ulcer disease or gastrointestinal bleeding. Patients with a
prior history of peptic ulcer disease and/or gastrointestinal bleeding who
use NSAIDs have a greater than 10-fold increased risk for developing a GI
bleed compared to patients with neither of these risk factors. Other
factors that increase the risk for GI bleeding in patients treated with
NSAIDs include concomitant use of oral corticosteroids or anticoagulants,
longer duration of NSAID therapy, smoking, use of alcohol, older age, and
poor general health status. Most spontaneous reports of fatal GI events
are in elderly or debilitated patients and therefore, special care should
be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients
treated with a NSAID, the lowest effective dose should be used for the
shortest possible duration. Patients and physicians should remain alert
for signs and symptoms of GI ulceration and bleeding during NSAID therapy
and promptly initiate additional evaluation and treatment if a serious GI
adverse event is suspected. This should include discontinuation of the
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NSAID until a serious GI adverse event is
patients, alternate therapies that do not
considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary
necrosis and other renal injury. Renal toxicity has also been seen in
patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a
nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may
precipitate overt renal decomposition. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver
dysfunction, those taking diuretics and ACE inhibitors, and the elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding
the use of Nalfon in patients with advanced renal disease. Therefore,
treatment with Nalfon is not recommended in patients with advanced renal
disease. (See CONTRAINDICATIONS) .
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients
without known prior exposure to Nalfon. Nalfon should not be given to
patients with the aspirin triad. This symptom complex typically occurs in
asthmatic patients who experience rhinitis with or without nasal polyps, or
who exhibit severe, potentially fatal bronchospasm after taking aspirin or
other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma) .
Emergency help should be sought in cases where an anaphylactoid reaction
ruled out. For
invol ve NSAIDs
high risk
should be
occurs.
Skin Reactions
NSAIDs, including Nalfon, can cause serious skin adverse events such as
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS)
, and toxic epidermal
necrolysis (TEN), which can be fatal. These serious events may occur
wi thout warning. Patients should be informed about the signs and symptoms
of serious skin manifestations and use of the drug should be discontinued
at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, Nalfon should be avoided
because it may cause premature closure of the ductus arteriosus.
Ocular
Studies to date have not shown changes in the eyes attributable to the
administration of Nalfon. However, adverse ocular effects have been
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observed with other anti-inflammatory drugs. Eye examinations, therefore,
should be performed if visual disturbances occur in patients taking Nalfon.
Central Nervous System
Caution should be exercised by patients whose activities require
alertness if they experience CNS side effects while taking Nalfon.
Hearing
Since the safety of Nalfon has not been established in patients with
impaired hearing, these patients should have periodic tests of auditory
function during prolonged therapy with Nalfon.
PRECAUTIONS
General
Nalfon cannot be expected to substitute for corticosteroids or to treat
corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may
lead to disease exacerbation. Patients on prolonged corticosteroid therapy
should have their therapy tapered slowly if a decision is made to
discontinue corticosteroids.
The pharmacological activity of Nalfon in reducing inflammation may
diminish the utility of these diagnostic signs in detecting complications
of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15%
of patients taking NSAIDs including Nalfon. These laboratory abnormalities
may progress, may remain unchanged, or may be transient with continuing
therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of
patients in clinical trials with NSAIDs. In addition, rare cases of severe
hepatic reactions, including jaundice and fatal fulminant hepatitis, liver
necrosis and hepatic failure, some of them with fatal outcomes have been
reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in
whom an abnormal liver test has occurred, should be evaluated for evidence
of the development of a more severe hepatic reaction while on therapy with
Nalfon. If clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g., eosinophilia, rash,
etc.), Nalfon should be discontinued.
l,
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including Nalfon.
This may be due to fluid retention, occult or gross GI blood loss, or an
incompletely described effect upon erythropoiesis. Patients on long-term
treatment with NSAIDs, including Nalfon, should have their hemoglobin or
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hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs
inhibit platelet aggregation and have been shown to prolong bleeding time
in some patients. Unlike aspirin, their effect on platelet function is
quantitatively less, of shorter duration, and reversible. Patients
receiving Nalfon who may be adversely affected by alterations in platelet
function, such as those with coagulation disorders or patients receiving
anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of
aspirin in patients with aspirin-sensitive asthma has been associated with
severe bronchospasm which can be fatal. Since cross reactivity, including
bronchospasm, between aspirin and other nonsteroidal anti - inflammatory
drugs has been reported in such aspirin-sensitive patients, Nalfon should
not be administered to patients with this form of aspirin sensitivity and
should be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before
initiating therapy with an NSAID and periodically during the course of
ongoing therapy. Patients should also be encouraged to read the NSAID
Medication Guide that accompanies each prescription dispensed.
1. Nalfon, like other NSAIDs, may cause serious CV side effects, such as
MI or stroke, which may result in hospitalization and even death.
Although serious CV events can occur without warning symptoms, patients
should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice
when observing any indicative sign or symptoms. Patients should be
apprised of the importance of this follow-up (see WARINGS,
Cardiovascular Effects) .
2. Nalfon, like other NSAIDs, can cause GI discomfort and, rarely,
serious GI side effects, such as ulcers and bleeding, which may result in
hospitalization and even death. Although serious GI tract ulcerations and
bleeding can occur without warning symptoms, patients should be alert for
the signs and symptoms of ulcerations and bleeding, and should ask for
medical advice when observing any indicative sign or symptoms including
epigastric pain, dyspepsia, melena, and hematemesis. Patients should be
apprised of the importance of this follow-up (see WARINGS,
Gastrointestinal Effects Risk of Ulceration, Bleeding, and
Perforation) .
3. Nalfon, like other NSAIDs, can cause serious skin side effects such
as exfoliative dermatitis, SJS, and TEN, which may result in
hospitalization and even death. Although serious skin reactions may occur
without warning, patients should be alert for the signs and symptoms of
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skin rash and blisters, fever, or other signs of hypersensitivity such as
itching, and should ask for medical advice when observing any indicative
signs or symptoms. Patients should be advised to stop the drug
immediately if they develop any type of rash and contact their physicians
as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained
weight gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice,
right upper quadrant tenderness, and "flu-like" symptoms). If these
occur, patients should be instructed to stop therapy and seek immediate
medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction
(e.g. difficulty breathing, swelling of the face or throat). If these
occur, patients should be instructed to seek immediate emergency help
(see WARINGS) .
7. In late pregnancy, as with other NSAIDs, Nalfon should be avoided
because it may cause premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without
warning symptoms, physicians should monitor for signs or symptoms of GI
bleeding. Patients on long-term treatment with NSAIDs should have their CBC
and a chemistry profile checked periodically. If clinical signs and
symptoms consistent with liver or renal disease develop, systemic
manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver
tests persist or worsen, Nalfon should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of
ACE-inhibitors. This interaction should be given consideration in patients
taking NSAIDs concomitantly with ACE-inhibitors.
Aspirin
The coadministration of aspirin decreases the biologic half -life of
fenoprofen because of an increase in metabolic clearance that results in a
greater amount of hydroxylated fenoprofen in the urine. Al though the
mechanism of interaction between fenoprofen and aspirin is not totally
known, enzyme induction and displacement of fenoprofen from plasma albumin
binding sites are possibil i ties. As with other NSAIDs, concomitant
administration of fenoprofen calcium and aspirin is not generally
recommended because of the potential of increased adverse effects.
Diuretics
i,
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Clinical studies, as well as post marketing observations, have shown
that Nalfon can reduce the natriuretic effect of furosemide and thiazides
in some patients. This response has been attributed to inhibition of renal
prostaglandin synthesis. During concomitant therapy with NSAIDs, the
patient should be observed closely for signs of renal failure (see
WARINGS, Renal Effects), as well as to assure diuretic efficacy.
Li thi um
NSAIDs have produced an elevation of plasma lithium levels and a
reduction in renal lithium clearance. The mean minimum lithium
concentration increased 15% and the renal clearance was decreased by
approximately 20%. These effects have been attributed to inhibition of
renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium
are administered concurrently, subj ects should be observed carefully for
signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate
accumulation in rabbit kidney slices. This may indicate that they could
enhance the toxicity of methotrexate. Caution should be used when NSAIDs
are administered concomitantly with methotrexate.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such
that users of both drugs together have a risk of serious GI bleeding higher
than users of either drug alone.
Phenobarbi tal
Chronic administration of phenobarbital, a known enzyme inducer, may be
associated with a decrease in the plasma half-life of fenoprofen. When
phenobarbital is added to or withdrawn from treatment, dosage adjustment of
Nalfon may be required.
Plasma Protein Binding
In vitro studies have shown that fenoprofen, because of its affinity for
albumin, may displace from their binding sites other drugs that are also
albumin bound, and this may lead to drug interactions. Theoretically,
fenoprofen could likewise be displaced. Patients receiving hydantoins,
sulfonamides, or sulfonylureas should be observed for increased activity of
these drugs and, therefore, signs of toxicity from these drugs.
Drug/Laboratory Test Interactions
Amerlex-M kit assay values of total and free triiodothyronine in
patients receiving Nalfon have been reported as falsely elevated on the
basis of a chemical cross-reaction that directly interferes with the assay.
Thyroid-stimulating hormone, total thyroxine, and thyrotropin-releasing
hormone response are not affected.
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Pregnancy
Teratogenic Effects. Pregnancy Category C.
Reproductive studies conducted in rats and rabbits have not demonstrated
evidence of developmental abnormalities. However, animal reproduction
studies are not always predictive of human response. There are no adequate
and well-controlled studies in pregnant women. Nalfon should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on
the fetal cardiovascular system (closure of ductus arteriosus), use during
pregnancy (particularly late pregnancy) should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit
prostaglandin synthesis, an increased incidence of dystocia, delayed
parturition, and decreased pup survival occurred. The effects of Nalfon on
labor and delivery in pregnant women are unknown.
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 Nalfon, 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 pediatric patients below the age of 18 have
not been established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly
(65 years and older) .
ADVERSE REACTIONS
During clinical studies for rheumatoid arthritis, osteoarthritis, or
mild to moderate pain and studies of pharmacokinetics, complaints were
compiled from a checklist of potential adverse reactions, and the following
data emerged. These encompass observations in 6,786 patients, including 188
observed for at least 52 weeks. For comparison, data are also presented
from complaints received from the 266 patients who received placebo in
these same trials. During short-term studies for analgesia, the incidence
of adverse reactions was markedly lower than that seen in longer-term
studies.
INCIDENCE GREATER THA 1%
Probable Causal Relationship
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Digestive System-During clinical trials with Nalfon, the most common
adverse reactions were gastrointestinal in nature and occurred in 20.8% of
patients
recei ving
Nalfon
as
compared
to
16.9%
of patients
receiving
placebo.
In
descending
order
of
frequency,
these
reactions
included
dyspepsia
(10.3%
Nalfon,
vs.
2.3%,
placebo) ,
nausea
(7.7%
vs.
7.1%) ,
constipation
(7% vs.
1. 5%) ,
vomiting
(2.6% vs.
1. 9%) ,
abdominal pain
(2%
l
vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because
of adverse gastrointestinal reactions in less than 2% of patients during
premarketing studies.
Nervous System -The most frequent adverse neurologic reactions were
headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5%
vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted
less frequently. Nalfon was discontinued in less than 0.5% of patients
because of these side effects during premarketing studies.
Skin and Appendages-Increased sweating (4.6% vs. 0.4%), pruritus (4.2%
vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. Nalfon was discontinued
in about 1% of patients because of an adverse effect related to the skin
during premarketing studies.
Special Senses-Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none),
and decreased hearing (1.6% vs. none) were reported. Nalfon was
discontinued in less than 0.5% of patients because of adverse effects
related to the special senses during premarketing studies.
Cardiovascular-Palpitations (2.5% vs. 0.4%). Nalfon was discontinued in
about 0.5% of patients because of adverse cardiovascular reactions during
premarketing studies.
Miscellaneous-Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%),
peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7%
vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%), and nasopharyngitis
( 1 . 2 % vs. none).
INCIDENCE LESS THA 1%
Probable Causal Relationship
The following adverse reactions, occurring in less than 1% of patients,
were reported in controlled clinical trials and voluntary reports made
since Nalfon was initially marketed. The probability of a causal
relationship exists between Nalfon and these adverse reactions:
Digestive System-Gastritis, peptic ulcer with/without perforation,
gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in
the stool. Increases in alkal ine phosphatase, LDH, SGOT, jaundice, and
cholestatic hepatitis were observed (see PRECAUTIONS) .
Genitourinary Tract-Renal failure, dysuria, cystitis, hematuria,
oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and
papillary necrosis (see WARINGS) .
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypersensitivity-Angioedema (angioneurotic edema) .
Hematologic-Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic
anemia, aplastic anemia, agranulocytosis, and pancytopenia.
MiscellaneouS-Anaphylaxis, urticaria, malaise, insomnia, and tachycardia.
INCIDENCE LESS THA 1%
Causal Relationship Unknown
Other reactions, reported either in clinical trials or spontaneously,
occurred in circumstances in which a causal relationship could not be
established. However, with these rarely reported reactions, the possibility
of such a relationship cannot be excluded. Therefore, these observations
are listed to alert the physician.
Skin and Appendages-Exfoliative dermatitis, toxic epidermal necrolysis,
Stevens-Johnson syndrome, and alopecia.
Digestive System-Aphthous ulcerations of the buccal mucosa, metallic
taste, and pancreatitis.
Cardiovascular-Atrial fibrillation, pulmonary edema,
electrocardiographic changes, and supraventricular tachycardia.
Nervous System-Depression, disorientation, seizures, and trigeminal
neuralgia.
Special Senses-Burning tongue, diplopia, and optic neuritis.
Miscellaneous-Personality change, lymphadenopathy, mastodynia, and
fever.
OVERDOSAGE
Signs and Symptoms-Symptoms of overdose appear within several hours and
generally involve the gastrointestinal and central nervous systems. They
include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache,
ataxia, tinnitus, tremor, drowsiness, and confusion. Hyperpyrexia,
tachycardia, hypotension, and acute renal failure may occur rarely
following overdose. Respiratory depression and metabolic acidosis have also
been reported following overdose with certain NSAIDs.
Treatment-To obtain up-to-date information about the treatment of
overdose, a good resource is your certified Regional Poison Control Center.
Telephone numbers of certified poison control centers are listed in the
Physicians' Desk Reference (PDR). In managing overdosage, consider the
possibility of multiple drug overdoses, interaction among drugs, and
unusual drug kinetics in your patient.
Protect the patient's airway and support ventilation and perfusion.
Meticulously monitor and maintain, within acceptable limits, the patient's
This label may not be the latest approved by FDA.
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vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from
the gastrointestinal tract may be decreased by giving activated charcoal,
which, in many cases, is more effective than emesis or lavage; consider
charcoal instead of or in addition to gastric emptying. Repeated doses of
charcoal over time may hasten elimination of some drugs that have been
absorbed. Safeguard the patient's airway when employing gastric emptying or
charcoal.
Alkalinization of the urine, forced diuresis,
hemodialysis, and charcoal hemoperfusion do not
elimination.
peritoneal dialysis,
enhance systemic drug
DOSAGE AN ADMINISTRATION
Carefully consider the potential benefits and risks of Nalfon and other
treatment options before deciding to use Nalfon. Use the lowest effective
dose for the shortest duration consistent with individual patient treatment
goals (see WARINGS) .
After observing the response to initial therapy with Nalfon, the dose
and frequency should be adjusted to suit an individual patient i s needs.
Analgesia
For the treatment of mild to moderate pain, the recommended dosage is
200 mg given orally every 4 to 6 hours, as needed.
Rheumatoid Arthritis and Osteoarthritis
For the relief of rheumatoid arthritis or osteoarthritis the recommended
dose is 300 to 600 mg given orally, 3 or 4 times a day. The dose should be
tailored to the needs of the patient and may be increased or decreased
depending on the severity of the symptoms. Dosage adjustments may be made
after initiation of drug therapy or during exacerbations of the disease.
Total daily dosage should not exceed 3,200 mg.
Nalfon may be administered with meals or with milk. Although the total
amount absorbed is not affected, peak blood levels are delayed and
diminished.
Patients with rheumatoid arthritis generally seem to require larger
doses of Nalfon than do those with osteoarthritis. The smallest dose that
yields acceptable control should be employed.
Al though improvement may be seen in a few days in many patients, an
additional 2 to 3 weeks may be required to gauge the full benefits of
therapy.
HOW SUPPLIED
i
L
NalfonCI (fenoprofen calcium capsules, USP) are available in:
The 200 mg* capsule is opaque yellow No. 97 cap and opaque white body,
imprinted with ~RX681" on the cap and body.
This label may not be the latest approved by FDA.
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NDC 0884-6600-10
Bottles of 100
* Equivalent to fenoprofen.
Preserve in well-closed containers.
Store at 200 - 250 C (680 - 770 F). (See USP Controlled Room Temperature) .
ATTENTION DISPENSER: Accompanying Medication Guide must be dispensed with
this product.
NalfonCI (nal-fon) capsules
generic name: fenoprofen calcium
Medication Guide
For
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID
medicines. )
What is the most important information I should know about medicines called
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that
can lead to death. This chance increases:
. with longer use of NSAID medicines
. in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery
called a ~coronary artery bypass graft (CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines
at any time during treatment. Ulcers and bleeding:
. can happen without warning symptoms
. may cause death
The chance of a person getting an ulcer or bleeding increases with:
. taking medicines called ~corticosteroids" and ~anticoagulants"
. longer use
. smoking
. drinking alcohol
. older age
. having poor heal th
i
\\
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NSAID medicines should only be used:
. exactly as prescribed
. at the lowest dose possible for your treatment
. for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:
. different types of arthritis
. menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
. if you had an asthma attack, hives, or other allergic reaction with
aspirin or any other NSAID medicine
. for pain right before or after heart bypass surgery
Tell your healthcare provider:
. about all of your medical conditions.
. -about all of the medicines you take. NSAIDs and some other medicines
can interact with each other and cause serious side effects. Keep a list
of your medicines to show to your healthcare provider and pharmacist.
. if you are pregnant. NSAID medicines should not be used by pregnant
women late in their pregnancy.
. if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs) ?
\
Serious side effects include:
. heart attack
. stroke
. high blood pressure
. heart failure from body swelling
(fluid retention)
. kidney problems including kidney
failure
. bleeding and ulcers in the stomach
and intestine
. low red blood cells (anemia)
. life-threatening skin reactions
. life-threatening allergic reactions
ther side effects include
.
stomach pain
.
constipation
.
diarrhea
.
gas
.
heartburn
.
nausea
vomiting
.
dizziness
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
. liver problems including liver failure
. asthma attacks in people who have asthma
Get emergency help right away if you have any of the following symptoms:
. shortness of breath or trouble breathing
. chest pain
. weakness in one part or side of your body
. slurred speech
. swelling of the face or throat
Stop your NSAID medicine and call your healthcare provider right away if
you have any of the following symptoms:
. nausea
. more tired or weaker than usual
. itching
. your skin or eyes look yellow
. stomach pain
. flu-like symptoms
. vomi t blood
· -there is blood in your bowel movement or it is black and sticky like
tar
. unusual weight gain
. skin rash or blisters with fever
. swelling of the arms and legs, hands and feet
These are not all the side effects with NSAID medicines.
healthcare provider or pharmacist for more information
Talk to your
about NSAID
medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
· Aspirin is an NSAID medicine but it does not increase the chance of a
heart attack. Aspirin can cause bleeding in the brain, stomach, and
intestines. Aspirin can also cause ulcers in the stomach and intestines.
· Some of these NSAID medicines are sold in lower doses without a
prescription (over-the-counter). Talk to your healthcare provider before
using over-the-counter NSAIDs for more than 10 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NSAID medicines that need a prescription
Generic
Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataf1¡ m, Voltaren, Arthrotec
(combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon,
Nalfon 200
Flurbiprofen
Ansaid
Ibuprof en
Motrin,
Tab-Profen, Vicoprofen*
( combined
with hydrocodone) ,
Combunox (combined wi th
oxycodone)
Indomethacin
Indocin,
Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic
Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox,
Anaprox DS, EC-Naproxyn,
Naprelan, Naprapac (copackaged
with lansoprazole)
Oxaprozin
Piroxicam
Sul indac
Tolmetin
Daypro
Feldene
Clinoril
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U. S. Food and Drug
Administration.
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC)
NSAIDs, and is usually used for less than 10 days to treat pain. The OTC
NSAID label warns that long term continuous use may increase the risk of
heart attack or stroke.
Manufactured for:
Pedinol Pharmacal Inc.
Farmingdale, NY 11735 USA
By: Ohm Laboratories, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
North Brunswick, NJ 08902 USA
February 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:19.648547
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017604s041lbl.pdf', 'application_number': 17604, 'submission_type': 'SUPPL ', 'submission_number': 41}
|
11,047
|
NALFON®
(fenoprofen calcium capsules, USP)
200 mg and 400 mg
Rx only
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk (See WARNINGS).
• Nalfon® is contraindicated for the treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of stomach or intestines,
which can be fatal. These events can occur at any time during use and
without warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal events (see WARNINGS).
DESCRIPTION
Nalfon® (fenoprofen calcium capsules, USP) is a nonsteroidal, anti-inflammatory,
antiarthritic drug. Nalfon capsules contain fenoprofen calcium as the dihydrate in an
amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol) of fenoprofen.
The 200 mg capsules contain cellulose, gelatin, iron oxides, silicone, titanium
dioxide, and other inactive ingredients. The 400 mg capsules contain gelatin, sodium
lauryl sulfate, iron oxide yellow, FD&C Blue 1, titanium dioxide, FD&C Red 40,
crospovidone, talc, and magnesium stearate. Chemically, Nalfon is an arylacetic acid
derivative.
The structural formula is as follows: Structural Formula
Benzeneacetic acid, α-methyl-3-phenoxy-,
calcium salt dihydrate, (±)-
This label may not be the latest approved by FDA.
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Nalfon is a white crystalline powder that has the structural formula
C30H26CaO6•2H2O representing a molecular weight of 558.65. At 25°C, it dissolves
to a 15 mg/mL solution in alcohol (95%). It is slightly soluble in water and insoluble
in benzene.
The pKa of Nalfon is a 4.5 at 25°C.
CLINICAL PHARMACOLOGY
Nalfon is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses
analgesic and antipyretic activities. Its exact mode of action is unknown, but it is
thought that prostaglandin synthetase inhibition is involved.
Results in humans demonstrate that fenoprofen has both anti-inflammatory and
analgesic actions. The emergence and degree of erythemic response were measured
in adult male volunteers exposed to ultraviolet irradiation. The effects of Nalfon,
aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs
demonstrated antierythemic activity.
In all patients with rheumatoid arthritis, the anti-inflammatory action of Nalfon has
been evidenced by relief of pain, increase in grip strength, and reductions in joint
swelling, duration of morning stiffness, and disease activity (as assessed by both the
investigator and the patient). The anti-inflammatory action of Nalfon has also been
evidenced by increased mobility (i.e., a decrease in the number of joints having
limited motion).
The use of Nalfon in combination with gold salts or corticosteroids has been studied
in patients with rheumatoid arthritis. The studies, however, were inadequate in
demonstrating whether further improvement is obtained by adding Nalfon to
maintenance therapy with gold salts or steroids. Whether or not Nalfon used in
conjunction with partially effective doses of a corticosteroid has a “steroid-sparing”
effect is unknown.
In patients with osteoarthritis, the anti-inflammatory and analgesic effects of Nalfon
have been demonstrated by reduction in tenderness as a response to pressure and
reductions in night pain, stiffness, swelling, and overall disease activity (as assessed
by both the patient and the investigator). These effects have also been demonstrated
by relief of pain with motion and at rest and increased range of motion in involved
joints.
In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown
Nalfon to be comparable to aspirin in controlling the aforementioned measures of
disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus
occurred less frequently in patients treated with Nalfon than in aspirin-treated
patients. It is not known whether Nalfon causes less peptic ulceration than does
aspirin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In patients with pain, the analgesic action of Nalfon has produced a reduction in pain
intensity, an increase in pain relief, improvement in total analgesia scores, and a
sustained analgesic effect.
Under fasting conditions, Nalfon is rapidly absorbed, and peak plasma levels of 50
µg/mL are achieved within 2 hours after oral administration of 600 mg doses. Good
dose proportionality was observed between 200 mg and 600 mg doses in fasting male
volunteers. The plasma half-life is approximately 3 hours. About 90% of a single
oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'
hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen.
Fenoprofen is highly bound (99%) to albumin.
The concomitant administration of antacid (containing both aluminum and
magnesium hydroxide) does not interfere with absorption of Nalfon.
There is less suppression of collagen-induced platelet aggregation with single doses
of Nalfon than there is with aspirin.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of Nalfon and other treatment
options before deciding to use Nalfon. Use the lowest effective dose for the shortest
duration consistent with individual patient treatment goals (see WARNINGS).
Nalfon is indicated:
• For relief of mild to moderate pain in adults.
• For relief of the signs and symptoms of rheumatoid arthritis.
• For relief of the signs and symptoms of osteoarthritis.
CONTRAINDICATIONS
Nalfon is contraindicated in patients who have shown hypersensitivity to fenoprofen
calcium.
Nalfon should not be given to patients who have experienced asthma, urticaria, or
allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal,
anaphylactic-like reactions to NSAIDs have been reported in such patients (see
WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting
Asthma).
Nalfon is contraindicated for the treatment of peri-operative pain in the setting of
coronary artery bypass graft (CABG) surgery (see WARNINGS).
Nalfon is contraindicated in patients with a history of significantly impaired renal
function (see WARNINGS – Advanced Renal Disease).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three
years duration have shown an increased risk of serious cardiovascular (CV)
thrombotic events, myocardial infarction, and stroke, which can be fatal. All
NSAIDs, both COX-2 selective and nonselective, may give a similar risk. Patients
with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an
NSAID, the lowest effective dose should be used for the shortest duration possible.
Physicians and patients should remain alert for the development of such events, even
in the absence of previous CV symptoms. Patients should be informed about the
signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased
risk of serious CV thrombotic events associated with NSAID use. The concurrent use
of aspirin and an NSAID does increase the risk of serious GI events (see GI
WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of
pain in the first 10-14 days following CABG surgery found an increased incidence of
myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including Nalfon, can lead to onset of new hypertension or worsening of
pre-existing hypertension, either of which may contribute to the increased incidence
of CV events. Patients taking thiazides or loop diuretics may have impaired response
to these therapies when taking NSAIDs. NSAIDs, including Nalfon, should be used
with caution in patients with hypertension. Blood pressure (BP) should be monitored
closely during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs.
Nalfon should be used with caution in patients with fluid retention, compromised
cardiac function or heart failure. The possibility of renal involvement should be
considered.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including Nalfon, can cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach, small
intestine, or large intestine, which can be fatal. These serious adverse events can
occur at any time, with or without warning symptoms, in patients treated with
NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation
caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and
in about 2-4% of patients treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI event at some
time during the course of therapy. However, even short-term therapy is not without
risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of
ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer
disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold
increased risk for developing a GI bleed compared to patients with neither of these
risk factors. Other factors that increase the risk for GI bleeding in patients treated
with NSAIDs include concomitant use of oral corticosteroids or anticoagulants,
longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and therefore, special care should be taken in treating this
population.
To minimize the potential risk for an adverse GI event in patients treated with a
NSAID, the lowest effective dose should be used for the shortest possible duration.
Patients and physicians should remain alert for signs and symptoms of GI ulceration
and bleeding during NSAID therapy and promptly initiate additional evaluation and
treatment if a serious GI adverse event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high
risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and
other renal injury. Renal toxicity has also been seen in patients in whom renal
prostaglandins have a compensatory role in the maintenance of renal perfusion. In
these patients, administration of a nonsteroidal anti-inflammatory drug may cause a
dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood
flow, which may precipitate overt renal decomposition. Patients at greatest risk of
this reaction are those with impaired renal function, heart failure, liver dysfunction,
those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of
NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of
Nalfon in patients with advanced renal disease. Therefore, treatment with Nalfon is
not recommended in patients with advanced renal disease. (See
CONTRAINDICATIONS).
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known
prior exposure to Nalfon. Nalfon should not be given to patients with the aspirin
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
triad. This symptom complex typically occurs in asthmatic patients who experience
rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal
bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS
and PRECAUTIONS - Preexisting Asthma). Emergency help should be sought in
cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including Nalfon, can cause serious skin adverse events such as exfoliative
dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN),
which can be fatal. These serious events may occur without warning. Patients should
be informed about the signs and symptoms of serious skin manifestations and use of
the drug should be discontinued at the first appearance of skin rash or any other sign
of hypersensitivity.
Pregnancy
Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by
pregnant women as premature closure of the ductus arteriosus in the fetus may occur.
Ocular
Studies to date have not shown changes in the eyes attributable to the administration
of Nalfon. However, adverse ocular effects have been observed with other anti
inflammatory drugs. Eye examinations, therefore, should be performed if visual
disturbances occur in patients taking Nalfon.
Central Nervous System
Caution should be exercised by patients whose activities require alertness if they
experience CNS side effects while taking Nalfon.
Hearing
Since the safety of Nalfon has not been established in patients with impaired hearing,
these patients should have periodic tests of auditory function during prolonged
therapy with Nalfon.
PRECAUTIONS
General
Nalfon cannot be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease
exacerbation. Patients on prolonged corticosteroid therapy should have their therapy
tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of Nalfon in reducing inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious,
painful conditions.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients
taking NSAIDs including Nalfon. These laboratory abnormalities may progress, may
remain unchanged, or may be transient with continuing therapy. Notable elevations
of ALT or AST (approximately three or more times the upper limit of normal) have
been reported in approximately 1% of patients in clinical trials with NSAIDs. In
addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant
hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have
been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an
abnormal liver test has occurred, should be evaluated for evidence of the development
of a more severe hepatic reaction while on therapy with Nalfon. If clinical signs and
symptoms consistent with liver disease develop, or if systemic manifestations occur
(e.g., eosinophilia, rash, etc.), Nalfon should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including Nalfon. This may
be due to fluid retention, occult or gross GI blood loss, or an incompletely described
effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including
Nalfon, should have their hemoglobin or hematocrit checked if they exhibit any signs
or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to
prolong bleeding time in some patients. Unlike aspirin, their effect on platelet
function is quantitatively less, of shorter duration, and reversible. Patients receiving
Nalfon who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be
carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients
with aspirin-sensitive asthma has been associated with severe bronchospasm which
can be fatal. Since cross reactivity, including bronchospasm, between aspirin and
other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive
patients, Nalfon should not be administered to patients with this form of aspirin
sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing therapy.
Patients should also be encouraged to read the NSAID Medication Guide that
accompanies each prescription dispensed.
1. Nalfon, like other NSAIDs, may cause serious CV side effects, such as MI or
stroke, which may result in hospitalization and even death. Although serious CV
events can occur without warning symptoms, patients should be alert for the signs
and symptoms of chest pain, shortness of breath, weakness, slurring of speech,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
and should ask for medical advice when observing any indicative sign or
symptoms. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Cardiovascular Effects).
2. Nalfon, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side
effects, such as ulcers and bleeding, which may result in hospitalization and even
death. Although serious GI tract ulcerations and bleeding can occur without
warning symptoms, patients should be alert for the signs and symptoms of
ulcerations and bleeding, and should ask for medical advice when observing any
indicative sign or symptoms including epigastric pain, dyspepsia, melena, and
hematemesis. Patients should be apprised of the importance of this follow-up (see
WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
Perforation).
3. Nalfon, like other NSAIDs, can cause serious skin side effects such as exfoliative
dermatitis, SJS, and TEN, which may result in hospitalization and even death.
Although serious skin reactions may occur without warning, patients should be
alert for the signs and symptoms of skin rash and blisters, fever, or other signs of
hypersensitivity such as itching, and should ask for medical advice when
observing any indicative signs or symptoms. Patients should be advised to stop
the drug immediately if they develop any type of rash and contact their physicians
as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or
edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity
(e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness,
and "flu-like" symptoms). If these occur, patients should be instructed to stop
therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g.
difficulty breathing, swelling of the face or throat). If these occur, patients should
be instructed to seek immediate emergency help (see WARNINGS).
7. Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by
pregnant women as premature closure of the ductus arteriosus in the fetus may
occur.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients
on long-term treatment with NSAIDs should have their CBC and a chemistry profile
checked periodically. If clinical signs and symptoms consistent with liver or renal
disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if
abnormal liver tests persist or worsen, Nalfon should be discontinued.
Drug Interactions
ACE-inhibitors
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs
concomitantly with ACE-inhibitors.
Aspirin
The coadministration of aspirin decreases the biologic half-life of fenoprofen because
of an increase in metabolic clearance that results in a greater amount of hydroxylated
fenoprofen in the urine. Although the mechanism of interaction between fenoprofen
and aspirin is not totally known, enzyme induction and displacement of fenoprofen
from plasma albumin binding sites are possibilities. As with other NSAIDs,
concomitant administration of fenoprofen calcium and aspirin is not generally
recommended because of the potential of increased adverse effects.
Diuretics
Clinical studies, as well as post marketing observations, have shown that Nalfon can
reduce the natriuretic effect of furosemide and thiazides in some patients. This
response has been attributed to inhibition of renal prostaglandin synthesis. During
concomitant therapy with NSAIDs, the patient should be observed closely for signs of
renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal
lithium clearance. The mean minimum lithium concentration increased 15% and the
renal clearance was decreased by approximately 20%. These effects have been
attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when
NSAIDs and lithium are administered concurrently, subjects should be observed
carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of
methotrexate. Caution should be used when NSAIDs are administered concomitantly
with methotrexate.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of
both drugs together have a risk of serious GI bleeding higher than users of either drug
alone.
Phenobarbital
Chronic administration of phenobarbital, a known enzyme inducer, may be associated
with a decrease in the plasma half-life of fenoprofen. When phenobarbital is added to
or withdrawn from treatment, dosage adjustment of Nalfon may be required.
Plasma Protein Binding
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In vitro studies have shown that fenoprofen, because of its affinity for albumin, may
displace from their binding sites other drugs that are also albumin bound, and this
may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced.
Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for
increased activity of these drugs and, therefore, signs of toxicity from these drugs.
Drug/Laboratory Test Interactions
Amerlex-M kit assay values of total and free triiodothyronine in patients receiving
Nalfon have been reported as falsely elevated on the basis of a chemical cross-
reaction that directly interferes with the assay. Thyroid-stimulating hormone, total
thyroxine, and thyrotropin-releasing hormone response are not affected.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term studies in animals have not been conducted to evaluate the carcinogenic
potential of fenoprofen. Studies have not been conducted to determine the effect of
fenoprofen on mutagenicity or fertility.
Pregnancy
Teratogenic Effects. Pregnancy Category C Prior to 30-Weeks Gestation; Category
D starting at 30-Weeks Gestation.
Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by
pregnant women as premature closure of the ductus arteriosus in the fetus may occur.
Nalfon can cause fetal harm when administered to a pregnant woman starting at 30
weeks gestation. If this drug is used during this time period in pregnancy, the patient
should be apprised of the potential hazard to a fetus. There are no adequate and well-
controlled studies in pregnant women. Prior to 30-weeks gestation, Nalfon should be
used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of
developmental abnormalities when given daily oral doses of 50 or 100 mg/kg
fenoprofen calcium, respectively (0.15 and 0.6 times the maximum human daily dose
of 3200 mg based on body surface area comparisons). However, animal reproduction
studies are not always predictive of human response.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
cardiovascular system (closure of ductus arteriosus), use during pregnancy
(particularly late pregnancy) should be avoided.
Labor and Delivery
The effects of Nalfon on labor and delivery in pregnant women are unknown. In rat
studies, maternal exposure to NSAIDs, as with other drugs known to inhibit
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and
decreased pup survival.
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 Nalfon, 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 pediatric patients below the age of 18 have not been
established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years
and older).
ADVERSE REACTIONS
During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate
pain and studies of pharmacokinetics, complaints were compiled from a checklist of
potential adverse reactions, and the following data emerged. These encompass
observations in 6,786 patients, including 188 observed for at least 52 weeks. For
comparison, data are also presented from complaints received from the 266 patients
who received placebo in these same trials. During short-term studies for analgesia,
the incidence of adverse reactions was markedly lower than that seen in longer-term
studies.
Adverse Drug Reactions Reported in ≥1% of Patients During Clinical Trials
Digestive System—During clinical trials with Nalfon, the most common adverse
reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving
Nalfon as compared to 16.9% of patients receiving placebo. In descending order of
frequency, these reactions included dyspepsia (10.3% Nalfon, vs. 2.3%, placebo),
nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%),
abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was
discontinued because of adverse gastrointestinal reactions in less than 2% of patients
during premarketing studies.
Nervous System —The most frequent adverse neurologic reactions were headache
(8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor
(2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Nalfon
was discontinued in less than 0.5% of patients because of these side effects during
premarketing studies.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Skin and Appendages—Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs.
0.8%), and rash (3.7% vs. 0.4%) were reported. Nalfon was discontinued in about
1% of patients because of an adverse effect related to the skin during premarketing
studies.
Special Senses—Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and
decreased hearing (1.6% vs. none) were reported. Nalfon was discontinued in less
than 0.5% of patients because of adverse effects related to the special senses during
premarketing studies.
Cardiovascular—Palpitations (2.5% vs. 0.4%). Nalfon was discontinued in about
0.5% of patients because of adverse cardiovascular reactions during premarketing
studies.
Miscellaneous—Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral
edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper
respiratory infection (1.5% vs. 5.6%), and nasopharyngitis (1.2% vs. none).
Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials
Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal
hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool. Increases in
alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous
ulcerations of the buccal mucosa, metallic taste, and pancreatitis (see
PRECAUTIONS).
Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes,
and supraventricular tachycardia.
Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia,
anuria, interstitial nephritis, nephrosis, and papillary necrosis (see WARNINGS).
Hypersensitivity—Angioedema (angioneurotic edema).
Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia,
aplastic anemia, agranulocytosis, and pancytopenia.
Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia.
Special Senses—Burning tongue, diplopia, and optic neuritis.
Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-
Johnson syndrome, and alopecia.
Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality
change, lymphadenopathy, mastodynia, and fever.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Signs and Symptoms—Symptoms of overdose appear within several hours and
generally involve the gastrointestinal and central nervous systems. They include
dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus,
tremor, drowsiness, and confusion. Hyperpyrexia, tachycardia, hypotension, and
acute renal failure may occur rarely following overdose. Respiratory depression and
metabolic acidosis have also been reported following overdose with certain NSAIDs.
Treatment—To obtain up-to-date information about the treatment of overdose, a good
resource is your certified Regional Poison Control Center. Telephone numbers of
certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
In managing overdosage, consider the possibility of multiple drug overdoses,
interaction among drugs, and unusual drug kinetics in your patient.
Protect the patient’s airway and support ventilation and perfusion. Meticulously
monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases,
serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be
decreased by giving activated charcoal, which, in many cases, is more effective than
lavage; consider charcoal instead of or in addition to gastric emptying. Repeated
doses of charcoal over time may hasten elimination of some drugs that have been
absorbed. Safeguard the patient’s airway when employing gastric emptying or
charcoal.
Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis, and
charcoal hemoperfusion do not enhance systemic drug elimination.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of Nalfon and other treatment
options before deciding to use Nalfon. Use the lowest effective dose for the shortest
duration consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with Nalfon, the dose and frequency
should be adjusted to suit an individual patient's needs.
Analgesia
For the treatment of mild to moderate pain, the recommended dosage is 200 mg given
orally every 4 to 6 hours, as needed.
Rheumatoid Arthritis and Osteoarthritis
For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the
recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose
should be tailored to the needs of the patient and may be increased or decreased
depending on the severity of the symptoms. Dosage adjustments may be made after
initiation of drug therapy or during exacerbations of the disease. Total daily dosage
should not exceed 3,200 mg.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nalfon may be administered with meals or with milk. Although the total amount
absorbed is not affected, peak blood levels are delayed and diminished.
Patients with rheumatoid arthritis generally seem to require larger doses of Nalfon
than do those with osteoarthritis. The smallest dose that yields acceptable control
should be employed.
Although improvement may be seen in a few days in many patients, an additional 2 to
3 weeks may be required to gauge the full benefits of therapy.
HOW SUPPLIED
Nalfon® (fenoprofen calcium capsules, USP) are available in:
The 200 mg* capsule is opaque yellow No. 97 cap and opaque white body, imprinted
with “RX681” on the cap and body.
NDC 0884-6600-10
Bottles of 100
The 400 mg* capsule is opaque green cap and opaque blue body, imprinted with
“NALFON 400 mg” on the cap and “EP 123” on the body.
NDC 0884-7308-09
Bottles of 90
NDC 0884-7308-50
Bottles of 500
* Equivalent to fenoprofen.
Preserve in well-closed containers.
Store at 20° - 25° C (68° - 77° F). (See USP Controlled Room Temperature).
ATTENTION DISPENSER: Accompanying Medication Guide must be
dispensed with this product.
Nalfon® (nal-fon) capsules
generic name: fenoprofen calcium
Medication Guide
For
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can
lead to death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NSAID medicines should never be used right before or after a heart surgery
called a “coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at
any time during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any
other NSAID medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can
interact with each other and cause serious side effects. Keep a list of your
medicines to show to your healthcare provider and pharmacist.
• if you are pregnant, NSAID medicines should not be used past 30-weeks of
pregnancy.
• if you are breastfeeding, talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)?
Serious side effects include:
Other side effects include:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• heart attack
• stomach pain
• stroke
• constipation
• high blood pressure
• diarrhea
• heart failure from body swelling (fluid retention)
• gas
• kidney problems including kidney failure
• heartburn
• bleeding and ulcers in the stomach and intestine
• nausea
• low red blood cells (anemia)
• vomiting
• life-threatening skin reactions
• dizziness
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat
Stop your NSAID medicine and call your healthcare provider right away if you
have any of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare
provider or pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack.
Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also
cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription
(over-the-counter). Talk to your healthcare provider before using over-the-counter
NSAIDs for more than 10 days.
NSAID medicines that need a prescription
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec
(combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined
With hydrocodone), Combunox (combined
with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon,
Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,
Naprelan, Naprapac (copackaged with
lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC)
NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID
label warns that long term continuous use may increase the risk of heart attack or
stroke.
Manufactured for:
Pedinol Pharmacal Inc.
Farmingdale, NY 11735 USA
By: Ohm Laboratories, Inc.
North Brunswick, NJ 08902 USA
And
By: Emcure Pharmaceuticals USA, Inc.
East Brunswick, NJ 08816 USA
July 2009
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/2009/017604s043lbl.pdf', 'application_number': 17604, 'submission_type': 'SUPPL ', 'submission_number': 43}
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4
HEPARIN SODIUM
5
INJECTION, USP
6
Rx only
7
8
DERIVED FROM PORCINE INTESTINAL MUCOSA.
9
Available as: Preservative Free or Contains Benzyl Alcohol or Parabens
10
DESCRIPTION:
11
Heparin is a heterogeneous group of straight-chain anionic mucopolysaccharides, called
12
glycosaminoglycans, having anticoagulant properties. Although others may be present, the
13
main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2
14
sulfamino-α-D-glucose 6-sulfate, (3) ß-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D
15
glucose and (5) α-L-iduronic acid. These sugars are present in decreasing amounts, usually
16
in the order (2)> (1)> (4)> (3)> (5), and are joined by glycosidic linkages, forming polymers
17
of varying sizes. Heparin is strongly acidic because of its content of covalently linked sulfate
18
and carboxylic acid groups. In heparin sodium, the acidic protons of the sulfate units are
19
partially replaced by sodium ions.
20
Heparin Sodium Injection, USP is a sterile solution of heparin sodium derived from
21
porcine intestinal mucosa, standardized for anticoagulant activity, in water for injection. It is
22
to be administered by intravenous or deep subcutaneous routes. The potency is determined
23
by a biological assay using a USP reference standard based on units of heparin activity per
24
milligram.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Structure of Heparin Sodium (representative subunits): structural formula
2
3
4
Heparin Sodium Injection, USP (porcine), preservative free, is available as follows:
5
Each mL of the 1,000 Units per mL preparation contains: 1,000 USP Heparin Units
6
(porcine); 9 mg sodium chloride; Water for Injection q.s. Made isotonic with sodium
7
chloride. Hydrochloric acid and/or sodium hydroxide may have been added for pH
8
adjustment (5.0-7.5).
9
Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available
10
as follows:
11
Each mL of the 5,000 Units per mL preparation contains: 5,000 USP Heparin Units
12
(porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for
13
Injection q.s. Hydrochloric acid and/or sodium hydroxide may have been added for pH
14
adjustment (5.0-7.5).
15
Heparin Sodium Injection, USP (porcine), preserved with parabens, is available as
16
follows:
17
Each mL of the 1,000 Units per mL preparation contains: 1,000 USP Heparin Units
18
(porcine); 9 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for
19
Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium
20
hydroxide may have been added for pH adjustment (5.0-7.5).
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Each mL of the 5,000 Units per mL preparation contains: 5,000 USP Heparin Units
2
(porcine); 5 mg sodium chloride; 1.5 mg methylparaben; 0.15 mg propylparaben; Water for
3
Injection q.s. Made isotonic with sodium chloride. Hydrochloric acid and/or sodium
4
hydroxide may have been added for pH adjustment (5.0-7.5).
5
Each mL of the 10,000 Units per mL preparation contains: 10,000 USP Heparin Units
6
(porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s.
7
Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0
8
7.5).
9
Each mL of the 20,000 Units per mL preparation contains: 20,000 USP Heparin Units
10
(porcine); 1.5 mg methylparaben; 0.15 mg propylparaben; Water for Injection q.s.
11
Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0
12
7.5).
13
CLINICAL PHARMACOLOGY:
14
Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots
15
both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation system.
16
Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit
17
thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin
18
to thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit
19
further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to
20
fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation
21
of the fibrin stabilizing factor.
22
Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full
23
therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
heparin.
2
Patients over 60 years of age, following similar doses of heparin, may have higher
3
plasma levels of heparin and longer activated partial thromboplastin times (APTTs)
4
compared with patients under 60 years of age.
5
Peak plasma levels of heparin are achieved two to four hours following subcutaneous
6
administration, although there are considerable individual variations. Loglinear plots of
7
heparin plasma concentrations with time, for a wide range of dose levels, are linear, which
8
suggests the absence of zero order processes. Liver and the reticuloendothelial system are
9
the sites of biotransformation. The biphasic elimination curve, a rapidly declining alpha
10
phase (t1⁄2 = 10 minutes) and after the age of 40 a slower beta phase, indicates uptake in
11
organs. The absence of a relationship between anticoagulant half-life and concentration half
12
life may reflect factors such as protein binding of heparin.
13
Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.
14
INDICATIONS AND USAGE:
15
Heparin Sodium Injection is indicated for:
16
Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its
17
extension;
18
Low-dose regimen for prevention of postoperative deep venous thrombosis and
19
pulmonary embolism in patients undergoing major abdominothoracic surgery or who, for
20
other reasons, are at risk of developing thromboembolic disease (see DOSAGE AND
21
ADMINISTRATION);
22
Prophylaxis and treatment of pulmonary embolism;
23
Atrial fibrillation with embolization;
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Diagnosis and treatment of acute and chronic consumptive coagulopathies
2
(disseminated intravascular coagulation);
3
Prevention of clotting in arterial and cardiac surgery;
4
Prophylaxis and treatment of peripheral arterial embolism.
5
Heparin may also be employed as an anticoagulant in blood transfusions,
6
extracorporeal circulation, and dialysis procedures and in blood samples for laboratory
7
purposes.
8
CONTRAINDICATIONS:
9
Heparin sodium should NOT be used in patients with the following conditions:
10
Severe thrombocytopenia;
11
When suitable blood coagulation tests, e.g., the whole blood clotting time, partial
12
thromboplastin time, etc., cannot be performed at appropriate intervals (this contraindication
13
refers to full-dose heparin; there is usually no need to monitor coagulation parameters in
14
patients receiving low-dose heparin);
15
An uncontrollable active bleeding state (see WARNINGS), except when this is due
16
to disseminated intravascular coagulation.
17
Pregnancy, Nursing Mothers, and Pediatric Use
18
Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol
19
to neonates, infants, pregnant women, or nursing mothers (see PRECAUTIONS,
20
Pregnancy, Nursing Mothers, and Pediatric Use). Benzyl alcohol has been associated with
21
serious adverse events and death, particularly in pediatric patients. Heparin Sodium
22
Injection, USP (porcine), preservative free, when indicated, should be used in these
23
populations.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
WARNINGS:
2
Heparin is not intended for intramuscular use.
3
Fatal Medication Errors
4
Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium
5
Injection is supplied in vials containing various strengths of heparin, including vials that
6
contain a highly concentrated solution of 10,000 units in 1 mL. Fatal hemorrhages have
7
occurred in pediatric patients due to medication errors in which 1 mL Heparin Sodium
8
Injection vials were confused with 1 mL “catheter lock flush” vials. Carefully examine all
9
Heparin Sodium Injection vials to confirm the correct vial choice prior to administration of
10
the drug.
11
Hypersensitivity
12
Patients with documented hypersensitivity to heparin should be given the drug only in clearly
13
life-threatening situations (see ADVERSE REACTIONS, Hypersensitivity).
14
Hemorrhage
15
Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained fall
16
in hematocrit, fall in blood pressure or any other unexplained symptom should lead to serious
17
consideration of a hemorrhagic event.
18
Heparin sodium should be used with extreme caution in disease states in which there
19
is increased danger of hemorrhage. Some of the conditions in which increased danger of
20
hemorrhage exists are:
21
22
Cardiovascular—Subacute bacterial endocarditis, severe hypertension.
23
24
Surgical—During and immediately following (a) spinal tap or spinal anesthesia or (b) major
6
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
7
1
surgery, especially involving the brain, spinal cord, or eye.
2
3
Hematologic—Conditions associated with increased bleeding tendencies, such as
4
hemophilia, thrombocytopenia and some vascular purpuras.
6
Gastrointestinal—Ulcerative lesions and continuous tube drainage of the stomach or small
7
intestine.
8
9
Other—Menstruation, liver disease with impaired hemostasis.
Coagulation Testing
11
When heparin sodium is administered in therapeutic amounts, its dosage should be regulated
12
by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if
13
hemorrhage occurs, heparin sodium should be promptly discontinued (see
14
OVERDOSAGE).
Thrombocytopenia
16
Thrombocytopenia has been reported to occur in patients receiving heparin with a reported
17
incidence of up to 30%. Platelet counts should be obtained at baseline and periodically
18
during heparin administration. Mild thrombocytopenia (count greater than 100,000/mm3)
19
may remain stable or reverse even if heparin is continued. However, thrombocytopenia of
any degree should be monitored closely. If the count falls below 100,000/mm3 or if recurrent
21
thrombosis develops (see Heparin-induced Thrombocytopenia and Heparin-induced
22
Thrombocytopenia and Thrombosis), the heparin product should be discontinued, and, if
23
necessary, an alternative anticoagulant administered.
24
Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and
Thrombosis (HITT)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Heparin-induced Thrombocytopenia (HIT) is a serious antibody-mediated reaction
2
resulting from irreversible aggregation of platelets. HIT may progress to the
3
development of venous and arterial thromboses, a condition referred to as Heparin-
4
induced Thrombocytopenia and Thrombosis (HITT). Thrombotic events may also be
5
the initial presentation for HITT. These serious thromboembolic events include deep
6
vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke,
7
myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis,
8
gangrene of the extremities that may lead to amputation, and possibly death.
9
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls
10
below 100,000/mm 3 or if recurrent thrombosis develops, the heparin product should be
11
promptly discontinued and alternative anticoagulants considered, if patients require
12
continued anticoagulation.
13
Delayed Onset of HIT and HITT
14
Heparin-induced Thrombocytopenia and Heparin-induced Thrombocytopenia and
15
Thrombosis can occur up to several weeks after the discontinuation of heparin therapy.
16
Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin
17
should be evaluated for HIT and HITT.
18
PRECAUTIONS:
19
General
20
Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced
21
Thrombocytopenia and Thrombosis (HITT)
22
See WARNINGS.
23
Heparin Resistance—Increased resistance to heparin is frequently encountered in fever,
8
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
9
1
thrombosis, thrombophlebitis, infections with thrombosing tendencies, myocardial infarction,
2
cancer and in postsurgical patients.
3
4
Increased Risk to Older Patients, Especially Women—A higher incidence of bleeding has
been reported in patients, particularly women, over 60 years of age.
6
Laboratory Tests
7
Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended
8
during the entire course of heparin therapy, regardless of the route of administration (see
9
DOSAGE AND ADMINISTRATION).
Drug Interactions
11
Oral Anticoagulants—Heparin sodium may prolong the one-stage prothrombin time.
12
Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at
13
least five hours after the last intravenous dose or 24 hours after the last subcutaneous dose
14
should elapse before blood is drawn, if a valid prothrombin time is to be obtained.
16
Platelet Inhibitors—Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen,
17
indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-
18
aggregation reactions (the main hemostatic defense of heparinized patients) may induce
19
bleeding and should be used with caution in patients receiving heparin sodium.
21
Other Interactions—Digitalis, tetracyclines, nicotine or antihistamines may partially
22
counteract the anticoagulant action of heparin sodium. Intravenous nitroglycerin
23
administered to heparinized patients may result in a decrease of the partial thromboplastin
24
time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful
monitoring of partial thromboplastin time and adjustment of heparin dosage are
26
recommended during coadministration of heparin and intravenous nitroglycerin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Drug/Laboratory Tests Interactions
2
Hyperaminotransferasemia—Significant elevations of aminotransferase (SGOT [S-AST] and
3
SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy subjects)
4
who have received heparin. Since aminotransferase determinations are important in the
5
differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, increases
6
that might be caused by drugs (like heparin) should be interpreted with caution.
7
Carcinogenesis, Mutagenesis, Impairment of Fertility
8
No long-term studies in animals have been performed to evaluate carcinogenic potential of
9
heparin. Also, no reproduction studies in animals have been performed concerning
10
mutagenesis or impairment of fertility.
11
Pregnancy
12
Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol,
13
to pregnant women (see CONTRAINDICATIONS, Pregnancy, Nursing Mothers, and
14
Pediatric Use and PRECAUTIONS, Pediatric Use). Heparin Sodium Injection, USP
15
(porcine), preservative free, when indicated, should be administered to pregnant women.
16
17
Teratogenic Effects: Pregnancy Category C—
18
Animal reproduction studies have not been conducted with heparin sodium. It is also not
19
known whether heparin sodium can cause fetal harm when administered to a pregnant
20
woman or can affect reproduction capacity. Heparin sodium should be given to a pregnant
21
woman only if clearly needed.
22
23
Nonteratogenic Effects—Heparin does not cross the placental barrier.
24
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Nursing Mothers
Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol,
to nursing mothers (see CONTRAINDICATIONS, Pregnancy, Nursing Mothers, and
Pediatric Use and PRECAUTIONS, Pediatric Use). Heparin Sodium Injection, USP
(porcine), preservative free, when indicated, should be administered to nursing mothers.
Heparin is not excreted in human milk.
Pediatric Use
See DOSAGE AND ADMINISTRATION, Pediatric Use.
Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl
alcohol, to neonates and infants (see CONTRAINDICATIONS, Pregnancy, Nursing
Mothers, and Pediatric Use). Heparin Sodium Injection, USP (porcine), preservative free,
when indicated, should be administered to neonates and infants. Benzyl alcohol has been
associated with serious adverse events and death, particularly in pediatric patients. The
“gasping syndrome,” (characterized by central nervous system depression, metabolic
acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in
the blood and urine) has been associated with benzyl alcohol dosages >99mg/kg/day in
neonates and low-birthweight neonates. Additional symptoms may include gradual
neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin
breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
Although normal therapeutic doses of this product deliver amounts of benzyl alcohol
that are substantially lower than those reported in association with the “gasping syndrome”,
the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature
and low-birthweight infants, as well as patients receiving high dosages, may be more likely
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
1
to develop toxicity. Practitioners administering this and other medications containing benzyl
2
alcohol should consider the combined daily metabolic load of benzyl alcohol from all
3
sources.
4
Geriatric Use
5
A higher incidence of bleeding has been reported in patients over 60 years of age, especially
6
women (see PRECAUTIONS, General). Clinical studies indicate that lower doses of
7
heparin may be indicated in these patients (see CLINICAL PHARMACOLOGY and
8
DOSAGE AND ADMINISTRATION).
9
ADVERSE REACTIONS:
10
Hemorrhage
11
Hemorrhage is the chief complication that may result from heparin therapy (see
12
WARNINGS). An overly prolonged clotting time or minor bleeding during therapy can
13
usually be controlled by withdrawing the drug (see OVERDOSAGE). It should be
14
appreciated that gastrointestinal or urinary tract bleeding during anticoagulant
15
therapy may indicate the presence of an underlying occult lesion. Bleeding can occur at
16
any site but certain specific hemorrhagic complications may be difficult to detect:
17
(a) Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during
18
anticoagulant therapy. Therefore, such treatment should be discontinued in patients who
19
develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of
20
corrective therapy should not depend on laboratory confirmation of the diagnosis, since any
21
delay in an acute situation may result in the patient’s death.
22
(b) Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive
23
age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
may be fatal.
(c) Retroperitoneal hemorrhage.
Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced
Thrombocytopenia and Thrombosis (HITT) and Delayed Onset of HIT and HITT
See WARNINGS.
Local Irritation
Local irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous
(intrafat) injection of heparin sodium. These complications are much more common after
intramuscular use, and such use is not recommended.
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 side of the feet, may occur (see WARNINGS and
PRECAUTIONS).
Certain episodes of painful, ischemic and cyanosed limbs have in the past been
attributed to allergic vasospastic reactions. Whether these are in fact identical to the
thrombocytopenia-associated complications, remains to be determined.
Miscellaneous
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.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT])
2
levels have occurred in a high percentage of patients (and healthy subjects) who have
3
received heparin.
4
OVERDOSAGE:
5
Symptoms
6
Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry stools
7
may be noted as the first sign of bleeding. Easy bruising or petechial formations may
8
precede frank bleeding.
9
Treatment
10
Neutralization of Heparin Effect—When clinical circumstances (bleeding) require reversal of
11
heparinization, protamine sulfate (1% solution) by slow infusion will neutralize heparin
12
sodium. No more than 50 mg should be administered, very slowly, in any 10 minute
13
period. Each mg of protamine sulfate neutralizes approximately 100 USP heparin units. The
14
amount of protamine required decreases over time as heparin is metabolized. Although the
15
metabolism of heparin is complex, it may, for the purpose of choosing a protamine dose, be
16
assumed to have a half-life of about 1/2 hour after intravenous injection.
17
Administration of protamine sulfate can cause severe hypotensive and anaphylactoid
18
reactions. Because fatal reactions often resembling anaphylaxis have been reported, the drug
19
should be given only when resuscitation techniques and treatment of anaphylactoid shock are
20
readily available.
21
For additional information consult the labeling of Protamine Sulfate Injection, USP
22
products.
23
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DOSAGE AND ADMINISTRATION:
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit. Slight
discoloration does not alter potency.
Confirm the choice of the correct Heparin Sodium Injection vial prior to
administration of the drug to a patient (see WARNINGS, Fatal Medication Errors). The
1 mL vial must not be confused with a “catheter lock flush” vial or other 1 mL vial of
inappropriate strength. Confirm that you have selected the correct medication and strength
prior to administration of the drug.
When heparin is added to an infusion solution for continuous intravenous
administration, the container should be inverted at least six times to ensure adequate mixing
and prevent pooling of the heparin in the solution.
Heparin sodium is not effective by oral administration and should be given by
intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e.,
above the iliac crest or abdominal fat layer) injection. The intramuscular route of
administration should be avoided because of the frequent occurrence of hematoma at
the injection site.
The dosage of heparin sodium should be adjusted according to the patient’s
coagulation test results. When heparin is given by continuous intravenous infusion, the
coagulation time should be determined approximately every four hours in the early stages of
treatment. When the drug is administered intermittently by intravenous injection,
coagulation tests should be performed before each injection during the early stages of
treatment and at appropriate intervals thereafter. Dosage is considered adequate when the
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole
blood clotting time is elevated approximately 2.5 to 3 times the control value. After deep
subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on
samples drawn four to six hours after the injection.
Periodic platelet counts, hematocrits and tests for occult blood in stool are
recommended during the entire course of heparin therapy, regardless of the route of
administration.
Converting to Oral Anticoagulant
When an oral anticoagulant of the coumarin or similar type is to be begun in patients already
receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be
determined at a time when heparin activity is too low to affect the prothrombin time. This is
about five hours after the last IV bolus and 24 hours after the last subcutaneous dose. If
continuous IV heparin infusion is used, prothrombin time can usually be measured at any
time.
In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant
should be the usual initial amount and thereafter prothrombin time should be determined at
the usual intervals. To ensure continuous anticoagulation, it is advisable to continue full
heparin therapy for several days after the prothrombin time has reached the therapeutic range.
Heparin therapy may then be discontinued without tapering.
Therapeutic Anticoagulant Effect With Full-Dose Heparin
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:
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
METHOD OF
RECOMMENDED
ADMINISTRATION
FREQUENCY
DOSE (based on
150 lb [68 kg] patient)
Deep Subcutaneous
(Intrafat) Injection
A different site
should be used for
each injection to
prevent the
development of
massive hematoma
Initial Dose
Every
8 hours
or
Every
12 hours
5,000 units by IV
injection, followed by
10,000 to 20,000 units of
a concentrated solution,
subcutaneously
8,000 to 10,000 units of a
concentrated solution
15,000 to 20,000 units of
a concentrated solution
Intermittent
Intravenous
Injection
Initial Dose
Every 4
to 6 hours
Intravenous Infusion
Initial Dose
Continuous
10,000 units, either
undiluted or in 50 to
100 mL of 0.9% Sodium
Chloride Injection, USP
5,000 to 10,000 units,
either undiluted or in 50
to 100 mL of 0.9%
Sodium Chloride
Injection, USP
5,000 units by IV
injection
20,000 to 40,000 units/24
hours in 1,000 mL of
0.9% Sodium Chloride
Injection, USP (or in any
compatible solution) for
infusion
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pediatric Use
Do not administer Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol,
to neonates and infants (see CONTRAINDICATIONS, Pregnancy, Nursing Mothers, and
Pediatric Use and PRECAUTIONS, Pediatric Use). When indicated, Heparin Sodium
Injection, USP (porcine), preservative free should be used in neonates and infants.
Follow recommendations of appropriate pediatric reference texts. In general, the
following dosage schedule may be used as a guideline:
Initial Dose:
50 units/kg (IV, infusion)
Maintenance Dose: 100 units/kg (IV, infusion) every four hours,
or 20,000 units/m2/24 hours continuously
Geriatric Use
Patients over 60 years of age may require lower doses of heparin.
Surgery of the Heart and Blood Vessels
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 of heparin sodium per kilogram of body weight 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.
Low-Dose Prophylaxis of Postoperative Thromboembolism
A number of well-controlled clinical trials have demonstrated that low-dose heparin
prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative
deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and
venography) and of clinical pulmonary embolism. The most widely used dosage has been
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven
days or until the patient is fully ambulatory, whichever is longer. The heparin is given by
deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to
minimize tissue trauma. A concentrated solution of heparin sodium is recommended. Such
prophylaxis should be reserved for patients over the age of 40 who are undergoing major
surgery. Patients with bleeding disorders and those having neurosurgery, spinal anesthesia,
eye surgery or potentially sanguineous operations should be excluded, as well as patients
receiving oral anticoagulants or platelet-active drugs (see WARNINGS). The value of such
prophylaxis in hip surgery has not been established. The possibility of increased bleeding
during surgery or postoperatively should be borne in mind. If such bleeding occurs,
discontinuance of heparin and neutralization with protamine sulfate are advisable. If clinical
evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses
of anticoagulants should be given unless contraindicated. All patients should be screened
prior to heparinization to rule out bleeding disorders, and monitoring should be performed
with appropriate coagulation tests just prior to surgery. Coagulation test values should be
normal or only slightly elevated. There is usually no need for daily monitoring of the effect
of low-dose heparin in patients with normal coagulation parameters.
Extracorporeal Dialysis
Follow equipment manufacturers’ operating directions carefully.
Blood Transfusion
Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent
coagulation. Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9%
Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of
2
whole blood.
3
Laboratory Samples
4
Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is
5
usually employed to prevent coagulation of the sample. Leukocyte counts should be
6
performed on heparinized blood within two hours after addition of the heparin. Heparinized
7
blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or
8
platelet counts.
9
HOW SUPPLIED:
10
Heparin Sodium Injection, USP (porcine), preservative free, is available as follows:
Product
NDC
No.
No.
27602
63323-276-02
1,000 USP Heparin
Units/mL, 2 mL fill in a 2
mL single dose, flip-top
vial, in packages of 25.
11
12
Preservative Free
13
Discard Unused Portion.
14
Do not use if solution is discolored or contains a precipitate.
15
16
Heparin Sodium Injection, USP (porcine) contains benzyl alcohol and is available as
17
follows:
Product
NDC
No.
No.
4710
63323-047-10
5,000 USP Heparin
Units/mL, 10 mL fill in a 10
mL multiple dose, flip-top
vial, in packages of 25.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
Use only if solution is clear and seal intact.
3
4
Heparin Sodium Injection, USP (porcine) contains parabens and is available as follows:
Product
NDC
No.
No.
504001*
63323-540-01
504011
63323-540-11
504031
63323-540-31
926201**
63323-262-01
504201*
63323-542-01
504207
63323-542-07
915501**
63323-915-01
5
6
*Packaged in a plastic or glass vial.
7
**Packaged in a plastic vial.
1,000 USP Heparin
Units/mL, 1 mL fill in a
3 mL vial.
1,000 USP Heparin
Units/mL, 10 mL fill in
a 10 mL vial.
1,000 USP Heparin
Units/mL, 30 mL fill in
a 30 mL vial.
5,000 USP Heparin
Units/mL, 1 mL fill in a
3 mL vial.
10,000 USP Heparin
Units/mL, 1 mL fill in a
3 mL vial.
10,000 USP Heparin
Units/mL, 5 mL fill in a
6 mL vial.
20,000 USP Heparin
Units/mL, 1 mL fill in a
3 mL vial.
8
The above products are available in multiple dose, flip-top vials packaged in 25.
9
Do not use if solution is discolored or contains a precipitate.
10
STORAGE:
11
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
12
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
c
o
m
pan
y l
ogo
1
REFERENCES:
2
1. Tahata T, Shigehito M, Kusuhara K, Ueda Y, et al. Delayed-Onset of Heparin Induced
3
Thrombocytopenia – A Case Report – J Jpn Assn Torca Surg. 1992;40(3):110-111.
4
2. Warkentin T, Kelton J. Delayed-Onset Heparin-Induced Thrombocytopenia and
5
Thrombosis. Annals of Internal Medicine. 2001;135:502-506.
6
3. Rice L, Attisha W, Drexler A, Francis J. Delayed-Onset Heparin Induced
7
Thrombocytopenia. Annals of Internal Medicine, 2002;136:210-215.
8
4. Dieck J., C. Rizo-Patron, et al. (1990). “A New Manifestation and Treatment Alternative
9
for Heparin-Induced Thrombosis.” Chest 98(1524-26).
10
5. Smythe M, Stephens J, Mattson. Delayed-Onset Heparin Induced Thrombocytopenia.
11
Annals of Emergency Medicine, 2005;45(4):417-419.
12
6. Divgi A. (Reprint), Thumma S., Hari P., Friedman K., Delayed Onset Heparin-Induced
13
Thrombocytopenia (HIT) Presenting After Undocumented Drug Exposure as Post-
14
Angiography Pulmonary Embolism. Blood. 2003;102(11):127b.
15
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:19.953471
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017029s120,017651s048lbl.pdf', 'application_number': 17651, 'submission_type': 'SUPPL ', 'submission_number': 48}
|
11,049
|
Forane ® (isoflurane, USP)
Proposed Package Insert
FORANE (isoflurane, USP)
Liquid For Inhalation
Rx only
DESCRIPTION
FORANE (isoflurane, USP), a nonflammable liquid administered by vaporizing, is a
general inhalation anesthetic drug. It is 1-chloro-2, 2,2-trifluoroethyl difluoromethyl
ether, and its structural formula is: Structural Formula
Some physical constants are:
Molecular weight
Boiling point at 760 mm Hg
20
Refractive index n D
Specific gravity 25°/25°C
Vapor pressure in mm Hg**
184.5
48.5°C (uncorr.)
1.2990-1.3005
20°C
25°C
30°C
35°C
1.496
238
295
367
450
**Equation for vapor pressure calculation:
log10Pvap =
A + B where
T
Partition coefficients at 37°C:
Water/gas
Blood/gas
Oil/gas
A = 8.056
B = -1664.58
T = °C + 273.16 (Kelvin)
0.61
1.43
90.8
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
Partition coefficients at 25°C – rubber and plastic
Conductive rubber/gas
62.0
Butyl rubber/gas
75.0
Polyvinyl chloride/gas
110.0
Polyethylene/gas
~2.0
Polyurethane/gas
~1.4
Polyolefin/gas
~1.1
Butyl acetate/gas
~2.5
Purity by gas
>99.9%
chromatography
Lower limit of
None
flammability in oxygen
or nitrous oxide at 9
joules/sec. and 23°C
Lower limit of
Greater than useful concentration in
flammability in oxygen
anesthesia.
or nitrous oxide at 900
joules/sec. and 23°C
Isoflurane is a clear, colorless, stable liquid containing no additives or chemical
stabilizers. Isoflurane has a mildly pungent, musty, ethereal odor. Samples stored in
indirect sunlight in clear, colorless glass for five years, as well as samples directly
exposed for 30 hours to a 2 amp, 115 volt, 60 cycle long wave U.V. light were unchanged
in composition as determined by gas chromatography. Isoflurane in one normal sodium
methoxide-methanol solution, a strong base, for over six months consumed essentially no
alkali, indicative of strong base stability. Isoflurane does not decompose in the presence
of soda lime (at normal operating temperatures), and does not attack aluminum, tin, brass,
iron or copper.
CLINICAL PHARMACOLOGY
FORANE (isoflurane, USP) is an inhalation anesthetic. The MAC (minimum alveolar
concentration) in man is as follows:
Age
100% Oxygen
70% N20
26±4
1.28
0.56
44±7
1.15
0.50
64±5
1.05
0.37
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild
pungency, which limits the rate of induction, although excessive salivation or
tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal
reflexes are readily obtunded. The level of anesthesia may be changed rapidly with
isoflurane. Isoflurane is a profound respiratory depressant. RESPIRATION MUST BE
MONITORED CLOSELY AND SUPPORTED WHEN NECESSARY. As anesthetic
dose is increased, tidal volume decreases and respiratory rate is unchanged. This
depression is partially reversed by surgical stimulation, even at deeper levels of
anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether
and enflurane, although the frequency is less than with enflurane.
Blood pressure decreases with induction of anesthesia but returns toward normal with
surgical stimulation. Progressive increases in depth of anesthesia produce corresponding
decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of
isoflurane required to reach a desired level of anesthesia and may reduce the arterial
hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With
controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing
depth of anesthesia, primarily through an increase in heart rate, which compensates for a
reduction in stroke volume. The hypercapnia, which attends spontaneous ventilation
during isoflurane anesthesia further increases heart rate and raises cardiac output above
awake levels. Isoflurane does not sensitize the myocardium to exogenously administered
epinephrine in the dog. Limited data indicate that subcutaneous injection of 0.25 mg of
epinephrine (50 mL of 1:200,000 solution) does not produce an increase in ventricular
arrhythmias in patients anesthetized with isoflurane.
Muscle relaxation is often adequate for intra-abdominal operations at normal levels of
anesthesia. Complete muscle paralysis can be attained with small doses of muscle
relaxants. ALL COMMONLY USED MUSCLE RELAXANTS ARE MARKEDLY
POTENTIATED WITH ISOFLURANE, THE EFFECT BEING MOST PROFOUND
WITH THE NONDEPOLARIZING TYPE. Neostigmine reverses the effect of
nondepolarizing muscle relaxants in the presence of isoflurane. All commonly used
muscle relaxants are compatible with isoflurane.
Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal
models 1,2; the drug is probably also a coronary dilator in humans. Isoflurane, like some
other coronary arteriolar dilators, has been shown to divert blood from collateral
dependent myocardium to normally perfused areas in an animal model (“coronary steal”) 3.
Clinical studies to date evaluating myocardial ischemia, infarction and death as outcome
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
parameters have not established that the coronary arteriolar dilation property of isoflurane
is associated with coronary steal or myocardial ischemia in patients with coronary artery
disease 4,5,6,7.
Pharmacokinetics
Isoflurane undergoes minimal biotransformation in man. In the postanesthesia period,
only 0.17% of the isoflurane taken up can be recovered as urinary metabolites.
INDICATIONS AND USAGE
FORANE (isoflurane, USP) may be used for induction and maintenance of general
anesthesia. Adequate data have not been developed to establish its application in
obstetrical anesthesia.
CONTRAINDICATIONS
Known sensitivity to FORANE (isoflurane, USP) or to other halogenated agents. Known
or suspected genetic susceptibility to malignant hyperthermia.
WARNINGS
Perioperative Hyperkalemia
Use of inhaled anesthetic agents has been associated with rare increases in serum
potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients
during the postoperative period. Patients with latent as well as overt neuromuscular
disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable.
Concomitant use of succinylcholine has been associated with most, but not all, of these
cases. These patients also experienced significant elevations in serum creatinine kinase
levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the
similarity in presentation to malignant hyperthermia, none of these patients exhibited
signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive
intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is
subsequent evaluation for latent neuromuscular disease.
Malignant Hyperthermia
In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle
hypermetabolic state leading to high oxygen demand and the clinical syndrome known as
malignant hyperthermia. The syndrome includes nonspecific features such as muscle
rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
should also be noted that many of these nonspecific signs may appear with light
anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an
elevated temperature, (which may rise rapidly early or late in the case, but usually is not
the first sign of augmented metabolism) and an increased usage of the CO absorption
2
system (hot canister). PaO and pH may decrease, and hyperkalemia and a base deficit
2
may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane),
administration of intravenous dantrolene sodium, and application of supportive therapy.
Such therapy includes vigorous efforts to restore body temperature to normal, respiratory
and circulatory support as indicated, and management of electrolyte-fluid-acid-base
derangements. (Consult prescribing information for dantrolene sodium intravenous for
additional information on patient management). Renal failure may appear later, and urine
flow should be sustained if possible.
Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing
predictable concentrations should be used. Hypotension and respiratory depression
increase as anesthesia is deepened.
Increased blood loss comparable to that seen with halothane has been observed in
patients undergoing abortions.
FORANE (isoflurane, USP) markedly increases cerebral blood flow at deeper levels of
anesthesia. There may be a transient rise in cerebral spinal fluid pressure, which is fully
reversible with hyperventilation.
PRECAUTIONS
General
As with any potent general anesthetic, FORANE (isoflurane, USP) should only be
administered in an adequately equipped anesthetizing environment by those who are
familiar with the pharmacology of the drug and qualified by training and experience to
manage the anesthetized patient.
Regardless of the anesthetics employed, maintenance of normal hemodynamics is
important to the avoidance of myocardial ischemia in patients with coronary artery
disease 4,5,6,7.
FORANE (isoflurane, USP), like some other inhalational anesthetics, can react with
desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide, which may
result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
barium hydroxide lime and soda lime become desiccated when fresh gases are passed
through the CO2 absorber canister at high flow rates over many hours or days. When a
clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the
administration of FORANE (isoflurane, USP).
As with other halogenated anesthetic agents, FORANE (isoflurane, USP) may cause
sensitivity hepatitis in patients who have been sensitized by previous exposure to
halogenated anesthetics (see CONTRAINDICATIONS).
Information for Patients
Isoflurane, as well as other general anesthetics, may cause a slight decrease in intellectual
function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in
moods and symptoms may persist for up to 6 days after administration.
Laboratory Tests
Transient increases in BSP retention, blood glucose and serum creatinine with decrease in
BUN, serum cholesterol and alkaline phosphatase have been observed.
Drug Interactions
Isoflurane potentiates the muscle relaxant effect of all muscle relaxants, most notably
nondepolarizing muscle relaxants, and MAC (minimum alveolar concentration) is
reduced by concomitant administration of N2O. See CLINICAL PHARMACOLOGY.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Swiss ICR mice were given isoflurane to determine whether such exposure might induce
neoplasia. Isoflurane was given at ½, ⅛ and 1/32 MAC for four in-utero exposures and
for 24 exposures to the pups during the first nine weeks of life. The mice were killed at
15 months of age. The incidence of tumors in these mice was the same as in untreated
control mice, which were given the same background gases, but not the anesthetic.
Pregnancy
Pregnancy Category C
Isoflurane has been shown to have a possible anesthetic-related fetotoxic effect in mice
when given in doses 6 times the human dose. There are no adequate and well-controlled
studies in pregnant women. Isoflurane should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
Nursing Mothers
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 isoflurane is administered to a
nursing woman.
ADVERSE REACTIONS
Adverse reactions encountered in the administration of FORANE (isoflurane, USP) are in
general dose dependent extensions of pharmacophysiologic effects and include
respiratory depression, hypotension and arrhythmias.
Shivering, nausea, vomiting and ileus have been observed in the postoperative period.
As with all other general anesthetics, transient elevations in white blood count have been
observed even in the absence of surgical stress. See WARNINGS for information
regarding malignant hyperthermia and elevated carboxyhemoglobin levels.
During marketing, there have been rare reports of mild, moderate and severe (some fatal)
postoperative hepatic dysfunction and hepatitis.
FORANE (isoflurane, USP) has also been associated with perioperative hyperkalemia
(see WARNINGS).
Post-Marketing Events:
The following adverse events have been identified during post-approval use of FORANE
(isoflurane, USP). Due to the spontaneous nature of these reports, the actual incidence
and relationship of FORANE (isoflurane, USP) to these events cannot be established with
certainty.
Cardiac Disorders: Cardiac arrest
Hepatobiliary Disorders: Hepatic necrosis, Hepatic failure .
OVERDOSAGE
In the event of overdosage, or what may appear to be overdosage, the following action
should be taken:
Stop drug administration, establish a clear airway, and initiate assisted or controlled
ventilation with pure oxygen.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
DOSAGE AND ADMINISTRATION
Premedication
Premedication should be selected according to the need of the individual patient, taking
into account that secretions are weakly stimulated by FORANE (isoflurane, USP), and
the heart rate tends to be increased. The use of anticholinergic drugs is a matter of choice.
Inspired Concentration
The concentration of isoflurane being delivered from a vaporizer during anesthesia
should be known. This may be accomplished by using:
a.
Vaporizers calibrated specifically for isoflurane;
b.
Vaporizers from which delivered flows can be calculated, such as vaporizers
delivering a saturated vapor, which is then diluted. The delivered concentration
from such a vaporizer may be calculated using the formula:
% isoflurane = 100 P F
v
v
FT (PA – PV)
=
Where: :
P
Pressure of atmosphere
A
=
P
Vapor pressure of isoflurane
V
=
FV
Flow of gas through vaporizer (mL/min)
=
FT
Total gas flow (mL/min)
Isoflurane contains no stabilizer. Nothing in the agent alters calibration or operation of
these vaporizers.
Induction
Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide
mixtures may produce coughing, breath holding, or laryngospasm. These difficulties may
be avoided by the use of a hypnotic dose of an ultra-short-acting barbiturate. Inspired
concentrations of 1.5 to 3.0% isoflurane usually produce surgical anesthesia in 7 to 10
minutes.
Maintenance
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
Surgical levels of anesthesia may be sustained with a 1.0 to 2.5% concentration when
nitrous oxide is used concomitantly. An additional 0.5 to 1.0% may be required when
isoflurane is given using oxygen alone. If added relaxation is required, supplemental
doses of muscle relaxants may be used.
The level of blood pressure during maintenance is an inverse function of isoflurane
concentration in the absence of other complicating problems. Excessive decreases may be
due to depth of anesthesia and in such instances may be corrected by lightening
anesthesia.
HOW SUPPLIED
FORANE (isoflurane, USP) is packaged in 100 mL and 250 mL amber-colored bottles.
100 mL
NDC 10019-360-40
250 mL
NDC 10019-360-60
FORANE (isoflurane, USP) is also supplied in the following aluminum bottles.
250 mL
NDC 10019-360-64
Safety and Handling
Occupational Caution
There is no specific work exposure limit established for FORANE (isoflurane, USP).
However, the National Institute for Occupational Safety and Health Administration
(NIOSH) recommends that no worker should be exposed at ceiling concentrations
greater than 2 ppm of any halogenated anesthetic agent over a sampling period not to
exceed one hour.
The predicted effects of acute overexposure by inhalation of FORANE (isoflurane, USP)
include headache, dizziness or (in extreme cases) unconsciousness. There are no
documented adverse effects of chronic exposure to halogenated anesthetic vapors (Waste
Anesthetic Gases or WAGs) in the workplace. Although results of some epidemiological
studies suggest a link between exposure to halogenated anesthetics and increased health
problems (particularly spontaneous abortion), the relationship is not conclusive. Since
exposure to WAGs is one possible factor in the findings for these studies, operating room
personnel, and pregnant women in particular, should minimize exposure. Precautions
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Forane ® (isoflurane, USP)
Proposed Package Insert
include adequate general ventilation in the operating room, the use of a well-designed and
well-maintained scavenging system, work practices to minimize leaks and spills while the
anesthetic agent is in use, and routine equipment maintenance to minimize leaks.
Storage
Store at room temperature 15°-30°C (59°-86°F). Isoflurane contains no additives and
has been demonstrated to be stable at room temperature for periods in excess of five
years.
Baxter and FORANE are trademarks of Baxter International Inc., registered in the United
States Patent and Trademark Office. Company logo
Manufactured for
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
Revised: February 2010
REFERENCES
1. J.C. Sill, et al, Anesthesiology 66:273-279, 1987
2. R.F. Hickey, et al, Anesthesiology 68:21-30, 1988
3. C.W. Buffington, et al, Anesthesiology 66:280-292, 1987
4. S. Reiz, et al, Anesthesiology 59:91-97, 1983
5. S. Slogoff and A.S. Keats, Anesthesiology 70:179-188, 1989
6. K.J. Tuman, et al, Anesthesiology 70:189-198, 1989
7. D.T. Mangano, Editorial Views, Anesthesiology 70:175-178, 1989
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:20.014610
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/017624s036lbl.pdf', 'application_number': 17624, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
11,048
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NALFON safely and effectively. See full prescribing information for
NALFON.
NALFON (fenoprofen calcium, USP) capsules, for oral use
Initial U.S. Approval: 1982
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning
• Non-Steroidal Anti-Inflammatory drugs (NSAIDs) cause an increased
risk of serious cardiovascular thrombotic events, including myocardial
infarction and stroke, which can be fatal. This risk may occur early in
treatment and may increase with duration of use. (5.1)
• NALFON is contraindicated in the setting of coronary artery bypass
graft (CABG) surgery (4, 5.1)
• NSAIDs cause an increased risk of serious gastrointestinal (GI)
adverse events including bleeding, ulceration, and perforation of
stomach or intestines, which can be fatal. These events can occur at
any time during use and without warning symptoms. Elderly patients
and patients with a prior history of peptic ulcer disease and/or GI
bleeding are at greater risk for serious GI events (5.2)
RECENT MAJOR CHANGES
Boxed Warning
5/2016
Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) ) 5/2016
Warnings and Precautions, Heart Failure and Edema (5.5)
5/2016
--------------------- INDICATIONS AND USAGE
--------------------------
NALFON is a nonsteroidal anti-inflammatory drug indicated for:
• Relief of mild to moderate pain in adults. (1)
• Relief of the signs and symptoms of rheumatoid arthritis. (1)
• Relief of the signs and symptoms of osteoarthritis. (1)
-------------------- DOSAGE AND ADMINISTRATION ------------------
• Use the lowest effective dosage for shortest duration consistent with
individual patient treatment goals (2.1)
• Analgesia: For the treatment of mild to moderate pain, the recommended
dosage is 200 mg given orally every 4 to 6 hours, as needed (2.1)
• Rheumatoid Arthritis and Osteoarthritis: For the relief of signs and
symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is
400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored
to the needs of the patient and may be increased or decreased depending on
the severity of the symptoms. Dosage adjustments may be made after
initiation of drug therapy or during exacerbations of the disease. Total daily
dosage should not exceed 3,200 mg.
------------------- DOSAGE FORMS AND STRENGTHS -----------------
NALFON (fenoprofen calcium) capsules: 200 mg and 400 mg (3)
---------------------------- CONTRAINDICATIONS
------------------------
• Known hypersensitivity to fenoprofen or any components of the drug
product (4)
• History of asthma, urticaria, or other allergic-type reactions after taking
aspirin or other NSAIDs (4)
• In the setting of CABG surgery (4)
-------------------- WARNINGS AND PRECAUTIONS -------------------
• Hepatotoxicity: Inform patients of warning signs and symptoms of
hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if
clinical signs and symptoms of liver disease develop (5.3)
• Hypertension: Patients taking some antihypertensive medications may have
impaired response to these therapies when taking NSAIDs. Monitor blood
pressure (5.4, 7)
• Heart Failure and Edema: Avoid use of NALFON in patients with severe
heart failure unless benefits are expected to outweigh risk of worsening
heart failure (5.5)
• Renal Toxicity: Monitor renal function in patients with renal or hepatic
impairment, heart failure, dehydration, or hypovolemia. Avoid use of
NALFON in patients with advanced renal disease unless benefits are
expected to outweigh risk of worsening renal function (5.6)
• Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction
occurs (5.7)
• Exacerbation of Asthma Related to Aspirin Sensitivity: NALFON is
contraindicated in patients with aspirin-sensitive asthma. Monitor patients
with preexisting asthma (without aspirin sensitivity) (5.8)
• Serious Skin Reactions: Discontinue NALFON at first appearance of skin
rash or other signs of hypersensitivity (5.9)
• Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant
women starting at 30 weeks gestation (5.10, 8.1)
• Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
any signs or symptoms of anemia (5.11, 7)
---------------------------- ADVERSE REACTIONS -------------------------
Most common adverse reactions are (incidence ≥ 5%) are Dyspepsia,
headache, somnolence, nausea, dizziness, constipation, nervousness, asthenia,
and peripheral edema.
To report SUSPECTED ADVERSE REACTIONS, contact Xspire
Pharma at 1-601-990-9497 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch (6)
---------------------------- DRUG INTERACTIONS -------------------------
• Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
Monitor patients for bleeding who are concominantly taking NALFON
with drugs that interfere with hemostasis. Concomitant use of NALFON
and analgesic doses of aspirin is not generally recommended (7)
• ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers:
Concomitant use with NALFON may diminish the antihypertensive effect
of these drugs. Monitor blood pressure (7)
• ACE Inhibitors and ARBs: Concomitant use with NALFON in elderly,
volume depleted, or those with renal impairment may result in deterioration
of renal function. In such high risk patients, monitor for signs of worsening
renal function (7)
• Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide
diuretics. Monitor patients to assure diuretic efficacy including
antihypertensive effects (7)
• Digoxin: Concomitant use with NALFON can increase serum
concentration and prolong half-life of digoxin. Monitor serum digoxin
levels (7)
----------------------- USE IN SPECIFIC POPULATIONS ---------------------
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases
the risk of premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)
Infertility: NSAIDs are associated with reversible infertility. Consider
withdrawal of NALFON in women who have difficulties conceiving (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: 5/2016
Reference ID: 3928124
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
------------------------------------------------------------------------------------------------------------------------------------------------------------------
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF SERIOUS CARDIOVASCULAR
AND GASTROINTESTINAL EVENTS
1 INDICATIONS AND USAGE
2. DOSAGE AND ADMINISTRATION
2.1 General Dosing Instructions
2.2 Analgesia
2.3 Rheumatoid Arthritis and Osteoarthritis
3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5. WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Thrombotic Events
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
5.3 Hepatotoxicity
5.4 Hypertension
5.5 Heart Failure and Edema
5.6 Renal Toxicity and Hyperkalemia
5.7 Anaphylactic Reactions
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
5.9 Serious Skin Reactions
5.10 Premature Closure of Fetal Ductus Arteriosus
5.11 Hematologic Toxicity
5.12 Masking of Inflammation and Fever
5.13 Laboratory Monitoring
5.14 Ocular Effects
5.15 Central Nervous System Effects
5.16 Impact on Hearing
6. ADVERSE REACTIONS
6.1 Clinical Trials Experience
7. DRUG INTERACTIONS
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
10. OVERDOSAGE
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
16. HOW SUPPLIED/STORAGE AND HANDLING
17. PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 3928124
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: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
Cardiovascular Thrombic Events
● Non-Steroidal Anti-Inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events,
including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase
with duration of use. [see Warnings and Precautions (5.1)].
● NALFON® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and
Warnings and precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
● NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and
perforation of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning
symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk
for serious GI events [see Warnings and Precautions (5.2)].
1. INDICATIONS AND USAGE
NALFON is indicated for:
Relief of mild to moderate pain in adults
Relief of the signs and symptoms of rheumatoid arthrites
Relief of the signs and symptoms of osteoarthritis
2. DOSAGE AND ADMINISTRATION
2.1 General Dosing Instructions
Carefully consider the potential benefits and risks of NALFON and other treatment options before deciding to use NALFON. Use the
lowest effective dose for the shortest duration consistent with individual patient treatment goals Use lowest effective dosage for the
shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
Nalfon may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are
delayed and diminished.
Patients with rheumatoid arthritis generally seem to require larger doses of Nalfon than do those with osteoarthritis. The smallest dose
that yields acceptable control should be employed.
Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full
benefits of therapy.
2.2
Analgesia
For the treatment of mild to moderate pain , the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed.
2.3
Rheumatoid Arthritis and Osteoarthritis
For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3
or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity
of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily
dosage should not exceed 3,200 mg.
3. DOSAGE FORMS AND STRENGTHS
Nalfon® (fenoprofen calcium, USP) capsules:
●
The 200 mg capsule is opaque yellow No. 97 cap and opaque white body, imprinted with "RX681" on the cap and body.
● The 400 mg capsule is opaque green cap and opaque blue body, imprinted with "NALFON 400 mg" on the cap and "EP 123" on
the body.
4. CONTRAINDICATIONS
NALFON is contraindicated in the following patients:
● Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to fenoprofen or any components of the drug
product [see Warnings and Precautions (5.7, 5.9)]
Reference ID: 3928124
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● History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal,
anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]
●
In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]
5. WARNINGS AND PRECAUTIONS
5.1
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of
serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on
available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV
thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk
factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV
thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV
thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest
duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment
course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the
steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated
with NSAID use. The concurrent use of aspirin and an NSAID, such as fenoprofen, increases the risk of serious gastrointestinal (GI)
events [see Warnings and Precautions (5.2)].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG
surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see
Contraindications (4)].
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI
period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this
same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12
per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-
MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of NALFON in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If NALFON is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
5.2
Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including NALFON, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and
perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper
GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in
approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term
NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for
developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients
treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or
selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing
reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated Patients:
●
Use the lowest effective dosage for the shortest possible duration.
●
Avoid administration of more than one NSAID at a time.
● Avoid use in patients at higher risk unless benefits are expected to outweigh theincreased risk of bleeding. For such patients, as
well as those with active GIbleeding, consider alternate therapies other than NSAIDs.
●
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
Reference ID: 3928124
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● If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue NALFON until a serious GI
adverse event is ruled out.
● In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI
bleeding [see Drug Interactions (7)].
5.3
Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-
treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver
necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including fenoprofen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right
upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NALFON immediately, and perform a clinical evaluation of
the patient.
5.4
Hypertension
NSAIDs, including NALFON, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics,
or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
5.5
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an
approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-
treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use
increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of fenoprofen may blunt the
CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor
blockers [ARBs]) [see Drug Interactions (7)].
Avoid the use of NALFON in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If NALFON is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
5.6
Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal
perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those
with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or
ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of NALFON in patients with advanced renal disease.
The renal effects of NALFON may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating NALFON. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NALFON [see Drug Interactions (7)]. Avoid the
use of NALFON in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal
function. If NALFON is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients
without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic
hypoaldosteronism state.
5.7
Anaphylactic Reactions
Fenoprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to fenoprofen and in
patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].
Seek emergency help if an anaphylactic reaction occurs.
Reference ID: 3928124
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For current labeling information, please visit https://www.fda.gov/drugsatfda
5.8
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by
nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity
between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NALFON is contraindicated in patients with
this form of aspirin sensitivity [see Contraindications (4)]. When NALFON is used in patients with preexisting asthma (without
known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.9
Serious Skin Reactions
NSAIDs, including fenopropfen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome
(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients
about the signs and symptoms of serious skin reactions, and to discontinue the use of NALFON at the first appearance of skin rash or
any other sign of hypersensitivity. NALFON is contraindicated in patients with previous serious skin reactions to NSAIDs [see
Contraindications (4)].
5.10 Premature Closure of Fetal Ductus Arteriosus
Fenoprofen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including NALFON, in pregnant
women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1)].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely
described effect on erythropoiesis. If a patient treated with NALFON has any signs or symptoms of anemia, monitor hemoglobin or
hematocrit.
NSAIDs, including NALFON, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders,
concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and
serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug
Interactions (7)].
5.12 Masking of Inflammation and Fever
The pharmacological activity of NALFON in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs
in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring
patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3,
5.6)].
5.14 Ocular Effects
Studies to date have not shown changes in the eyes attributable to the administration of NALFON. However, adverse ocular effects
have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur
in patients taking NALFON.
5.15 Central Nervous System Effects
Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking NALFON.
5.16 Impact on Hearing
Since the safety of NALFON has not been established in patients with impaired hearing, these patients should have periodic tests of
auditory function during prolonged therapy with NALFON.
6. ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
●
Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
●
GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
●
Hepatotoxicity [see Warnings and Precautions (5.3)]
●
Hypertension [see Warnings and Precautions (5.4)]
●
Heart Failure and Edema [see Warnings and Precautions (5.5)]
●
Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
●
Anaphylactic Reactions [see Warnings and Precautions (5.7)]
Reference ID: 3928124
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For current labeling information, please visit https://www.fda.gov/drugsatfda
●
Serious Skin Reactions [see Warnings and Precautions (5.9)]
●
Hematologic Toxicity [see Warnings and Precautions (5.11)]
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.
During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints
were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in
6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from
the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions
was markedly lower than that seen in longer-term studies.
Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials
Digestive System — During clinical trials with Nalfon, the most common adverse reactions were gastrointestinal in nature and
occurred in 20.8% of patients receiving Nalfon as compared to 16.9% of patients receiving placebo. In descending order of frequency,
these reactions included dyspepsia (10.3% Nalfon vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting
(2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse
gastrointestinal reactions in less than 2% of patients during premarketing studies.
Nervous System — The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%).
Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Nalfon was
discontinued in less than 0.5% of patients because of these side effects during premarketing studies.
Skin and Appendages— Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported.
Nalfon was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies.
Special Senses — Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported.
Nalfon was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing
studies.
Cardiovascular — Palpitations (2.5% vs. 0.4%). Nalfon was discontinued in about 0.5% of patients because of adverse cardiovascular
reactions during premarketing studies.
Miscellaneous — Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs.
none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%), and nasopharyngitis (1.2% vs. none).
Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials
Digestive System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and
blood in the stool. Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the
buccal mucosa, metallic taste, and pancreatitis.
Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia.
Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis, and
papillary necrosis.
Hypersensitivity—Angioedema (angioneurotic edema).
Hematologic—Purpura, bruising, hemorrhage, thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and
pancytopenia.
Nervous System—Depression, disorientation, seizures, and trigeminal neuralgia.
Special Senses—Burning tongue, diplopia, and optic neuritis.
Skin and Appendages—Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia.
Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia, personality change, lymphadenopathy, mastodynia, and fever.
7. DRUG INTERACTIONS
See Table 1 for clinically significant drug interactions with fenoprophen.
Table 1: Clinically Significant Drug Interactions with Fenoprofen
Drugs That Interfere with Hemostasis
Clinical
Impact:
• Fenoprofen and anticoagulants such as warfarin have a synergistic effect on bleeding.
The concomitant use of fenoprofen and anticoagulants have an increased risk of serious
Reference ID: 3928124
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bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control and
cohort epidemiological studies showed that concomitant use of drugs that interfere with
serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an
NSAID alone.
Intervention: Monitor patients with concomitant use of NALFON with anticoagulants (e.g., warfarin),
antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and
serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings
and Precautions (5.11)].
Aspirin
Clinical
Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses
of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a
clinical study, the concomitant use of an NSAID and aspirin was associated with a
significantly increased incidence of GI adverse reactions as compared to use of the NSAID
alone [see Warnings and Precautions (5.2)].
Intervention: Concomitant use of NALFON and analgesic doses of aspirin is not generally recommended
because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
NALFON is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical
Impact:
• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme
(ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including
propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy), or
have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs
may result in deterioration of renal function, including possible acute renal failure. These
effects are usually reversible.
Intervention: • During concomitant use of NALFON and ACE-inhibitors, ARBs, or betablockers,
monitor blood pressure to ensure that the desired blood pressure is obtained.
• During concomitant use of NALFON ACE-inhibitors or ARBs in patients who are
elderly, volume-depleted, or have impaired renal function, monitor for signs of
worsening renal function [see Warnings and Precautions (5.6)].
• When these drugs are administered concomitantly, patients should be adequately
hydrated. Assess renal function at the beginning of the concomitant treatment
and periodically thereafter.
Diuretics
Clinical
Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the
natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients.
This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of NALFON with diuretics, observe patients for signs of worsening
renal function, in addition to assuring diuretic efficacy including antihypertensive effects
[see Warnings and Precautions (5.6)].
Digoxin
Clinical
Impact:
The concomitant use of fenoprofen with digoxin has been reported to increase the serum
concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of NALFON and digoxin, monitor serum digoxin levels.
Lithium
Clinical
Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium
clearance. The mean minimum lithium concentration increased 15%, and the renal clearance
decreased by approximately 20%. This effect has been attributed to NSAID inhibition of
renal prostaglandin synthesis.
Intervention: During concomitant use of NALFON and lithium, monitor patients for signs of lithium
toxicity.
Methotrexate
Clinical
Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate
toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Reference ID: 3928124
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Intervention: During concomitant use of NALFON and methotrexate, monitor patients for methotrexate
toxicity.
Cyclosporine
Clinical
Impact:
Concomitant use of NALFON and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of NALFON and cyclosporine, monitor patients for signs of
worsening renal function.
NSAIDs and Salicylates
Clinical
Impact:
Concomitant use of fenoprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate)
increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and
Precautions (5.2)].
Intervention: The concomitant use of fenoprofen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical
Impact:
Concomitant use of NALFON and pemetrexed may increase the risk of pemetrexed
associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing
information).
Intervention: During concomitant use of NALFON and pemetrexed, in patients with renal impairment
whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression,
renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided
for a period of two days before, the day of, and two days following administration of
pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with
longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should
interrupt dosing for at least five days before, the day of, and two days following pemetrexed
administration.
Phenobarbital
Clinical
Impact:
Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a
decrease in the plasma half-life of fenoprofen.
Intervention: When phenobarbital is added to or withdrawn from treatment, dosage adjustment of
NALFON may be required.
Hydantoins, sulfonamides, or sulfonylureas
Clinical
Impact:
In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace
from their binding sites other drugs that are also albumin bound, and this may lead to drug
interactions. Theoretically, fenoprofen could likewise be displaced.
Intervention: Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for
increased activity of these drugs and, therefore, signs of toxicity from these drugs.
Drug/Laboratory Test Interactions
Amerlex-M kit assay values of total and free triiodothyronine in patients receiving Nalfon have been reported as falsely elevated on
the basis of a chemical cross-reaction that directly interferes with the assay. Thyroid-stimulating hormone, total thyroxine, and
thyrotropin-releasing hormone response are not affected. Thus, results of the Amerlex-M kit assay should be interpreted with caution
in these patients.
8. USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
Use of NSAIDs, including NALFON, during the third trimester of pregnancy increases the risk of premature closure of the fetal
ductus arteriosus. Avoid use of NSAIDs, including NALFON, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of NALFON in pregnant women. Data from observational studies regarding
potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major
malformations, and 15-20% for pregnancy loss.
Reference ID: 3928124
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In animal reproduction studies, embryo-fetal lethality and skeletal abnormalities were noted in offspring of pregnant rabbits following
oral administration of fenoprofen during organogenesis at 0.6 times the maximum human daily dose of 3200 mg/day. However, there
were no major malformations noted following oral administration of fenoprofen calcium to pregnant rats and rabbits during
organogenesis at exposures up to 0.3 and 0.6 times the maximum human daily dose of 3200 mg/day.
Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst
implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as fenoprofen, resulted
in increased pre- and post-implantation loss.
Clinical Considerations
Labor or Delivery
There are no studies on the effects of NALFON during labor or delivery. In animal studies, NSAIDS, including fenoprofen, inhibit
prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Data
Human Data
There are no adequate and well-controlled studies of NALFON in pregnant women. Data from observational studies regarding
potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.
Animal data
Pregnant rats were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.15 times and 0.3 times the maximum human daily
dose (MHDD) of 3200 mg/day based on body surface area comparison) during the period of organogenesis. No major malformations
were noted and there was no evidence of maternal toxicity at these doses, however, the exposures were below the exposures that will
occur in humans.
Pregnant rabbits were treated with fenoprofen using oral doses of 50 or 100 mg/kg (0.3 times and 0.6 times the MHDD of 3200
mg/day based on body surface area comparison) during the period of organogenesis. Maternal toxicity (mortality) was noted in the
high dose animals. Although no major malformations were noted, there was an increased incidence of embryo-fetal lethality and
skeletal abnormalities were present at 0.6 times the MHDD.
Pregnant rats were treated from Gestation Day 14 through Post-Natal Day 20 with oral doses of fenoprofen of 6.25, 12.5, 25, 50, or
100 mg/kg (0.02, 0.04, 0.08, 0.15, or 0.3 times the MDD of 3200 mg/day based on body surface area comparison). All doses
produced significant toxicity, including vaginal bleeding, prolonged parturition, increased stillbirths, and maternal deaths.
Pregnant rats were treated from Gestation Day 6 through Gestation Day 19 and Post Partum Day 1 to 20 (excluding parturition) with
an oral dose of fenoprofen of 100 mg/kg (0.3 times the MDD of 3200 mg/day based on body surface area comparison) demonstrated
only a small increase in the incidence of impaired parturition despite the presence of maternal toxicity (gastrointestinal ulceration and
renal toxicity).
8.2
Lactation
Risk Summary
In a published study, after a dose of 600 mg every 6 hours for 4 days in postpartum mothers, breastmilk fenoprofen levels were
reportedly 1.6% of those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with
the mother’s clinical need for NALFON and any potential adverse effects on the breastfed infant from the NALFON or from the
underlying maternal condition.
8.3
Females and Males of Reproductive Potential
Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NALFON, may delay or prevent rupture of
ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that
administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandinmediated follicular rupture required for
ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of
NSAIDs, including NALFON, in women who have difficulties conceiving or who are undergoing investigation of infertility.
8.4
Pediatric Use
Safety and effectiveness in pediatric patients under the age of 18 have not been established.
8.5
Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal,
and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low
end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)].
Reference ID: 3928124
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10. OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric
pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal
failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)].
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider
emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic
cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the
recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein
binding.
For additional information about overdosage treatment contact a poison control center (1-800-222-1222).
11. DESCRIPTION
NALFON (fenoprofen calcium, USP) capsules is a nonsteroidal, anti-inflammatory drug available in 200 mg and 400 mg capsule form
for oral administration.
The 200 mg capsule is opaque yellow No. 97 cap and opaque white body, imprinted with “RX681” on the cap and body.
The 400 mg capsule is opaque green cap and opaque blue body, imprinted with “NALFON 400 mg" on the cap and “EP 123” on the
body.
The chemical name is Benzenaecetic acid, α-methyl-3-phenoxy-, calcium salt dihydrate, (±)-. The molecular weight is 558.65. Its
molecular formula is C30H26CaO6•2H2O, and it has the following chemical structure. structural formula
Fenoprofen Calcium is an arylacetic acid derivative. It is a white crystalline powder. At 25°C, it dissolves to a 15 mg/mL solution in
alcohol (95%). It is slightly soluble in water and insoluble in benzene.The pKa of fenoprofen calcium is 4.5 at 25°C.
Nalfon capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol)
of fenoprofen..
Inactive ingredients in Nalfon capsules are crospovidone, magnesium stearate, sodium lauryl sulfate, and talc. In addition, the 200 mg
capsules contain gelatin, titanium dioxide, yellow iron oxide, and red iron oxide, and the 400 mg capsules contain gelatin, D&C
Yellow #10, FD&C Blue #1, FD&C Red #40, FD&C Yellow #6, and titanium dioxide.
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Fenoprofen has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of NALFON, like that of other NSAIDs, is not completely understood but involves inhibition of
cyclooxygenase (COX-1 and COX-2).
Fenoprofen is a potent inhibitor of prostaglandin synthesis in vitro. Fenoprofen concentrations reached during therapy have produced
in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.
Prostaglandins are mediators of inflammation. Because fenoprofen is an inhibitor of prostaglandin synthesis, its mode of action may
be due to a decrease of prostaglandins in peripheral tissues.
12.3 Pharmacokinetics
Absorption
Under fasting conditions, fenoprofen is rapidly absorbed, and peak plasma levels of 50 mcg/L are achieved within 2 hours after oral
administration of 600 mg doses. Good dose proportionality was observed between 200 and 600 mg doses in fasting male volunteers.
Distribution
Fenoprofen is highly bound (99%) to albumin.
Reference ID: 3928124
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Elimination
Metabolism
The plasma half-life is approximately 3 hours.
Excretion
About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxyfenoprofen glucuronide, the
major urinary metabolites of fenoprofen.
Specific Populations
Geriatrics
Peak plasma levels of fenoprofen in normal elderly volunteers were similar to those observed in normal young volunteers. Elderly
volunteers had a mean plasma clearance of 2.2 L/hour while plasma clearance of fenoprofen in normal young volunteers ranged from
3 to 3.5 L/hour. The overall elimination rate constant, plasma half-life and ratio of renal to nonrenal clearance of fenoprofen was the
same in elderly and young volunteers. The 30 to 60% decrease in plasma clearance is due to a decrease in the volume of distribution in
the body.
Drug Interaction Studies
Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free
NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug
interactions of NSAIDs with aspirin [see Drug Interactions (7)].
Antacid: The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with
absorption of fenoprofen.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate the carcinogenic potential of fenoprofen have not been conducted.
Mutagenesis
Studies to evaluate the genotoxic potential of fenoprofen have not been conducted.
Impairment of Fertility
Female and Male rats were treated with 60 to 70 mg/kg/day or 120 to 150 mg/kg/day fenoprofen calcium via the diet (approximately
0.2 or 0.4 times the maximum human daily dose of 3200 mg/day based on body surface area comparison, respectively). Male rats
were treated from 77 days prior to mating and during mating. Female rats were treated from 14 days prior to mating and through
gestation. Pregnancy rates were slightly reduced in the low and high dose groups compared to controls. There was no adverse effect
on implantations, resorptions, or live fetuses.
14. CLINICAL STUDIES
NALFON is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode
of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved.
Results in humans demonstrate that fenoprofen has both anti-inflammatory and analgesic actions. The emergence and degree of
erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of NALFON, aspirin, and
indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity.
In all patients with rheumatoid arthritis, the anti-inflammatory action of NALFON has been evidenced by relief of pain, increase in
grip strength, and reductions in joint swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator
and the patient). The anti-inflammatory action of NALFON has also been evidenced by increased mobility (i.e., a decrease in the
number of joints having limited motion).
The use of NALFON in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The
studies, however, were inadequate in demonstrating whether further improvement is obtained by adding NALFON to maintenance
therapy with gold salts or steroids. Whether or not NALFON used in conjunction with partially effective doses of a corticosteroid has
a “steroid-sparing” effect is unknown.
In patients with osteoarthritis, the anti-inflammatory and analgesic effects of NALFON have been demonstrated by reduction in
tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both
the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased
range of motion in involved joints.
In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown NALFON to be comparable to aspirin in
controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus
Reference ID: 3928124
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For current labeling information, please visit https://www.fda.gov/drugsatfda
occurred less frequently in patients treated with NALFON than in aspirin-treated patients. It is not known whether NALFON causes
less peptic ulceration than does aspirin.
In patients with pain, the analgesic action of Nalfon has produced a reduction in pain intensity, an increase in pain relief, improvement
in total analgesia scores, and a sustained analgesic effect.
16. HOW SUPPLIED/STORAGE AND HANDLING
Nalfon® (fenoprofen calcium, USP) are available in capsule form for oral administration, and are supplied as following:
● The 200 mg capsule has an opaque yellow No. 97 cap and an opaque white body, imprinted with "RX681" on the cap and body.
NDC 42195-0600-10 Bottles of 100.
● The 400 mg capsule has an opaque green cap and an opaque blue body, imprinted with "NALFON 400 mg" on the cap and "EP
123" on the body.
NDC 42195-0308-09 Bottles of 90.
NDC 42195-0308-50 Bottles of 500.
Storage:
Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP
Controlled Room Temperature].
Preserve in well-closed containers.
17. PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed.
Inform patients, families, or their caregivers of the following information before initiating therapy with NALFON and periodically
during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness,
or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions
(5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to
their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the
increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right
upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NALFON and seek immediate medical
therapy [see Warnings and Precautions (5.3)].
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or
edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)].
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to
seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].
Serious Skin Reactions
Advise patients to stop NALFON immediately if they develop any type of rash and to contact their healthcare provider as soon as
possible [see Warnings and Precautions (5.9)].
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including NALFON, may be associated with a
reversible delay in ovulation [see Use in Specific Populations (8.3)]
Fetal Toxicity
Inform pregnant women to avoid use of NALFON and other NSAIDs starting at 30 weeks gestation because of the risk of the
premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].
Reference ID: 3928124
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of NALFON with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended
due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug
Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or
insomnia.
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with NALFON until they talk to their healthcare provider [see Drug
Interactions (7)].
Manufactured for:
Xspire Pharma
Ridgeland, MS. 39157
Issued: 05/ 2016
Reference ID: 3928124
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3928124
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment
and may increase:
o with increasing doses of NSAIDs
o with longer use of NSAIDs
Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)."
Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may
have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the
mouth to the stomach), stomach and intestines:
o anytime during use
o without warning symptoms
o that may cause death
The risk of getting an ulcer or bleeding increases with:
o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
o increasing doses of NSAIDs
o longer use of NSAIDs
o smoking
o drinking alcohol
o older age
o poor health
o advanced liver disease
o bleeding problems
NSAIDs should only be used:
o exactly as prescribed
o at the lowest dose possible for your treatment
o for the shortest time needed
What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions
such as different types of arthritis, menstrual cramps, and other types of short-term pain.
Who should not take NSAIDs?
Do not take NSAIDs:
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
right before or after heart bypass surgery.
Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you:
have liver or kidney problems
have high blood pressure
have asthma
are pregnant or plan to become pregnant. Talk to your healthcare provivder if you are considering taking
NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.
are breastfeeding or plan to breast feed.
Tell your healthcare provider about all of the medicines you take, including prescription or over-the
counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with
each other and cause serious side effects. Do not start taking any new medicine without talking to your
healthcare provider first.
What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See “What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?”
new or worse high blood pressure
heart failure
liver problems including liver failure
Reference ID: 3928124
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
kidney problems including kidney failure
low red blood cells (anemia)
life-threatening skin reactions
life-threatening allergic reactions
Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea,
vomiting, and dizziness.
Get emergency help right away if you get any of the following symptoms:
shortness of breath or trouble breathing
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat
Stop taking your NSAID and call your healthcare provider right away if you get any of the following
symptoms:
nausea
more tired or weaker than usual
diarrhea
itching
your skin or eyes look yellow
indigestion or stomach pain
flu-like symptoms
vomit blood
there is blood in your bowel movement or
it is black and sticky like tar
unusual weight gain
skin rash or blisters with fever
swelling of the arms, legs, hands and
feet
If you take too much of your NSAID, call your healthcare provider or get medical help right away.
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or
pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Other information about NSAIDs
Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in
the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare
provider before using over-the-counter NSAIDs for more than 10 days.
General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the
same symptoms that you have. It may harm them.
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist
or healthcare provider for information about NSAIDs that is written for health professionals.
Manufactured for:
Xspire Pharma
Ridgeland, MS. 39157
For more information, go to www.nalfon.com or call 1-601-990-9497.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: 05/ 2016
Reference ID: 3928124
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/2016/017604s046lbl.pdf', 'application_number': 17604, 'submission_type': 'SUPPL ', 'submission_number': 46}
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1
TOLECTIN® DS
(tolmetin sodium)
Capsules
TOLECTIN® 600
(tolmetin sodium)
Tablets
For Oral Administration
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk
factors for cardiovascular disease may be at greater risk. (See WARNINGS.)
• TOLECTIN is contraindicated for the treatment of peri-operative pain in the
setting
of
coronary
artery
bypass
graft
(CABG)
surgery
(see
CONTRAINDICATIONS and WARNINGS.).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events
including bleeding, ulceration, and perforation of the stomach or intestines,
which can be fatal. These events can occur at any time during use and without
warning symptoms. Elderly patients are at greater risk for serious
gastrointestinal events. (See WARNINGS.)
DESCRIPTION
TOLECTIN DS (tolmetin sodium) capsules for oral administration contain tolmetin
sodium as the dihydrate in an amount equivalent to 400 mg of tolmetin. Each capsule
contains 36 mg (1.568 mEq) of sodium and the following inactive ingredients:
gelatin, magnesium stearate, corn starch, talc, FD&C Red No. 3, FD&C Yellow No.
6 and titanium dioxide.
TOLECTIN 600 (tolmetin sodium) tablets for oral administration contain tolmetin
sodium as the dihydrate in an amount equivalent to 600 mg of tolmetin. Each tablet
contains 54 mg (2.35 mEq) of sodium and the following inactive ingredients:
cellulose, silicon dioxide, crospovidone, hydroxypropyl methyl cellulose, magnesium
stearate, polyethylene glycol, corn starch, titanium dioxide, FD&C Yellow No. 6 and
D&C Yellow No. 10.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
The pKa of tolmetin is 3.5 and tolmetin sodium is freely soluble in water.
Tolmetin sodium is a nonselective nonsteroidal anti-inflammatory agent. The
structural formula is:
Sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate.
CLINICAL PHARMACOLOGY
Studies in animals have shown TOLECTIN (tolmetin sodium) to possess
anti-inflammatory, analgesic, and antipyretic activity. In the rat, TOLECTIN prevents
the development of experimentally induced polyarthritis and also decreases
established inflammation.
The mode of action for TOLECTIN is not known. However, studies in laboratory
animals and man have demonstrated that the anti-inflammatory action of TOLECTIN
is not due to pituitary-adrenal stimulation. TOLECTIN inhibits prostaglandin
synthetase in vitro and lowers the plasma level of prostaglandin E in man. This
reduction in prostaglandin synthesis may be responsible for the anti-inflammatory
action. TOLECTIN does not appear to alter the course of the underlying disease in
man.
In patients with rheumatoid arthritis and in normal volunteers, tolmetin sodium is
rapidly and almost completely absorbed with peak plasma levels being reached within
30-60 minutes after an oral therapeutic dose. In controlled studies, the time to reach
peak tolmetin plasma concentration is approximately 20 minutes longer following
administration of a 600 mg tablet, compared to an equivalent dose given as 200 mg
tablets. The clinical meaningfulness of this finding, if any, is unknown. Tolmetin
displays a biphasic elimination from the plasma consisting of a rapid phase with a
half-life of 1 to 2 hours followed by a slower phase with a half-life of about 5 hours.
Peak plasma levels of approximately 40 µg/mL are obtained with a 400 mg oral dose.
Essentially all of the administered dose is recovered in the urine in 24 hours either as
an inactive oxidative metabolite or as conjugates of tolmetin. An 18-day multiple
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
dose study demonstrated no accumulation of tolmetin when compared with a single
dose.
In two fecal blood loss studies of 4 to 6 days duration involving 15 subjects each,
TOLECTIN did not induce an increase in blood loss over that observed during a
4-day drug-free control period. In the same studies, aspirin produced a greater blood
loss than occurred during the drug-free control period, and a greater blood loss than
occurred during the TOLECTIN treatment period. In one of the two studies,
indomethacin produced a greater fecal blood loss than occurred during the drug-free
control period; in the second study, indomethacin did not induce a significant increase
in blood loss.
TOLECTIN is effective in treating both the acute flares and in the long-term
management of the symptoms of rheumatoid arthritis, osteoarthritis and juvenile
rheumatoid arthritis.
In patients with either rheumatoid arthritis or osteoarthritis, TOLECTIN is as
effective as aspirin and indomethacin in controlling disease activity, but the frequency
of the milder gastrointestinal adverse effects and tinnitus was less than in
aspirin-treated patients, and the incidence of central nervous system adverse effects
was less than in indomethacin-treated patients.
In patients with juvenile rheumatoid arthritis, TOLECTIN is as effective as aspirin in
controlling disease activity, with a similar incidence of adverse reactions. Mean
SGOT values, initially elevated in patients on previous aspirin therapy, remained
elevated in the aspirin group and decreased in the TOLECTIN group.
TOLECTIN has produced additional therapeutic benefit when added to a regimen of
gold salts and, to a lesser extent, with corticosteroids. TOLECTIN should not be used
in conjunction with salicylates since greater benefit from the combination is not
likely, but the potential for adverse reactions is increased.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of TOLECTIN and other treatment
options before deciding to use TOLECTIN. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see
WARNINGS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
TOLECTIN (tolmetin sodium) is indicated for the relief of signs and symptoms of
rheumatoid arthritis and osteoarthritis. TOLECTIN is indicated in the treatment of
acute flares and the long-term management of the chronic disease.
TOLECTIN is also indicated for treatment of juvenile rheumatoid arthritis. The safety
and effectiveness of TOLECTIN have not been established in pediatric patients under
2 years of age (see PRECAUTIONS: Pediatric Use and DOSAGE AND
ADMINSTRATION).
CONTRAINDICATIONS
TOLECTIN is contraindicated in patients with known hypersensitivity to tolmetin
sodium.
TOLECTIN should not be given to patients who have experienced asthma, urticaria
or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal,
anaphylactic-like reactions to NSAIDs have been reported in such patients (see
WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting
Asthma).
TOLECTIN is contraindicated for the treatment of peri-operative pain in the setting
of coronary artery bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDS of up to three
years duration have shown an increased risk of serious cardiovascular (CV)
thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs,
both COX-2 selective and nonselective, may have a similar risk. Patients with known
CV disease or risk factors for CV disease may be at greater risk. To minimize the
potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and
patients should remain alert for the development of such events, even in the absence
of previous CV symptoms. Patients should be informed about the signs and/or
symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased
risk of serious CV thrombotic events associated with NSAID use. The concurrent use
of aspirin and an NSAID does increase the risk of serious GI events (see
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
WARNINGS: Gastrointestinal (GI) Effects—Risk of Ulceration, Bleeding, and
Perforation).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of
pain in the first 10 to 14 days following CABG surgery found an increased incidence
of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including TOLECTIN, can lead to onset of new hypertension or worsening
of preexisting hypertension, either of which may contribute to the increased incidence
of CV events. Patients taking thiazides or loop diuretics may have impaired response
to these therapies when taking NSAIDs. NSAIDs, including TOLECTIN, should be
used with caution in patients with hypertension. Blood pressure (BP) should be
monitored closely during the initiation of NSAID treatment and throughout the course
of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs.
TOLECTIN should be used with caution in patients with fluid retention or heart
failure.
Gastrointestinal (GI) Effects—Risk of Ulceration, Bleeding, and
Perforation
NSAIDs, including TOLECTIN, can cause serious gastrointestinal adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach, small
intestine or large intestine, which can be fatal. These serious adverse events can occur
at any time, with or without warning symptoms in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by
NSAIDS occur in approximately 1% of patients treated for 3 to 6 months, and in
about 2 to 4% of patients treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI event at some
time during the course of therapy. However, even short-term therapy is not without
risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of
ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer
disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold
increased risk for developing a GI bleed compared to patients with neither of these
risk factors. Other factors that increase the risk for GI bleeding in patients treated
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
with NSAIDs include concomitant use of oral corticosteroids or anticoagulants,
longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or
debilitated patients and, therefore, special care should be taken in treating this
population.
To minimize the potential risk for an adverse GI event in patients treated with an
NSAID, the lowest effective dose should be used for the shortest possible duration.
Patients and physicians should remain alert for signs and symptoms of GI ulceration
and bleeding during NSAID therapy and promptly initiate additional evaluation and
treatment if a serious GI adverse event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-
risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and
other renal injury. including reports of aAcute interstitial nephritis with hematuria,
proteinuria, and occasionally nephrotic syndrome have been reported in patients
treated with TOLECTIN. Renal toxicity has also been seen in patients in whom renal
prostaglandins have a compensatory role in the maintenance of renal perfusion. In
these patients, administration of an NSAID may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, which may precipitate
overt renal decompensation. Patients at greatest risk of this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking diuretics and
ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical trials regarding the use of
TOLECTIN in patients with advanced renal disease. Therefore, treatment with
TOLECTIN is not recommended in these patients with advanced renal disease. If
TOLECTIN therapy must be initiated, close monitoring of the patient’s renal function
is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients with known
prior exposure to TOLECTIN. TOLECTIN should not be given to patients with the
aspirin triad. This symptom complex typically occurs in asthmatic patients who
experience rhinitis with or without nasal polyps, or who exhibit severe, potentially
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
fatal
bronchospasm
after
taking
aspirin
or
other
NSAIDS
(see
CONTRAINDICATIONS
and
PRECAUTIONS:
Preexisting
Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including TOLECTIN, can cause serious skin adverse events such as
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis (TEN), which can be fatal. These serious events may occur without
warning. Patients should be informed about the signs and symptoms of serious skin
manifestations and use of the drug should be discontinued at the first appearance of
skin rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided because it
may cause premature closure of the ductus arteriosus (see also PRECAUTIONS:
Pregnancy).
PRECAUTIONS
General
TOLECTIN cannot be expected to substitute for corticosteroids or to treat
corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to
disease exacerbation. Patients on prolonged corticosteroid therapy should have their
therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of TOLECTIN in reducing fever and inflammation may
diminish the utility of these diagnostic signs in detecting complications of presumed
noninfectious, painful conditions.
Ophthalmological Effects
Because of ocular changes observed in animals and of reports of adverse eye findings
with NSAIDs, it is recommended that patients who develop visual disturbances
during treatment with TOLECTIN have ophthalmologic evaluations.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients
taking NSAIDs, including TOLECTIN. These laboratory abnormalities may progress,
may remain unchanged, or may be transient with continuing therapy. Notable
elevations of ALT or AST (approximately three or more times the upper limit of
normal) have been reported in approximately 1% of patients in clinical trials with
NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal
outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an
abnormal liver test has occurred should be evaluated for evidence of the development
of a more severe hepatic reaction while on therapy with TOLECTIN. If clinical signs
and symptoms consistent with liver disease develop, or if systemic manifestations
occur (e.g., eosinophilia, rash, etc.), TOLECTIN should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including TOLECTIN. This
may be due to fluid retention, occult or gross GI blood loss, or an incompletely
described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs,
including TOLECTIN, should have their hemoglobin or hematocrit checked if they
exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and
have been shown to prolong bleeding time in some patients. Unlike aspirin, their
effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving TOLECTIN who may be adversely affected by alterations in
platelet function, such as those with coagulation disorders or patients receiving
anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients
with aspirin-sensitive asthma has been associated with severe bronchospasm which
can be fatal. Since cross reactivity, including bronchospasm, between aspirin and
other NSAIDs has been reported in such aspirin-sensitive patients, TOLECTIN
should not be administered to patients with this form of aspirin sensitivity and should
be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating
therapy with an NSAID and periodically during the course of ongoing therapy.
Patients should also be encouraged to read the NSAID Medication Guide that
accompanies each prescription dispensed.
1. TOLECTIN, like other NSAIDs, may cause serious CV side effects, such as
MI or stroke, which may result in hospitalization and even death. Although
serious CV events can occur without warning symptoms, patients should be
alert for the signs and symptoms of chest pain, shortness of breath, weakness,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
slurring of speech, and should ask for medical advice when observing any
indicative signs or symptoms. Patients should be apprised of the importance of
this follow-up (see WARNINGS: Cardiovascular Effects).
2. TOLECTIN, like other NSAIDs, can cause GI discomfort and, rarely, serious
GI side effects, such as ulcers and bleeding, which may result in
hospitalization and even death. Although serious GI tract ulcerations and
bleeding can occur without warning symptoms, patients should be alert for the
signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric
pain, dyspepsia, melena, and hematemesis Patients should be apprised of the
importance of this follow-up (see WARNINGS: Gastrointestinal (GI)
Effects—Risk of Ulceration, Bleeding, and Perforation).
3. TOLECTIN, like other NSAIDs, can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and
even death. Although serious skin reactions may occur without warning,
patients should be alert for the signs and symptoms of skin rash and blisters,
fever, or other signs of hypersensitivity, such as itching, and should ask for
medical advise when observing any indicative signs or symptoms. Patients
should be advised to stop the drug immediately if they develop any type of
rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper
quadrant tenderness, and “flu-like” symptoms). If these occur, patients should
be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g.,
difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided
because it may cause premature closure of the ductus arteriosus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning
symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients
on long-term treatment with NSAIDs should have their CBC and a chemistry profile
checked periodically. If clinical signs and symptoms consistent with liver or renal
disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if
abnormal liver tests persist or worsen, TOLECTIN should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-
inhibitors. This interaction should be given consideration in patients taking NSAIDs
concomitantly with ACE-inhibitors.
Aspirin
As with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is
not generally recommended because of the potential of increased adverse effects.
Diuretics
Clinical studies, as well as post-marketing observations, have shown that NSAIDs
can reduce the natriuretic effect of furosemide and thiazides in some patients. This
response has been attributed to inhibition of renal prostaglandin synthesis. During
concomitant therapy with NSAIDs, the patient should be observed closely for signs of
renal failure, as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal
lithium clearance. The mean minimum lithium concentration increased 15% and the
renal clearance was decreased by approximately 20%. These effects have been
attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when
NSAIDs and lithium are administered concurrently, subjects should be observed
carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in
rabbit kidney slices. This may indicate that they could enhance the toxicity of
methotrexate. Caution should be used when NSAIDs are administered concomitantly
with methotrexate.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of
both drugs together have a risk of serious GI bleeding higher than users of either drug
alone.
The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin,
and tolmetin does not alter the prothrombin time of normal volunteers. However,
increased prothrombin time and bleeding have been reported in patients on
concomitant TOLECTIN and warfarin therapy. Therefore, caution should be
exercised when administering TOLECTIN to patients on anticoagulants.
Hypoglycemic Agents
In adult diabetic patients under treatment with either sulfonylureas or insulin there is
no change in the clinical effects of either TOLECTIN or the hypoglycemic agents.
Drug/Laboratory Test Interactions
The metabolites of tolmetin sodium in urine have been found to give positive tests for
proteinuria using tests which rely on acid precipitation as their endpoint
(e.g., sulfosalicylic acid). No interference is seen in the tests for proteinuria using
dye-impregnated commercially available reagent strips (e.g., Albustix®, Uristix®,
etc.).
Drug-Food Interactions
In a controlled single-dose study, administration of TOLECTIN with milk had no
effect on peak plasma tolmetin concentrations, but decreased total tolmetin
bioavailability by 16%. When TOLECTIN was taken immediately after a meal, peak
plasma tolmetin concentrations were reduced by 50% while total bioavailability was
again decreased by 16%.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tolmetin sodium did not possess any carcinogenic liability in the following long-term
studies: a 24-month study in rats at doses as high as 75 mg/kg/day, and an 18-month
study in mice at doses as high as 50 mg/kg/day.
No mutagenic potential of tolmetin sodium was found in the Ames
Salmonella-Microsomal Activation Test.
Reproductive studies revealed no impairment of fertility in animals. Effects on
parturition have been shown, however, as with other prostaglandin inhibitors. This
information is detailed in the Pregnancy section.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Pregnancy
Teratogenic Effects: Pregnancy Category C
Reproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the
maximum clinical dose based on a body weight of 60 kg) revealed no evidence of
teratogenesis or impaired fertility due to TOLECTIN. However, animal reproduction
studies are not always predictive of human response. There are no adequate and well-
controlled studies in pregnant women. TOLECTIN should be used in pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of NSAIDs on the fetal cardiovascular system (closure
of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin
synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup
survival occurred. The effects of TOLECTIN on labor and delivery in pregnant
women are unknown.
Nursing Mothers
Tolmetin sodium has been shown to be secreted in human milk. Because of the
potential for serious adverse reactions in nursing infants from tolmetin sodium, 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 pediatric patients below the age of 2 years have not been
established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years
and older).
ADVERSE REACTIONS
The adverse reactions which have been observed in clinical trials encompass
observations in about 4370 patients treated with TOLECTIN (tolmetin sodium), over
800 of whom have undergone at least one year of therapy. These adverse reactions,
reported below by body system, are among those typical of nonsteroidal
anti-inflammatory drugs and, as expected, gastrointestinal complaints were most
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
frequent. In clinical trials with TOLECTIN, about 10% of patients dropped out
because of adverse reactions, mostly gastrointestinal in nature.
Incidence Greater Than 1%
The following adverse reactions which occurred more frequently than 1 in 100 were
reported in controlled clinical trials.
Gastrointestinal: Nausea (11%), dyspepsia,* gastrointestinal distress,* abdominal
pain,* diarrhea,* flatulence,* vomiting,* constipation, gastritis, and peptic ulcer.
Forty percent of the ulcer patients had a prior history of peptic ulcer disease and/or
were receiving concomitant anti-inflammatory drugs including corticosteroids, which
are known to produce peptic ulceration.
Body as a Whole: Headache, * asthenia, * chest pain
Cardiovascular: Elevated blood pressure, * edema*
Central Nervous System: Dizziness, * drowsiness, depression
Metabolic/Nutritional: Weight gain, * weight loss*
Dermatologic: Skin irritation
Special Senses: Tinnitus, visual disturbance
Hematologic: Small and transient decreases in hemoglobin and hematocrit not
associated with gastrointestinal bleeding have occurred. These are similar to changes
reported with other nonsteroidal anti-inflammatory drugs.
Urogenital: Elevated BUN, urinary tract infection
*Reactions occurring in 3% to 9% of patients treated with TOLECTIN. Reactions
occurring in fewer than 3% of the patients are unmarked.
Incidence Less Than 1%
(Causal Relationship Probable)
The following adverse reactions were reported less frequently than 1 in
100 controlled clinical trials or were reported since marketing. The probability exists
that there is a causal relationship between TOLECTIN and these adverse reactions.
Gastrointestinal: Gastrointestinal bleeding with or without evidence of peptic ulcer,
perforation, glossitis, stomatitis, hepatitis, liver function abnormalities.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Body as a Whole: Anaphylactoid reactions, fever, lymphadenopathy, serum sickness
Hematologic:
Hemolytic
anemia,
thrombocytopenia,
granulocytopenia,
agranulocytosis
Cardiovascular: Congestive heart failure in patients with marginal cardiac function.
Dermatologic: Urticaria, purpura, erythema multiforme, toxic epidermal necrolysis
Urogenital: Hematuria, proteinuria, dysuria, renal failure
Incidence Less Than 1%
(Causal Relationship Unknown)
Other adverse reactions were reported less frequently than 1 in 100 in controlled
clinical trials or were reported since marketing, but a causal relationship between
TOLECTIN and the reaction could not be determined. These rarely reported reactions
are being listed as alerting information for the physician since the possibility of a
causal relationship cannot be excluded.
Body as a Whole: Epistaxis
Special Senses: Optic neuropathy, retinal and macular changes
MANAGEMENT OF OVERDOSAGE
In the event of overdosage, the stomach should be emptied by inducing vomiting or
by gastric lavage followed by the administration of activated charcoal.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of TOLECTIN and other treatment
options before deciding to use TOLECTIN. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see
WARNINGS).
After observing the response to initial therapy with TOLECTIN, the dose and
frequency should be adjusted to suit an individual patient’s needs.
For the relief of rheumatoid arthritis or osteoarthritis, the recommended starting dose
for adults is 400 mg three times daily (1200 mg daily), preferably including a dose on
arising and a dose at bedtime. To achieve optimal therapeutic effect the dose should
be adjusted according to the patient’s response after one or two weeks. Control is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
usually achieved at doses of 600-1800 mg daily in divided doses (generally t.i.d.).
Doses larger than 1800 mg/day have not been studied and are not recommended.
For the relief of juvenile rheumatoid arthritis, the recommended starting dose for
pediatric patients (2 years and older) is 20 mg/kg/day in divided doses (t.i.d. or q.i.d.).
When control has been achieved, the usual dose ranges from 15 to 30 mg/kg/day.
Doses higher than 30 mg/kg/day have not been studied, and, therefore, are not
recommended.
A therapeutic response to TOLECTIN (tolmetin sodium) can be expected in a few
days to a week. Progressive improvement can be anticipated during succeeding weeks
of therapy. If gastrointestinal symptoms occur, TOLECTIN can be administered with
antacids
other
than
sodium
bicarbonate.
TOLECTIN
bioavailability
and
pharmacokinetics are not significantly affected by acute or chronic administration of
magnesium and aluminum hydroxides; however, bioavailability is affected by food or
milk (see PRECAUTIONS: Drug-Food Interaction).
HOW SUPPLIED
TOLECTIN® DS (tolmetin sodium) capsules 400 mg (colored orange opaque with
contrasting parallel bands, imprinted “TOLECTIN DS” and “McNEIL”), NDC
0045-0414, bottles of 100 and 500.
TOLECTIN® 600 (tolmetin sodium) tablets 600 mg (colored orange, film coated,
imprinted “TOLECTIN 600” and “McNEIL”), NDC 0045-0416, bottles of 100 and
500.
Dispense in tight, light-resistant container as defined in the official compendium.
Store at controlled room temperature (15°-30°C, 59°-86°F). Protect from light.
ORTHO-McNEIL logo
OMP DIVISION
ORTHO-McNEIL PHARMACEUTICAL, INC.
Raritan, NJ 08869
Printed in U.S.A.
©OMP 2006
Revised
Month
2006
XXXXXXX
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines
called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke
that can lead to death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart
surgery called a “coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and
intestines at any time during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat
(inflammation) from medical conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or
any other NSAID medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can
interact with each other and cause serious side effects. Keep a list of your
medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant
women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid
retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and
intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following
symptoms:
• shortness of breath or trouble
breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your
body
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
Stop your NSAID medicine and call your healthcare provider right away
if you have any of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and
sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs,
hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare
provider or pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart
attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin
can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription
(over-the-counter). Talk to your healthcare provider before using over-the-counter
NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with
hydrocodone), Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan,
Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:20.145962
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017628s067,018084s051lbl.pdf', 'application_number': 17628, 'submission_type': 'SUPPL ', 'submission_number': 67}
|
11,054
|
FLORONE®
diflorasone diacetate cream, USP
0.05%
Not For Ophthalmic Use
DESCRIPTION
Each gram of FLORONE Cream contains 0.5 mg
diflorasone diacetate in a cream base.
Chemically, diflorasone diacetate is: 6α,9-Difluoro-
11β, 17, 21-trihydroxy-16β-methylpregna-1,4-diene-
3,20-dione 17,21-diacetate.
The structural formula is represented below:
FLORONE Cream contains diflorasone diacetate in
an emulsified and hydrophilic cream base of pro-
pylene glycol, stearic acid, polysorbate 60, sorbitan
monostearate and monooleate, sorbic acid, citric
acid and water. The corticosteroid is formulated as a
solution in the vehicle using 15 percent propylene
glycol to optimize drug delivery.
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, anti-
pruritic and vasoconstrictive actions.
The mechanism of anti-inflammatory activity of the
topical corticosteroids is unclear. Various laboratory
methods, including vasoconstrictor assays, are used
to compare and predict potencies and/or clinical effi-
cacies of the topical corticosteroids. There is some
evidence to suggest that a recognizable correlation
exists between vasoconstrictor potency and thera-
peutic efficacy in man.
Pharmacokinetics
The extent of percutaneous absorption of topical cor-
ticosteroids is determined by many factors including
the vehicle, the integrity of the epidermal barrier,
and the use of occlusive dressings.
Topical corticosteroids can be absorbed from normal
intact skin. Inflammation and/or other disease pro-
cesses in the skin increase percutaneous absorp-
tion. Occlusive dressings substantially increase the
percutaneous absorption of topical corticosteroids.
Thus, occlusive dressings may be a valuable thera-
peutic adjunct for treatment of resistant dermatoses.
(See DOSAGE AND ADMINISTRATION.)
Once absorbed through the skin, topical cortico-
steroids are handled through pharmacokinetic path-
ways similar to systemically administered cortico-
steroids. Corticosteroids are bound to plasma
proteins in varying degrees. They 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.
INDICATIONS AND USAGE
Topical corticosteroids are indicated for relief of the
inflammatory and pruritic manifestations of cortico-
steroid responsive dermatoses.
CONTRAINDICATIONS
Topical steroids are contraindicated in those patients
with a history of hypersensitivity to any of the com-
ponents of the preparation.
PRECAUTIONS
C
H
CH3
CH2OCCH3
OCCH3
CH3
O
O
O
H
H
H
O
H
F
HO
CH3
F
FLORONE
diflorasone diacetate
cream, USP
FPO
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General
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.
Conditions which augment systemic absorption
include the application of the more potent steroids,
use over large surface areas, prolonged use, and the
addition of occlusive dressings.
Therefore, patients receiving a large dose of a
potent topical steroid applied to a large surface area
or under an occlusive dressing should be evaluated
periodically for evidence of HPA axis suppression by
using the urinary free cortisol and ACTH stimulation
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 steroid.
Recovery of HPA axis function is generally prompt
and complete upon discontinuation of the drug.
Infrequently, signs and symptoms of steroid
withdrawal may occur, requiring supplemental
systemic corticosteroids.
Pediatric patients may absorb proportionally larger
amounts of topical corticosteroids and thus be more
susceptible to systemic toxicity. (See PRE-
CAUTIONS—Pediatric Use.)
If irritation develops, topical corticosteroids should
be discontinued and appropriate therapy instituted.
In the presence of dermatological infections, the use
of an appropriate antifungal or antibacterial agent
should be instituted. If a favorable response does
not occur promptly, the corticosteroid should be dis-
continued until the infection has been adequately
controlled.
Information for the Patient
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 con-
tact with the eyes.
2. Patients should be advised not to use this med-
ication for any disorder other than for which it was
prescribed.
3. The treated skin area should not be bandaged or
otherwise covered or wrapped as to be occlusive
unless directed by the physician.
4. Patients should report any signs of local adverse
reactions especially under occlusive dressing.
5. Parents of pediatric patients should be advised
not to use tight-fitting diapers or plastic pants on
an infant or child being treated in the diaper area,
as these garments may constitute occlusive
dressings.
Laboratory Tests
The following tests may be helpful in evaluating the
HPA axis suppression:
Urinary free cortisol test
ACTH stimulation test
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Long-term animal studies have not been performed
to evaluate the carcinogenic potential or the effect of
topical corticosteroids on fertility.
Studies to determine mutagenicity with prednisolone
and hydrocortisone have revealed negative results.
Pregnancy Category C
Corticosteroids are generally teratogenic in labora-
tory animals when administered systemically at rela-
tively low dosage levels. The more potent cortico-
steroids have been shown to be teratogenic after
dermal application in laboratory animals. There are
no adequate and well-controlled studies in pregnant
women on teratogenic effects from topically applied
corticosteroids. Therefore, topical corticosteroids
should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. Drugs
of this class should not be used extensively on preg-
nant patients, in large amounts, or for prolonged
periods of time.
Nursing Mothers
It is not known whether topical administration of
corticosteroids could result in sufficient systemic
absorption to produce detectable quantities in breast
milk. Systemically administered corticosteroids are
secreted into breast milk in quantities not likely to
have a deleterious effect on the infant. Nevertheless,
caution should be exercised when topical cortico-
steroids are administered to a nursing woman.
Pediatric Use
Safety and effectiveness of FLORONE in pediatric
patients have not been established. Because of a
higher ratio of skin surface area to body mass, pedi-
atric patients are at greater risk than adults of HPA-
axis suppression when they are treated with topical
corticosteroids. They are, therefore, also at greater
risk of glucocorticosteroid insufficiency after with-
drawal of treatment and of Cushing’s syndrome while
on treatment. Adverse effects including striae have
been reported with inappropriate use of topical corti-
costeroids in pediatric patients.
HPA-axis suppression, Cushing’s syndrome, and
intracranial hypertension have been reported in pedi-
atric patients receiving topical corticosteroids.
Manifestations of adrenal suppression in pediatric
patients include linear growth retardation, delayed
weight gain, low plasma cortisol levels, and absence
of response to ACTH stimulation. Manifestations of
intracranial hypertension include bulging fontanelles,
headaches, and bilateral papilledema.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
The following local adverse reactions have been
reported with topical corticosteroids, but may occur
more frequently with the use of occlusive dressings.
These reactions are listed in an approximate
decreasing order of occurrence:
Burning
Itching
Irritation
Dryness
Folliculitis
Hypertrichosis
Acneiform eruptions
Hypopigmentation
Perioral dermatitis
Allergic contact dermatitis
Maceration of the skin
Secondary infection
Skin atrophy
Striae
Miliaria
OVERDOSAGE
Topically applied corticosteroids can be absorbed in
sufficient amounts to produce systemic effects. (See
PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Topical corticosteroids are generally applied to the
affected area as a thin film from one to four times
daily depending on the severity of the condition.
Occlusive dressings may be used for the manage-
ment of psoriasis or recalcitrant conditions.
If an infection develops, the use of occlusive dress-
ings should be discontinued and appropriate antimi-
crobial therapy instituted.
HOW SUPPLIED
FLORONE Cream is available in 30 gram and 60
gram collapsible tubes.
Store at controlled room temperature 20° to 25° C
(68° to 77° F) [see USP].
%only
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, Michigan 49001
Revised May 2003
DAW123B
691312
FLORONE
brand of diflorasone diacetate cream, USP
0.05%
(continued below)
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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Page 3
FLORONE®
diflorasone diacetate cream, USP
0.05%
Not For Ophthalmic Use
DESCRIPTION
Each gram of FLORONE Cream contains 0.5 mg diflorasone diacetate in a cream base.
Chemically, diflorasone diacetate is: 6α,9-Difluoro-11β, 17, 21-trihydroxy-16β-methylpregna-1,4-
diene-3,20-dione 17,21-diacetate.
The structural formula is represented below:
FLORONE Cream contains diflorasone diacetate in an emulsified and hydrophilic cream base of
propylene glycol, stearic acid, polysorbate 60, sorbitan monostearate and monooleate, sorbic acid,
citric acid and water. The corticosteroid is formulated as a solution in the vehicle using 15 percent
propylene glycol to optimize drug delivery.
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various
laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or
clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable
correlation exists between vasoconstrictor potency and therapeutic efficacy in man.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-741/S-022
Page 4
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.
Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease
processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the
percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable
therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.)
Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways
similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in
varying degrees. They 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.
INDICATIONS AND USAGE
Topical corticosteroids are indicated for relief of the inflammatory and pruritic manifestations of
corticosteroid responsive dermatoses.
CONTRAINDICATIONS
Topical steroids are contraindicated in those patients with a history of hypersensitivity to any of the
components of the preparation.
PRECAUTIONS
General
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.
Conditions which augment systemic absorption include the application of the more potent steroids, use
over large surface areas, prolonged use, and the addition of occlusive dressings.
Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or
under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by
using the urinary free cortisol and ACTH stimulation 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 steroid.
Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.
Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic
corticosteroids.
Pediatric patients may absorb proportionally larger amounts of topical corticosteroids and thus be more
susceptible to systemic toxicity. (See PRECAUTIONS—Pediatric Use.)
If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent
should be instituted. If a favorable response does not occur promptly, the corticosteroid should be
discontinued until the infection has been adequately controlled.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-741/S-022
Page 5
Information for the Patient
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. Patients should be advised not to use this medication for any disorder other than for which it was
prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive
unless directed by the physician.
4. Patients should report any signs of local adverse reactions especially under occlusive dressing.
5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on an
infant or child being treated in the diaper area, as these garments may constitute occlusive
dressings.
Laboratory Tests
The following tests may be helpful in evaluating the HPA axis suppression:
Urinary free cortisol test
ACTH stimulation test
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect
of topical corticosteroids on fertility.
Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative
results.
Pregnancy Category C
Corticosteroids are generally teratogenic in laboratory animals when administered systemically at
relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after
dermal application in laboratory animals. There are no adequate and well-controlled studies in
pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical
corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts,
or for prolonged periods of time.
Nursing Mothers
It is not known whether topical administration of corticosteroids could result in sufficient systemic
absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids
are secreted into breast milk in quantities not likely to have a deleterious effect on the infant.
Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of FLORONE in pediatric patients have not been established. Because of a
higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of HPA-
axis suppression when they are treated with topical corticosteroids. They are, therefore, also at greater
risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing ’s syndrome
while on treatment. Adverse effects including striae have been reported with inappropriate use of
topical corticosteroids in pediatric patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-741/S-022
Page 6
HPA-axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in
pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric
patients include linear growth retardation, delayed weight gain, 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 diflorasone diacetate topical formulations did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects.
ADVERSE REACTIONS
The following local adverse reactions have been reported with topical corticosteroids, but may occur
more frequently with the use of occlusive dressings. These reactions are listed in an approximate
decreasing order of occurrence:
Burning
Itching
Irritation
Dryness
Folliculitis
Hypertrichosis
Acneiform eruptions
Hypopigmentation
Perioral dermatitis
Allergic contact dermatitis
Maceration of the skin
Secondary infection
Skin atrophy
Striae
Miliaria
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects.
(See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Topical corticosteroids are generally applied to the affected area as a thin film from one to four times
daily depending on the severity of the condition.
Occlusive dressings may be used for the management of psoriasis or recalcitrant conditions.
If an infection develops, the use of occlusive dressings should be discontinued and appropriate
antimicrobial therapy instituted.
HOW SUPPLIED
FLORONE Cream is available in 30 gram and 60 gram collapsible tubes.
Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP].
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-741/S-022
Page 7
Rx only
Pharmacia & Upjohn Company
A subsidiary of Pharmacia Corporation
Kalamazoo, Michigan 49001
Revised [updated revision date]
[updated code]
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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ORTHO-NOVUM® Tablets (norethindrone/ethinyl estradiol)
and MODICON® Tablets (norethindrone/ethinyl estradiol)
WARNINGS: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING
Cigarette smoking increases the risk of serious cardiovascular events from
combination oral contraceptive use. This risk increases with age, particularly in
women over 35 years of age, and with the number of cigarettes smoked. For this
reason, combination oral contraceptives, including ORTHO-NOVUM and
MODICON, should not be used by women who are over 35 years of age and smoke.
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
COMBINED ORAL CONTRACEPTIVES
Each of the following products is a combined oral contraceptive containing the
progestational compound norethindrone and the estrogenic compound ethinyl
estradiol.
ORTHO-NOVUM® 7/7/7 Tablets
Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol.
Inactive ingredients include lactose, magnesium stearate and pregelatinized corn
starch. Each light peach tablet contains 0.75 mg of norethindrone and 0.035 mg of
ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose,
magnesium stearate and pregelatinized corn starch. Each peach tablet contains 1 mg
of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include
FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch.
Each green tablet contains only inert ingredients, as follows: D&C Yellow
No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium
stearate, microcrystalline cellulose and pregelatinized corn starch.
ORTHO-NOVUM® 1/35 Tablets
Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol.
Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and
pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed
under green tablets in ORTHO-NOVUM® 7/7/7.
MODICON® Tablets
Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol.
Inactive ingredients include lactose, magnesium stearate and pregelatinized corn
Reference ID: 3383539
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
starch. Each green tablet contains only inert ingredients, as listed under green tablets
in ORTHO-NOVUM® 7/7/7.
The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn
3-one, and for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17
diol. Their structural formulas are as follows:
Norethindrone
Ethinyl estradiol
CLINICAL PHARMACOLOGY
Combined Oral Contraceptives
Combined oral contraceptives act by suppression of gonadotropins. Although the
primary mechanism of this action is inhibition of ovulation, other alterations include
changes in the cervical mucus (which increase the difficulty of sperm entry into the
uterus) and the endometrium (which reduce the likelihood of implantation).
INDICATIONS AND USAGE
ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® Tablets are
indicated for the prevention of pregnancy in women who elect to use this product as a
method of contraception.
Oral contraceptives are highly effective. Table 1 lists the typical accidental pregnancy
rates for users of combined oral contraceptives and other methods of contraception.
The efficacy of these contraceptive methods, except sterilization, the IUD, and the
NORPLANT® System depends upon the reliability with which they are used. Correct
and consistent use of methods can result in lower failure rates.
Table 1:
Percentage of Women Experiencing an Unintended Pregnancy During the First
Year of Typical Use and the First Year of Perfect Use of Contraception and the
Percentage Continuing Use at the End of the First Year. United States.
% of Women Experiencing an Unintended
Pregnancy within the First Year of Use
% of Women Continuing
Use at One Year*
Method
Typical Use†
Perfect Use‡
(1)
(2)
(3)
(4)
Chance#
85
85
SpermicidesÞ
26
6
40
Periodic abstinence
25
63
2
Reference ID: 3383539
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1:
Percentage of Women Experiencing an Unintended Pregnancy During the First
Year of Typical Use and the First Year of Perfect Use of Contraception and the
Percentage Continuing Use at the End of the First Year. United States.
% of Women Experiencing an Unintended % of Women Continuing
Pregnancy within the First Year of Use
Use at One Year*
Method
Typical Use†
Perfect Use‡
(1)
(2)
(3)
(4)
Calendar
9
Ovulation Method
3
Sympto-Thermalß
2
Post-Ovulation
1
Capà
Parous Women
40
26
42
Nulliparous Women
20
9
56
Sponge
Parous Women
40
20
42
Nulliparous Women
20
9
56
Diaphragmà
20
6
56
Withdrawal
19
4
Condomè
Female (Reality®)
21
5
56
Male
14
3
61
Pill
5
71
Progestin Only
0.5
Combined
0.1
IUD
Progesterone T
2.0
1.5
81
Copper T380A
0.8
0.6
78
LNg 20
0.1
0.1
81
Depo-Provera®
0.3
0.3
70
Norplant® and Norplant-2®
0.05
0.05
88
Female Sterilization
0.5
0.5
100
Male Sterilization
0.15
0.10
100
Reference ID: 3383539
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1:
Percentage of Women Experiencing an Unintended Pregnancy During the First
Year of Typical Use and the First Year of Perfect Use of Contraception and the
Percentage Continuing Use at the End of the First Year. United States.
% of Women Experiencing an Unintended % of Women Continuing
Pregnancy within the First Year of Use
Use at One Year*
Method
Typical Use†
Perfect Use‡
(1)
(2)
(3)
(4)
Adapted from Hatcher et al, 1998, Ref. # 1.
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse
reduces the risk of pregnancy by at least 75%.§
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶
Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK,
Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY:
Irvington Publishers, 1998.
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one
year.
† Among typical couples who initiate use of a method (not necessarily for the first time), the
percentage who experience an accidental pregnancy during the first year if they do not stop use for
any other reason.
‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it
perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy
during the first year if they do not stop use for any other reason.
§ The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose
12 hours after the first dose. The Food and Drug Administration has declared the following brands of
oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white
pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light-orange pills),
Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills).
¶ However, to maintain effective protection against pregnancy, another method of contraception must
be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle
feeds are introduced, or the baby reaches six months of age.
# The percents becoming pregnant in columns (2) and (3) are based on data from populations where
contraception is not used and from women who cease using contraception in order to become
pregnant. Among such populations, about 89% become pregnant within one year. This estimate was
lowered slightly (to 85%) to represent the percent who would become pregnant within one year
among women now relying on reversible methods of contraception if they abandoned contraception
altogether.
Þ Foams, creams, gels, vaginal suppositories, and vaginal film.
ß Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body
temperature in the post-ovulatory phases.
à With spermicidal cream or jelly.
è Without spermicides.
ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35 and MODICON® have not been
studied for and are not indicated for use in emergency contraception.
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the following
conditions:
Thrombophlebitis or thromboembolic disorders
Reference ID: 3383539
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A past history of deep vein thrombophlebitis or thromboembolic disorders
Known thrombophilic conditions
Cerebral vascular or coronary artery disease (current or history)
Valvular heart disease with complications
Persistent blood pressure values of 160 mm Hg systolic or 100 mg Hg
diastolic96
Diabetes with vascular involvement
Headaches with focal neurological symptoms
Major surgery with prolonged immobilization
Known or suspected carcinoma of the breast
Carcinoma
of
the
endometrium
or
other
known
or
suspected
estrogen-dependent neoplasia
Undiagnosed abnormal genital bleeding
Cholestatic jaundice of pregnancy or jaundice with prior pill use
Acute or chronic hepatocellular disease with abnormal liver function
Hepatic adenomas or carcinomas
Known or suspected pregnancy
Hypersensitivity to any component of this product
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular events from
combination oral contraceptive use. This risk increases with age, particularly in
women over 35 years of age, and with the number of cigarettes smoked. For this
reason, combination oral contraceptives, including ORTHO-NOVUM and
MODICON, should not be used by women who are over 35 years of age and
smoke.
The use of oral contraceptives is associated with increased risks of several serious
conditions including myocardial infarction, thromboembolism, stroke, hepatic
neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality
is very small in healthy women without underlying risk factors. The risk of morbidity
and mortality increases significantly in the presence of other underlying risk factors
such as hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following
information relating to these risks.
The information contained in this package insert is principally based on studies
carried out in patients who used oral contraceptives with higher formulations of
Reference ID: 3383539
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
estrogens and progestogens than those in common use today. The effect of long-term
use of the oral contraceptives with lower formulations of both estrogens and
progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types:
retrospective or case control studies and prospective or cohort studies. Case control
studies provide a measure of the relative risk of a disease, namely, a ratio of the
incidence of a disease among oral contraceptive users to that among nonusers. The
relative risk does not provide information on the actual clinical occurrence of a
disease. Cohort studies provide a measure of attributable risk, which is the difference
in the incidence of disease between oral contraceptive users and nonusers. The
attributable risk does provide information about the actual occurrence of a disease in
the population (adapted from refs. 2 and 3 with the author’s permission). For further
information, the reader is referred to a text on epidemiological methods.
1. Thromboembolic Disorders and Other Vascular Problems
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral contraceptive
use. This risk is primarily in smokers or women with other underlying risk factors for
coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity,
and diabetes. The relative risk of heart attack for current oral contraceptive users has
been estimated to be two to six.4–10 The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute
substantially to the incidence of myocardial infarctions in women in their mid-thirties
or older with smoking accounting for the majority of excess cases.11 Mortality rates
associated with circulatory disease have been shown to increase substantially in
smokers, especially in those 35 years of age and older, and in nonsmokers over the
age of 40 among women who use oral contraceptives. (See Figure 1).
Reference ID: 3383539
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 1.
Circulatory Disease Mortality Rates per 100,000 Women-Years by Age,
Smoking Status and Oral Contraceptive Use
(Adapted from P.M. Layde and V. Beral, ref. #12.)
Oral contraceptives may compound the effects of well-known risk factors, such as
hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some
progestogens are known to decrease HDL cholesterol and cause glucose intolerance,
while estrogens may create a state of hyperinsulinism.14–18 Oral contraceptives have
been shown to increase blood pressure among users (see Section 9 in WARNINGS).
Similar effects on risk factors have been associated with an increased risk of heart
disease. Oral contraceptives must be used with caution in women with cardiovascular
disease risk factors.
b. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the use
of oral contraceptives is well established. Case control studies have found the relative
risk of users compared to nonusers to be 3 for the first episode of superficial venous
thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for
women with predisposing conditions for venous thromboembolic disease.2,3,19–24
Cohort studies have shown the relative risk to be somewhat lower, about 3 for new
cases and about 4.5 for new cases requiring hospitalization.25 The risk of
thromboembolic disease associated with oral contraceptives is not related to length of
use and disappears after pill use is stopped.2
A two- to four-fold increase in relative risk of post-operative thromboembolic
complications has been reported with the use of oral contraceptives.9 The relative risk
of venous thrombosis in women who have predisposing conditions is twice that of
women without such medical conditions.26 If feasible, oral contraceptives should be
discontinued at least four weeks prior to and for two weeks after elective surgery of a
type associated with an increase in risk of thromboembolism and during and
Reference ID: 3383539
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
following prolonged immobilization. Since the immediate postpartum period is also
associated with an increased risk of thromboembolism, oral contraceptives should be
started no earlier than four weeks after delivery in women who elect not to breastfeed.
c. Cerebrovascular diseases
Oral contraceptives have been shown to increase both the relative and attributable
risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in
general, the risk is greatest among older (>35 years), hypertensive women who also
smoke. Hypertension was found to be a risk factor for both users and nonusers, for
both types of strokes, and smoking interacted to increase the risk of stroke.27–29
In a large study, the relative risk of thrombotic strokes has been shown to range from
3 for normotensive users to 14 for users with severe hypertension.30 The relative risk
of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral
contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers
who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with
severe hypertension.30 The attributable risk is also greater in older women.3
d. Dose-related risk of vascular disease from oral contraceptives
A positive association has been observed between the amount of estrogen and
progestogen in oral contraceptives and the risk of vascular disease.31–33 A decline in
serum high density lipoproteins (HDL) has been reported with many progestational
agents.14–16 A decline in serum high density lipoproteins has been associated with an
increased incidence of ischemic heart disease. Because estrogens increase HDL
cholesterol, the net effect of an oral contraceptive depends on a balance achieved
between doses of estrogen and progestogen and the activity of the progestogen used
in the contraceptives. The activity and amount of both hormones should be
considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles
of therapeutics. For any particular estrogen/progestogen combination, the dosage
regimen prescribed should be one which contains the least amount of estrogen and
progestogen that is compatible with a low failure rate and the needs of the individual
patient. New acceptors of oral contraceptive agents should be started on preparations
containing the lowest estrogen content which is judged appropriate for the individual
patient.
e. Persistence of risk of vascular disease
There are two studies which have shown persistence of risk of vascular disease for
ever-users of oral contraceptives. In a study in the United States, the risk of
developing myocardial infarction after discontinuing oral contraceptives persists for
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at least 9 years for women 40–49 years who had used oral contraceptives for five or
more years, but this increased risk was not demonstrated in other age groups.8 In
another study in Great Britain, the risk of developing cerebrovascular disease
persisted for at least 6 years after discontinuation of oral contraceptives, although
excess risk was very small.34 However, both studies were performed with oral
contraceptive formulations containing 50 micrograms or higher of estrogens.
2. Estimates of Mortality From Contraceptive Use
One study gathered data from a variety of sources which have estimated the mortality
rate associated with different methods of contraception at different ages (Table 2).
These estimates include the combined risk of death associated with contraceptive
methods plus the risk attributable to pregnancy in the event of method failure. Each
method of contraception has its specific benefits and risks. The study concluded that
with the exception of oral contraceptive users 35 and older who smoke, and 40 and
older who do not smoke, mortality associated with all methods of birth control is low
and below that associated with childbirth. The observation of an increase in risk of
mortality with age for oral contraceptive users is based on data gathered in the
1970’s.35 Current clinical recommendation involves the use of lower estrogen dose
formulations and a careful consideration of risk factors. In 1989, the Fertility and
Maternal Health Drugs Advisory Committee was asked to review the use of oral
contraceptives in women 40 years of age and over. The Committee concluded that
although cardiovascular disease risks may be increased with oral contraceptive use
after age 40 in healthy non-smoking women (even with the newer low-dose
formulations), there are also greater potential health risks associated with pregnancy
in older women and with the alternative surgical and medical procedures which may
be necessary if such women do not have access to effective and acceptable means of
contraception. The Committee recommended that the benefits of low-dose oral
contraceptive use by healthy non-smoking women over 40 may outweigh the possible
risks.
Of course, older women, as all women who take oral contraceptives, should take an
oral contraceptive which contains the least amount of estrogen and progestogen that is
compatible with a low failure rate and individual patient needs.
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Table 2:
ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS
ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE
WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE
Method of control and outcome
15–19
20–24
25–29
30–34
35–39
40–44
No fertility-control methods*
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives non-smoker†
0.3
0.5
0.9
1.9
13.8
31.6
Oral contraceptives smoker†
2.2
3.4
6.6
13.5
51.1
117.2
IUD†
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
Adapted from H.W. Ory, ref. #35.
* Deaths are birth-related
† Deaths are method-related
3. Carcinoma of the Reproductive Organs and Breasts
Numerous epidemiological studies have been performed on the incidence of breast,
endometrial, ovarian and cervical cancer in women using oral contraceptives. The
risk of having breast cancer diagnosed may be slightly increased among current and
recent users of COCs. However, this excess risk appears to decrease over time after
COC discontinuation and by 10 years after cessation the increased risk disappears.
Some studies report an increased risk with duration of use while other studies do not
and no consistent relationships have been found with dose or type of steroid. Some
studies have found a small increase in risk for women who first use COCs before age
20. Most studies show a similar pattern of risk with COC use regardless of a woman’s
reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous OC users tend to be less clinically
advanced than in nonusers.
Women who currently have or have had breast cancer should not use oral
contraceptives because breast cancer is usually a hormonally-sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an increase
in the risk of cervical intraepithelial neoplasia in some populations of women.45–48
However, there continues to be controversy about the extent to which such findings
may be due to differences in sexual behavior and other factors.
In spite of many studies of the relationship between oral contraceptive use and breast
and cervical cancers, a cause-and-effect relationship has not been established.
4. Hepatic Neoplasia
Benign hepatic adenomas are associated with oral contraceptive use, although the
incidence of benign tumors is rare in the United States. Indirect calculations have
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estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk
that increases after four or more years of use especially with oral contraceptives of
higher dose.49 Rupture of benign, hepatic adenomas may cause death through
intra-abdominal hemorrhage.50,51
Studies from Britain have shown an increased risk of developing hepatocellular
carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers
are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver
cancers in oral contraceptive users approaches less than one per million users.
5. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use of
oral contraceptives. Oral contraceptives should be discontinued if there is
unexplained partial or complete loss of vision; onset of proptosis or diplopia;
papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic
measures should be undertaken immediately.
6. Oral Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in
women who have used oral contraceptives prior to pregnancy.56,57 The majority of
recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac
concerned,55,56,58,59
anomalies and limb reduction defects are
when taken
inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not
be used as a test for pregnancy. Oral contraceptives should not be used during
pregnancy to treat threatened or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods,
pregnancy should be ruled out. If the patient has not adhered to the prescribed
schedule, the possibility of pregnancy should be considered at the time of the first
missed period. Oral contraceptive use should be discontinued if pregnancy is
confirmed.
7. Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery
in users of oral contraceptives and estrogens.60,61 More recent studies, however, have
shown that the relative risk of developing gallbladder disease among oral
contraceptive users may be minimal.62–64 The recent findings of minimal risk may be
related to the use of oral contraceptive formulations containing lower hormonal doses
of estrogens and progestogens.
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8. Carbohydrate and Lipid Metabolic Effects
Oral contraceptives have been shown to cause a decrease in glucose tolerance in a
significant percentage of users.17 This effect has been shown to be directly related to
estrogen dose.65 Progestogens increase insulin secretion and create insulin resistance,
this effect varying with different progestational agents.17,66 However, in the non-
diabetic woman, oral contraceptives appear to have no effect on fasting blood
glucose.67 Because of these demonstrated effects, prediabetic and diabetic women in
particular should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the
pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides
and lipoprotein levels have been reported in oral contraceptive users.
9. Elevated Blood Pressure
Women with significant hypertension should not be started on hormonal
contraception.92 An increase in blood pressure has been reported in women taking
oral contraceptives68 and this increase is more likely in older oral contraceptive
users69 and with extended duration of use.61 Data from the Royal College of General
Practitioners12 and subsequent randomized trials have shown that the incidence of
hypertension increases with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases, or renal
disease70 should be encouraged to use another method of contraception. If these
women elect to use oral contraceptives, they should be monitored closely and if a
clinically significant persistent elevation of blood pressure (BP) occurs
( 160 mm Hg systolic or 100 mm Hg diastolic) and cannot be adequately
controlled, oral contraceptives should be discontinued. In general, women who
develop hypertension during hormonal contraceptive therapy should be switched to a
non-hormonal contraceptive. If other contraceptive methods are not suitable,
hormonal contraceptive therapy may continue combined with antihypertensive
therapy. Regular monitoring of BP throughout hormonal contraceptive therapy is
recommended.96 For most women, elevated blood pressure will return to normal after
stopping oral contraceptives, and there is no difference in the occurrence of
hypertension between former and never users.68–71
10. Headache
The onset or exacerbation of migraine or development of headache with a new pattern
which is recurrent, persistent or severe requires discontinuation of oral contraceptives
and evaluation of the cause.
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11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral
contraceptives, especially during the first three months of use. Nonhormonal causes
should be considered and adequate diagnostic measures taken to rule out malignancy
or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal
vaginal bleeding. If pathology has been excluded, time or a change to another
formulation may solve the problem. In the event of amenorrhea, pregnancy should be
ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially
when such a condition was preexistent.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
1. General
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
2. Physical Examination and Follow-Up
It is good medical practice for all women to have annual history and physical
examinations, including women using oral contraceptives. The physical examination,
however, may be deferred until after initiation of oral contraceptives if requested by
the woman and judged appropriate by the clinician. The physical examination should
include special reference to blood pressure, breasts, abdomen and pelvic organs,
including cervical cytology, and relevant laboratory tests. In case of undiagnosed,
persistent or recurrent abnormal vaginal bleeding, appropriate measures should be
conducted to rule out malignancy. Women with a strong family history of breast
cancer or who have breast nodules should be monitored with particular care.
3. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they
elect to use oral contraceptives. Some progestogens may elevate LDL levels and may
render the control of hyperlipidemias more difficult.
4. Liver Function
If jaundice develops in any woman receiving such drugs, the medication should be
discontinued. Steroid hormones may be poorly metabolized in patients with impaired
liver function.
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5. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be
prescribed with caution, and only with careful monitoring, in patients with conditions
which might be aggravated by fluid retention.
6. Emotional Disorders
Women with a history of depression should be carefully observed and the drug
discontinued if depression recurs to a serious degree.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should
be assessed by an ophthalmologist.
8. Drug Interactions
Consult the labeling of concurrently-used drugs to obtain further information about
interactions with hormonal contraceptives or the potential for enzyme alterations.
Effects of Other Drugs on Combined Hormonal Contraceptives
Substances decreasing the plasma concentrations of COCs and potentially
diminishing the efficacy of COCs:
Drugs or herbal products that induce certain enzymes, including cytochrome P450
3A4 (CYP3A4), may decrease the plasma concentrations of COCs and potentially
diminish the effectiveness of CHCs or increase breakthrough bleeding. Some drugs or
herbal products that may decrease the effectiveness of hormonal contraceptives
include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin,
oxcarbazepine, rifampicin, topiramate, rifabutin, rufinamide, aprepitant, and products
containing St. John’s wort. Interactions between hormonal contraceptives and other
drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel
women to use an alternative method of contraception or a back-up method when
enzyme inducers are used with CHCs, and to continue back-up contraception for 28
days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of COCs:
Co-administration of atorvastatin or rosuvastatin and certain COCs containing EE
increase AUC values for EE by approximately 20-25%. Ascorbic acid and
acetaminophen may increase plasma EE concentrations, possibly by inhibition of
conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole,
grapefruit juice, or ketoconazole may increase plasma hormone concentrations.
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Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease
inhibitors and non-nucleoside reverse transcriptase inhibitors:
Significant changes (increase or decrease) in the plasma concentrations of estrogen
and/or progestin have been noted in some cases of co-administration with HIV
protease inhibitors (decrease [e.g., nelfinavir, ritonavir, darunavir/ritonavir,
(fos)amprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir] or increase
[e.g., indinavir and atazanavir/ritonavir]) /HCV protease inhibitors (decrease [e.g.,
boceprevir and telaprevir]) or with non-nucleoside reverse transcriptase inhibitors
(decrease [e.g., nevirapine] or increase [e.g., etravirine]).
Colesevelam: Colesevelam, a bile acid sequestrant, given together with a combination
oral hormonal contraceptive, has been shown to significantly decrease the AUC of
EE. A drug interaction between the contraceptive and colesevelam was decreased
when the two drug products were given 4 hours apart.
Effects of Combined Hormonal Contraceptives on Other Drugs
COCs containing EE may inhibit the metabolism of other compounds (e.g.,
cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and increase
their plasma concentrations. COCs have been shown to decrease plasma
concentrations of acetaminophen, clofibric acid, morphine, salicylic acid, temazepam
and lamotrigine. Significant decrease in plasma concentration of lamotrigine has been
shown, likely due to induction of lamotrigine glucuronidation. This may reduce
seizure control; therefore, dosage adjustments of lamotrigine may be necessary.
Women on thyroid hormone replacement therapy may need increased doses of
thyroid hormone because serum concentrations of thyroid-binding globulin increases
with use of COCs.
9. Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by
oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased
antithrombin 3; increased norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating
total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by
column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting
the elevated TBG, free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
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d. Sex-binding globulins are increased and result in elevated levels of total
circulating sex steroids and corticoids; however, free or biologically active
levels remain unchanged.
e. Triglycerides may be increased and levels of various other lipids and
lipoproteins may be affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This may
be of clinical significance if a woman becomes pregnant shortly after
discontinuing oral contraceptives.
10. Carcinogenesis
See WARNINGS.
11. Pregnancy
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS.
12. Nursing Mothers
Small amounts of oral contraceptive steroids have been identified in the milk of
nursing mothers and a few adverse effects on the child have been reported, including
jaundice and breast enlargement. In addition, combined oral contraceptives given in
the postpartum period may interfere with lactation by decreasing the quantity and
quality of breast milk. If possible, the nursing mother should be advised not to use
combined oral contraceptives but to use other forms of contraception until she has
completely weaned her child.
13. Pediatric Use
Safety and efficacy of ORTHO-NOVUM® Tablets and MODICON® Tablets have
been established in women of reproductive age. Safety and efficacy are expected to
be the same for postpubertal adolescents under the age of 16 and for users 16 years
and older. Use of this product before menarche is not indicated.
14. Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated
in this population.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
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ADVERSE REACTIONS
An increased risk of the following serious adverse reactions has been associated with
the use of oral contraceptives (See WARNINGS).
Thrombophlebitis and venous thrombosis with or without embolism
Arterial thromboembolism
Pulmonary embolism
Myocardial infarction
Cerebral hemorrhage
Cerebral thrombosis
Hypertension
Gallbladder disease
Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the use of
oral contraceptives:
Mesenteric thrombosis
Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral
contraceptives and are believed to be drug-related:
Nausea
Vomiting
Gastrointestinal symptoms (such as abdominal cramps and bloating)
Breakthrough bleeding
Spotting
Change in menstrual flow
Amenorrhea
Temporary infertility after discontinuation of treatment
Edema
Melasma which may persist
Breast changes: tenderness, enlargement, secretion
Change in weight (increase or decrease)
Change in cervical erosion and secretion
Diminution in lactation when given immediately postpartum
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Cholestatic jaundice
Migraine
Allergic reaction, including rash, urticaria, angioedema
Mental depression
Reduced tolerance to carbohydrates
Vaginal candidiasis
Change in corneal curvature (steepening)
Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives
and a causal association has been neither confirmed nor refuted:
Pre-menstrual syndrome
Cataracts
Changes in appetite
Cystitis-like syndrome
Headache
Nervousness
Dizziness
Hirsutism
Loss of scalp hair
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Vaginitis
Porphyria
Impaired renal function
Hemolytic uremic syndrome
Acne
Changes in libido
Colitis
Budd-Chiari Syndrome
The following adverse reactions were also reported in clinical trials or during
post-marketing experience: Gastrointestinal Disorders: diarrhea, pancreatitis;
Musculoskeletal and Connective Tissue Disorders: muscle spasms, back pain;
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Reproductive System and Breast Disorders vulvovaginal pruritus, pelvic pain,
dysmenorrhea, vulvovaginal dryness; Psychiatric Disorders: anxiety, mood
swings, mood altered; Skin and Subcutaneous Tissue Disorders: pruritus,
photosensitivity reaction; General Disorders and Administration Site Conditions:
edema peripheral, fatigue, irritability, asthenia, malaise; Neoplasms Benign,
Malignant, and Unspecified (Including Cysts and Polyps): breast cancer, breast
mass, breast neoplasm, cervix carcinoma; Immune System Disorders:
anaphylactic/anaphylactoid
reaction;
Hepatobiliary
Disorders:
hepatitis,
cholelithiasis.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
oral contraceptives by young children. Overdosage may cause nausea, and withdrawal
bleeding may occur in females.
NON-CONTRACEPTIVE HEALTH BENEFITS
The following non-contraceptive health benefits related to the use of combined oral
contraceptives are supported by epidemiological studies which largely utilized oral
contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl
estradiol or 0.05 mg mestranol.73–78
Effects on menses:
increased menstrual cycle regularity
decreased blood loss and decreased incidence of iron deficiency anemia
decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
decreased incidence of functional ovarian cysts
decreased incidence of ectopic pregnancies
Other effects:
decreased incidence of fibroadenomas and fibrocystic disease of the breast
decreased incidence of acute pelvic inflammatory disease
decreased incidence of endometrial cancer
decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION
To achieve maximum contraceptive effectiveness, ORTHO-NOVUM® Tablets and
MODICON® Tablets must be taken exactly as directed and at intervals not exceeding
24 hours. ORTHO-NOVUM® Tablets and MODICON® Tablets are available with the
DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also
available.
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Sunday Start
When taking ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® ,
the first "active" tablet should be taken on the first Sunday after menstruation begins.
If the period begins on Sunday, the first "active" tablet should be taken that day. Take
one active tablet daily for 21 days followed by one green "reminder" tablet daily for
7 days. After 28 tablets have been taken, a new course is started the next day
(Sunday). For the first cycle of a Sunday Start regimen, another method of
contraception such as a condom or spermicide should be used until after the first
7 consecutive days of administration.
If the patient misses one (1) "active" tablet in Weeks 1, 2, or 3, the tablet should be
taken as soon as she remembers. If the patient misses two (2) "active" tablets in Week
1 or Week 2, the patient should take two (2) tablets the day she remembers and two
(2) tablets the next day; and then continue taking one (1) tablet a day until she
finishes the pack. The patient should be instructed to use a back-up method of birth
control such as a condom or spermicide if she has sex in the seven (7) days after
missing pills. If the patient misses two (2) "active" tablets in the third week or misses
three (3) or more "active" tablets in a row, the patient should continue taking one
tablet every day until Sunday. On Sunday the patient should throw out the rest of the
pack and start a new pack that same day. The patient should be instructed to use a
back-up method of birth control if she has sex in the seven (7) days after missing
pills.
Complete instructions to facilitate patient counseling on proper pill usage may be
found in the Detailed Patient Labeling ("How to Take the Pill" section).
Day 1 Start
The
dosage
of
ORTHO-NOVUM®
7/7/7,
ORTHO-NOVUM®
1/35,
and
MODICON®, for the initial cycle of therapy, is one "active" tablet administered daily
from the 1st through the 21st day of the menstrual cycle, counting the first day of
menstrual flow as "Day 1" followed by one green "reminder" tablet daily for 7 days.
Tablets are taken without interruption for 28 days. After 28 tablets have been taken, a
new course is started the next day.
If the patient misses one (1) "active" tablet in Weeks 1, 2, or 3, the tablet should be
taken as soon as she remembers. If the patient misses two (2) "active" tablets in Week
1 or Week 2, the patient should take two (2) tablets the day she remembers and two
(2) tablets the next day; and then continue taking one (1) tablet a day until she
finishes the pack. The patient should be instructed to use a back-up method of birth
control such as a condom or spermicide if she has sex in the seven (7) days after
missing pills. If the patient misses two (2) "active" tablets in the third week or misses
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three (3) or more "active" tablets in a row, the patient should throw out the rest of the
pack and start a new pack that same day. The patient should be instructed to use a
back-up method of birth control if she has sex in the seven (7) days after missing
pills.
Complete instructions to facilitate patient counseling on proper pill usage may be
found in the Detailed Patient Labeling ("How to Take the Pill" section).
The use of ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® for
contraception may be initiated 4 weeks postpartum in women who elect not to
breastfeed. When the tablets are administered during the postpartum period, the
increased risk of thromboembolic disease associated with the postpartum period must
be considered. (See CONTRAINDICATIONS and WARNINGS concerning
thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) The
possibility of ovulation and conception prior to initiation of medication should be
considered.
(See Discussion of Dose-Related Risk of Vascular Disease from Oral
Contraceptives.)
ADDITIONAL INSTRUCTIONS
Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients
discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of
irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In
undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate
diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology
has been excluded, time or a change to another formulation may solve the problem.
Changing to an oral contraceptive with a higher estrogen content, while potentially
useful in minimizing menstrual irregularity, should be done only if necessary since
this may increase the risk of thromboembolic disease.
Use of oral contraceptives in the event of a missed menstrual period:
1. If the patient has not adhered to the prescribed schedule, the possibility of
pregnancy should be considered at the time of the first missed period and oral
contraceptive use should be discontinued if pregnancy is confirmed.
2. If the patient has adhered to the prescribed regimen and misses two
consecutive periods, pregnancy should be ruled out.
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HOW SUPPLIED
ORTHO-NOVUM® 7/7/7 Tablets are available in a blister card with a DIALPAK®
Tablet Dispenser (unfilled) (NDC 50458-178-00). The blister card contains 28 tablets,
as follows: 7 white, round, flat-faced, beveled edged tablets imprinted with
"Ortho 535" on both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol), 7
light peach, round, flat-faced, beveled edged tablets imprinted with "Ortho 75" on
both sides (0.75 mg norethindrone and 0.035 mg ethinyl estradiol), 7 peach, round,
flat-faced, beveled edged tablets imprinted with "Ortho 135" on both sides (1 mg
norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round, flat-faced, beveled
edged tablets imprinted "Ortho" on both sides containing inert ingredients. ORTHO
NOVUM® 7/7/7 Tablets are packaged in a carton containing 6 blister cards and 6
unfilled DIALPAK® Tablet Dispensers (NDC 50458-178-15).
ORTHO-NOVUM® 7/7/7 is available for clinic usage in a VERIDATE® Tablet
Dispenser (unfilled) and VERIDATE® refills (NDC 50458-178-20).
ORTHO-NOVUM® 1/35 Tablets are available in a blister card with a DIALPAK®
Tablet Dispenser (unfilled) (NDC 50458-176-00). The blister card contains 28 tablets,
as follows: 21 peach, round, flat-faced, beveled edged tablets imprinted "Ortho 135"
on both sides (1 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green,
round, flat-faced, beveled edged tablets imprinted "Ortho" on both sides containing
inert ingredients. ORTHO-NOVUM® 1/35 Tablets are packaged in a carton
containing 6 blister cards and 6 unfilled DIALPAK® Tablet Dispensers (NDC 50458
176-15).
MODICON® Tablets are available in a blister card with a DIALPAK® Tablet
Dispenser (unfilled) (NDC 50458-171-00). The blister card contains 28 tablets, as
follows: 21 white, round, flat-faced, beveled edged tablets imprinted "Ortho 535" on
both sides (0.5 mg norethindrone and 0.035 mg ethinyl estradiol) and 7 green, round,
flat-faced, beveled edged tablets imprinted "Ortho" on both sides containing inert
ingredients. MODICON® Tablets are packaged in a carton containing 6 blister cards
and 6 unfilled DIALPAK® Tablet Dispensers (NDC 50458-171-15).
Store at 25°C (77°F), excursions permitted to 15°–30°C (59°–86°F).
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54. Forman D, Vincent TJ, Doll R. Cancer of the liver and oral contraceptives. Br
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Pharmacol 2010;50:554–565.
BRIEF SUMMARY PATIENT PACKAGE INSERT
Oral contraceptives, also known as "birth control pills" or "the pill," are taken to
prevent pregnancy and when taken correctly without missing any pills, have a failure
Reference ID: 3383539
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For current labeling information, please visit https://www.fda.gov/drugsatfda
rate of approximately 1% per year. The typical failure rate is approximately 5% per
year when women who miss pills are included. For most women oral contraceptives
are also free of serious or unpleasant side effects. However, forgetting to take pills
considerably increases the chances of pregnancy.
For the majority of women, oral contraceptives can be taken safely. But there are
some women who are at high risk of developing certain serious diseases that can be
fatal or may cause temporary or permanent disability. The risks associated with
taking oral contraceptives increase significantly if you:
smoke
have high blood pressure, diabetes, high cholesterol
have or have had clotting disorders, heart attack, stroke, angina pectoris,
cancer of the breast or sex organs, jaundice or malignant or benign liver
tumors.
Although cardiovascular disease risks may be increased with oral contraceptive use
after age 40 in healthy, non-smoking women (even with the newer low-dose
formulations), there are also greater potential health risks associated with pregnancy
in older women.
You should not take the pill if you suspect you are pregnant or have unexplained
vaginal bleeding.
Do not use ORTHO-NOVUM® or MODICON® if you smoke cigarettes and are
over 35 years old. Smoking increases your risk of serious cardiovascular side
effects (heart and blood vessel problems) from combination oral contraceptives,
including death from heart attack, blood clots or stroke. This risk increases with
age and the number of cigarettes you smoke.
Most side effects of the pill are not serious. The most common such effects are
nausea, vomiting, bleeding between menstrual periods, weight gain, breast
tenderness, and difficulty wearing contact lenses. These side effects, especially
nausea and vomiting, may subside within the first three months of use.
The serious side effects of the pill occur very infrequently, especially if you are in
good health and are young. However, you should know that the following medical
conditions have been associated with or made worse by the pill:
1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism),
stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood
vessels in the heart (heart attack or angina pectoris) or other organs of the
Reference ID: 3383539
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body. As mentioned above, smoking increases the risk of heart attacks and
strokes and subsequent serious medical consequences.
2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors.
These benign liver tumors can rupture and cause fatal internal bleeding. In
addition, some studies report an increased risk of developing liver cancer.
However, liver cancers are rare.
3. High blood pressure, although blood pressure usually returns to normal when
the pill is stopped.
The symptoms associated with these serious side effects are discussed in the detailed
leaflet given to you with your supply of pills. Notify your healthcare professional if
you notice any unusual physical disturbances while taking the pill. In addition, drugs
such as rifampin, bosentan, as well as some seizure medicines and herbal preparations
containing St. John’s wort (Hypericum perforatum) may decrease oral contraceptive
effectiveness.
Oral contraceptives may interact with lamotrigine (LAMICTAL®), a seizure medicine
used for epilepsy. This may increase the risk of seizures so your healthcare
professional may need to adjust the dose of lamotrigine.
Various studies give conflicting reports on the relationship between breast cancer and
oral contraceptive use. Oral contraceptive use may slightly increase your chance of
having breast cancer diagnosed, particularly after using hormonal contraceptives at a
younger age. After you stop using hormonal contraceptives, the chances of having
breast cancer diagnosed begin to go back down. You should have regular breast
examinations by a healthcare professional and examine your own breasts monthly.
Tell your healthcare professional if you have a family history of breast cancer or if
you have had breast nodules or an abnormal mammogram. Women who currently
have or have had breast cancer should not use oral contraceptives because breast
cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in
women who use oral contraceptives. However, this finding may be related to factors
other than the use of oral contraceptives. There is insufficient evidence to rule out the
possibility that the pill may cause such cancers.
Taking the combination pill provides some important non-contraceptive benefits.
These include less painful menstruation, less menstrual blood loss and anemia, fewer
pelvic infections, and fewer cancers of the ovary and the lining of the uterus.
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Be sure to discuss any medical condition you may have with your healthcare
professional. Your healthcare professional will take a medical and family history
before prescribing oral contraceptives and will examine you. The physical
examination may be delayed to another time if you request it and the healthcare
professional believes that it is a good medical practice to postpone it. You should be
reexamined at least once a year while taking oral contraceptives. Your pharmacist
should have given you the detailed patient information labeling which gives you
further information which you should read and discuss with your healthcare
professional.
This product (like all oral contraceptives) is intended to prevent pregnancy. It
does not protect against transmission of HIV (AIDS) and other sexually
transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea,
hepatitis B, and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY
DAY AT THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY
FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF
PILLS. If you feel sick to your stomach, do not stop taking the pill. The
problem will usually go away. If it doesn’t go away, check with your
healthcare professional.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING,
even when you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a
little sick to your stomach.
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5. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME
MEDICINES, your pills may not work as well. Use a back-up method (such
as a condom or spermicide) until you check with your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to
your healthcare professional about how to make pill taking easier or about
using another method of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE
INFORMATION IN THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK.
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is
followed by 1 week of green "reminder" pills (without hormones).
ORTHO-NOVUM® 7/7/7: There are 7 white "active" pills, 7 light peach "active"
pills, 7 peach "active" pills and 7 green "reminder" pills.
ORTHO-NOVUM® 1/35: There are 21 peach "active" pills and 7 green "reminder"
pills.
MODICON®: There are 21 white "active" pills and 7 green "reminder" pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide)
to use as a back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills.
ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® are available
with the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start
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is also provided. Decide with your healthcare professional which is the best day for
you. Pick a time of day that will be easy to remember.
SUNDAY START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period begins on
Sunday, start the pack the same day.
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period begins on
Sunday, start the pack the same day.
MODICON®: Take the first white "active" pill of the first pack on the Sunday after
your period starts, even if you are still bleeding. If your period begins on Sunday,
start the pack the same day.
Use another method of birth control such as a condom or spermicide as a back-up
method if you have sex anytime from the Sunday you start your first pack until the
next Sunday (7 days).
DAY 1 START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack during
the first 24 hours of your period.
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack during
the first 24 hours of your period.
MODICON®: Take the first white "active" pill of the first pack during the first 24
hours of your period.
You will not need to use a back-up method of birth control, since you are starting the
pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE
PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods
or feel sick to your stomach (nausea). Do not skip pills even if you do not
have sex very often.
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2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF
PILLS:
Start the next pack on the day after your last green "reminder" pill. Do not
wait any days between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO-NOVUM® 7/7/7:
If you MISS 1 white, light peach, or peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light peach "active" pills in a row in WEEK 1 OR WEEK 2
of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
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If you MISS 3 OR MORE white, light peach, or peach "active" pills in a row (during
the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
ORTHO-NOVUM® 1/35:
If you MISS 1 peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
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THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE peach "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
MODICON®:
If you MISS 1 white "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
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3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 2 white "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
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A REMINDER
If you forget any of the 7 green "reminder" pills in Week 4: THROW AWAY the
pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need
a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE
PILLS YOU HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your
healthcare professional.
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DETAILED PATIENT LABELING
PLEASE NOTE: This labeling is revised from time to time as important new
medical information becomes available. Therefore, please review this labeling
carefully.
The following oral contraceptive products contain a combination of an estrogen and
progestogen, the two kinds of female hormones:
ORTHO-NOVUM® 7/7/7
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Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each
light peach tablet contains 0.75 mg norethindrone and 0.035 mg ethinyl estradiol.
Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each
green tablet contains inert ingredients.
ORTHO-NOVUM® 1/35
Each peach tablet contains 1 mg norethindrone and 0.035 mg ethinyl estradiol. Each
green tablet contains inert ingredients.
MODICON®
Each white tablet contains 0.5 mg norethindrone and 0.035 mg ethinyl estradiol. Each
green tablet contains inert ingredients.
INTRODUCTION
Any woman who considers using oral contraceptives (the birth control pill or the pill)
should understand the benefits and risks of using this form of birth control. This
patient labeling will give you much of the information you will need to make this
decision and will also help you determine if you are at risk of developing any of the
serious side effects of the pill. It will tell you how to use the pill properly so that it
will be as effective as possible. However, this labeling is not a replacement for a
careful discussion between you and your healthcare professional. You should discuss
the information provided in this labeling with him or her, both when you first start
taking the pill and during your revisits. You should also follow your healthcare
professional’s advice with regard to regular check-ups while you are on the pill.
EFFECTIVENESS OF ORAL CONTRACEPTIVES
Oral contraceptives or "birth control pills" or "the pill" are used to prevent pregnancy
and are more effective than other non-surgical methods of birth control. When they
are taken correctly without missing any pills, the chance of becoming pregnant is
approximately 1% (1 pregnancy per 100 women per year of use). Typical failure rates
are approximately 5% per year including women who do not always take the pills
exactly as directed. The chance of becoming pregnant increases with each missed pill
during a menstrual cycle.
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In comparison, typical failure rates for other methods of birth control during the first
year of use are as follows:
Implant: <1%
Male sterilization: <1%
Injection: <1%
Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%
Condom alone (male): 14%
Diaphragm with spermicides: 20%
Condom alone (female): 21%
Spermicides alone: 26%
Periodic abstinence: 25%
Vaginal sponge: 20 to 40%
Withdrawal: 19%
Female sterilization: <1%
No methods: 85%
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Do not use ORTHO-NOVUM® or MODICON® if you smoke cigarettes and are
over 35 years old. Smoking increases your risk of serious cardiovascular side
effects (heart and blood vessel problems) from combination oral contraceptives,
including death from heart attack, blood clots or stroke. This risk increases with
age and the number of cigarettes you smoke.
Some women should not use the pill. For example, you should not take the pill if you
have any of the following conditions:
A history of heart attack or stroke
Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or
eyes
A history of blood clots in the deep veins of your legs
An inherited problem that makes your blood clot more than normal
Chest pain (angina pectoris)
Known or suspected breast cancer or cancer of the lining of the uterus, cervix
or vagina
Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare
professional)
Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy
or during previous use of the pill
Liver tumor (benign or cancerous)
Known or suspected pregnancy
Valvular heart disease with complications
Severe hypertension
Diabetes with vascular involvement
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Headaches with focal neurological symptoms
If you plan to have surgery with prolonged bed rest
Hypersensitivity to any component of this product.
Tell your healthcare professional if you have ever had any of these conditions. Your
healthcare professional can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have or have had:
Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or
mammogram
Diabetes
Elevated cholesterol or triglycerides
High blood pressure
Migraine or other headaches or epilepsy
Mental depression
Gallbladder, liver, heart or kidney disease
History of scanty or irregular menstrual periods
Women with any of these conditions should be checked often by their healthcare
professional if they choose to use oral contraceptives.
Also, be sure to inform your healthcare professional if you smoke or are on any
medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risk of developing blood clots
Blood clots and blockage of blood vessels are one of the most serious side effects of
taking oral contraceptives and can cause death or serious disability. In particular, a
clot in the legs can cause thrombophlebitis and a clot that travels to the lungs can
cause a sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur
in the blood vessels of the eye and may cause blindness, double vision, or impaired
vision.
If you take oral contraceptives and need elective surgery, need to stay in bed for a
prolonged illness or injury or have recently delivered a baby, you may be at risk of
developing blood clots. You should consult your healthcare professional about
stopping oral contraceptives three to four weeks before surgery and not taking oral
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contraceptives for two weeks after surgery or during bed rest. You should also not
take oral contraceptives soon after delivery of a baby. It is advisable to wait for at
least four weeks after delivery if you are not breastfeeding or four weeks after a
second trimester abortion. If you are breastfeeding, you should wait until you have
weaned your child before using the pill. (See also the section on Breastfeeding in
General Precautions.)
The risk of circulatory disease in oral contraceptive users may be higher in users of
high-dose pills and may be greater with longer duration of oral contraceptive use. In
addition, some of these increased risks may continue for a number of years after
stopping oral contraceptives. The risk of abnormal blood clotting increases with age
in both users and nonusers of oral contraceptives, but the increased risk from the oral
contraceptive appears to be present at all ages. For women aged 20 to 44, it is
estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each
year because of abnormal clotting. Among nonusers in the same age group, about 1 in
20,000 would be hospitalized each year. For oral contraceptive users in general, it has
been estimated that in women between the ages of 15 and 34 the risk of death due to a
circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the rate is
about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be about
1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for
nonusers.
2. Heart attacks and strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or
rupture of blood vessels in the brain) and angina pectoris and heart attacks (blockage
of blood vessels in the heart). Any of these conditions can cause death or serious
disability.
Smoking greatly increases the possibility of suffering heart attacks and strokes.
Furthermore, smoking and the use of oral contraceptives greatly increase the chances
of developing and dying of heart disease.
3. Gallbladder disease
Oral contraceptive users probably have a greater risk than nonusers of having
gallbladder disease, although this risk may be related to pills containing high doses of
estrogens.
4. Liver tumors
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In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These
benign liver tumors can rupture and cause fatal internal bleeding. In addition, some
studies report an increased risk of developing liver cancer. However, liver cancers are
rare.
5. Cancer of the reproductive organs and breasts
Various studies give conflicting reports on the relationship between breast cancer and
oral contraceptive use. Oral contraceptive use may slightly increase your chance of
having breast cancer diagnosed, particularly after using hormonal contraceptives at a
younger age. After you stop using hormonal contraceptives, the chances of having
breast cancer diagnosed begin to go back down. You should have regular breast
examinations by a healthcare professional and examine your own breasts monthly.
Tell your healthcare professional if you have a family history of breast cancer or if
you have had breast nodules or an abnormal mammogram. Women who currently
have or have had breast cancer should not use oral contraceptives because breast
cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in
women who use oral contraceptives. However, this finding may be related to factors
other than the use of oral contraceptives. There is insufficient evidence to rule out the
possibility that the pill may cause such cancers.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR
PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing
certain diseases which may lead to disability or death. An estimate of the number of
deaths associated with different methods of birth control and pregnancy has been
calculated and is shown in the following table.
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ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS
ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY
FERTILITY CONTROL METHOD ACCORDING TO AGE
Method of control and outcome
15-19
20-24
25-29
30-34
35-39
40-44
No fertility-control methods*
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives non-smoker†
0.3
0.5
0.9
1.9
13.8
31.6
Oral contraceptives smoker†
2.2
3.4
6.6
13.5
51.1
117.2
IUD†
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/ spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
* Deaths are birth-related
† Deaths are method-related
In the above table, the risk of death from any birth control method is less than the risk
of childbirth, except for oral contraceptive users over the age of 35 who smoke and
pill users over the age of 40 even if they do not smoke. It can be seen in the table that
for women aged 15 to 39, the risk of death was highest with pregnancy (7-26 deaths
per 100,000 women, depending on age). Among pill users who do not smoke, the risk
of death was always lower than that associated with pregnancy for any age group,
although over the age of 40, the risk increases to 32 deaths per 100,000 women,
compared to 28 associated with pregnancy at that age. However, for pill users who
smoke and are over the age of 35, the estimated number of deaths exceeds those for
other methods of birth control. If a woman is over the age of 40 and smokes, her
estimated risk of death is four times higher (117/100,000 women) than the estimated
risk associated with pregnancy (28/100,000 women) in that age group.
The suggestion that women over 40 who do not smoke should not take oral
contraceptives is based on information from older, higher-dose pills. An Advisory
Committee of the FDA discussed this issue in 1989 and recommended that the
benefits of low-dose oral contraceptive use by healthy, non-smoking women over
40 years of age may outweigh the possible risks.
WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives, call
your healthcare professional immediately:
Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating
a possible clot in the lung)
Pain in the calf (indicating a possible clot in the leg)
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Crushing chest pain or heaviness in the chest (indicating a possible heart
attack)
Sudden severe headache or vomiting, dizziness or fainting, disturbances of
vision or speech, weakness, or numbness in an arm or leg (indicating a
possible stroke)
Sudden partial or complete loss of vision (indicating a possible clot in the eye)
Breast lumps (indicating possible breast cancer or fibrocystic disease of the
breast; ask your healthcare professional to show you how to examine your
breasts)
Severe pain or tenderness in the stomach area (indicating a possibly ruptured
liver tumor)
Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood
(possibly indicating severe depression)
Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by
fever, fatigue, loss of appetite, dark colored urine, or light colored bowel
movements (indicating possible liver problems)
SIDE EFFECTS OF ORAL CONTRACEPTIVES
1. Vaginal bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills.
Irregular bleeding may vary from slight staining between menstrual periods to
breakthrough bleeding which is a flow much like a regular period. Irregular bleeding
occurs most often during the first few months of oral contraceptive use, but may also
occur after you have been taking the pill for some time. Such bleeding may be
temporary and usually does not indicate any serious problems. It is important to
continue taking your pills on schedule. If the bleeding occurs in more than one cycle
or lasts for more than a few days, talk to your healthcare professional.
2. Contact lenses
If you wear contact lenses and notice a change in vision or an inability to wear your
lenses, contact your healthcare professional.
3. Fluid retention
Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or
ankles and may raise your blood pressure. If you experience fluid retention, contact
your healthcare professional.
4. Melasma
A spotty darkening of the skin is possible, particularly of the face, which may persist.
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5. Other side effects
Other side effects may include nausea, vomiting and diarrhea, muscle cramps, change
in appetite, headache, nervousness, depression, dizziness, loss of scalp hair, rash,
vaginal infections, pancreatitis, skin sensitivity to the sun or ultraviolet and allergic
reactions.
If any of these side effects bother you, call your healthcare professional.
GENERAL PRECAUTIONS
1. Missed periods and use of oral contraceptives before or during early
pregnancy
There may be times when you may not menstruate regularly after you have completed
taking a cycle of pills. If you have taken your pills regularly and miss one menstrual
period, continue taking your pills for the next cycle but be sure to inform your
healthcare professional before doing so. If you have not taken the pills daily as
instructed and missed a menstrual period, you may be pregnant. If you missed two
consecutive menstrual periods, you may be pregnant. Check with your healthcare
professional immediately to determine whether you are pregnant. Do not continue to
take oral contraceptives until you are sure you are not pregnant, but continue to use
another method of contraception.
There is no conclusive evidence that oral contraceptive use is associated with an
increase in birth defects, when taken inadvertently during early pregnancy.
Previously, a few studies had reported that oral contraceptives might be associated
with birth defects, but these findings have not been seen in more recent studies.
Nevertheless, oral contraceptives should not be used during pregnancy. You should
check with your healthcare professional about risks to your unborn child of any
medication taken during pregnancy.
2. While breastfeeding
If you are breastfeeding, consult your healthcare professional before starting oral
contraceptives. Some of the drug will be passed on to the child in the milk. A few
adverse effects on the child have been reported, including yellowing of the skin
(jaundice) and breast enlargement. In addition, combined oral contraceptives may
decrease the amount and quality of your milk. If possible, do not use combined oral
contraceptives while breastfeeding. You should use another method of contraception
since breastfeeding provides only partial protection from becoming pregnant and this
partial protection decreases significantly as you breastfeed for longer periods of time.
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You should consider starting combined oral contraceptives only after you have
weaned your child completely.
3. Laboratory tests
If you are scheduled for any laboratory tests, tell your healthcare professional you are
taking birth control pills. Certain blood tests may be affected by birth control pills.
4. Drug interactions
Tell your healthcare provider about all medicines and herbal products that you take.
Some medicines and herbal products may make hormonal birth control less effective,
including, but not limited to:
•
certain seizure medicines (carbamazepine, felbamate, oxcarbazepine,
phenytoin, rufinamide, and topiramate)
•
aprepitant
•
barbiturates
•
bosentan
•
colesevelam
•
griseofulvin
•
certain combinations of HIV medicines (nelfinavir, ritonavir, ritonavir
boosted protease inhibitors)
•
certain non nucleoside reverse transcriptase inhibitors (nevirapine)
•
rifampin and rifabutin
•
St. John’s wort
Use another birth control method (such as a condom and spermicide or diaphragm
and spermicide) when you take medicines that may make ORTHO-NOVUM® 7/7/7,
ORTHO-NOVUM® 1/35, or MODICON® less effective.
Some medicines and grapefruit juice may increase your level of the hormone ethinyl
estradiol if used together, including:
•
acetaminophen
•
ascorbic acid
•
medicines that affect how your liver breaks down other medicines
(itraconazole, ketoconazole, voriconazole, and fluconazole)
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•
certain HIV medicines (atazanavir, indinavir)
•
atorvastatin
•
rosuvastatin
•
etravirine
Hormonal birth control methods may interact with lamotrigine, a seizure medicine
used for epilepsy. This may increase the risk of seizures, so your healthcare provider
may need to adjust the dose of lamotrigine.
Women on thyroid replacement therapy may need increased doses of thyroid
hormone.
Know the medicines you take. Keep a list of them to show your doctor and
pharmacist when you get a new medicine.
5. Sexually transmitted diseases
This product (like all oral contraceptives) is intended to prevent pregnancy. It
does not protect against transmission of HIV (AIDS) and other sexually
transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea,
hepatitis B, and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
a. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY
DAY AT THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
b. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY
FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF
PILLS. If you feel sick to your stomach, do not stop taking the pill. The
problem will usually go away. If it doesn’t go away, check with your
healthcare professional.
Reference ID: 3383539
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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
c. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING,
even when you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a
little sick to your stomach.
d. IF YOU HAVE VOMITING OR DIARRHEA, or IF YOU TAKE SOME
MEDICINES, including some antibiotics, your pills may not work as well.
Use a back-up method (such as a condom or spermicide) until you check with
your healthcare professional.
e. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to
your healthcare professional about how to make pill taking easier or about
using another method of birth control.
f. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE
INFORMATION IN THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK.
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is
followed by 1 week of green "reminder" pills (without hormones).
ORTHO-NOVUM® 7/7/7: There are 7 white "active" pills, 7 light peach
"active" pills, 7 peach "active" pills and 7 green "reminder" pills.
ORTHO-NOVUM® 1/35: There are 21 peach "active" pills and 7 green
"reminder" pills.
MODICON®: There are 21 white "active" pills and 7 green "reminder" pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS
FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT
PACKAGE INSERT.
Reference ID: 3383539
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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
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as a condom or spermicide)
to use as a back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills.
ORTHO-NOVUM® 7/7/7, ORTHO-NOVUM® 1/35, and MODICON® are available
with the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start
is also provided. Decide with your healthcare professional which is the best day for
you. Pick a time of day that will be easy to remember.
SUNDAY START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period begins on
Sunday, start the pack the same day.
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period begins on
Sunday, start the pack the same day.
MODICON®: Take the first white "active" pill of the first pack on the Sunday after
your period starts, even if you are still bleeding. If your period begins on Sunday,
start the pack the same day.
Use another method of birth control such as a condom or spermicide as a back-up
method if you have sex anytime from the Sunday you start your first pack until the
next Sunday (7 days).
DAY 1 START:
ORTHO-NOVUM® 7/7/7: Take the first white "active" pill of the first pack during
the first 24 hours of your period.
ORTHO-NOVUM® 1/35: Take the first peach "active" pill of the first pack during
the first 24 hours of your period.
MODICON®: Take the first white "active" pill of the first pack during the
first 24 hours of your period.
Reference ID: 3383539
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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
You will not need to use a back-up method of birth control, since you are starting the
pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE
PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods
or feel sick to your stomach (nausea). Do not skip pills even if you do not
have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last green "reminder" pill. Do not wait
any days between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO-NOVUM® 7/7/7:
If you MISS 1 white, light peach, or peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light peach "active" pills in a row in WEEK 1 OR WEEK 2
of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
Reference ID: 3383539
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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
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE white, light peach, or peach "active" pills in a row (during
the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
ORTHO-NOVUM® 1/35:
If you MISS 1 peach "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 peach "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
Reference ID: 3383539
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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
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 2 peach "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE peach "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
MODICON®:
If you MISS 1 white "active" pill:
Reference ID: 3383539
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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
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 2 white "active" pills in a row in THE 3RD WEEK:
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE white "active" pills in a row (during the first 3 weeks):
1a. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the
pack and start a new pack of pills that same day.
1b. If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
Reference ID: 3383539
56
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom or
spermicide) as a back-up method for those 7 days.
A REMINDER
If you forget any of the 7 green "reminder" pills in Week 4: THROW AWAY the
pills you missed. Keep taking 1 pill each day until the pack is empty. You do not need
a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE
PILLS YOU HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your
healthcare professional.
PREGNANCY DUE TO PILL FAILURE
Combined Oral Contraceptives
The incidence of pill failure resulting in pregnancy is approximately one percent
(i.e., one pregnancy per 100 women per year) if taken every day as directed, but more
typical failure rates are 5%. If failure does occur, the risk to the fetus is minimal.
PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral
contraceptives, especially if you had irregular menstrual cycles before you used oral
contraceptives. It may be advisable to postpone conception until you begin
menstruating regularly once you have stopped taking the pill and desire pregnancy.
There does not appear to be any increase in birth defects in newborn babies when
pregnancy occurs soon after stopping the pill.
OVERDOSAGE
Serious ill effects have not been reported following ingestion of large doses of oral
contraceptives by young children. Overdosage may cause nausea and withdrawal
bleeding in females. In case of overdosage, contact your healthcare professional or
pharmacist.
OTHER INFORMATION
Reference ID: 3383539
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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
Your healthcare professional will take a medical and family history before
prescribing oral contraceptives and will examine you. The physical examination may
be delayed to another time if you request it and the healthcare professional believes
that it is a good medical practice to postpone it. You should be reexamined at least
once a year. Be sure to inform your healthcare professional if there is a family history
of any of the conditions listed previously in this leaflet. Be sure to keep all
appointments with your healthcare professional, because this is a time to determine if
there are early signs of side effects of oral contraceptive use.
Do not use the drug for any condition other than the one for which it was prescribed.
This drug has been prescribed specifically for you; do not give it to others who may
want birth control pills.
HEALTH BENEFITS FROM ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of combined oral contraceptives may
provide certain benefits. They are:
menstrual cycles may become more regular
blood flow during menstruation may be lighter and less iron may be lost.
Therefore, anemia due to iron deficiency is less likely to occur.
pain or other symptoms during menstruation may be encountered less
frequently
ectopic (tubal) pregnancy may occur less frequently
noncancerous cysts or lumps in the breast may occur less frequently
acute pelvic inflammatory disease may occur less frequently
oral contraceptive use may provide some protection against developing two
forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.
If you want more information about birth control pills, ask your healthcare
professional. They have a more technical leaflet called the Professional Labeling,
which you may wish to read.
Store
at
25°C
(77°F),
excursions
permitted
to
15°–30°C
(59°–86°F).
Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674
Mfd. for:
Reference ID: 3383539
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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
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised October 2013
Reference ID: 3383539
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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
|
custom-source
|
2025-02-12T13:44:20.656550
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017735Orig1s104,017919Orig1s086,018985Orig1s050lbl.pdf', 'application_number': 17735, 'submission_type': 'SUPPL ', 'submission_number': 104}
|
11,052
|
DrytecTM
(Technetium Tc99m Generator)
For the Production of Sodium Pertechnetate Tc99m Injection
Diagnostic Radiopharmaceutical
For intravenous use only
Rx ONLY
DESCRIPTION
The Drytec (Technetium Tc99m Generator) is prepared with fission-produced molybdenum
Mo99 adsorbed on alumina in a lead-shielded column and provides a means for obtaining sterile
pyrogen-free solutions of Sodium Pertechnetate Tc99m Injection in sodium chloride. The eluate
should be crystal clear. With a pH of 4.5-7.5, hydrochloric acid and/or sodium hydroxide may
have been used for Mo99 solution pH adjustment. Over the life of the generator, each elution
will provide a yield of > 90% of the theoretical amount of technetium Tc99m available from the
molybdenum Mo99 on the generator column.
Each eluate of the generator should not contain more than 0.0056 MBq (0.15 µCi) of
molybdenum Mo99 per 37 MBq (1 mCi) of technetium Tc99m per administered dose at the time
of administration, and not more than 10 µg of aluminum per mL of the generator eluate, both of
which must be determined by the user before administration.
Since the eluate does not contain an antimicrobial agent, it should not be used after twelve hours
from the time of generator elution.
PHYSICAL CHARACTERISTICS
Technetium Tc99m decays by an isomeric transition with a physical half-life of 6.02 hours. The
principal photon that is useful for detection and imaging studies is listed in Table 1.
Table 1.
Principal Radiation Emission Data
Radiation
Mean %/Disintegration
Mean Energy (keV)
Gamma-2
89.07
140.5
EXTERNAL RADIATION
The specific gamma ray constant for technetium Tc99m is 0.795 R/hr-mCi at 1 cm. The first
half-value thickness is 0.023 cm of lead (Pb). A range of values for the relative attenuation of the
radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb
is shown in Table 2. For example, the use of 0.27 cm of Pb will attenuate the radiation emitted
by a factor of about 1000.
1
Reference ID: 3803549
This label may not be the latest approved by FDA.
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Table 2.
Radiation Attenuation by Lead (Pb) Shielding
Shield Thickness (Pb) cm
Coefficient of Attenuation
0.023
0.5
0.09
10-1
0.18
10-2
0.27
10-3
0.33
10-4
Molybdenum Mo99 decays to technetium Tc99m with a molybdenum Mo99 half-life of 2.75
days. The physical decay characteristics of molybdenum Mo99 are such that only 86.8% of the
decaying molybdenum Mo99 nuclei form technetium Tc99m. Generator elutions may be made at
any time, but the amount of technetium Tc99m available will depend on the time interval since
the last elution. After six hours approximately 47% of maximum technetium Tc99m is available.
Ninety-two percent is reached after 24 hours. To correct for physical decay of each radionuclide,
the fractions that remain at selected intervals of time are shown in Tables 3 and 4.
Table 3.
Physical Decay Chart: Molybdenum Mo99 (Half-Life 66 Hours)
Days
Percent Remaining
Days
Percent Remaining
Days
Percent Remaining
0*
100.0
7
17.1
14
2.9
1
77.7
8
13.3
15
2.3
2
60.4
9
10.3
20
0.6
3
46.9
10
8.0
25
0.2
4
36.5
11
6.3
30
0.1
5
28.4
12
4.9
6
22.0
13
3.8
*Calibration time
Table 4.
Physical Decay Chart: Technetium Tc99m (Half-Life 6.02 Hours)
Hours
Percent Remaining
Hours
Percent Remaining
0*
100.0
7
44.7
1
89.1
8
39.8
2
79.4
9
35.5
3
70.8
10
31.6
4
63.1
11
28.2
5
56.2
12
25.1
6
50.1
*Elution time
2
Reference ID: 3803549
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For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
The pertechnetate ion distributes in the body similarly to the iodide ion, but is not organified
when trapped in the thyroid gland. It also concentrates in the thyroid gland, salivary glands,
gastric mucosa, and choroid plexus. However, in contrast to the iodide ion, the pertechnetate ion
is released unchanged from the thyroid gland.
After intravascular administration, the pertechnetate ion gradually equilibrates with the
extracellular space. A fraction is promptly excreted via the kidneys.
Following the administration of Sodium Pertechnetate Tc99m Injection as an eye drop, the drug
mixes with tears within the conjunctival space. Within seconds to minutes it leaves the
conjunctival space and escapes into the inferior meatus of the nose through the nasolacrimal
drainage system. During this process the pertechnetate ion passes through the canaliculi, the
lacrimal sac and the nasolacrimal duct. In the event of any anatomical or functional blockage of
the drainage system there will be a backflow resulting in tearing (epiphora). Thus, the
pertechnetate escapes the conjunctival space in the tears.
While the major part of the pertechnetate escapes within a few minutes of normal drainage and
tearing, it has been documented that there is some degree of transconjunctival absorption with a
fractional turnover rate of 0.015/min. in normal individuals, 0.021/min. in patients without any
sac, and 0.027/min. in patients with inflamed conjunctiva due to chronic dacryocystitis.
Individual values may vary, but these rates are probably representative and indicate that the
maximum possible pertechnetate absorbed will remain below one thousandth of that used in
other routine diagnostic procedures.
INDICATIONS AND USAGE
The Drytec (Technetium Tc99m Generator) is a source of sodium pertechnetate Tc99m for use in
the preparation of FDA-approved diagnostic radiopharmaceuticals, as described in the labeling
of these diagnostic radiopharmaceutical kits.
Sodium Pertechnetate Tc99m Injection is used IN ADULTS as an agent for:
Thyroid Imaging
Salivary Gland Imaging
Urinary Bladder Imaging (direct isotopic cystography) for detection of vesico-ureteral reflux
Nasolacrimal Drainage System Imaging (dacryoscintigraphy)
Sodium Pertechnetate Tc99m Injection is used IN PEDIATRIC PATIENTS as an agent for:
Thyroid Imaging
Urinary Bladder Imaging (direct isotopic cystography) for the detection of vesico-ureteral reflux
CONTRAINDICATIONS
None known.
3
Reference ID: 3803549
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For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Radiation risks associated with the use of Sodium Pertechnetate Tc99m Injection are greater in
pediatric patients than in adults. In general, the younger the patient, the greater the risk owing to
greater absorbed radiation doses and longer life expectancy. These greater risks should be taken
firmly into account in all benefit-risk assessments involving pediatric patients.
Long-term cumulative radiation exposure is associated with increased risk of cancer.
PRECAUTIONS
General
Drytec generators received in advance of the calibration date and time will contain higher
amounts of radioactive material. Care should be taken to assure that the generator is properly
shielded. As in the use of any radioactive material, care should be taken to minimize radiation
exposure to the patient consistent with proper patient management and to insure minimum
radiation exposure to occupational workers.
After the termination of the nasolacrimal imaging procedure, blowing the nose and washing the
eyes with sterile distilled water or an isotonic sodium chloride solution will further minimize the
radiation dose.
Radiopharmaceuticals should be used only by physicians who are qualified by training and
experience in the safe use and handling of radionuclides, and whose experience and training have
been approved by the appropriate government agency authorized to license the use of
radionuclides.
Since the eluate does not contain an antimicrobial agent, it should not be used after twelve hours
from the time of generator elution.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term animal studies have been performed to evaluate carcinogenic potential, mutagenic
potential, or whether technetium Tc99m may affect fertility in males or females.
Pregnancy Category C
Animal reproductive studies have not been conducted with technetium Tc99m. It is also not
known whether technetium Tc99m can cause fetal harm when administered to a pregnant woman
or can affect reproductive capacity. Technetium Tc99m should be given to pregnant women only
if the expected benefits to be gained clearly outweigh the potential hazards.
Ideally, examinations using radiopharmaceuticals, especially those elective in nature, of a
woman of childbearing capability should be performed during the first few (approximately 10)
days following the onset of menses.
Nursing Mothers
Technetium Tc99m is excreted in human milk during lactation, and therefore formula feedings
should be substituted for breast feedings.
4
Reference ID: 3803549
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
See INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION. See also
description of additional risk under WARNINGS.
ADVERSE REACTIONS
Allergic reactions including anaphylaxis have been reported infrequently following the
administration of sodium pertechnetate Tc99m.
DOSAGE AND ADMINISTRATION
Sodium Pertechnetate Tc99m Injection is usually administered by intravascular injection. For
imaging the urinary bladder and ureters (direct isotopic cystography), the Sodium Pertechnetate
Tc99m Injection is instilled aseptically into the bladder via a urethral catheter, following which
the catheter is flushed with approximately 200 mL of sterile saline directly into the bladder. The
dosage employed varies with each diagnostic procedure. When imaging the nasolacrimal
drainage system, instill the Sodium Pertechnetate Tc99m Injection by the use of a device such as
a micropipette or similar method which will ensure the accuracy of the dose.
The suggested dose ranges employed for various diagnostic indications in average ADULT
patients (70 kg) are:
Indication
Megabecquerels (MBq)
Millicuries (mCi)
Vesico-ureteral imaging
18.5 - 37
0.5 - 1
Thyroid gland imaging
37 - 370
1 - 10
Salivary gland imaging
37 - 185
1 - 5
Nasolacrimal drainage system imaging
3.70 (max.)
0.100 (max.)
The recommended dosage ranges in PEDIATRIC PATIENTS are:
Vesico-ureteral imaging
18.5 - 37 MBq (0.5 - 1 mCi)
Thyroid gland imaging
2.2 - 2.96 MBq (60 - 80 µCi) per kg body weight.
The patient dose should be measured by a suitable radioactivity calibration system immediately
prior to administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit.
The solution to be administered as the patient dose should be crystal clear and contain no
particulate matter.
RADIATION DOSIMETRY
The estimated absorbed radiation doses to an average ADULT and PEDIATRIC patient from an
intravenous injection of a maximum dose of 1110 MBq (30 mCi) of Sodium Pertechnetate
Tc99m Injection distributed uniformly in the total body are shown in Tables 5 and 6.
5
Reference ID: 3803549
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Table 5.
Adult Absorbed Radiation Doses (mGy) from Intravenous Administration
Organ
Absorbed Radiation Dose Per Unit
Activity Administered (mGy/mCi)
Adrenals
0.14
Urinary Bladder Wall
0.67
Bone Surfaces
0.20
Brain
0.07
Breasts
0.07
Gallbladder Wall
0.27
Stomach Wall
0.96
Small Intestine
0.59
ULI Wall
2.11
LLI Wall
7.77
Heart Wall
0.12
Kidneys
0.19
Liver
0.14
Lungs
0.09
Muscle
0.12
Ovaries
0.37
Pancreas
0.21
Red Marrow
0.13
Skin
0.07
Spleen
0.16
Testes
0.10
Thymus
0.09
Thyroid
0.81
Uterus
0.30
Remaining Tissues
0.13
Effective Dose (mSv/mCi)
0.48
NOTE: To obtain radiation absorbed dose in rads from the above table, divide individual organ values by a factor
of 10 (does not apply for effective dose).
6
Reference ID: 3803549
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Table 6.
Pediatric Absorbed Radiation Doses Per Unit Activity (mGy/mCi) from
Intravenous Injection
Age
15 years
10 years
5 years
1 year
Organ
Adrenals
0.17
0.27
0.41
0.70
Urinary Bladder Wall
0.85
1.11
1.22
2.22
Bone Surfaces
0.24
0.36
0.52
0.96
Brain
0.09
0.15
0.24
0.44
Breasts
0.09
0.13
0.21
0.41
Gallbladder Wall
0.37
0.59
0.85
1.30
Stomach Wall
1.26
1.78
2.89
5.92
Small Intestine
0.74
1.15
1.74
3.03
ULI Wall
2.70
4.44
7.40
14.06
LLI Wall
1.04
1.67
2.66
4.81
Heart Wall
0.15
0.23
0.34
0.63
Kidneys
0.22
0.32
0.48
0.78
Liver
0.18
0.30
0.48
0.81
Lungs
0.13
0.19
0.29
0.52
Muscle
0.15
0.22
0.33
0.59
Ovaries
0.37
0.67
0.96
1.67
Pancreas
0.27
0.41
0.59
1
Red Marrow
0.17
0.24
0.33
0.56
Skin
0.08
0.13
0.21
0.37
Spleen
0.2
0.30
0.44
0.78
Testes
0.14
0.22
0.32
0.59
Thymus
0.12
0.17
0.28
0.52
Thyroid
1.33
2.04
4.44
8.14
Uterus
0.37
0.56
0.81
1.37
Remaining Tissues
0.13
0.24
0.36
0.63
Effective Dose (mSv/mCi)
0.63
0.96
1.55
2.92
NOTE: To obtain radiation absorbed dose in rads from the above table, divide individual organ values by a factor
of 10 (does not apply for effective dose).
7
Reference ID: 3803549
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The estimated absorbed radiation doses to an average ADULT from the instillation of Sodium
Pertechnetate Tc99m Injection for imaging the nasolacrimal drainage system are shown in
Table 7.
Table 7.
Absorbed Radiation Doses from Dacryoscintigraphy
Absorbed Radiation Dose
Organ
mGy/3.7 MBq
rad/100 µCi
Eye Lens:
If lacrimal fluid turnover is 16%/min.
0.140
0.014
If lacrimal fluid turnover is 100%/min.
0.022
0.002
If drainage system is blocked
4.020
0.402
Total Body
0.011
0.001
Ovaries*
0.030
0.003
Testes*
0.009
0.001
Thyroid*
0.130
0.013
*Assuming no blockage of drainage system.
In pediatric patients, an average 30 minute exposure to 37 MBq (1 mCi) of Sodium Pertechnetate
Tc99m Injection following instillation for direct cystography, results in an estimated absorbed
radiation dose shown in Table 8.
Table 8.
Pediatric Absorbed Radiation Dose from Cystography
Age
Bladder wall dose,
Gonadal dose,
mGy (rad)
mGy (rad)
1 year
3.6 (0.36)
0.15 (0.015)
5 years
2.0 (0.2)
0.095 (0.0095)
10 years
1.3 (0.13)
0.066 (0.0066)
15 years
0.92 (0.092)
0.046 (0.0046)
8
Reference ID: 3803549
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HOW SUPPLIED
Sodium Pertechnetate Tc99m Injection is supplied as a molybdenum Mo99 / Drytec (Technetium
Tc99m Generator) in sizes of molybdenum Mo99 from 2.5 GBq up to 100 GBq, 68 mCi up to
2703 mCi, at reference date and time specified on the generator label.
The Drytec (Technetium Tc99m Generator) contains the following amount of molybdenum
Mo99 at the reference time and date stated on the label.
NDC #
Mo99 (GBq)
Mo99 (mCi)
NDC #
Mo99 (GBq)
Mo99 (mCi)
17156-601-51 2.5
68
17156-610-60
15
405
17156-602-52 4
108
17156-611-61
20
541
17156-603-53 5
135
17156-612-62
25
676
17156-604-54 6
162
17156-613-63
30
811
17156-605-55 7.5
203
17156-614-64
40
1,081
17156-606-56 8.5
230
17156-615-65
50
1,351
17156-607-57 9
243
17156-616-66
60
1,622
17156-608-58 10
270
17156-617-67
75
2,027
17156-609-59 12.5
338
17156-618-68
100
2,703
The Drytec (Technetium Tc99m Generator) consists of:
1. Sterile generator
2. Elution pack
The following items are provided in the Elution pack:
• 5 x 30 mL Evacuated vials for collection of the generator eluate
• 5 x 20 mL Saline eluent vials each containing Sodium Chloride Injection 0.9% USP. Not for
direct administration.
• 3 Sterile inlet spike protectors - to maintain sterility of the generator system if the saline vial is
removed between elutions
• 5 Sterile closed cell foam collection needle protectors - to maintain sterility of the generator
system between elutions
• 5 Spare sterile needles - to enable the user to replace the collection needle
• 6 Courtesy labels - to record the activity, volume and time of elution
• 1 Package insert
9
Reference ID: 3803549
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Additional quantities of these components are supplied at the customer's request to allow further
elution of the generator. Additional components will be supplied as either one of the following
two packs:
Saline vials pack
The saline vials pack is available in 5 mL, 10 mL or 20 mL volume to allow the generator eluate
to be collected at varying radioactive concentrations. Each pack contains 20 vials of Sodium
Chloride Injection 0.9% USP, not for direct administration, packed in an outer carton.
Evacuated vials pack
Each evacuated vials pack contains the following components for the elution of the generator
packed in an outer carton.
• 10 x 30 mL Evacuated vials for collection of the generator eluate
• 6 Sterile inlet spike protectors - to maintain sterility of the generator system if the saline vial is
removed between elutions
• 10 Sterile closed cell foam collection needle protectors - to maintain sterility of the generator
system between elutions
• 10 Spare sterile needles - to enable the user to replace the collection needle
• 12 Courtesy labels - to record the activity, volume and time of elution
Storage
Store the generator and the eluate, Sodium Pertechnetate Tc99m Injection, below 25°C (77°F).
Do not freeze.
Store the saline eluent vial below 25°C (77°F). Do not freeze.
Storage should be in accordance with local regulations for radioactive materials.
PREPARATION
This radiopharmaceutical may be received, used and administered only by authorized persons in
designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the
regulations and/or appropriate licenses of the regulatory authorities (see DISPOSAL).
The administration of radiopharmaceuticals creates risks for other persons from external
radiation or contamination from spills of urine, vomiting, etc. Take appropriate radiation
protection precautions in accordance with national regulations.
10
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Instructions for elution of the Drytec (Technetium Tc99m Generator)
Elution instructions
The facilities used for elutions should comply with the appropriate regulations for safe
radiological handling. Strict aseptic techniques should be used during the elution of the generator
to ensure sterility of the generator eluate. To avoid unsatisfactory performance it is important to
adhere to the following sequence of elution steps.
FIRST ELUTION
(1) Remove the generator and accompanying accessories from their packaging. Place the
generator on a flat, level surface, in a suitably authorized and shielded location. Do not
remove the spike and needle protectors until you are ready to carry out the first elution.
(2) Select a saline vial containing the required volume of saline.
(3) Remove the flip-top from the saline vial and swab the saline vial closure using a bactericidal
swab and allow to dry.
(4) Remove the spike protector.
(5) Place the saline vial onto the spike, ensuring that it is fully pushed to the bottom of the inlet
well. Partial rotation will assist the positioning of the vial.
(6) Select an evacuated collection vial, remove the flip top cap, and swab the collection vial
closure using a bactericidal swab and allow to dry. Prior to placing the collection vial inside
the collection vial shield, remove the shield lid and ensure that the vial contact surfaces of
the shield have been swabbed using the bactericidal swab provided. Replace the collection
vial shield screw-locked cap. The collection shield push- fit top is not required until the
elution has been completed.
(7) Remove the collection point protector by turning it counter-clockwise. Ensure that the luer
type filter attached to the collection point protector is also removed. Retain the collection
point protector for use when returning the generator. Immediately fit a collection needle
provided in the accessory pack. Do not remove the collection needle sheath until you are
ready to place the collection vial on the needle.
(8) Remove the collection needle sheath and place the collection vial shield on to the collection
needle, aligning the side location into its guide, and the window to the front. Push down to
ensure that the vial is fully located on the collection needle.
(9) Allow at least 3 minutes for the elution to complete. Elution is complete when all vigorous
bubbling has ceased inside the collection vial. Do not remove either the saline vial or
collection vial until after elution is complete.
(10) Slowly remove the collection vial shield to prevent damage to the collection needle and
replace the push-fit top for added radiation protection.
(11) Cover with a new collection needle protector from the accessory pack to preserve sterility.
(12) To preserve sterility leave the empty saline vial in place until the next elution.
11
Reference ID: 3803549
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SUBSEQUENT ELUTIONS
Using a new sanitized saline vial of the required volume repeat steps 5–12.
If the collection needle needs to be changed, remove the damaged needle and swab the collection
well to ensure sterility is maintained and fit a new needle. Place a collection needle protector
over the new needle.
Following expiry, a spare spike protector and the retained collection point protector should be
used to cover the spike and collection point respectively.
ELUTION VOLUME AND YIELD OF TECHNETIUM Tc99m
Due to the elution characteristics of the different column designs, the recommended minimum
elution volume for lead shielded generators is 5 mL (2.5 to 30 GBq Mo99). For depleted uranium
shielded generators (40 to 100 GBq Mo99) the recommended minimum elution volume is 10
mL. If 5 mL elutions are used a higher radioactive concentration will be obtained, but a small
yield reduction is likely.
The Drytec Technetium Tc99m Generator is calibrated in terms of the amount of molybdenum
Mo99 loaded on the column. The available technetium Tc99m at any time depends on the time
before or after reference (due to the decay of molybdenum Mo99, the time elapsed since the
previous elution (due to “growth” of technetium Tc99m) and on the decay characteristics of
molybdenum Mo99 (86.8% of all decay yields technetium Tc99m). The percentages listed in
Tables 9 and 10 may be used to calculate the available technetium Tc99m activity using the
following method.
First, multiply the stated reference activity by the appropriate factor from Table 9 (which allows
for decay of molybdenum Mo99). Then multiply the product by the appropriate percentage from
Table 10 (which allows for the growth of technetium Tc99m and for decay characteristics of
molybdenum Mo99).
The actual yield of technetium Tc99m will vary slightly due to variation in elution efficiency
from generator to generator. It will typically not be less than 90% of the available technetium
Tc99m activity.
12
Reference ID: 3803549
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Table 9: Molybdenum Mo99 decay factors at various times from generator reference time
(molybdenum Mo99 half-life 66 hours)
Days from generator reference time
(hrs)
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2.00
13.8123
10.7349
8.3432
6.4844
5.0397
3.9169
3.0442
2.3660
1.8388
1.4291
1.1107
0.8633
4.00
13.5252
10.5118
8.1698
6.3496
4.9349
3.8354
2.9809
2.3168
1.8006
1.3994
1.0876
0.8453
6.00
13.2441
10.2933
8.0000
6.2176
4.8324
3.7557
2.9190
2.2686
1.7632
1.3704
1.0650
0.8278
8.00
12.9688
10.0794
7.8337
6.0884
4.7319
3.6777
2.8583
2.2215
1.7265
1.3419
1.0429
0.8105
10.00
12.6992
9.8699
7.6709
5.9618
4.6336
3.6012
2.7989
2.1753
1.6906
1.3140
1.0212
0.7937
12.00
12.4353
9.6647
7.5114
5.8379
4.5373
3.5264
2.7407
2.1301
1.6555
1.2867
1.0000
0.7772
14.00
12.1768
9.4638
7.3553
5.7166
4.4429
3.4531
2.6837
2.0858
1.6211
1.2599
0.9792
0.7610
16.00
11.9237
9.2671
7.2024
5.5978
4.3506
3.3813
2.6280
2.0425
1.5874
1.2337
0.9589
0.7452
18.00
11.6758
9.0745
7.0527
5.4814
4.2602
3.3110
2.5733
2.0000
1.5544
1.2081
0.9389
0.7297
20.00
11.4332
8.8859
6.9061
5.3675
4.1716
3.2422
2.5198
1.9584
1.5221
1.1830
0.9194
0.7146
22.00
11.1955
8.7012
6.7626
5.2559
4.0849
3.1748
2.4675
1.9177
1.4905
1.1584
0.9003
0.6997
24.00
10.9628
8.5203
6.6220
5.1467
4.0000
3.1088
2.4162
1.8779
1.4595
1.1343
0.8816
0.6852
Days from generator reference time
(hrs)
2
3
4
5
6
7
8
9
10
11
12
13
14
2.00
0.6709
0.5215
0.4053
0.3150
0.2448
0.1903
0.1479
0.1149
0.0893
0.0694
0.0540
0.0419
0.0326
4.00
0.6570
0.5106
0.3969
0.3084
0.2397
0.1863
0.1448
0.1125
0.0875
0.0680
0.0528
0.0411
0.0319
6.00
0.6433
0.5000
0.3886
0.3020
0.2347
0.1824
0.1418
0.1102
0.0856
0.0666
0.0517
0.0402
0.0313
8.00
0.6300
0.4896
0.3805
0.2957
0.2299
0.1786
0.1388
0.1079
0.0839
0.0652
0.0507
0.0394
0.0306
10.00
0.6169
0.4794
0.3726
0.2896
0.2251
0.1749
0.1360
0.1057
0.0821
0.0638
0.0496
0.0386
0.0300
12.00
0.6040
0.4695
0.3649
0.2836
0.2204
0.1713
0.1331
0.1035
0.0804
0.0625
0.0486
0.0378
0.0293
14.00
0.5915
0.4597
0.3573
0.2777
0.2158
0.1677
0.1304
0.1013
0.0787
0.0612
0.0476
0.0370
0.0287
16.00
0.5792
0.4502
0.3499
0.2719
0.2113
0.1642
0.1277
0.0992
0.0771
0.0599
0.0466
0.0362
0.0281
18.00
0.5672
0.4408
0.3426
0.2663
0.2069
0.1608
0.1250
0.0972
0.0755
0.0587
0.0456
0.0354
0.0275
20.00
0.5554
0.4316
0.3355
0.2607
0.2026
0.1575
0.1224
0.0951
0.0739
0.0575
0.0447
0.0347
0.0270
22.00
0.5438
0.4227
0.3285
0.2553
0.1984
0.1542
0.1199
0.0932
0.0724
0.0563
0.0437
0.0340
0.0264
24.00
0.5325
0.4139
0.3217
0.2500
0.1943
0.1510
0.1174
0.0912
0.0709
0.0551
0.0428
0.0333
0.0259
13
Reference ID: 3803549
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 10: Factors allowing for growth of technetium Tc99m at various times following the
previous elution of technetium Tc99 half-life 6.02 hours)
Hours
Factor
Hours
Factor
Hours
Factor
Hours
Factor
Hours
Factor
Hours
Factor
1
0.094
9
0.579
17
0.788
25
0.879
33
0.918
41
0.936
2
0.179
10
0.615
18
0.804
26
0.884
34
0.921
42
0.937
3
0.256
11
0.648
19
0.818
27
0.892
35
0.924
43
0.938
4
0.324
12
0.678
20
0.831
28
0.898
36
0.926
44
0.940
5
0.386
13
0.705
21
0.843
29
0.903
37
0.929
45
0.941
6
0.442
14
0.729
22
0.853
30
0.907
38
0.930
46
0.941
7
0.492
15
0.751
23
0.863
31
0.911
39
0.932
47
0.941
8
0.538
16
0.771
24
0.871
32
0.915
40
0.934
48
0.942
TECHNETIUM Tc99m ASSAY PROCEDURE
The Sodium Pertechnetate Tc99m Injection eluate may be assayed using an ionization chamber
dose calibrator. The manufacturer’s instructions for operation of the dose calibrator should be
followed for measurement of technetium Tc99m and molybdenum Mo99 activity in the
generator eluate. The molybdenum Mo99 / technetium Tc99m ratio should be determined at the
time of elution prior to administration, and from that ratio, the expiration time (up to 12 hours) of
the eluate mathematically determined. Each eluate should meet or exceed the purity requirements
of the current United States Pharmacopeia; that is, not more than 0.0056 MBq (0.15 µCi) of
molybdenum Mo99 per 37 MBq (1 mCi) of technetium Tc99m per administered dose at the time
of administration.
RADIOMETRIC MOLYBDENUM TEST PROCEDURE
This method is based on the fact that most technetium Tc99m radiation can be readily shielded
and only the more energetic gamma rays from molybdenum Mo99 (739KeV and 778KeV) are
counted in the 550-850KeV energy range. The entire Sodium Pertechnetate Tc99m Injection
eluate may be assayed for molybdenum Mo99 activity as follows:
1. A cesium Cs137 reference source which has the same geometry as the generator eluate must
be used to standardize the well counter.
2. Determine the background after setting the window to the 550-850KeV energy range.
3. Count the technetium Tc99m eluate in its lead shield (thereby shielding out technetium
Tc99m) by placing over the well or probe.
4. Count the cesium Cs137 reference source in the same shield geometry for the same time
period.
5. Compute molybdenum Mo99 activity in the Sodium Pertechnetate Tc99m Injection eluate as
follows:
μCi molybdenum =
μCi simulated Mo99 x net cpm Eluate
Mo99 (total)
net cpm simulated Mo99 reference source
14
Reference ID: 3803549
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Divide this number by the mCi of technetium Tc99m. This result (μCi Mo99/mCi Tc99m) can be
converted to MBq Mo99/MBq Tc99m by multiplying by 10-3. The U.S. Pharmacopeia and the
U.S. Nuclear Regulatory Commission or equivalent Agreement State regulations specify a limit
of 0.0056 MBq of molybdenum Mo99 per 37 MBq of technetium Tc99m (0.15 μCi of Mo99 /
mCi of Tc99m) at the time of administration to each patient.
MOLYBDENUM Mo99 BREAKTHROUGH TEST
1. Determine the amount of technetium Tc99m eluted (MBq, mCi).
2. Place the Sodium Pertechnetate Tc99m Injection eluate in a lead container. Place lid on
container and put the entire container in the chamber.
3. Record the amount of molybdenum Mo99 (MBq, mCi) on the most sensitive scale.
4. Divide the MBq, mCi molybdenum Mo99 by the MBq, mCi technetium Tc99m. Correct for
decay and shielding effect, if necessary.
The molybdenum Mo99/technetium Tc99m ratio should be determined at the time of elution
prior to administration, and from that ratio, the expiration time (up to twelve hours) of the eluate
mathematically determined. Each Sodium Pertechnetate Tc99m Injection eluate should meet or
exceed purity requirement of the current official United States Pharmacopeia.
COLORIMETRIC ALUMINIUM TEST PROCEDURE
Obtain an aluminium ion indicator kit and determine the aluminium ion concentration of the
Sodium Pertechnetate Tc99m Injection eluate per the manufacturer’s instructions. The
concentration must not exceed 10 µg/mL of eluate.
DISPOSAL: All components shipped with the Drytec (Technetium Tc99m Generator) should be
monitored for contamination prior to disposing into routine trash systems. The technetium
Tc99m should not be disposed of into routine trash systems. The generator should be disposed
through a USNRC or Agreement State licensed disposal agency or by a method approved by the
appropriate regulatory authority. Spent generators may be returned; full return instructions of
generators to GE Healthcare are provided separately and are available upon request.
EXPIRATION DATE
The expiry date for the generator is 24 days from the date of manufacture. The reference and
expiry dates are stated on the generator label. The Drytec (Technetium Tc99m Generator) should
not be used after expiration date.
For multidose use, the Sodium Pertechnetate Tc99m Injection eluate should be used within
twelve (12) hours of the generator elution time. If the eluate is used to reconstitute a kit, the
radio-labeled kit should not be used after twelve (12) hours from the time of generator elution or
six (6) hours after reconstitution of the kit, whichever is earlier.
The shelf-life for the sodium chloride eluent is 3 years.
Since the Sodium Pertechnetate Tc99m Injection eluate does not contain an antimicrobial agent,
it should not be used after twelve hours from the time of generator elution.
15
Reference ID: 3803549
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DISPOSAL
Expired generators containing lead shielding (2.5 to 30 GBq Mo99) could normally be disposed
of by the user as radioactive waste in accordance with the conditions specified by the local
regulatory authority. If local regulations for disposal require that the generator be dismantled,
please contact GE Healthcare. Arrangements may be made for the return of lead shielded
generators to GE Healthcare if required.
Generators containing depleted uranium and tungsten shielding (40 to 100 GBq Mo99) must be
returned to GE Healthcare after expiry. Full return instructions describing how to return
generators to GE Healthcare are provided separately. Users are reminded that all packaging,
documentation and methods of transportation used must be in compliance with international
transport regulations and all local regulations and codes of practice that relate to such matters.
This generator is approved for use by persons licensed by the Illinois Emergency Management
Agency pursuant to Section 330.260(a), (b) or (c) and 32 IL. Adm. Code 335.4010 or under
equivalent licenses of the US NRC or an Agreement State.
GE Healthcare, Medi-Physics, Inc.
Arlington Heights, IL 60004 U.S.A.
Manufactured by:
GE Healthcare Ltd., HP7 9LL, UK
Customer Service: 800-292-8514
Professional Services: 800-654-0118
Drytec is a trademark of General Electric Company or one of its subsidiaries.
GE and the GE Monogram are trademarks of General Electric Company.
© 2015 General Electric Company - All rights reserved.
Revised June 2015
16
Reference ID: 3803549
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/2015/017693s029lbl.pdf', 'application_number': 17693, 'submission_type': 'SUPPL ', 'submission_number': 29}
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NDA 17-765/S-024
Page 2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-765/S-024
Page 3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-765/S-024
Page 4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-765/S-024
Page 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/2003/17765scp024_cloderm_lbl.pdf', 'application_number': 17765, 'submission_type': 'SUPPL ', 'submission_number': 24}
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s
truc
tur
al formula
NDA 17-760/S-017
Page 3
FML®
(fluorometholone ophthalmic ointment) 0.1%
sterile
DESCRIPTION
FML® (fluorometholone ophthalmic ointment) 0.1 % is a sterile, topical anti-inflammatory agent
for ophthalmic use.
Chemical Name
Fluorometholone: 9-Fluoro-11β, 17-dihydroxy-6α-methylpregna-1,4-diene-3,20-dione
Structural Formula:
Contains
Active: fluorometholone 0.1%. Preservative: phenylmercuric acetate (0.0008%). Inactives:
mineral oil; petrolatum (and) lanolin alcohol; and white petrolatum.
CLINICAL PHARMACOLOGY
Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably
delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte
migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar
formation associated with inflammation.
There is no generally accepted explanation for the mechanism of action of ocular corticosteroids.
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.
Corticosteroids are capable of producing a rise in intraocular pressure. In clinical studies of
documented steroid-responders, fluorometholone demonstrated a significantly longer average
time to produce a rise in intraocular pressure than dexamethasone phosphate; however, in a small
percentage of individuals, a significant rise in intraocular pressure occurred within one week.
The ultimate magnitude of the rise was equivalent for both drugs.
Reference ID: 3258815
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-760/S-017
Page 4
INDICATIONS AND USAGE
FML® ointment is indicated for the treatment of corticosteroid-responsive inflammation of the
palpebral and bulbar conjunctiva, cornea and anterior segment of the globe.
CONTRAINDICATIONS
FML® ointment is contraindicated in most viral diseases of the cornea and conjunctiva,
including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also
in mycobacterial infection of the eye and fungal diseases of ocular structures.
FML® ointment is also contraindicated in individuals with known or suspected hypersensitivity
to any of the ingredients of this preparation and to other corticosteroids.
WARNINGS
Prolonged use of corticosteroids may increase intraocular pressure in susceptible individuals,
resulting in glaucoma with damage to the optic nerve, defects in visual acuity and fields of
vision, and in posterior subcapsular cataract formation. Prolonged use may also suppress the host
immune response and thus increase the hazard of secondary ocular infections.
Various ocular diseases and long-term use of topical corticosteroids have been known to cause
corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or
scleral tissue may lead to perforation.
Acute purulent infections of the eye may be masked or activity enhanced by the presence of
corticosteroid medication.
If this product is used for 10 days or longer, intraocular pressure should be routinely monitored
even though it may be difficult in children and uncooperative patients. Steroids should be used
with caution in the presence of glaucoma. Intraocular pressure should be checked frequently.
The use of steroids after cataract surgery may delay healing and increase the incidence of bleb
formation.
Use of ocular steroids may prolong the course and may exacerbate the severity of many viral
infections of the eye (including herpes simplex). Employment of a corticosteroid medication in
the treatment of patients with a history of herpes simplex requires great caution; frequent slit
lamp microscopy is recommended.
PRECAUTIONS
General
The initial prescription and renewal of the medication order beyond 8 grams of FML® ointment
should be made by a physician only after examination of the patient with the aid of
magnification, such as slit lamp biomicroscopy, and, where appropriate, fluorescein staining. If
signs and symptoms fail to improve after two days, the patient should be re-evaluated.
Reference ID: 3258815
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-760/S-017
Page 5
As fungal infections of the cornea are particularly prone to develop coincidentally with long-
term local corticosteroid applications, fungal invasion should be suspected in any persistent
corneal ulceration where a corticosteroid has been used or is in use. Fungal cultures should be
taken when appropriate.
If this product is used for 10 days or longer, intraocular pressure should be monitored (see
WARNINGS).
Ophthalmic ointments may retard corneal healing.
Information for Patients
If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should
be advised to discontinue use of the medication and consult a physician.
This product is sterile when packaged. To prevent contamination, care should be taken to avoid
touching the tube tip to eyelids or to any other surface. The use of this tube by more than one
person may spread infection. Keep tube tightly closed when not in use. Keep out of the reach of
children.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been conducted in animals or in humans to evaluate the possibility of these
effects with fluorometholone.
Pregnancy
Teratogenic effects. Pregnancy Category C
Fluorometholone has been shown to be embryocidal and teratogenic in rabbits when
administered at low multiples of the human ocular dose. Fluorometholone was applied ocularly
to rabbits daily on days 6 - 18 of gestation, and dose-related fetal loss and fetal abnormalities
including cleft palate, deformed rib cage, anomalous limbs and neural abnormalities such as
encephalocele, craniorachischisis, and spina bifida were observed. There are no adequate and
well-controlled studies of fluorometholone in pregnant women, and it is not known whether
fluorometholone can cause fetal harm when administered to a pregnant woman. Fluorometholone
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nursing Mothers
It is not known whether topical ophthalmic administration of corticosteroids could result in
sufficient systemic absorption to produce detectable quantities in human milk. Systemically
administered corticosteroids appear in human milk and could suppress growth, interfere with
endogenous corticosteroid production, or cause other untoward effects. Because of the potential
for serious adverse reactions in nursing infants from fluorometholone, 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.
Reference ID: 3258815
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-760/S-017
Page 6
Pediatric Use:
Safety and effectiveness in infants below the age of two years have not been established.
Geriatric use:
No overall differences in safety or effectiveness have been observed between elderly and
younger patients.
ADVERSE REACTIONS
Adverse reactions include, in decreasing order of frequency, elevation of intraocular pressure
(IOP) with possible development of glaucoma and infrequent optic nerve damage, posterior
subcapsular cataract formation, and delayed wound healing.
Although systemic effects are extremely uncommon, there have been rare occurrences of
systemic hypercorticoidism after use of topical dermatologic steroids applied to the skin.
Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis
and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival
hyperemia, loss of accommodation and ptosis have occasionally been reported following local
use of corticosteroids.
The development of secondary ocular infection (bacterial, fungal, and viral) has occurred. Fungal
and viral infections of the cornea are particularly prone to develop coincidentally with long-term
applications of steroids. The possibility of fungal invasion should be considered in any persistent
corneal ulceration where steroid treatment has been used (see WARNINGS).
Other adverse events reported with the use of fluorometholone include: allergic reactions;
foreign body sensation; erythema of eyelid; eyelid edema/eye swelling; eye discharge; eye pain;
eye pruritus; lacrimation increased; ocular irritation; rash; taste perversion; visual disturbance
(blurry vision); and visual field defect.
DOSAGE AND ADMINISTRATION
A small amount (approximately 1/2 inch ribbon) of ointment should be applied to the
conjunctival sac one to three times daily. During the initial 24 to 48 hours, the dosing frequency
may be increased to one application every four hours. Care should be taken not to discontinue
therapy prematurely.
If signs and symptoms fail to improve after two days, the patient should be re-evaluated (see
PRECAUTIONS).
The dosing of FML® ointment may be reduced, but care should be taken not to discontinue
therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by
gradually decreasing the frequency of applications.
HOW SUPPLIED
Reference ID: 3258815
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-760/S-017
Page 7
FML® (fluorometholone ophthalmic ointment) 0.1 % is supplied in a collapsible aluminum tube
with a black low density polyethylene screw cap in the following size: 3.5 g in 3.5 g tube – NDC
0023-0316-04.
Storage: Store at 15º - 25º C (59º - 77º F).
Avoid exposure to temperatures above 40°C (104° F).
Revised: 02/2013
© 2013 Allergan, Inc.
Irvine, CA 92612, U.S.A.
® marks owned by Allergan, Inc.
Made in the U.S.A.
Reference ID: 3258815
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/2013/017760s017lbl.pdf', 'application_number': 17760, 'submission_type': 'SUPPL ', 'submission_number': 17}
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NDA 17-766/S-029
Page 5
Y36-002-547
PACKAGE INSERT
5.4% NephrAmine® (Essential Amino Acid Injection)
Protect from light until use. Rx only
DESCRIPTION
5.4% NephrAmine (Essential Amino Acid Injection) is a sterile, nonpyrogenic solution
containing crystalline essential amino acids plus histidine. Each 250 mL unit provides Rose’s
recommended daily intake of essential amino acids1 plus 625 mg of histidine, considered
essential for uremics. The total nitrogen content of a 250 mL unit is approximately 1.6 grams (10
g of protein equivalent) in 14 grams of amino acids. All amino acids designated USP are the “L”
isomer.
EACH 100 ML CONTAINS:
Histidine USP*
0.25 g
Isoleucine USP
0.56 g
Leucine USP
0.88 g
Lysine
0.64 g
(added as Lysine Acetate USP 0.90 g)
Methionine USP
0.88 g
Phenylalanine USP
0.88 g
Threonine USP
0.40 g
Tryptophan USP
0.20 g
Valine USP
0.64 g
Cysteine
<0.014 g
(as Cysteine HCl•H2O USP <0.020 g)
Sodium Bisulfite (as an antioxidant)
<0.05 g
Water for Injection USP qs
pH adjusted with Sodium Hydroxide NF as required
pH: 6.5 (6.0-7.0)
Calculated Osmolarity: 435 mOsmol/liter
Total Nitrogen: Approx. 0.65 g/100 mL
Concentration of Electrolytes (mEq/liter): Sodium 5; Chloride <3; Acetate Approx. 44
*Histidine is considered an essential amino acid in uremic patients.
1Rose WC: the sequence of events leading to the establishment of the amino acid needs of man. am j public health; 1968: 58
(11):2020-2027.
CLINICAL PHARMACOLOGY
NephrAmine provides an intravenously compatible mixture of essential amino acids which,
when infused with hypertonic dextrose as a source of calories, plus electrolytes, minerals, and
vitamins, provides in a small volume of fluid all ingredients (with the exception of essential fatty
acids) needed for total parenteral nutrition in patients with renal disease.
Infusion of NephrAmine and hypertonic dextrose provides essential amino acids and calories for
protein synthesis to promote improved cellular metabolic balance. Infusion of these components
can decrease the rate of rise of blood urea nitrogen and minimize deterioration of serum
potassium, magnesium, and phosphorus balance in patients with impaired renal function. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 6
extent to which essential amino acids and calories promote incorporation of waste urea nitrogen
into newly synthesized amino acids in man, as it does in experimental animals, is, so far, not
established.
The accelerated decrease in serum creatinine levels seen in patients with limited extra-renal
complications suggests that treatment with NephrAmine and hypertonic dextrose leads to earlier
return of renal function in patients with potentially reversible acute renal failure. By providing
nutritional support and promoting biochemical improvement as well as earlier return of renal
function, NephrAmine and hypertonic dextrose decrease morbidity associated with acute renal
failure.
It is thought that acetate from Iysine acetate, under the condition of parenteral nutrition, does not
impact net acid-base balance when renal and respiratory functions are normal. Clinical evidence
seems to support this thinking; however, confirmatory experimental evidence is not available.
The amounts of sodium and chloride present are not of clinical significance.
INDICATIONS AND USAGE
5.4% NephrAmine® (Essential Amino Acid Injection) is indicated for adult and pediatric use, in
conjunction with other measures, to provide nutritional support for uremic patients, particularly
when oral nutrition is infeasible or impractical. See WARNINGS, PRECAUTIONS, Pediatric
Use, Special Precautions in Pediatric Patients, and DOSAGE AND ADMINISTRATION.
CONTRAINDICATIONS
NephrAmine is contraindicated in patients with severe, uncorrected electrolyte and acid-base
imbalance, hyperammonemia, decreased (subcritical) circulating blood volume, inborn errors of
amino acid metabolism, or hypersensitivity to one or more amino acids present in the solution.
WARNINGS
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 µg/kg/day accumulate
aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may
occur at even lower rates of administration.
This product contains sodium bisulfite, 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.
Safe and effective use of central venous nutrition requires a knowledge of nutrition as well as
clinical expertise in recognition and treatment of the complications which can occur. Frequent
clinical evaluation and laboratory determinations are necessary for proper monitoring of
central venous nutrition. Laboratory tests should include measurement of blood sugar,
electrolyte, and serum protein concentrations; kidney and liver function tests; and evaluation of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 7
acid-base balance and fluid balance. Other laboratory tests may be suggested by the patient’s
condition.
NephrAmine does not replace dialysis and conventional supportive therapy in patients with renal
failure.
Administration of NephrAmine to pediatric patients, especially in high dose ranges, may result in
hyperammonemia. Administration of NephrAmine to infants, particularly neonates and low birth
weight infants, may result in elevated plasma amino acid levels (e.g., hypermethionemia) and
hyperammonemia. In these very young age groups, amino acid formulations developed
specifically for nutritional support of infants and pediatric patients, should be considered.
Clinically significant hypokalemia, hypophosphatemia, or hypomagnesemia may occur as a
result of therapy with NephrAmine and hypertonic dextrose and replacement therapy may
become necessary.
Administration of nitrogen in any form to patients with marked hepatic insufficiency or hepatic
coma may result in plasma amino acid imbalances, hyperammonemia, or central nervous system
deterioration. NephrAmine should, therefore, be used with caution in such patients.
The intravenous administration of these solutions can cause fluid and/or solute overload resulting
in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary
edema. The risk of dilutional states is inversely proportional to the solute concentration of the
solution infused. The risk of solute overload causing congested states with peripheral and
pulmonary edema is directly proportional to the concentration of the solution.
Conservative doses of amino acids should be given, dictated by the nutritional status of the
patient.
PRECAUTIONS
General
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. Significant deviations
from normal concentrations may require the use of additional electrolyte supplements.
In order to promote urea nitrogen reutilization in patients with renal failure, it is essential to
provide adequate calories with minimal amounts of the essential amino acids, and to severely
restrict the intake of nonessential nitrogen. Hypertonic dextrose solutions are a convenient and
metabolically effective source of concentrated calories.
Fluid balance must be carefully monitored in patients with renal failure and care should be taken
to avoid circulatory overload, particularly in association with cardiac insufficiency.
In patients with myocardial infarct, infusion of amino acids should always be accompanied by
dextrose, since in anoxia, free fatty acids cannot be utilized by the myocardium, and energy must
be produced anaerobically from glycogen or glucose.
Strongly hypertonic nutrient solutions should be administered through an indwelling intravenous
catheter with the tip located in the superior vena cava.
Special care must be taken when giving hypertonic dextrose to glucose-intolerant patients such
as diabetic or prediabetic and uremic patients, especially when the latter are receiving peritoneal
dialysis. To prevent severe hyperglycemia in such patients, insulin may be required.
Administration of glucose at a rate exceeding the patient’s utilization may lead to hyperglycemia,
coma, and death.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 8
Administration of amino acids without carbohydrates may result in the accumulation of ketone
bodies in the blood. Correction of this ketonemia may be achieved by the administration of
carbohydrates.
Abrupt cessation of hypertonic dextrose infusion may result in rebound hypoglycemia.
When 5.4% NephrAmine® (Essential Amino Acid Injection) is subjected to changes in
temperature, there is a chance that some transient crystallization of amino acids may occur.
Thorough shaking of the bottle for about one minute should redissolve the amino acids. If the
amino acids do not completely redissolve, the bottle must be rejected.
To minimize the risk of possible incompatibilities arising from mixing this solution with other
additives that may be prescribed, the final infusate should be inspected for cloudiness or
precipitation immediately after mixing, prior to administration, and periodically during
administration.
Use only if solution is clear and vacuum is present.
Drug product contains no more than 25 µg/L of aluminum.
Laboratory Tests
Frequent clinical evaluation and laboratory determinations are necessary for proper
monitoring during administration.
Laboratory tests should include measurement of blood sugar, electrolyte, and serum protein
concentrations; kidney and liver function tests; and evaluation of acid-base balance and fluid
balance. Other laboratory tests may be suggested by the patient’s condition.
Drug Interactions
Some additives may be incompatible. Consult with pharmacist. When introducing additives, use
aseptic techniques. Mix thoroughly. Do not store.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No in vitro or in vivo carcinogenesis, mutagenesis, or fertility studies have been conducted with
5.4% NephrAmine® (Essential Amino Acid Injection).
Pregnancy - Teratogenic Effects - Pregnancy Category C.
Animal reproduction studies have not been conducted with 5.4% NephrAmine (Essential Amino
Acid Injection). It is also not known whether NephrAmine can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. NephrAmine should be
given to a pregnant woman only if clearly needed.
Labor and Delivery
Information is unknown.
Nursing Mothers
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 NephrAmine 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
NDA 17-766/S-029
Page 9
Pediatric Use
Safety and effectiveness of amino acid injections in pediatric patients have not been established
by adequate and well-controlled studies. However, the use of amino acid injections in pediatric
patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen
balance is well established in the medical literature. See INDICATIONS AND USAGE,
WARNINGS, and DOSAGE AND ADMINISTRATION.
Geriatric Use
NephrAmine has not been studied in geriatric patients. Elderly patients are known to be more
prone to fluid overload and electrolyte imbalance than younger patients. This may be related to
impairment of renal function which is more frequent in an elderly population. As a result the
need for careful monitoring of fluid and electrolyte therapy is greater in the elderly. All patients,
including the elderly, require an individual dose of all parenteral nutrition products to be
determined by the physician on an individual case-by-case basis, which will be based on body
weight, clinical condition and the results of laboratory monitoring tests. There is no specific
geriatric dose. See WARNINGS.
Special Precautions for Central Venous Nutrition
Administration by central venous catheter should be used only by those familiar with this
technique and its complications.
Central venous nutrition may be associated with complications which can be prevented or
minimized by careful attention to all aspects of the procedure including solution preparation,
administration, and patient monitoring. It is essential that a carefully prepared protocol,
based on current medical practices, be followed, preferably by an experienced team.
Although a detailed discussion of the complications of central venous nutrition is beyond the
scope of this insert, the following summary lists those based on current literature:
Technical. The placement of a central venous catheter should be regarded as a surgical
procedure. One should be fully acquainted with various techniques of catheter insertion as well
as recognition and treatment of complications. For details of techniques and placement sites,
consult the medical literature. X-ray is the best means of verifying catheter placement.
Complications known to occur from the placement of central venous catheters are
pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial
plexus, malposition of the catheter, formation of arterio-venous fistula, phlebitis, thrombosis, and
air and catheter embolus.
Septic. The constant risk of sepsis is present during central venous nutrition. Since contaminated
solutions and infusion catheters are potential sources of infection, it is imperative that the
preparation of parenteral nutrition solutions and the placement and care of catheters be
accomplished under controlled aseptic conditions.
Parenteral nutrition solutions should ideally be prepared in the hospital pharmacy under a
laminar flow hood. The key factor in their preparation is careful aseptic technique to avoid
inadvertent touch contamination during mixing of solutions and subsequent admixtures.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 10
Parenteral nutrition solutions should be used promptly after mixing. Any storage should be under
refrigeration for as brief a time as possible. Administration time for a single bottle and set should
never exceed 24 hours.
Consult the medical literature for a discussion of the management of sepsis during central venous
nutrition. In brief, typical management includes replacing the solution being administered with a
fresh container and set, and the remaining contents are cultured for bacterial or fungal
contamination. If sepsis persists and another source of infection is not identified, the catheter is
removed, the proximal tip cultured, and a new catheter reinserted when the fever has subsided.
Nonspecific, prophylactic antibiotic treatment is not recommended. Clinical experience indicates
that the catheter is likely to be the prime source of infection as opposed to aseptically prepared
and properly stored solutions.
Metabolic. The following metabolic complications have been reported: metabolic acidosis,
hypophosphatemia, alkalosis, hyperglycemia and glycosuria, osmotic diuresis and dehydration,
rebound hypoglycemia, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte
imbalances, and elevated plasma amino acid levels and hyperammonemia in infants and pediatric
patients. Frequent clinical evaluation and laboratory determinations are necessary, especially
during the first few days of central venous nutrition, to prevent or minimize these complications.
Special Precautions in Patients with Renal Insufficiency
Frequent laboratory studies are necessary in patients with renal insufficiency due to underlying
metabolic abnormalities. Hyperglycemia, a frequent complication, may not be reflected by
glycosuria in renal failure. Blood glucose, therefore, must be determined frequently, often every
six hours to guide dosage of dextrose and insulin if required.
Serum concentrations of potassium, phosphorus, and magnesium may dramatically decline with
successful treatment, individually or together; these substances should be supplemented as
required. Special care must be taken to avoid hypokalemia in digitalized patients, or those with
cardiac arrhythmias.
Special Precautions in Pediatric Patients
5.4% NephrAmine® (Essential Amino Acid Injection) should be used with special caution in
pediatric patients, due to limited clinical experience.
Laboratory and clinical monitoring of pediatric patients, especially when nutritionally depleted,
must be extensive and frequent. Initial total daily dose should be low, and increased slowly.
Dosage of NephrAmine above one gram of essential amino acids per kilogram body weight per
day is not recommended.
For infants, especially neonates and low birth weight infants, amino acid formulations developed
specifically for nutritional support of infants and pediatric patients should be considered. If
NephrAmine is administered to these very young patients, extra caution in frequent monitoring
of plasma amino acid levels and serum ammonia is strongly recommended.
Frequent monitoring of blood glucose is required in neonates, low birth-weight, or septic infants
as infusion of hypertonic dextrose carries a greater risk of hyperglycemia in such patients.
The absence of arginine in NephrAmine may accentuate the risk of hyperammonemia in infants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 11
ADVERSE REACTIONS
See WARNINGS and Special Precautions for Central Venous Nutrition.
Reactions which may occur because of the solution or the technique of administration include
febrile response, infection at the site of injection, venous thrombosis, and hypervolemia.
Symptoms may result from an excess or deficit of one or more of the ions present in the solution
infused, therefore, frequent monitoring of electrolyte levels is essential.
Infrequent instances of hyperammonemia have been reported following administration of
essential amino acid solutions to patients with massive gastrointestinal hemorrhage, nonuremic
infants and pediatric patients or following administration of higher than recommended doses to
adult or pediatric patients. Elevated plasma amino acid levels (hypermethionemia) have also
been reported in infants especially in higher dosage ranges. Elevated serum ammonia levels,
plasma amino acid levels, and clinical symptoms may subside when the infusions are
discontinued.
Phosphorus deficiency may lead to impaired tissue oxygenation and acute hemolytic anemia.
Relative to calcium, excessive phosphorus intake can precipitate hypocalcemia with cramps,
tetany, and muscular hyperexcitability.
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.
OVERDOSAGE
In the event of a fluid or solute overload during parenteral therapy, reevaluate the patient’s
condition and institute appropriate corrective treatment.
DOSAGE AND ADMINISTRATION
The objective of nutritional management of renal decompensation is the provision of sufficient
amino acid and caloric support for protein synthesis without greatly exceeding the renal capacity
to excrete metabolic wastes.
Three grams of nitrogen per day provided as essential amino acids with adequate calories
produce nitrogen equilibrium in many stable patients with chronic uremia. Although nitrogen
requirements may be higher in stressed or acutely uremic patients, or those on dialysis, provision
of additional nitrogen may not be possible due to fluid intake limits or glucose intolerance.
The usual methods of determining individual patient requirements for amino acids such as
nitrogen balance or daily body weight are difficult to perform or interpret in the uremic patient.
Therefore, dosage is guided by the patient’s fluid intake limits and glucose and nitrogen
tolerances, as well as metabolic and clinical response. Rate of rise of blood urea nitrogen
generally diminishes with infusion of essential amino acids. However, excessive intake of dietary
protein or increased protein catabolism may alter this response.
Adult Use
Generally, 250 to 500 mL of 5.4% NephrAmine® (Essential Amino Acid Injection), containing
approximately 1.6 to 3.2 grams of nitrogen (in 13.4 to 26.8 grams of essential amino acids), are
given daily. Adequate calories should be provided simultaneously. Each 250 mL of NephrAmine
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 12
is typically mixed aseptically with 500 mL of 70% dextrose to yield a solution of 1.8%
NephrAmine in 47% dextrose. This mixture provides a calorie-to-nitrogen ratio of 744:1.
Pediatric Use
Initial total daily dose should be low and increased slowly. As the dose is increased, frequent
laboratory and clinical monitoring is strongly recommended, especially in very young patients, to
avoid clinically significant elevations of serum ammonia and plasma amino acid levels. Dosage
of NephrAmine above one gram of essential amino acids per kg of body weight per day is not
recommended. In pediatric patients, the final solution should not exceed twice normal serum
osmolarity (718 mOsmol/L).
Use of 5.4% NephrAmine in pediatric patients is governed by the same considerations that affect
the use of any amino acid solution in pediatrics. The amount administered is dosed on the basis
of grams of amino acids/kg of body weight/day. Two to three g/kg of body weight for infants
with adequate calories are generally sufficient to satisfy protein needs and promote positive
nitrogen balance. Solution administrated by peripheral vein should not exceed twice normal
serum osmolarity (718 mOsmol/L).
See INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, Pediatric Use, and
Special Precautions in Pediatric Patients.
Fat emulsion coadministration should be considered when prolonged (more than 5 days)
parenteral nutrition is required in order to prevent essential fatty acid deficiency (E.F.A.D.).
Serum lipids should be monitored for evidence of E.F.A.D. in patients maintained on fat free
TPN.
Electrolyte supplementation may be required. Undiluted NephrAmine® (Essential Amino Acid
Injection) contains 5 mEq/liter of sodium. Elevated serum potassium, phosphorus, and
magnesium levels generally decrease during treatment with NephrAmine. Although these effects
are beneficial, especially in acute renal failure, in some instances the reduction may be so great
that supplementation of these electrolytes is required, especially in the presence of cardiac
arrhythmias or digitalis toxicity. During periods of anuria or oliguria, electrolyte
supplementation should be done with caution, even if serum levels are in the low normal range.
Compatibility of electrolyte additives to the 5.4% NephrAmine/hypertonic dextrose mixture
must be considered, and potentially incompatible ions such as calcium and phosphate may be
added to alternate infusion bottles to avoid precipitation. In patients with hyperchloremic or other
metabolic acidosis, sodium and potassium may be added as acetate or lactate salts to provide
bicarbonate precursor. The electrolyte content of NephrAmine must be considered when
calculating daily electrolyte intake. Serum electrolytes, including magnesium and phosphorus,
should be monitored frequently.
If a patient’s nutritional intake is primarily parenteral, vitamins, especially the water soluble
vitamins, should also be provided.
Hypertonic mixtures of essential amino acids and dextrose may be safely administered by
continuous infusion through a central venous catheter with the tip located in the superior vena
cava. Initial infusion rates should be slow, generally 20-30 mL/hour. Increases by increments of
10 mL/hour each 24 hours are recommended to a maximum of 60-100 mL/hour. If
administration rate should fall behind schedule, no attempt to “catch up” to planned intake
should be made.
Administration rate is governed by the patient’s nitrogen, fluid, and glucose tolerance. Uremic
patients are frequently glucose intolerant, especially in association with peritoneal dialysis, and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 13
may require the administration of exogenous insulin to prevent hyperglycemia. Blood glucose
levels must be determined frequently. To prevent rebound hypoglycemia, a solution containing
5% dextrose should be administered when hypertonic dextrose infusions are abruptly
discontinued.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
Care must be taken to avoid incompatible admixtures. Consult with pharmacist.
HOW SUPPLIED
5.4% NephrAmine (Essential Amino Acid Injection) is supplied sterile and nonpyrogenic in
glass containers with solid stoppers packaged 12 per case.
NDC
Cat. No.
Size
5.4% NEPHRAMINE
(ESSENTIAL AMINO ACID INJECTION)
0264-1909-55
S9092-SS
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.
PROTECT FROM LIGHT UNTIL USE.
Revised: July 2003
NephrAmine is a registered trademark of B. Braun Medical Inc.
Made in USA
Directions for Use of B. Braun Glass Containers with Solid Stoppers
Designed for use with a vented set.
Before use, perform the following checks:
1.
Inspect each container. Read the label. Ensure solution is the one ordered and is within
the expiration date. Check the security of bail and band.
2.
Invert container and carefully inspect the solution in good light for cloudiness, haze, or
particulate matter; check the bottle for cracks or other damage. In checking for cracks, do
not be confused by normal surface marks and seams on the bottom and sides of the bottle.
These are not flaws. Look for bright reflections that have depth and penetrate into the
wall of the bottle. Reject any such bottle.
3.
To remove the outer closure, lift the tear tab and pull up, over, and down until it is below
the stopper (See Figure 1). Use a circular pulling motion on the tab until it breaks away.
4.
Grasp and remove the metal disk, exercising caution not to touch the exposed sterile
stopper surface.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 17-766/S-029
Page 14
Warning: Some additives may be incompatible. Consult with pharmacist. When introducing
additives, use aseptic techniques. Mix thoroughly. Do not store.
5.
Refer to Directions for Use of the set being used. Insert the set spike into the large round
outlet port of the stopper and hang container.
6.
After admixture and during administration, reinspect the solution frequently. If any
evidence of solution contamination or instability is found or if the patient exhibits any
signs of fever, chills or other reactions not readily explainable, discontinue administration
immediately and notify the physician.
7.
When adding medication to the container during administration, swab the triangular
medication site, inject medication and mix thoroughly by gentle agitation.
8.
Spiking, additions, or transfers should be made immediately after exposing the sterile
stopper surface. Check for vacuum at first puncture of stopper. Admixture by needle or
syringe should be made through the triangular ( ∆ ) medication site; contents should be
drawn by vacuum into the bottle. Admixture by spiked vial should be through the outlet
port (See Figure 2). If contents of initial addition are not drawn into the bottle, vacuum is
not present and the unit should be discarded. Each addition/transfer will reduce the
vacuum remaining in the bottle.
9.
If the first puncture of the stopper is the administration set spike, insert the spike fully
into the outlet port of the stopper and promptly invert the bottle. Verify vacuum by
observing rising air bubbles. Do not use the bottle if vacuum is not present.
10.
If admixture or set insertion is not performed immediately following removal of
protective metal disk, swab stopper surface.
B. BRAUN MEDICAL INC.
IRVINE CA USA 92614-5895
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/2004/17766scs029_nephramine_lbl.pdf', 'application_number': 17766, 'submission_type': 'SUPPL ', 'submission_number': 29}
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11,056
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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/2001/17760s9lbl.pdf', 'application_number': 17760, 'submission_type': 'SUPPL ', 'submission_number': 9}
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11,063
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Ativan®
CIV
(lorazepam)
Tablets
Rx only
DESCRIPTION
Ativan (lorazepam), an antianxiety agent, has the chemical formula, 7-chloro-5-
(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one:
C15H10Cl2N2O2
MW: 321.16
It is a nearly white powder almost insoluble in water. Each Ativan (lorazepam)
tablet, to be taken orally, contains 0.5 mg, 1 mg, or 2 mg of lorazepam. The
inactive ingredients present are lactose monohydrate, magnesium stearate,
microcrystalline cellulose, polacriline potassium.
CLINICAL PHARMACOLOGY
Studies in healthy volunteers show that in single high doses Ativan (lorazepam)
has a tranquilizing action on the central nervous system with no appreciable
effect on the respiratory or cardiovascular systems.
Ativan (lorazepam) is readily absorbed with an absolute bioavailability of 90
percent. Peak concentrations in plasma occur approximately 2 hours following
administration. The peak plasma level of lorazepam from a 2 mg dose is
approximately 20 ng/mL.
The mean half-life of unconjugated lorazepam in human plasma is about 12
hours and for its major metabolite, lorazepam glucuronide, about 18 hours. At
clinically relevant concentrations, lorazepam is approximately 85% bound to
plasma proteins. Ativan (lorazepam) is rapidly conjugated at its 3-hydroxy group
into lorazepam glucuronide which is then excreted in the urine. Lorazepam
glucuronide has no demonstrable CNS activity in animals.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The plasma levels of lorazepam are proportional to the dose given. There is no
evidence of accumulation of lorazepam on administration up to six months.
Studies comparing young and elderly subjects have shown that advancing age
does not have a significant effect on the pharmacokinetics of lorazepam.
However, in one study involving single intravenous doses of 1.5 to 3 mg of Ativan
Injection, mean total body clearance of lorazepam decreased by 20% in 15
elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects
of 19 to 38 years of age.
INDICATIONS AND USAGE
Ativan (lorazepam) is indicated for the management of anxiety disorders or for
the short-term relief of the symptoms of anxiety or anxiety associated with
depressive symptoms. Anxiety or tension associated with the stress of everyday
life usually does not require treatment with an anxiolytic.
The effectiveness of Ativan (lorazepam) in long-term use, that is, more than 4
months, has not been assessed by systematic clinical studies. The physician
should periodically reassess the usefulness of the drug for the individual patient.
CONTRAINDICATIONS
Ativan (lorazepam) is contraindicated in patients with
- hypersensitivity to benzodiazepines or to any components of the formulation.
- acute narrow-angle glaucoma.
WARNINGS
Pre-existing depression may emerge or worsen during use of benzodiazepines
including lorazepam. Ativan (lorazepam) is not recommended for use in patients
with a primary depressive disorder or psychosis.
Use of benzodiazepines, including lorazepam, both used alone and in
combination with other CNS depressants, may lead to potentially fatal respiratory
depression. (See PRECAUTIONS, Clinically Significant Drug Interactions)
Use of benzodiazepines, including lorazepam, may lead to physical and
psychological dependence.
As with all patients on CNS-depressant drugs, patients receiving lorazepam
should be warned not to operate dangerous machinery or motor vehicles and
that their tolerance for alcohol and other CNS depressants will be diminished.
Physical And Psychological Dependence
The use of benzodiazepines, including lorazepam, may lead to physical and
psychological dependence. The risk of dependence increases with higher doses
and longer term use and is further increased in patients with a history of
alcoholism or drug abuse or in patients with significant personality disorders. The
dependence potential is reduced when lorazepam is used at the appropriate
dose for short-term treatment. Addiction-prone individuals (such as drug addicts
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
or alcoholics) should be under careful surveillance when receiving lorazepam or
other psychotropic agents.
In general, benzodiazepines should be prescribed for short periods only (e.g. 2- 4
weeks). Extension of the treatment period should not take place without
reevaluation of the need for continued therapy. Continuous long-term use of
product is not recommended. Withdrawal symptoms (e.g. rebound insomnia) can
appear following cessation of recommended doses after as little as one week of
therapy. Abrupt discontinuation of product should be avoided and a gradual
dosage-tapering schedule followed after extended therapy.
Abrupt termination of treatment may be accompanied by withdrawal symptoms.
Symptoms reported following discontinuation of benzodiazepines include
headache, anxiety, tension, depression, insomnia, restlessness, confusion,
irritability, sweating, rebound phenomena, dysphoria, dizziness, derealization,
depersonalization, hyperacusis, numbness/tingling of extremities, hypersensitivity
to light, noise, and physical contact/perceptual changes, involuntary movements,
nausea, vomiting, diarrhea, loss of appetite, hallucinations/delirium,
convulsions/seizures, tremor, abdominal cramps, myalgia, agitation, palpitations,
tachycardia, panic attacks, vertigo, hyperreflexia, short-term memory loss, and
hyperthermia. Convulsions/seizures may be more common in patients with pre-
existing seizure disorders or who are taking other drugs that lower the convulsive
threshold such as antidepressants.
There is evidence that tolerance develops to the sedative effects of
benzodiazepines.
Lorazepam may have abuse potential, especially in patients with a history of drug
and/or alcohol abuse.
PRECAUTIONS
In patients with depression, a possibility for suicide should be borne in mind;
benzodiazepines should not be used in such patients without adequate anti-
depressant therapy.
Lorazepam should be used with caution in patients with compromised respiratory
function (e.g. COPD, sleep apnea syndrome).
Elderly or debilitated patients may be more susceptible to the sedative effects of
lorazepam. Therefore, these patients should be monitored frequently and have
their dosage adjusted carefully according to patient response; the initial dosage
should not exceed 2 mg.
Paradoxical reactions have been occasionally reported during benzodiazepine
use. Such reactions may be more likely to occur in children and the elderly.
Should these occur, use of the drug should be discontinued.
The usual precautions for treating patients with impaired renal and hepatic
function should be observed. As with all benzodiazepines, the use of lorazepam
may worsen hepatic encephalopathy; therefore, lorazepam should be used with
caution in patients with severe hepatic insufficiency and/or encephalopathy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage for patients with severe hepatic insufficiency should be adjusted carefully
according to patient response; lower doses may be sufficient in such patients.
In patients where gastrointestinal or cardiovascular disorders coexist with
anxiety, it should be noted that lorazepam has not been shown to be of
significant benefit in treating the gastrointestinal or cardiovascular component.
Esophageal dilation occurred in rats treated with lorazepam for more than one
year at 6 mg/kg/day. The no-effect dose was 1.25 mg/kg/day (approximately 6
times the maximum human therapeutic dose of 10 mg per day). The effect was
reversible only when the treatment was withdrawn within two months of first
observation of the phenomenon. The clinical significance of this is unknown.
However, use of lorazepam for prolonged periods and in geriatric patients
requires caution, and there should be frequent monitoring for symptoms of upper
G.I. disease.
Safety and effectiveness of Ativan (lorazepam) in children of less than 12 years
have not been established.
Information For Patients
To assure the safe and effective use of Ativan (lorazepam), patients should be
informed that, since benzodiazepines may produce psychological and physical
dependence, it is advisable that they consult with their physician before either
increasing the dose or abruptly discontinuing this drug.
Essential Laboratory Tests
Some patients on Ativan (lorazepam) have developed leukopenia, and some
have had elevations of LDH. As with other benzodiazepines, periodic blood
counts and liver-function tests are recommended for patients on long-term
therapy.
Clinically Significant Drug Interactions
The benzodiazepines, including Ativan (lorazepam), produce increased CNS-
depressant effects when administered with other CNS depressants such as
alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics,
antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants,
and anesthetics.
Concomitant use of clozapine and lorazepam may produce marked sedation,
excessive salivation, hypotension, ataxia, delirium, and respiratory arrest.
Concurrent administration of lorazepam with valproate results in increased
plasma concentrations and reduced clearance of lorazepam. Lorazepam dosage
should be reduced to approximately 50% when coadministered with valproate.
Concurrent administration of lorazepam with probenecid may result in a more
rapid onset or prolonged effect of lorazepam due to increased half-life and
decreased total clearance. Lorazepam dosage needs to be reduced by
approximately 50% when coadministered with probenecid.
The effects of probenecid and valproate on lorazepam may be due to inhibition of
glucuronidation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Administration of theophylline or aminophylline may reduce the sedative effects
of benzodiazepines, including lorazepam.
Carcinogenesis And Mutagenesis
No evidence of carcinogenic potential emerged in rats during an 18-month study
with Ativan (lorazepam). No studies regarding mutagenesis have been
performed.
Pregnancy
Reproductive studies in animals were performed in mice, rats, and two strains of
rabbits. Occasional anomalies (reduction of tarsals, tibia, metatarsals, malrotated
limbs, gastroschisis, malformed skull, and microphthalmia) were seen in drug-
treated rabbits without relationship to dosage. Although all of these anomalies
were not present in the concurrent control group, they have been reported to
occur randomly in historical controls. At doses of 40 mg/kg and higher, there was
evidence of fetal resorption and increased fetal loss in rabbits which was not
seen at lower doses.
The clinical significance of the above findings is not known. However, an
increased risk of congenital malformations associated with the use of minor
tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first
trimester of pregnancy has been suggested in several studies. Because the use
of these drugs is rarely a matter of urgency, the use of lorazepam during this
period should be avoided. The possibility that a woman of childbearing potential
may be pregnant at the time of institution of therapy should be considered.
Patients should be advised that if they become pregnant, they should
communicate with their physician about the desirability of discontinuing the drug.
In humans, blood levels obtained from umbilical cord blood indicate placental
transfer of lorazepam and lorazepam glucuronide. Infants of mothers who
ingested benzodiazepines for several weeks or more preceding delivery have
been reported to have withdrawal symptoms during the postnatal period.
Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression,
apnea, feeding problems, and impaired metabolic response to cold stress have
been reported in neonates born of mothers who have received benzodiazepines
during the late phase of pregnancy or at delivery.
Nursing Mothers
Lorazepam has been detected in human breast milk; therefore, it should not be
administered to breast-feeding women, unless the expected benefit to the
woman outweighs the potential risk to the infant.
Sedation and inability to suckle have occurred in neonates of lactating mothers
taking benzodiazepines. Infants of lactating mothers should be observed for
pharmacological effects (including sedation and irritability).
Geriatric Use
Clinical studies of Ativan generally were not adequate to determine whether
subjects aged 65 and over respond differently than younger subjects; however,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the incidence of sedation and unsteadiness was observed to increase with age
(see ADVERSE REACTIONS).
Age does not appear to have a significant effect on lorazepam kinetics (see
CLINICAL PHARMACOLOGY).
Clinical circumstances, some of which may be more common in the elderly, such
as hepatic or renal impairment, should be considered. Greater sensitivity (e.g.,
sedation) of some older individuals cannot be ruled out. In general, dose
selection for an elderly patient should be cautious, and lower doses may be
sufficient in these patients (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Most adverse reactions to benzodiazepines, including CNS effects and
respiratory depression, are dose dependent, with more severe effects occurring
with high doses.
In a sample of about 3500 patients treated for anxiety, the most frequent adverse
reaction to Ativan (lorazepam) was sedation (15.9%), followed by dizziness
(6.9%), weakness (4.2%), and unsteadiness (3.4%). The incidence of sedation
and unsteadiness increased with age.
Other adverse reactions to benzodiazepines, including lorazepam are fatigue,
drowsiness, amnesia, memory impairment, confusion, disorientation,
depression, unmasking of depression, disinhibition, euphoria, suicidal
ideation/attempt, ataxia, asthenia, extrapyramidal symptoms,
convulsions/seizures tremor, vertigo, eye-function/visual disturbance (including
diplopia and blurred vision), dysarthria/slurred speech, change in libido,
impotence, decreased orgasm; headache, coma; respiratory depression, apnea,
worsening of sleep apnea, worsening of obstructive pulmonary disease;
gastrointestinal symptoms including nausea, change in appetite, constipation,
jaundice, increase in bilirubin, increase in liver transaminases, increase in
alkaline phosphatase; hypersensitivity reactions, anaphylactic/oid reactions;
dermatological symptoms, allergic skin reactions, alopecia; SIADH,
hyponatremia; thrombocytopenia, agranulocytosis, pancytopenia; hypothermia;
and autonomic manifestations.
Paradoxical reactions, including anxiety, excitation, agitation, hostility,
aggression, rage, sleep disturbances/insomnia, sexual arousal, and
hallucinations may occur. Small decreases in blood pressure and hypotension
may occur but are usually not clinically significant, probably being related to the
relief of anxiety produced by Ativan (lorazepam).
OVERDOSAGE
In postmarketing experience, overdose with lorazepam has occurred
predominantly in combination with alcohol and/or other drugs. Therefore, in the
management of overdosage , it should be borne in mind that multiple agents may
have been taken.
Symptoms
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Overdosage of benzodiazepines is usually manifested by varying degrees of
central nervous system depression ranging from drowsiness to coma. In mild
cases, symptoms include drowsiness, mental confusion, paradoxical reactions,
dysarthria and lethargy. In more serious cases, and especially when other drugs
or alcohol were ingested, symptoms may include ataxia, hypotonia, hypotension,
cardiovascular depression, respiratory depression, hypnotic state, coma, and
death.
MANAGEMENT
General supportive and symptomatic measures are recommended; vital signs must be
monitored and the patient closely observed. When there is a risk of aspiration, induction
of emesis is not recommended. Gastric lavage may be indicated if performed soon after
ingestion or in symptomatic patients. Administration of activated charcoal may also limit
drug absorption. Hypotension, though unlikely, usually may be controlled with
norepinephrine bitartrate injection. Lorazepam is poorly dialyzable. Lorazepam
glucuronide, the inactive metabolite, may be highly dialyzable.
The benzodiazepine antagonist flumazenil may be used in hospitalized patients
as an adjunct to, not as a substitute for, proper management of benzodiazepine
overdose. The prescriber should be aware of a risk of seizure in association
with flumazenil treatment, particularly in long-term benzodiazepine users
and in cyclic antidepressant overdose. The complete flumazenil package
insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS
should be consulted prior to use.
DOSAGE AND ADMINISTRATION
Ativan (lorazepam) is administered orally. For optimal results, dose, frequency of
administration, and duration of therapy should be individualized according to
patient response. To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available.
The usual range is 2 to 6 mg/day given in divided doses, the largest dose being
taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day.
For anxiety, most patients require an initial dose of 2 to 3 mg/day given b.i.d. or
t.i.d.
For insomnia due to anxiety or transient situational stress, a single daily dose of
2 to 4 mg may be given, usually at bedtime.
For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided
doses is recommended, to be adjusted as needed and tolerated.
The dosage of Ativan (lorazepam) should be increased gradually when needed
to help avoid adverse effects. When higher dosage is indicated, the evening dose
should be increased before the daytime doses.
How Supplied
Ativan® (lorazepam) Tablets are available in the following dosage strengths:
0.5 mg, white, five-sided tablet with a raised "A" on one side and "BPI" and "63"
impressed on reverse side.
NDC 64455-063-01 – Bottles of 100 tablets
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1 mg, white, five-sided tablet with a raised "A" on one side and "BPI" and "64"
impressed on scored reverse side
NDC 64455-064-01 – Bottles of 100 tablets
NDC 64455-064-10 – Bottles of 1000 tablets
2 mg, white, five-sided tablet with a raised "A" and impressed "2" on one side
and "BPI" and "65" impressed on scored reverse side.
NDC 64455-065-01 – Bottles of 100 tablets
The appearance of these tablets is a registered trademark of Biovail Laboratories
Incorporated.
BOTTLES:
Keep tightly closed.
Store at controlled room temperature 20° to 25° C (68° to 77° F).
Dispense in a tight container.
Manufactured by:
Wyeth Pharmaceuticals Inc.
Philadelphia, PA, 19101, USA
Distributed by:
Biovail Pharmaceuticals, Inc.
Bridgewater, NJ, 08807, USA
Pharmaceuticals, Inc.
Made and Printed in USA
CI XXXX-X
Rev 03/07
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/2007/017794s034s035lbl.pdf', 'application_number': 17794, 'submission_type': 'SUPPL ', 'submission_number': 35}
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11,062
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GLUCOTROL®
(glipizide)
TABLETS
For Oral Use
DESCRIPTION
GLUCOTROL (glipizide) is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazine-
carboxamido)ethyl]phenyl]sulfonyl]urea. The molecular formula is C21H27N5O4S; the molecular
weight is 445.55; the structural formula is shown below:
Ch
emical Structure of Glucotrol (glipizide)
H
Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols,
but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. GLUCOTROL tablets for
oral use are available in 5 and 10 mg strengths.
Inert ingredients are: colloidal silicon dioxide; lactose; microcrystalline cellulose; starch;
stearic acid.
CLINICAL PHARMACOLOGY
Mechanism of Action: The primary mode of action of GLUCOTROL in experimental animals
appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and
is thus dependent on functioning beta cells in the pancreatic islets. In humans GLUCOTROL
appears to lower the blood glucose acutely by stimulating the release of insulin from the
pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The
mechanism by which GLUCOTROL lowers blood glucose during long-term administration has
not been clearly established. In man, stimulation of insulin secretion by GLUCOTROL in
response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
even on long-term GLUCOTROL administration, but the postprandial insulin response continues
to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs
within 30 minutes after an oral dose of GLUCOTROL in diabetic patients, but elevated insulin
levels do not persist beyond the time of the meal challenge. Extrapancreatic effects may play a
part in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
Blood sugar control persists in some patients for up to 24 hours after a single dose of
GLUCOTROL, even though plasma levels have declined to a small fraction of peak levels by
that time (see Pharmacokinetics below).
Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea
drugs, including GLUCOTROL. Alternatively, GLUCOTROL may be effective in some patients
who have not responded or have ceased to respond to other sulfonylureas.
Other Effects: It has been shown that GLUCOTROL therapy was effective in controlling blood
sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for
NIDDM.
In a placebo-controlled, crossover study in normal volunteers, GLUCOTROL had no antidiuretic
activity, and, in fact, led to a slight increase in free water clearance.
Pharmacokinetics:
Gastrointestinal absorption of GLUCOTROL in man is uniform, rapid, and essentially complete.
Peak plasma concentrations occur 1–3 hours after a single oral dose. The half-life of elimination
ranges from 2–4 hours in normal subjects, whether given intravenously or orally. The metabolic
and excretory patterns are similar with the two routes of administration, indicating that first-pass
metabolism is not significant. GLUCOTROL does not accumulate in plasma on repeated oral
administration. Total absorption and disposition of an oral dose was unaffected by food in
normal volunteers, but absorption was delayed by about 40 minutes. Thus GLUCOTROL was
more effective when administered about 30 minutes before, rather than with, a test meal in
diabetic patients. Protein binding was studied in serum from volunteers who received either oral
or intravenous GLUCOTROL and found to be 98–99% one hour after either route of
administration. The apparent volume of distribution of GLUCOTROL after intravenous
administration was 11 liters, indicative of localization within the extracellular fluid
compartment. In mice no GLUCOTROL or metabolites were detectable autoradiographically in
the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another
study, however, very small amounts of radioactivity were detected in the fetuses of rats given
labelled drug.
The metabolism of GLUCOTROL is extensive and occurs mainly in the liver. The primary
metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in
the urine. Less than 10% unchanged GLUCOTROL is found in the urine.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
GLUCOTROL is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus.
CONTRAINDICATIONS
GLUCOTROL is contraindicated in patients with:
1. Known hypersensitivity to the drug.
2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition
should be treated with insulin.
WARNINGS
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY:
The administration of oral hypoglycemic drugs has been reported to be associated with
increased cardiovascular mortality as compared to treatment with diet alone or diet plus
insulin. This warning is based on the study conducted by the University Group Diabetes
Program (UGDP), a long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in
patients with non-insulin-dependent diabetes. The study involved 823 patients who were
randomly assigned to one of four treatment groups (Diabetes, 19, supp. 2: 747–830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of
tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately
2½ times that of patients treated with diet alone. A significant increase in total mortality
was not observed, but the use of tolbutamide was discontinued based on the increase in
cardiovascular mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these results, the
findings of the UGDP study provide an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of GLUCOTROL and of alternative
modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this study,
it is prudent from a safety standpoint to consider that this warning may also apply to other
oral hypoglycemic drugs in this class, in view of their close similarities in mode of action
and chemical structure.
PRECAUTIONS
General
Macrovascular Outcomes: There have been no clinical studies establishing conclusive
evidence of macrovascular risk reduction with GLUCOTROL or any other anti-diabetic drug.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Renal and Hepatic Disease: The metabolism and excretion of GLUCOTROL may be slowed in
patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such
patients, it may be prolonged and appropriate management should be instituted.
Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper
patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Renal
or hepatic insufficiency may cause elevated blood levels of GLUCOTROL and the latter may
also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic
reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary
insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.
Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking
beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is
deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one
glucose-lowering drug is used.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is
exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At
such times, it may be necessary to discontinue GLUCOTROL and administer insulin.
The effectiveness of any oral hypoglycemic drug, including GLUCOTROL, in lowering blood
glucose to a desired level decreases in many patients over a period of time, which may be due to
progression of the severity of the diabetes or to diminished responsiveness to the drug. This
phenomenon is known as secondary failure, to distinguish it from primary failure in which the
drug is ineffective in an individual patient when first given.
Hemolytic Anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD)
deficiency with sulfonylurea agents can lead to hemolytic anemia. Because GLUCOTROL
belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD
deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports,
hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
Laboratory Tests: Blood and urine glucose should be monitored periodically. Measurement of
glycosylated hemoglobin may be useful.
Information for Patients: Patients should be informed of the potential risks and advantages of
GLUCOTROL and of alternative modes of therapy. They should also be informed about the
importance of adhering to dietary instructions, of a regular exercise program, and of regular
testing of urine and/or blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its
development should be explained to patients and responsible family members. Primary and
secondary failure should also be explained.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Physician Counseling Information for Patients:
In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of
treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper
dietary management alone may be effective in controlling the blood glucose and symptoms of
hyperglycemia. The importance of regular physical activity should also be stressed, and
cardiovascular risk factors should be identified and corrective measures taken where possible.
Use of GLUCOTROL or other antidiabetic medications must be viewed by both the physician
and patient as a treatment in addition to diet and not as a substitution or as a convenient
mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet
alone may be transient, thus requiring only short-term administration of GLUCOTROL or other
antidiabetic medications. Maintenance or discontinuation of GLUCOTROL or other antidiabetic
medications should be based on clinical judgment using regular clinical and laboratory
evaluations.
Drug Interactions: The hypoglycemic action of sulfonylureas may be potentiated by certain
drugs including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are
highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins,
monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are
administered to a patient receiving GLUCOTROL, the patient should be observed closely for
hypoglycemia. When such drugs are withdrawn from a patient receiving GLUCOTROL, the
patient should be observed closely for loss of control. In vitro binding studies with human serum
proteins indicate that GLUCOTROL binds differently than tolbutamide and does not interact
with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings
to the clinical situation and in the use of GLUCOTROL with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs
include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,
estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel
blocking drugs, and isoniazid. When such drugs are administered to a patient receiving
GLUCOTROL, the patient should be closely observed for loss of control. When such drugs are
withdrawn from a patient receiving GLUCOTROL, the patient should be observed closely for
hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe
hypoglycemia has been reported. Whether this interaction also occurs with the intravenous,
topical, or vaginal preparations of miconazole is not known. The effect of concomitant
administration of DIFLUCAN® (fluconazole) and GLUCOTROL has been demonstrated in a
placebo-controlled crossover study in normal volunteers. All subjects received GLUCOTROL
alone and following treatment with 100 mg of DIFLUCAN as a single daily oral dose for 7 days.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The mean percentage increase in the GLUCOTROL AUC after fluconazole administration was
56.9% (range: 35 to 81).
Carcinogenesis, Mutagenesis, Impairment of Fertility: A twenty month study in rats and an
eighteen month study in mice at doses up to 75 times the maximum human dose revealed no
evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly
negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects
on fertility.
Pregnancy: Pregnancy Category C: GLUCOTROL (glipizide) was found to be mildly fetotoxic
in rat reproductive studies at all dose levels (5–50 mg/kg). This fetotoxicity has been similarly
noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and
believed to be directly related to the pharmacologic (hypoglycemic) action of
GLUCOTROL. In studies in rats and rabbits no teratogenic effects were found. There are no
adequate and well controlled studies in pregnant women. GLUCOTROL should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because recent information suggests that abnormal blood glucose levels during pregnancy are
associated with a higher incidence of congenital abnormalities, many experts recommend that
insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in
neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This
has been reported more frequently with the use of agents with prolonged half-lives. If
GLUCOTROL is used during pregnancy, it should be discontinued at least one month before the
expected delivery date.
Nursing Mothers: Although it is not known whether GLUCOTROL is excreted in human milk,
some sulfonylurea drugs are known to be excreted in human milk. Because the potential for
hypoglycemia in nursing infants may exist, 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.
If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin
therapy should be considered.
Pediatric Use: Safety and effectiveness in children have not been established.
Geriatric Use: A determination has not been made whether controlled clinical studies of
GLUCOTROL included sufficient numbers of subjects aged 65 and over to define a difference in
response 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
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In U.S. and foreign controlled studies, the frequency of serious adverse reactions reported was
very low. Of 702 patients, 11.8% reported adverse reactions and in only 1.5% was
GLUCOTROL discontinued.
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.
Gastrointestinal: Gastrointestinal disturbances are the most common reactions. Gastrointestinal
complaints were reported with the following approximate incidence: nausea and diarrhea, one in
seventy; constipation and gastralgia, one in one hundred. They appear to be dose-related and
may disappear on division or reduction of dosage. Cholestatic jaundice may occur rarely with
sulfonylureas: GLUCOTROL should be discontinued if this occurs.
Dermatologic: Allergic skin reactions including erythema, morbilliform or maculopapular
eruptions, urticaria, pruritus, and eczema have been reported in about one in seventy patients.
These may be transient and may disappear despite continued use of GLUCOTROL; if skin
reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity
reactions have been reported with sulfonylureas.
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see
PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas.
Metabolic: Hepatic porphyria and disulfiram-like reactions have been reported with
sulfonylureas. In the mouse, GLUCOTROL pretreatment did not cause an accumulation of
acetaldehyde after ethanol administration. Clinical experience to date has shown that
GLUCOTROL has an extremely low incidence of disulfiram-like alcohol reactions.
Endocrine Reactions: Cases of hyponatremia and the syndrome of inappropriate antidiuretic
hormone (SIADH) secretion have been reported with this and other sulfonylureas.
Miscellaneous: Dizziness, drowsiness, and headache have each been reported in about one in
fifty patients treated with GLUCOTROL. They are usually transient and seldom require
discontinuance of therapy.
Laboratory Tests: The pattern of laboratory test abnormalities observed with GLUCOTROL
was similar to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT,
LDH, alkaline phosphatase, BUN and creatinine were noted. One case of jaundice was reported.
The relationship of these abnormalities to GLUCOTROL is uncertain, and they have rarely been
associated with clinical symptoms.
OVERDOSAGE
There is no well documented experience with GLUCOTROL overdosage. The acute oral toxicity
was extremely low in all species tested (LD50 greater than 4 g/kg).
Overdosage of sulfonylureas including GLUCOTROL can produce hypoglycemia. Mild
hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close
monitoring should continue until the physician is assured that the patient is out of danger. Severe
hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently,
but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma
is diagnosed or suspected, the patient should be given a rapid intravenous injection of
concentrated (50%) glucose solution. This should be followed by a continuous infusion of a
more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above
100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since
hypoglycemia may recur after apparent clinical recovery. Clearance of GLUCOTROL from
plasma would be prolonged in persons with liver disease. Because of the extensive protein
binding of GLUCOTROL, dialysis is unlikely to be of benefit.
DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with GLUCOTROL
or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the
patient’s blood glucose must also be monitored periodically to determine the minimum effective
dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the
maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an
adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated
hemoglobin levels may also be of value in monitoring the patient’s response to therapy.
Short-term administration of GLUCOTROL may be sufficient during periods of transient loss of
control in patients usually controlled well on diet.
In general, GLUCOTROL should be given approximately 30 minutes before a meal to achieve
the greatest reduction in postprandial hyperglycemia.
Initial Dose: The recommended starting dose is 5 mg, given before breakfast. Geriatric patients
or those with liver disease may be started on 2.5 mg.
Titration: Dosage adjustments should ordinarily be in increments of 2.5–5 mg, as determined by
blood glucose response. At least several days should elapse between titration steps. If response
to a single dose is not satisfactory, dividing that dose may prove effective. The maximum
recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and
given before meals of adequate caloric content. The maximum recommended total daily dose is
40 mg.
Maintenance: Some patients may be effectively controlled on a once-a-day regimen, while
others show better response with divided dosing. Total daily doses above 15 mg should
ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to
long-term patients.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or
hepatic function, the initial and maintenance dosing should be conservative to avoid
hypoglycemic reactions (see PRECAUTIONS section).
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many stable
non-insulin-dependent diabetic patients receiving insulin may be safely placed on
GLUCOTROL. When transferring patients from insulin to GLUCOTROL, the following general
guidelines should be considered:
For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued
and GLUCOTROL therapy may begin at usual dosages. Several days should elapse between
GLUCOTROL titration steps.
For patients whose daily insulin requirement is greater than 20 units, the insulin dose should
be reduced by 50% and GLUCOTROL therapy may begin at usual dosages. Subsequent
reductions in insulin dosage should depend on individual patient response. Several days
should elapse between GLUCOTROL titration steps.
During the insulin withdrawal period, the patient should test urine samples for sugar and ketone
bodies at least three times daily. Patients should be instructed to contact the prescriber
immediately if these tests are abnormal. In some cases, especially when patient has been
receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization
during the transition period.
Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class
hypoglycemics, no transition period is necessary when transferring patients to GLUCOTROL.
Patients should be observed carefully (1–2 weeks) for hypoglycemia when being transferred
from longer half-life sulfonylureas (e.g., chlorpropamide) to GLUCOTROL due to potential
overlapping of drug effect.
HOW SUPPLIED
GLUCOTROL tablets are white, dye-free, scored, diamond-shaped, and imprinted as follows:
5 mg–Pfizer 411; 10 mg–Pfizer 412.
5 mg Bottles:
100’s (NDC 0049-4110-66) (NDC 59012-411-66);
500’s (NDC 0049-4110-73) (NDC 59012-411-73);
UNIT DOSE 100’s (NDC 0049-4110-41) (NDC 59012-411-41).
10 mg Bottles: 100’s (NDC 0049-4120-66) (NDC 59012-412-66);
500’s (NDC 0049-4120-73) (NDC 59012-412-73);
UNIT DOSE 100’s (NDC 0049-4120-41) (NDC 59012-412-41).
RECOMMENDED STORAGE: Store below 86°F (30°C).
Rx only
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pfizer Logo
LAB-0114-4.02.4
Revised FebruarySeptember 20098
10
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/2009/017783s020lbl.pdf', 'application_number': 17783, 'submission_type': 'SUPPL ', 'submission_number': 20}
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11,060
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NDC 0234-0575-40
Lot number and expiration date printed on bottom of container.
Laundering/Cleaning Instructions.
Chlorhexidine gluconate skin cleansers will cause stains if used with
chlorine releasing products. Rinse completely and use only
non-chlorine detergents. See website for more details.
www.hibiclens.com
57540-00-MHC
Active ingredient
Chlorhexidine gluconate
solution 4.0% w/v .......................................... Antiseptic
Uses
■ antimicrobial skin cleanser helps reduce bacteria that
potentially can cause disease
■ for skin wound and general skin cleansing
■ surgical hand scrub
■ healthcare personnel handwash
Warnings
For external use only
Do not use
■ if you are allergic to chlorhexidine gluconate or any
other ingredients in this preparation
■ as a patient preoperative skin preparation of the head
or face
■ in contact with the meninges
■ in the genital area
■ on wounds that involve more than the
superficial layers of skin
When using this product
■ keep out of eyes, ears, and mouth. May cause serious
and permanent eye injury if placed or kept in the eye
during surgical procedures, or may cause deafness
when instilled in the middle ear through perforated
eardrums.
■ if contact occurs in any of these areas, rinse with cold
water right away
Stop use and ask a doctor if irritation, sensitization, or
allergic reaction occurs and lasts for 72 hours. These may
be signs of a serious condition.
Keep out of reach of children. If swallowed, get
medical help or contact a Poison Control Center right
away.
Directions
■ use with care in premature infants or infants under 2
months of age. These products may cause irritation or
chemical burns.
■ skin wound and general skin cleansing.
Thoroughly rinse the area to be cleansed with water.
Apply the minimum amount of the product necessary
to cover the skin or wound area and wash gently. Rinse
thoroughly.
■ surgical hand scrub. Wet hands and forearms with
water. Scrub for 3 minutes with about 5mL of the
product with a brush. Rinse thoroughly under running
water. Repeat. Dry thoroughly.
■ healthcare personnel handwash.
Wet hands with water. Dispense about 5mL of the
product into cupped hands and wash in a vigorous
manner for 15 seconds. Rinse and dry thoroughly.
Other information
■ store between 20-25°C (68-77°F)
■ avoid excessive heat above 40°C (104°F)
Inactive ingredients
fragrance, gluconolactone, isopropyl alcohol 4% w/v,
lauramine oxide, poloxamer 237,
purified water and red 40
Questions? 1-800-843-8497
Drug Facts
Purpose
Drug Facts (continued)
Component no:
Font size:
Component Type:
Created by:
Artwork version:
Date:
57540-00
6 pt (bullet texts)
Label
Anders Hansen
4
151112
PMS 318
PMS 315
Diecut
Colour information
Mölnlycke Health Care, Gamlestadsvägen 3C, SE-402 52, Göteborg. anders.hansen@molnlycke.com tel: +46 31 722 33 46.
This artwork was created based on internal procedure T-085.
57/16" (138,11 mm)
33/8" (85,72 mm)
Reference ID: 3858075
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/2015/017768s042lbl.pdf', 'application_number': 17768, 'submission_type': 'SUPPL ', 'submission_number': 42}
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SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 1 DRAFT LABELING
XXXXXXXX
PRODUCT
INFORMATION
DIPROSONE®
brand of betamethasone
dipropionate
Lotion, USP 0.05% w/w
(potency expressed as betamethasone)
For Dermatologic Use Only-
Not for Ophthalmic Use
DESCRIPTION DIPROSONE Lotion contains betamethasone dipropionate, USP, a
synthetic adrenocorticosteroid, for dermatologic use. Betamethasone, an analog of
prednisolone, has high corticosteroid activity and slight mineralocorticoid activity.
Betamethasone dipropionate is the 17, 21-dipropionate ester of betamethasone.
Chemically, betamethasone dipropionate is 9-Fluoro-11β,17,21-trihydroxy-16β-
methylpregna-1,4-diene-3,20-dione
17,21-dipropionate,
with
the
empirical
formula
C28H37FO7, a molecular weight of 504.6, and the following structural formula:
Betamethasone dipropionate is a white to creamy white, odorless crystalline
powder, insoluble in water.
Each gram of DIPROSONE Lotion 0.05% w/w contains: 0.643 mg betamethasone
dipropionate, USP (equivalent to 0.5 mg betamethasone) in a lotion base of isopropyl
alcohol, USP (39.25%) and purified water, USP; slightly thickened with carbomer 974P;
the pH is adjusted to approximately 4.7 with sodium hydroxide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 2 DRAFT LABELING
CLINICAL PHARMACOLOGY The corticosteroids are a class of compounds comprising
steroid hormones, secreted by the adrenal cortex and their synthetic analogs. In
pharmacologic doses corticosteroids are used primarily for their anti-inflammatory and/or
immunosuppressive effects.
Topical corticosteroids, such as betamethasone dipropionate, are effective in the
treatment of corticosteroid-responsive dermatoses primarily because of their anti-
inflammatory, antipruritic, and vasoconstrictive actions. However, while the physiologic,
pharmacologic, and clinical effects of the corticosteroids are well known, the exact
mechanisms of their actions in each disease are uncertain. 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 increase percutaneous absorption. Occlusive
dressings substantially increase the percutaneous absorption of topical corticosteroids.
(See DOSAGE AND ADMINISTRATION.)
Once absorbed through the skin, topical corticosteroids are handled through
pharmacokinetic
pathways
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.
Twenty-five pediatric patients ages 6 to 12 years, with atopic dermatitis, were
enrolled in an open-label, hypothalamic-pituitary-adrenal (HPA) axis safety study.
DIPROSONE Lotion was applied twice daily for 2 to 3 weeks over a mean body surface
area of 45% (range 35% to 72%). In 11 of 15 (73%) evaluable patients, adrenal
suppression was indicated by either a ≤ 5 mcg/dL pre-stimulation cortisol, or a cosyntropin
post-stimulation cortisol ≤ 18 mcg/dL and an increase of < 7 mcg/dL from the baseline
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 3 DRAFT LABELING
cortisol.
Studies performed with DIPROSONE Lotion indicate that it is in the medium
range of potency as compared with other topical corticosteroids.
INDICATIONS AND USAGE DIPROSONE Lotion is a medium-potency corticosteroid
indicated for relief of the inflammatory and pruritic manifestations of corticosteroid-
responsive dermatoses in patients 13 years and older.
CONTRAINDICATIONS DIPROSONE Lotion is contraindicated in patients who are
hypersensitive to betamethasone dipropionate, to other corticosteroids, or to any
ingredient in these preparations.
PRECAUTIONS General 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.
Conditions which augment systemic absorption include the application of the more
potent steroids, use over large surface areas, prolonged use, and the addition of occlusive
dressings. Use of more than one corticosteroid-containing product at the same time may
increase
total
systemic
glucocorticoid
exposure.
(See
DOSAGE
AND
ADMINISTRATION.)
Therefore, patients receiving a large dose of a potent topical steroid applied to a
large surface area should be evaluated periodically for evidence of HPA axis suppression
by using the urinary-free cortisol and ACTH stimulation 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 steroid.
Recovery of HPA axis function is generally prompt and complete upon
discontinuation of the drug. In an open-label pediatric study of 15 evaluable patients, of
the 11 subjects who showed evidence of suppression, 6 subjects were tested 2 weeks
after discontinuation of DIPROSONE Lotion, 0.05%, and 4 of the 6 (67%) had complete
recovery of HPA axis function. Infrequently, signs and symptoms of steroid withdrawal
may occur, requiring supplemental systemic corticosteroids.
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SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 4 DRAFT LABELING
Pediatric
patients
may
absorb
proportionally
larger
amounts
of
topical
corticosteroids and thus be more susceptible to systemic toxicity. (See PRECAUTIONS-
Pediatric Use.)
If irritation develops, topical corticosteroids should be discontinued and appropriate
therapy instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or
antibacterial agent should be instituted. If a favorable response does not occur promptly,
the corticosteroid should be discontinued until the infection has been adequately
controlled.
Information for Patients This information is intended to aid in the safe and effective use
of this medication. It is not a disclosure of all possible adverse or intended effects.
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. Patients should be advised not to use this medication 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 as to
be occlusive. (See DOSAGE AND ADMINISTRATION.)
4. Patients should report any signs of local adverse reactions.
5. Other corticosteroid-containing products should not be used with DIPROSONE Lotion
without first talking to your physician.
Laboratory Tests The following tests may be helpful in evaluating HPA axis suppression:
Urinary-free cortisol test
ACTH stimulation test
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SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 5 DRAFT LABELING
Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term animal studies
have not been performed to evaluate the carcinogenic potential of betamethasone
dipropionate.
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 0.5 and 4 fold the
estimated maximum human dose based on a mg/m2 comparison, respectively.
Pregnancy: Teratogenic effects: Pregnancy Category C: Corticosteroids are generally
teratogenic in laboratory animals when administered systemically at relatively low dosage
levels.
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 0.03 fold the
estimated maximum human dose based on a mg/m2 comparison. The abnormalities
observed included umbilical hernias, cephalocele and cleft palates.
Some corticosteroids have been shown to be teratogenic after dermal application in
laboratory animals. There are no adequate and well-controlled studies in pregnant women
on teratogenic effects from topically applied corticosteroids. Therefore, topical
corticosteroids should be used during pregnancy only if the potential benefit justifies the
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SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 6 DRAFT LABELING
potential risk to the fetus. Drugs of this class should not be used extensively on pregnant
patients, in large amounts, or for prolonged periods of time.
Nursing Mothers It is not known whether topical administration of corticosteroids could
result in sufficient systemic absorption to produce detectable quantities in breast milk.
Systemically administered corticosteroids are secreted into breast milk in quantities not
likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised
when topical corticosteroids are prescribed for a nursing woman.
Pediatric Use Use of DIPROSONE Lotion, 0.05% in pediatric patients 12 years of age
and younger is not recommended. (See CLINICAL PHARMACOLOGY and ADVERSE
REACTIONS Sections.)
In an open-label study, 11 of 15 (73%) evaluable pediatric
patients (aged 6 years-12 years old) using DIPROSONE Lotion for treatment of atopic
dermatitis for 2-3 weeks demonstrated adrenal suppression. (See
CLINICAL
PHARMACOLOGY - Pharmacokinetics.)
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 area to body weight ratio.
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and
intracranial hypertension have been reported in pediatric patients receiving topical
corticosteroids. Manifestations of adrenal suppression in pediatric patients include linear
growth retardation, delayed weight gain, low plasma cortisol levels, and absence of
response to ACTH stimulation. Manifestations of intracranial hypertension include bulging
fontanelles, headaches, and bilateral papilledema.
Administration of topical corticosteroids to pediatric patients should be limited to the
least amount compatible with an effective therapeutic regimen. Chronic corticosteroid
therapy may interfere with the growth and development of pediatric patients.
ADVERSE REACTIONS The following local adverse reactions are reported infrequently
when DIPROSONE Lotion is used as recommended in the DOSAGE
AND
ADMINISTRATION section. These reactions are listed in an approximate decreasing
order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis,
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SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 7 DRAFT LABELING
acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis,
maceration of the skin, secondary infection, skin atrophy, striae, miliaria.
Adverse reactions reported to be possibly or probably related to treatment with
DIPROSONE Lotion during a pediatric study include: paresthesia (burning), erythema,
erythematous rash, and dry skin. These adverse reactions each occurred in a different
patient; 4% of the 25 patient population, respectively. An adverse reaction reported to be
possibly or probably related to treatment in 2 different patients, 8%, of the 25 patients is
puritis.
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.
OVERDOSAGE Topically applied corticosteroids can be absorbed in sufficient amounts
to produce systemic effects. (See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Apply a few drops of DIPROSONE Lotion to the affected area and massage lightly
until it disappears. Apply twice daily, in the morning and at night. For the most effective
and economical use, apply nozzle very close to affected area and gently squeeze bottle.
DIPROSONE Lotion is not to be used with occlusive dressings.
HOW SUPPLIED DIPROSONE Lotion 0.05% w/w is available in 20-mL (18.7-g) (NDC
0085-0028-04) and 60-mL (56.2-g) (NDC 0085-0028-06) plastic squeeze bottles; boxes of
one. Protect from light. Store in carton until contents are used.
Store DIPROSONE Lotion between 2°°and 30°°C (36°° and 86°°F).
Schering Corporation
Kenilworth, NJ 07033 USA
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SCH 11460
SECTION 2
DIPROSONE LOTION PAGE 8 DRAFT LABELING
Rev. 5/01
B-XXXXXXXX
YYYYYYYY
Copyright © 1974, 1991, 1999, 2001
Schering Corporation. All rights reserved.
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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.
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This label may not be the latest approved by FDA.
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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.
--------------------------------------------------------------------------------------------------------
/s/
---------------------
Jonathan Wilkin
10/3/01 10:07:50 AM
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|
custom-source
|
2025-02-12T13:44:21.322443
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/17781s15lbl.pdf', 'application_number': 17781, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
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company logo
Miacalcin®
(calcitonin-salmon)
Injection, Synthetic
Rx only
DESCRIPTION
Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in
mammals and by the ultimobranchial gland of birds and fish.
Miacalcin® (calcitonin-salmon) Injection, Synthetic is a synthetic polypeptide of 32 amino
acids in the same linear sequence that is found in calcitonin of salmon origin. This is shown
by the following graphic formula: graphic formula
It is provided in sterile solution for subcutaneous or intramuscular injection. Each milliliter
contains: calcitonin-salmon 200 I.U., acetic acid, USP, 2.25 mg; phenol, USP, 5.0 mg; sodium
acetate trihydrate, USP, 2.0 mg; sodium chloride, USP, 7.5 mg; water for injection, USP, qs to
1.0 mL.
The activity of Miacalcin Injection is stated in International Units based on bioassay in
comparison with the International Reference Preparation of calcitonin-salmon for Bioassay,
distributed by the National Institute for Biological Standards and Control, Holly Hill, London.
CLINICAL PHARMACOLOGY
Calcitonin acts primarily on bone, but direct renal effects and actions on the gastrointestinal
tract are also recognized. Calcitonin-salmon appears to have actions essentially identical to
calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration
of action. The actions of calcitonin on bone and its role in normal human bone physiology are
still incompletely understood.
Bone: Single injections of calcitonin cause a marked transient inhibition of the ongoing bone
resorptive process. With prolonged use, there is a persistent, smaller decrease in the rate of
bone resorption. Histologically, this is associated with a decreased number of osteoclasts and
Reference ID: 3118265
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an apparent decrease in their resorptive activity. Decreased osteocytic resorption may also be
involved. There is some evidence that initially bone formation may be augmented by
calcitonin through increased osteoblastic activity. However, calcitonin will probably not
induce a long-term increase in bone formation.
Animal studies indicate that endogenous calcitonin, primarily through its action on bone,
participates with parathyroid hormone in the homeostatic regulation of blood calcium. Thus,
high blood calcium levels cause increased secretion of calcitonin which, in turn, inhibits bone
resorption. This reduces the transfer of calcium from bone to blood and tends to return blood
calcium to the normal level. The importance of this process in humans has not been
determined. In normal adults, who have a relatively low rate of bone resorption, the
administration of exogenous calcitonin results in only a slight decrease in serum calcium. In
normal children and in patients with generalized Paget’s disease, bone resorption is more
rapid and decreases in serum calcium are more pronounced in response to calcitonin.
Paget’s Disease of Bone (osteitis deformans): Paget's disease is a disorder of uncertain
etiology characterized by abnormal and accelerated bone formation and resorption in one or
more bones. In most patients, only small areas of bone are involved and the disease is not
symptomatic. In a small fraction of patients, however, the abnormal bone may lead to bone
pain and bone deformity, cranial and spinal nerve entrapment, or spinal cord compression.
The increased vascularity of the abnormal bone may lead to high output congestive heart
failure.
Active Paget’s disease involving a large mass of bone may increase the urinary
hydroxyproline excretion (reflecting breakdown of collagen-containing bone matrix) and
serum alkaline phosphatase (reflecting increased bone formation).
Calcitonin-salmon, presumably by an initial blocking effect on bone resorption, causes a
decreased rate of bone turnover with a resultant fall in the serum alkaline phosphatase and
urinary hydroxyproline excretion in approximately 2/3 of patients treated. These biochemical
changes appear to correspond to changes toward more normal bone, as evidenced by a small
number of documented examples of: 1) radiologic regression of Pagetic lesions,
2) improvement of impaired auditory nerve and other neurologic function, 3) decreases
(measured) in abnormally elevated cardiac output. These improvements occur extremely
rarely, if ever, spontaneously (elevated cardiac output may disappear over a period of years
when the disease slowly enters a sclerotic phase; in the cases treated with calcitonin, however,
the decreases were seen in less than one year.)
Some patients with Paget’s disease, who have good biochemical and/or symptomatic
responses initially, later relapse. Suggested explanations have included the formation of
neutralizing antibodies and the development of secondary hyperparathyroidism, but neither
suggestion appears to explain adequately the majority of relapses.
Although the parathyroid hormone levels do appear to rise transiently during each
hypocalcemic response to calcitonin, most investigators have been unable to demonstrate
persistent hypersecretion of parathyroid hormone in patients treated chronically with
calcitonin-salmon.
Circulating antibodies to calcitonin after 2-18 months’ treatment have been reported in about
half of the patients with Paget’s disease in whom antibody studies were done, but calcitonin
treatment remained effective in many of these cases. Occasionally, patients with high
Reference ID: 3118265
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antibody titers are found. These patients usually will have suffered a biochemical relapse of
Paget’s disease and are unresponsive to the acute hypocalcemic effects of calcitonin.
Hypercalcemia: In clinical trials, calcitonin-salmon has been shown to lower the elevated
serum calcium of patients with carcinoma (with or without demonstrated metastases), multiple
myeloma, or primary hyperparathyroidism (lesser response). Patients with higher values for
serum calcium tend to show greater reduction during calcitonin therapy. The decrease in
calcium occurs about 2 hours after the first injection and lasts for about 6-8 hours. Calcitonin
salmon given every 12 hours maintained a calcium lowering effect for about 5-8 days, the
time period evaluated for most patients during the clinical studies. The average reduction of 8
hour post-injection serum calcium during this period was about 9%.
Kidney: Calcitonin increases the excretion of filtered phosphate, calcium, and sodium by
decreasing their tubular reabsorption. In some patients, the inhibition of bone resorption by
calcitonin is of such magnitude that the consequent reduction of filtered calcium load more
than compensates for the decrease in tubular reabsorption of calcium. The result in these
patients is a decrease rather than an increase in urinary calcium.
Transient increases in sodium and water excretion may occur after the initial injection of
calcitonin. In most patients, these changes return to pretreatment levels with continued
therapy.
Gastrointestinal Tract: Increasing evidence indicates that calcitonin has significant actions on
the gastrointestinal tract. Short-term administration results in marked transient decreases in
the volume and acidity of gastric juice and in the volume and the trypsin and amylase content
of pancreatic juice. Whether these effects continue to be elicited after each injection of
calcitonin during chronic therapy has not been investigated.
Metabolism: Information from animal studies with calcitonin-salmon and from clinical
studies with calcitonins of porcine and human origin suggest that calcitonin-salmon is rapidly
metabolized by conversion to smaller inactive fragments, primarily in the kidneys, but also in
the blood and peripheral tissues. A small amount of unchanged hormone and its inactive
metabolites are excreted in the urine.
The absolute bioavailability of salmon calcitonin is approximately 66% and 71% after
intramuscular (i.m.) or subcutaneous (s.c.) injection, respectively. After subcutaneous
administration, peak plasma levels are reached in approximately 23 minutes. The terminal
half-life is approximately 58 minutes for i.m. administration and 59 to 64 minutes for s.c.
administration. The apparent volume of distribution is 0.15-0.3 L/kg.
It appears that calcitonin-salmon cannot cross the placental barrier and its passage to the
cerebrospinal fluid or to breast milk has not been determined.
INDICATIONS AND USAGE
Miacalcin® (calcitonin-salmon) Injection, Synthetic is indicated for the treatment of
symptomatic Paget’s disease of bone, for the treatment of hypercalcemia, and for the
treatment of postmenopausal osteoporosis.
Paget’s Disease: At the present time, effectiveness has been demonstrated principally in
patients with moderate to severe disease characterized by polyostotic involvement with
elevated serum alkaline phosphatase and urinary hydroxyproline excretion.
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In these patients, the biochemical abnormalities were substantially improved (more than 30%
reduction) in about 2/3 of patients studied, and bone pain was improved in a similar fraction.
A small number of documented instances of reversal of neurologic deficits have occurred,
including improvement in the basilar compression syndrome, and improvement of spinal cord
and spinal nerve lesions. At present, there is too little experience to predict the likelihood of
improvement of any given neurologic lesion. Hearing loss, the most common neurologic
lesion of Paget’s disease, is improved infrequently (4 of 29 patients studied audiometrically).
Patients with increased cardiac output due to extensive Paget’s disease have had measured
decreases in cardiac output while receiving calcitonin. The number of treated patients in this
category is still too small to predict how likely such a result will be.
The large majority of patients with localized, especially monostotic disease do not develop
symptoms and most patients with mild symptoms can be managed with analgesics. There is
no evidence that the prophylactic use of calcitonin is beneficial in asymptomatic patients,
although treatment may be considered in exceptional circumstances in which there is
extensive involvement of the skull or spinal cord with the possibility of irreversible
neurologic damage. In these instances, treatment would be based on the demonstrated effect
of calcitonin on Pagetic bone, rather than on clinical studies in the patient population in
question.
Hypercalcemia: Miacalcin Injection is indicated for early treatment of hypercalcemic
emergencies, along with other appropriate agents, when a rapid decrease in serum calcium is
required, until more specific treatment of the underlying disease can be accomplished. It may
also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids
and furosemide, oral phosphate or corticosteroids, or other agents.
Postmenopausal Osteoporosis: Miacalcin Injection is indicated for the treatment of
postmenopausal osteoporosis in females greater than 5 years postmenopause with low bone
mass relative to healthy premenopausal females. Miacalcin Injection should be reserved for
patients who refuse or cannot tolerate estrogens or in whom estrogens are contraindicated.
Use of Miacalcin Injection is recommended in conjunction with adequate calcium and
vitamin D intake to prevent the progressive loss of bone mass. No evidence currently exists to
indicate whether or not Miacalcin Injection decreases the risk of vertebral crush fractures or
spinal deformity. A recent controlled study, which was discontinued prior to completion
because of questions regarding its design and implementation, failed to demonstrate any
benefit of salmon calcitonin on fracture rate. No adequate controlled trials have examined the
effect of salmon calcitonin injection on vertebral bone mineral density beyond 1 year of
treatment. Two placebo-controlled studies with salmon calcitonin have shown an increase in
total body calcium at 1 year, followed by a trend to decreasing total body calcium (still above
baseline) at 2 years. The minimum effective dose of Miacalcin Injection for prevention of
vertebral bone mineral density loss has not been established. It has been suggested that those
postmenopausal patients having increased rates of bone turnover may be more likely to
respond to anti-resorptive agents such as Miacalcin Injection.
CONTRAINDICATIONS
Clinical allergy to synthetic calcitonin-salmon.
Reference ID: 3118265
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WARNINGS
Allergic Reactions
Because calcitonin is a polypeptide, the possibility of a systemic allergic reaction exists.
Administration of calcitonin-salmon has been reported in a few cases to cause serious
allergic-type reactions (e.g., bronchospasm, swelling of the tongue or throat, anaphylactic
shock), including very rare reports of death attributed to anaphylaxis. The usual provisions
should be made for the emergency treatment of such a reaction should it occur. Allergic
reactions should be differentiated from generalized flushing and hypotension.
For patients with suspected sensitivity to calcitonin, skin testing should be considered prior to
treatment utilizing a dilute, sterile solution of Miacalcin® (calcitonin-salmon) Injection,
Synthetic. Physicians may wish to refer patients who require skin testing to an allergist. A
detailed skin testing protocol is available from the Medical Services Department of Novartis
Pharmaceuticals Corporation.
The incidence of osteogenic sarcoma is known to be increased in Paget’s disease. Pagetic
lesions, with or without therapy, may appear by X-ray to progress markedly, possibly with
some loss of definition of periosteal margins. Such lesions should be evaluated carefully to
differentiate these from osteogenic sarcoma.
PRECAUTIONS
Drug Interactions
Concomitant use of calcitonin and lithium may lead to a reduction in plasma lithium
concentrations due to increased urinary clearance of lithium. The dose of lithium may need to
be adjusted.
General
The administration of calcitonin possibly could lead to hypocalcemic tetany under special
circumstances although no cases have yet been reported. Provisions for parenteral calcium
administration should be available during the first several administrations of calcitonin.
Laboratory Tests
Periodic examinations of urine sediment of patients on chronic therapy are recommended.
Coarse granular casts and casts containing renal tubular epithelial cells were reported in
young adult volunteers at bed rest who were given calcitonin-salmon to study the effect of
immobilization on osteoporosis. There was no other evidence of renal abnormality and the
urine sediment became normal after calcitonin was stopped. Urine sediment abnormalities
have not been reported by other investigators.
Instructions for the Patient
Careful instruction in sterile injection technique should be given to the patient, and to other
persons who may administer Miacalcin® (calcitonin-salmon) Injection, Synthetic.
Reference ID: 3118265
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Carcinogenesis, Mutagenesis, and Impairment of Fertility
An increased incidence of pituitary adenomas has been observed in one-year toxicity studies
in Sprague-Dawley rats administered calcitonin-salmon at dosages of 20 and 80 I.U./kg/day
and in Fisher 344 rats given 80 I.U./kg/day. The relevance of these findings to humans is
unknown. Calcitonin-salmon was not mutagenic in tests using Salmonella typhimurium,
Escherichia coli, and Chinese Hamster V79 cells.
Pregnancy: Teratogenic Effects
Category C
Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when
given in doses 14-56 times the dose recommended for human use. Since calcitonin does not
cross the placental barrier, this finding may be due to metabolic effects on the pregnant
animal. There are no adequate and well-controlled studies in pregnant women. Miacalcin
Injection should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Nursing Mothers
It is not known whether this drug is excreted in human milk. As a general rule, nursing should
not be undertaken while a patient is on this drug since many drugs are excreted in human
milk. Calcitonin has been shown to inhibit lactation in animals.
Pediatric Use
Disorders of bone in children referred to as juvenile Paget’s disease have been reported rarely.
The relationship of these disorders to adult Paget’s disease has not been established and
experience with the use of calcitonin in these disorders is very limited. There is no adequate
data to support the use of Miacalcin Injection in children.
ADVERSE REACTIONS
Gastrointestinal System
Nausea with or without vomiting has been noted in about 10% of patients treated with
calcitonin. It is most evident when treatment is first initiated and tends to decrease or
disappear with continued administration.
Dermatologic/Hypersensitivity
Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been
reported in about 10% of patients. Flushing of face or hands occurred in about 2-5% of
patients. Skin rashes, nocturia, pruritus of the ear lobes, feverish sensation, pain in the eyes,
poor appetite, abdominal pain, edema of feet, and salty taste have been reported in patients
treated with calcitonin-salmon. Administration of calcitonin-salmon has been reported in a
few cases to cause serious allergic-type reactions (e.g., bronchospasm, swelling of the tongue
or throat, anaphylactic shock), including very rare reports of death attributed to anaphylaxis.
(see WARNINGS).
In addition, the following adverse events were reported with Miacalcin Injection.
Reference ID: 3118265
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Body as a Whole – General Disorders: influenza-like symptoms, fatigue, edema (facial,
peripheral, and generalized),
Musculoskeletal/Collagen: arthralgia, musculoskeletal pain
Cardiovascular: hypertension
Gastrointestinal: abdominal pain, diarrhea,
Immune System Disorders: hypersensitivity, anaphylactic and anaphylactoid reactions,
anaphylactic shock
Urinary System: polyuria
Central and Peripheral Nervous System: dizziness, headache, tremor.
Vision: visual disturbance
OVERDOSAGE
A dose of l000 I.U. subcutaneously may produce nausea and vomiting as the only adverse
effects. Doses of 32 units per kg per day for 1-2 days demonstrate no other adverse effects.
Data on chronic high-dose administration are insufficient to judge toxicity.
DOSAGE AND ADMINISTRATION
Paget’s Disease: The recommended starting dose of Miacalcin® (calcitonin-salmon)
Injection, Synthetic in Paget's disease is 100 I.U. (0.5 mL) per day administered
subcutaneously (preferred for outpatient self-administration) or intramuscularly. Drug effect
should be monitored by periodic measurement of serum alkaline phosphatase and 24-hour
urinary hydroxyproline (if available) and evaluations of symptoms. A decrease toward normal
of the biochemical abnormalities is usually seen, if it is going to occur, within the first few
months. Bone pain may also decrease during that time. Improvement of neurologic lesions,
when it occurs, requires a longer period of treatment, often more than one year.
In many patients, doses of 50 I.U. (0.25 mL) per day or every other day are sufficient to
maintain biochemical and clinical improvement. At the present time, however, there are
insufficient data to determine whether this reduced dose will have the same effect as the
higher dose on forming more normal bone structure. It appears preferable, therefore, to
maintain the higher dose in any patient with serious deformity or neurological involvement.
In any patient with a good response initially who later relapses, either clinically or
biochemically, the possibility of antibody formation should be explored. The patient may be
tested for antibodies by an appropriate specialized test or evaluated for the possibility of
antibody formation by critical clinical evaluation.
Patient compliance should also be assessed in the event of relapse.
In patients who relapse, whether because of antibodies or for unexplained reasons, a dosage
increase beyond 100 I.U. per day does not usually appear to elicit an improved response.
Hypercalcemia: The recommended starting dose of Miacalcin Injection in hypercalcemia is
4 I.U./kg body weight every 12 hours by subcutaneous or intramuscular injection. If the
response to this dose is not satisfactory after one or two days, the dose may be increased to
Reference ID: 3118265
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8 I.U./kg every 12 hours. If the response remains unsatisfactory after two more days, the dose
may be further increased to a maximum of 8 I.U./kg every 6 hours.
Postmenopausal Osteoporosis: The minimum effective dose of Miacalcin Injection for the
prevention of vertebral bone mineral density loss has not been established. Data from a single
one-year placebo-controlled study with salmon calcitonin injection suggested that 100 I.U.
(subcutaneously or intramuscularly) every other day might be effective in preserving vertebral
bone mineral density. Baseline and interval monitoring of biochemical markers of bone
resorption/turnover (e.g., fasting AM, second-voided urine hydroxyproline to creatinine ratio)
and of bone mineral density may be useful in achieving the minimum effective dose. Patients
should also receive supplemental calcium such as calcium carbonate 1.5 g daily and an
adequate vitamin D intake (400 units daily). An adequate diet is also essential.
If the volume of Miacalcin Injection to be injected exceeds 2 mL, intramuscular injection is
preferable and multiple sites of injection should be used.
Miacalcin vials should be inspected visually. If the solution is not clear and colorless, or
contains any particles, or if the vial is damaged, do not administer the solution.
HOW SUPPLIED
Miacalcin® (calcitonin-salmon) Injection, Synthetic is available as a sterile solution in
individual 2 mL vials containing 200 I.U. per mL ......................................NDC 0078-0149-23
Store in refrigerator between 2°C-8°C (36°F-46°F).
Manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2011-XX
Month Year
Reference ID: 3118265
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:21.524673
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017808s034lbl.pdf', 'application_number': 17808, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,065
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
MIACALCIN injection safely and effectively. See full prescribing
information for MIACALCIN injection.
MIACALCIN® (calcitonin-salmon) injection, synthetic, for subcutaneous
or intramuscular use
Initial U.S. Approval: 1975
-------------------------------RECENT MAJOR CHANGES-----------------------
Indications and Usage (1.4)
03/2014
Warnings and Precautions (5.3)
03/2014
----------------------------INDICATIONS AND USAGE---------------------------
Miacalcin synthetic injection is a calcitonin, indicated for the following
conditions:
Treatment of symptomatic Paget’s disease of bone when alternative
treatments are not suitable (1.1)
Treatment of hypercalcemia (1.2)
Treatment of postmenopausal osteoporosis when alternative treatments are
not suitable. Fracture reduction efficacy has not been demonstrated (1.3)
Limitations of Use:
Due to the possible association between malignancy and calcitonin-salmon
use, the need for continued therapy should be re-evaluated on a periodic
basis (1.4, 5.3)
----------------------DOSAGE AND ADMINISTRATION-----------------------
Symptomatic Paget’s disease of bone: 100 International Units daily. Ensure
adequate calcium and vitamin D intake (2.1, 2.5)
Hypercalcemia: start with 4 International Units/kg body weight every 12
hours. Increase to 8 International Units/kg every 12 hours if no
improvement in 1-2 days. Increase further to 8 International Units/kg every
6 hours if no improvement after 2 more days (2.2)
Postmenopausal osteoporosis: 100 International Units daily. Ensure
adequate calcium and vitamin D intake (2.3, 2.5)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Injection: 200 International Units per mL sterile solution in 2 mL multi-
dose vials (3)
----------------------------CONTRAINDICATIONS------------------------------
Hypersensitivity to calcitonin-salmon or any of the excipients (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
Serious hypersensitivity reactions, including reports of fatal anaphylaxis
have been reported. Consider skin testing prior to treatment in patients with
suspected hypersensitivity to calcitonin-salmon (5.1)
Hypocalcemia has been reported. Ensure adequate intake of calcium and
vitamin D (5.2)
Malignancy: A meta-analysis of 21 clinical trials suggests an increased risk
of overall malignancies in calcitonin-salmon-treated patients (5.3, 6.1)
Circulating antibodies to calcitonin-salmon may develop, and may cause
loss of response to treatment (5.4)
------------------------------ADVERSE REACTIONS-------------------------------
Most common adverse reactions are nausea with or without vomiting (10%),
injection site inflammation (10%), and flushing of the face or hands (2-5%)
(6)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA
1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
Concomitant use of calcitonin-salmon and lithium may lead to a reduction
in plasma lithium concentrations due to increased urinary clearance of
lithium. The dose of lithium may require adjustment (7)
-----------------------USE IN SPECIFIC POPULATIONS------------------------
There are no data to support use in children (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 03/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Treatment of Paget’s Disease of Bone
1.2
Treatment of Hypercalcemia
1.3
Treatment of Postmenopausal Osteoporosis
1.4
Important Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1
Paget’s Disease of Bone
2.2
Hypercalcemia
2.3
Postmenopausal Osteoporosis
2.4
Preparation and Administration
2.5
Recommendations for Calcium and Vitamin D Supplementation
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
5.2
Hypocalcemia
5.3
Malignancy
5.4
Antibody Formation
5.5
Urine Sediment Abnormalities
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
6.3
Immunogenicity
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 Paget’s Disease of Bone
14.2 Hypercalcemia
14.3 Postmenopausal Osteoporosis
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3467860
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 Paget’s Disease of Bone
Miacalcin injection is indicated for the treatment of symptomatic Paget’s disease of bone in patients with moderate to
severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary
hydroxyproline excretion. There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in
asymptomatic patients. Miacalcin injection should be used only in patients who do not respond to alternative treatments or
for whom such treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who
are intolerant or unwilling to use other therapies).
1.2
Treatment of Hypercalcemia
Miacalcin injection is indicated for the early treatment of hypercalcemic emergencies, along with other appropriate agents,
when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be
accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and
furosemide, oral phosphate or corticosteroids, or other agents.
1.3
Treatment of Postmenopausal Osteoporosis
Miacalcin injection is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years
postmenopause. The evidence of efficacy for calcitonin-salmon injection is based on increases in total body calcium
observed in clinical trials. Fracture reduction efficacy has not been demonstrated. Miacalcin injection should be reserved
for patients for whom alternative treatments are not suitable (e.g., patients for whom other therapies are contraindicated or
for patients who are intolerant or unwilling to use other therapies).
1.4
Important Limitations of Use
Due to the possible association between malignancy and calcitonin-salmon use, the need for continued therapy should be
re-evaluated on a periodic basis [see Warnings and Precautions (5.3)].
2
DOSAGE AND ADMINISTRATION
2.1
Paget’s Disease of Bone
The recommended dose of Miacalcin injection for treatment of symptomatic Paget's disease of bone is 100 International
Units (0.5 mL) per day administered subcutaneously or intramuscularly.
2.2
Hypercalcemia
The recommended starting dose of Miacalcin injection for early treatment of hypercalcemia is 4 International Units/kg
body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory
after one or two days, the dose may be increased to 8 International Units/kg every 12 hours. If the response remains
unsatisfactory after two more days, the dose may be further increased to a maximum of 8 International Units/kg every 6
hours.
2.3
Postmenopausal Osteoporosis
The recommended dose of Miacalcin injection for treatment of postmenopausal osteoporosis in women greater than 5
years postmenopause is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. The
minimum effective dose of Miacalcin injection for the prevention of vertebral bone mineral density loss has not been
established.
2.4
Preparation and Administration
Visually inspect Miacalcin vials. Miacalcin injection is a clear, colorless, solution. If the solution is not clear and
colorless, or contains any particles, or if the vial is damaged, do not administer the solution.
If the volume of Miacalcin injection to be injected exceeds 2 mL, intramuscular injection is preferable and the total dose
should be distributed across multiple sites of injection.
Instruct patients to use sterile injection technique when administering Miacalcin injection, and to dispose of needles
properly.
Reference ID: 3467860
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.5
Recommendations for Calcium and Vitamin D Supplementation
Patients who use Miacalcin injection for treatment of postmenopausal osteoporosis should receive adequate calcium (at
least 1000 mg elemental calcium per day) and Vitamin D (at least 400 International Units per day).
3
DOSAGE FORMS AND STRENGTHS
Miacalcin injection is available as a clear, colorless, sterile solution of synthetic calcitonin-salmon in individual 2 mL
multi-dose vials containing 200 International Units per mL.
4
CONTRAINDICATIONS
Hypersensitivity to calcitonin-salmon or any of the excipients. Reactions have included anaphylaxis with death,
bronchospasm, and swelling of the tongue or throat [see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
Serious hypersensitivity reactions have been reported in patients receiving Miacalcin injection, e.g., bronchospasm,
swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Appropriate medical support and
monitoring measures should be readily available when Miacalcin injection is administered. If anaphylaxis or other severe
hypersensitivity/allergic reactions occur, initiate appropriate treatment [see Contraindications (4)].
For patients with suspected hypersensitivity to calcitonin-salmon, skin testing should be considered prior to treatment
utilizing a dilute, sterile solution of Miacalcin injection. Healthcare providers may wish to refer patients who require skin
testing to an allergist. A detailed skin testing protocol is available from the Medical Services Department of Novartis
Pharmaceuticals Corporation.
5.2
Hypocalcemia
Hypocalcemia associated with tetany (i.e. muscle cramps, twitching) and seizure activity has been reported with
Miacalcin injection therapy. Hypocalcemia must be corrected before initiating therapy. Other disorders affecting mineral
metabolism (such as vitamin D deficiency) should also be effectively treated. In patients at risk for hypocalcemia,
provisions for parenteral calcium administration should be available during the first several administrations of calcitonin
salmon and serum calcium and symptoms of hypocalcemia should be monitored. Use of Miacalcin injection for the
treatment of Paget’s disease or postmenopausal osteoporosis is recommended in conjunction with an adequate intake of
calcium and vitamin D [see Dosage and Administration (2.5)].
5.3
Malignancy
In a meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray or investigational oral
formulations), the overall incidence of malignancies reported was higher among calcitonin-salmon-treated patients (4.1%)
compared with placebo-treated patients (2.9%). This suggests an increased risk of malignancies in calcitonin-salmon
treated patients compared to placebo-treated patients. It is not possible to exclude an increased risk when calcitonin
salmon is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual
patient should be carefully considered against possible risks [see Adverse Reactions (6.1)].
5.4
Antibody Formation
Circulating antibodies to calcitonin-salmon have been reported with Miacalcin injection. The possibility of antibody
formation should be considered in any patient with an initial response to Miacalcin injection who later stops responding to
treatment [see Adverse Reactions (6.3)].
5.5
Urine Sediment Abnormalities
Coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers at bed rest
who were given injectable calcitonin-salmon to study the effect of immobilization on osteoporosis. There was no other
evidence of renal abnormality and the urine sediment normalized after calcitonin-salmon was stopped. Periodic
examinations of urine sediment should be considered.
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Hypersensitivity Reactions, including anaphylaxis [see Warnings and Precautions (5.1)]
Reference ID: 3467860
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypocalcemia [see Warnings and Precautions (5.2)]
Malignancy [see Warnings and Precautions (5.3)]
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 safety of calcitonin-salmon injection was assessed in open-label trials several months to two years in duration. The
most common adverse reactions are discussed below.
Nausea: Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin-salmon. It is
most evident when treatment is first initiated and tends to decrease or disappear with continued administration.
Dermatologic Reactions: Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been
reported in about 10% of patients. Flushing of face or hands occurred in about 2-5% of patients. Skin rashes and pruritus
of the ear lobes have also been reported.
Other Adverse Reactions: Nocturia, feverish sensation, pain in the eyes, poor appetite, abdominal pain, pedal edema,
and salty taste have been reported in patients treated with calcitonin-salmon injection.
Malignancy
A meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray or investigational oral
formulations) was conducted to assess the risk of malignancies in calcitonin-salmon-treated patients compared to placebo-
treated patients. The trials in the meta-analysis ranged in duration from 6 months to 5 years and included a total of 10883
patients (6151 treated with calcitonin-salmon and 4732 treated with placebo). The overall incidence of malignancies
reported in these 21 trials was higher among calcitonin-salmon-treated patients (254/6151 or 4.1%) compared with
placebo-treated patients (137/4732 or 2.9%). Findings were similar when analyses were restricted to the 18 nasal spray
only trials [calcitonin-salmon 122/2712 (4.5%); placebo 30/1309 (2.3%)].
The meta-analysis results suggest an increased risk of overall malignancies in calcitonin-salmon-treated patients compared
to placebo-treated patients when all 21 trials are included and when the analysis is restricted to the 18 nasal spray only
trials (see Table 1). It is not possible to exclude an increased risk when calcitonin-salmon is administered by the
subcutaneous, intramuscular, or intravenous route because these routes of administration were not investigated in the
meta-analysis. The increased malignancy risk seen with the meta-analysis was heavily influenced by a single large 5-year
trial, which had an observed risk difference of 3.4% [95% CI (0.4%, 6.5%)]. Imbalances in risks were still observed when
analyses excluded basal cell carcinoma (see Table 1); the data were not sufficient for further analyses by type of
malignancy. A mechanism for these observations has not been identified. Although a definitive causal relationship
between calcitonin-salmon use and malignancies cannot be established from this meta-analysis, the benefits for the
individual patient should be carefully evaluated against all possible risks [see Warnings and Precautions (5.3)].
Table 1: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated
Patients
Patients
Malignancies
Risk Difference1
(%)
95% Confidence Interval2 (%)
All (nasal spray + oral)
All
1.0
(0.3, 1.6)
All (nasal spray + oral)
Excluding basal cell
carcinoma
0.5
(-0.1, 1.2)
All (nasal spray only)
All
1.4
(0.3, 2.6)
All (nasal spray only)
Excluding basal cell
carcinoma
0.8
(-0.2, 1.8)
1 The overall adjusted risk difference is the difference between the percentage of patients who had any malignancy (or malignancy excluding
basal cell carcinoma) in calcitonin-salmon and placebo treatment groups, using the Mantel-Haenszel (MH) fixed-effect method. A risk
difference of 0 is suggestive of no difference in malignancy risks between the treatment groups.
2 The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect method.
Reference ID: 3467860
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For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2
Postmarketing Experience
Because postmarketing adverse 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 following adverse reactions have been reported during post-approval use of Miacalcin injection.
Allergic / Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving
calcitonin-salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to
anaphylaxis.
Hypocalcemia: Hypocalcemia with tetany (i.e. muscle cramps, twitching) and seizure activity have been reported.
Body as a Whole: influenza-like symptoms, fatigue, edema (facial, peripheral, and generalized)
Musculoskeletal: arthralgia, musculoskeletal pain
Cardiovascular: hypertension
Gastrointestinal: abdominal pain, diarrhea
Urinary System: polyuria
Nervous System: dizziness, headache, paresthesia, tremor
Vision: visual disturbance
6.3
Immunogenicity
Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of
Miacalcin may trigger the development of anti-calcitonin antibodies. Circulating antibodies to calcitonin-salmon after 2
18 months of treatment have been reported in about one-half of the patients with Paget’s disease in whom antibody studies
were done. In some cases, high antibody titers are found; these patients usually will have a loss of response to treatment
[see Warnings and Precautions (5.4)].
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the
observed incidence of a positive antibody test result may be influenced by several factors, including assay methodology,
sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons,
comparison of antibodies among different calcitonin-salmon products may be misleading.
7
DRUG INTERACTIONS
No formal drug interaction studies have been performed with Miacalcin injection.
Concomitant use of calcitonin-salmon and lithium may lead to a reduction in plasma lithium concentrations due to
increased urinary clearance of lithium. The dose of lithium may require adjustment.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C:
Risk Summary
There are no adequate and well-controlled studies in pregnant women. Miacalcin injection should be used during
pregnancy only if the potential benefit justifies the use as compared with potential risks to the patient and fetus. Based on
animal data, Miacalcin is predicted to have low probability of increasing the risk of adverse developmental outcomes
above background risk.
Animal Data
Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous
injection in doses 4-18 times the parenteral dose recommended for human use (of 54 International Units/m2).
No embryo/fetal toxicities related to Miacalcin were reported from maternal subcutaneous daily doses in rats up to 80
International Units /kg/day from gestation day 6 to 15.
Reference ID: 3467860
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. No studies have been conducted to assess the impact of
Miacalcin on milk production in humans, its presence in human breast milk, or its effects on the breast-fed child. Because
many drugs are excreted in human milk, caution should be exercised when Miacalcin is administered to a nursing woman.
Calcitonin has been shown to inhibit lactation in rats.
8.4
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5
Geriatric Use
Clinical studies of Miacalcin injection did not include sufficient numbers of subjects aged 65 years and older 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.
10
OVERDOSAGE
The pharmacologic actions of Miacalcin injection suggest that hypocalcemic tetany could occur in overdose. Therefore,
provisions for parenteral administration of calcium should be available for the treatment of overdose.
A dose of calcitonin-salmon l000 International Units subcutaneously may produce nausea and vomiting. Doses of 32
International Units per kg per day for 1-2 days demonstrate no other adverse effects. Data on chronic high-dose
administration are insufficient to assess toxicity.
11
DESCRIPTION
Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the
ultimobranchial gland of birds and fish.
Miacalcin (calcitonin-salmon) injection, synthetic is a synthetic polypeptide of 32 amino acids in the same linear sequence
that is found in calcitonin of salmon origin. This is shown by the following graphic formula: formula
It is provided in sterile solution for subcutaneous or intramuscular injection. Each milliliter contains: calcitonin-salmon
200 International Units.
Inactive Ingredients (per mL): acetic acid, USP, 2.25 mg; phenol, USP, 5.0 mg; sodium acetate trihydrate, USP, 2.0 mg;
sodium chloride, USP, 7.5 mg; water for injection, USP.
The activity of Miacalcin injection is stated in International Units based on bioassay in comparison with the International
Reference Preparation of calcitonin-salmon for Bioassay, distributed by the National Institute for Biological Standards
and Control, Holly Hill, London.
Reference ID: 3467860
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
Calcitonin-salmon is a calcitonin receptor agonist. Calcitonin-salmon acts primarily on bone, but direct renal effects and
actions on the gastrointestinal tract are also recognized. Calcitonin-salmon appears to have actions essentially identical to
calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration of action.
The actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated,
although calcitonin receptors have been discovered in osteoclasts and osteoblasts.
12.2
Pharmacodynamics
Bone
Single injections of calcitonin-salmon caused a marked transient inhibition of the ongoing bone resorptive process. With
prolonged use, there is a persistent, smaller decrease in the rate of bone resorption. Histologically, this is associated with a
decreased number of osteoclasts and an apparent decrease in their resorptive activity.
In healthy adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin-salmon
results in decreases in serum calcium within the limits of the normal range. In healthy children and in patients whose bone
resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin-salmon.
Kidney
Studies with injectable calcitonin-salmon show increases in the excretion of filtered phosphate, calcium, and sodium by
decreasing their tubular reabsorption.
Gastrointestinal Tract
Some evidence from studies with injectable preparations suggests that calcitonin-salmon may have effects on the
gastrointestinal tract. Short-term administration of injectable calcitonin-salmon results in marked transient decreases in the
volume and acidity of gastric juice and in the volume and the trypsin and amylase content of pancreatic juice. Whether
these effects continue to be elicited after each injection of calcitonin-salmon during chronic therapy has not been
investigated.
12.3
Pharmacokinetics
The absolute bioavailability of calcitonin-salmon is approximately 66% and 71% after intramuscular or subcutaneous
injection, respectively. After subcutaneous administration, peak plasma levels are reached in approximately 23
minutes. The terminal half-life is approximately 58 minutes for intramuscular administration and 59 to 64 minutes for
subcutaneous administration. The apparent volume of distribution is 0.15-0.3 L/kg.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
The incidence of pituitary adenomas was increased in rats after one and two years of subcutaneous exposure to synthetic
calcitonin-salmon. The significance of this finding to humans is unknown because pituitary adenomas are very common in
rats as they age, the pituitary adenomas did not transform into metastatic tumors, there were no other clear treatment-
related neoplasms, and synthetic calcitonin-salmon related neoplasms were not observed in mice after two years of
dosing.
Rat findings:
The only clear neoplastic finding in rats dosed subcutaneously with calcitonin-salmon was an increase in the incidence of
pituitary adenomas in male Fisher 344 rats and female Sprague Dawley rats after one year of dosing and male Sprague
Dawley rats dosed for one and two years. In female Sprague Dawley rats, the incidence of pituitary adenomas after two
years was high in all treatment groups (between 80% and 92% including the control groups) such that a treatment-related
effect could not be distinguished from natural background incidence. The lowest dose in male Sprague Dawley rats that
developed an increased incidence of pituitary adenomas after two years of dosing (1.7 International Units/kg/day) is
approximately 1/6th of the maximum recommended subcutaneous dose in humans (100 International Units/day) based on
body surface area conversion between rats and humans. The findings suggest that calcitonin-salmon reduced the latency
period for development of non-functioning pituitary adenomas.
Reference ID: 3467860
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For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Mouse findings:
No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with synthetic
calcitonin-salmon at doses up to 800 International Units/kg/day. The 800 International Units/kg/day dose is approximately
39 times the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface
area conversion between mice and humans.
Mutagenesis
Synthetic calcitonin-salmon tested negative for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia
coli (2 strains), with and without rat liver metabolic activation, and was not clastogenic in a chromosome aberration test in
Chinese Hamster V79 cells. There was no evidence that calcitonin-salmon was clastogenic in the in vivo mouse
micronucleus test.
Fertility
Effects of calcitonin-salmon on fertility have not been assessed in animals.
CLINICAL STUDIES
14.1
Paget’s Disease of Bone
The trials used for the basis of approval for calcitonin-salmon injection for treatment of Paget’s disease of bone were
conducted in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum
alkaline phosphatase and urinary hydroxyproline excretion. In open-label clinical trials of several months to two years
duration with historical controls, biochemical abnormalities were substantially improved (more than 30% reduction) in
about 2/3 of patients studied and bone pain was improved in a similar fraction. A small number of documented instances
of reversal of neurologic deficits have occurred, including improvement in the basilar compression syndrome, and
improvement of spinal cord and spinal nerve lesions. There is too little experience to predict the likelihood of
improvement of any given neurologic lesion. Hearing loss is improved infrequently (4 of 29 patients studied by
audiometry). Patients with increased cardiac output due to extensive Paget’s disease of bone have had measured decreases
in cardiac output while receiving calcitonin-salmon. The number of treated patients in this category is too small to predict
how likely such a result will be.
There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in asymptomatic patients.
14.2
Hypercalcemia
In four open-label clinical trials enrolling 53 patients, calcitonin-salmon has been shown to lower elevated serum calcium
levels of patients with carcinoma (with or without metastases), multiple myeloma, and primary hyperparathyroidism
(lesser response). These patients were treated with calcitonin-salmon only when other methods of lowering serum calcium
(hydration, oral phosphate, corticosteroids) were unsuccessful or unsuitable. With patients’ pre-therapy serum calcium
levels as controls, reduction in serum calcium was evident within 1-2 hours of administration. The peak effect occurred
within 24-48 hours of injection and administration of calcitonin-salmon every 12 hours maintained a hypocalcemic effect
for approximately 5-8 days, the time period evaluated for most patients in the clinical trials. The average reduction of 8
hour post-injection serum calcium was approximately 9% (2-3 mg/dL). Patients with higher values of serum calcium
tended to show greater reductions during calcitonin-salmon treatment.
14.3
Postmenopausal Osteoporosis
The trials used for the basis of approval for calcitonin-salmon injection for treatment of postmenopausal osteoporosis
were two randomized, open-label, 2-year studies in postmenopausal women 50 – 74 years of age with total body calcium
<85% of expected normal, and vertebral osteopenia (by x-ray criteria) and/or at least one atraumatic compression fracture.
The primary efficacy endpoint was total body calcium measured by neutron activation analysis. Patients were randomized
to calcitonin-salmon injection 100 International Units daily (subcutaneously or intramuscularly) at bedtime, or control. All
subjects received daily supplements of 1200 mg calcium carbonate and 400 International Units of vitamin D.
In both studies, total body calcium increased from baseline with calcitonin-salmon therapy at 1 year, followed by a trend
to decreasing total body calcium (still above baseline) at 2 years.
Thoracic and lumbar spine X-rays (AP/lateral) were obtained yearly. For the two studies combined (34 calcitonin-salmon
and 35 control subjects), in the first year there was a total of 6 new vertebral compression fractures in the calcitonin
salmon group and 5 in the control group. In the second year there were 7 new fractures in each group.
Reference ID: 3467860
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No evidence currently exists to indicate whether Miacalcin injection decreases the risk of osteoporotic fracture. A
controlled study, which was prematurely discontinued, failed to demonstrate any benefit of calcitonin-salmon on fracture
rate.
No adequate controlled trials have examined the effect of calcitonin-salmon injection on vertebral bone mineral density
beyond 1 year of treatment. Therefore, the minimum effective dose of Miacalcin injection for prevention of vertebral bone
mineral density loss has not been established.
In clinical studies of postmenopausal osteoporosis, bone biopsy and radial bone mass assessments at baseline and after 26
months of daily injectable calcitonin-salmon indicate that calcitonin therapy results in the formation of normal bone.
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Miacalcin (calcitonin-salmon) injection, synthetic is available as a sterile solution in individual 2 mL multi-dose vials
containing 200 International Units per mL .......................NDC 0078-0149-23
Storage and Handling
Store in refrigerator between 2°C-8°C (36°F-46°F).
17
PATIENT COUNSELING INFORMATION
Instruct patients and other persons who may administer Miacalcin injection in sterile injection technique. Also instruct
patients to dispose of needles properly [see Dosage and Administration (2.4)].
Inform patients of the potential increase in risk of malignancy [see Warnings and Precautions (5.3)].
Advise patients with postmenopausal osteoporosis or Paget’s disease of bone to maintain an adequate calcium (at least
1000 mg elemental calcium per day) and Vitamin D (at least 400 International Units per day) intake [see Dosage and
Administration (2.5)].
Instruct patients to seek emergency medical help or go to the nearest hospital emergency room right away if they
develop any signs or symptoms of a serious allergic reaction [see Warnings and Precautions (5.1)].
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T201X-XX
March 2014
Reference ID: 3467860
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:21.698245
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/017808s035lbl.pdf', 'application_number': 17808, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
11,066
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
MIACALCIN injection safely and effectively. See full prescribing
information for MIACALCIN injection.
MIACALCIN® (calcitonin-salmon) injection, synthetic, for subcutaneous
or intramuscular use
Initial U.S. Approval: 1975
-------------------------------RECENT MAJOR CHANGES----------------------
Indications and Usage (1.4)
3/2014
Warnings and Precautions (5.3)
3/2014
----------------------------INDICATIONS AND USAGE---------------------------
Miacalcin synthetic injection is a calcitonin, indicated for the following
conditions:
•
Treatment of symptomatic Paget’s disease of bone when alternative
treatments are not suitable (1.1)
•
Treatment of hypercalcemia (1.2)
•
Treatment of postmenopausal osteoporosis when alternative treatments
are not suitable. Fracture reduction efficacy has not been demonstrated
(1.3)
Limitations of Use:
• Due to the possible association between malignancy and calcitonin-salmon
use, the need for continued therapy should be re-evaluated on a periodic
basis (1.4, 5.3)
----------------------DOSAGE AND ADMINISTRATION----------------------
• Symptomatic Paget’s disease of bone: 100 International Units daily. Ensure
adequate calcium and vitamin D intake (2.1, 2.5)
• Hypercalcemia: start with 4 International Units/kg body weight every 12
hours. Increase to 8 International Units/kg every 12 hours if no
improvement in 1-2 days. Increase further to 8 International Units/kg every
6 hours if no improvement after 2 more days (2.2)
• Postmenopausal osteoporosis: 100 International Units daily. Ensure
adequate calcium and vitamin D intake (2.3, 2.5)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
• Injection: 200 International Units per mL sterile solution in 2 mL multi-
dose vials (3)
----------------------------CONTRAINDICATIONS-----------------------------
Hypersensitivity to calcitonin-salmon or any of the excipients (4)
-----------------------WARNINGS AND PRECAUTIONS-----------------------
• Serious hypersensitivity reactions, including reports of fatal anaphylaxis
have been reported. Consider skin testing prior to treatment in patients with
suspected hypersensitivity to calcitonin-salmon (5.1)
• Hypocalcemia has been reported. Ensure adequate intake of calcium and
vitamin D (5.2)
• Malignancy: A meta-analysis of 21 clinical trials suggests an increased risk
of overall malignancies in calcitonin-salmon-treated patients (5.3, 6.1)
• Circulating antibodies to calcitonin-salmon may develop, and may cause
loss of response to treatment (5.4)
------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions are nausea with or without vomiting (10%),
injection site inflammation (10%), and flushing of the face or hands (2-5%)
(6)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA
1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS------------------------------
• Concomitant use of calcitonin-salmon and lithium may lead to a reduction
in plasma lithium concentrations due to increased urinary clearance of
lithium. The dose of lithium may require adjustment (7)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
• There are no data to support use in children (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 2/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Treatment of Paget’s Disease of Bone
1.2
Treatment of Hypercalcemia
1.3
Treatment of Postmenopausal Osteoporosis
1.4
Important Limitations of Use
2
DOSAGE AND ADMINISTRATION
2.1
Paget’s Disease of Bone
2.2
Hypercalcemia
2.3
Postmenopausal Osteoporosis
2.4
Preparation and Administration
2.5
Recommendations for Calcium and Vitamin D Supplementation
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
5.2
Hypocalcemia
5.3
Malignancy
5.4
Antibody Formation
5.5
Urine Sediment Abnormalities
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
6.3
Immunogenicity
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 Paget’s Disease of Bone
14.2 Hypercalcemia
14.3 Postmenopausal Osteoporosis
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3696059
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 Paget’s Disease of Bone
Miacalcin injection is indicated for the treatment of symptomatic Paget’s disease of bone in patients with moderate to
severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary
hydroxyproline excretion. There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in
asymptomatic patients. Miacalcin injection should be used only in patients who do not respond to alternative treatments or
for whom such treatments are not suitable (e.g., patients for whom other therapies are contraindicated or for patients who
are intolerant or unwilling to use other therapies).
1.2
Treatment of Hypercalcemia
Miacalcin injection is indicated for the early treatment of hypercalcemic emergencies, along with other appropriate agents,
when a rapid decrease in serum calcium is required, until more specific treatment of the underlying disease can be
accomplished. It may also be added to existing therapeutic regimens for hypercalcemia such as intravenous fluids and
furosemide, oral phosphate or corticosteroids, or other agents.
1.3
Treatment of Postmenopausal Osteoporosis
Miacalcin injection is indicated for the treatment of postmenopausal osteoporosis in women greater than 5 years
postmenopause. The evidence of efficacy for calcitonin-salmon injection is based on increases in total body calcium
observed in clinical trials. Fracture reduction efficacy has not been demonstrated. Miacalcin injection should be reserved
for patients for whom alternative treatments are not suitable (e.g., patients for whom other therapies are contraindicated or
for patients who are intolerant or unwilling to use other therapies).
1.4
Important Limitations of Use
Due to the possible association between malignancy and calcitonin-salmon use, the need for continued therapy should be
re-evaluated on a periodic basis [see Warnings and Precautions (5.3)].
2
DOSAGE AND ADMINISTRATION
2.1
Paget’s Disease of Bone
The recommended dose of Miacalcin injection for treatment of symptomatic Paget's disease of bone is 100 International
Units (0.5 mL) per day administered subcutaneously or intramuscularly.
2.2
Hypercalcemia
The recommended starting dose of Miacalcin injection for early treatment of hypercalcemia is 4 International Units/kg
body weight every 12 hours by subcutaneous or intramuscular injection. If the response to this dose is not satisfactory
after one or two days, the dose may be increased to 8 International Units/kg every 12 hours. If the response remains
unsatisfactory after two more days, the dose may be further increased to a maximum of 8 International Units/kg every 6
hours.
2.3
Postmenopausal Osteoporosis
The recommended dose of Miacalcin injection for treatment of postmenopausal osteoporosis in women greater than 5
years postmenopause is 100 International Units (0.5 mL) per day administered subcutaneously or intramuscularly. The
minimum effective dose of Miacalcin injection for the prevention of vertebral bone mineral density loss has not been
established.
2.4
Preparation and Administration
Visually inspect Miacalcin vials. Miacalcin injection is a clear, colorless, solution. If the solution is not clear and
colorless, or contains any particles, or if the vial is damaged, do not administer the solution.
If the volume of Miacalcin injection to be injected exceeds 2 mL, intramuscular injection is preferable and the total dose
should be distributed across multiple sites of injection.
Instruct patients to use sterile injection technique when administering Miacalcin injection, and to dispose of needles
properly.
Reference ID: 3696059
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.5
Recommendations for Calcium and Vitamin D Supplementation
Patients who use Miacalcin injection for treatment of postmenopausal osteoporosis should receive adequate calcium (at
least 1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day).
3
DOSAGE FORMS AND STRENGTHS
Miacalcin injection is available as a clear, colorless, sterile solution of synthetic calcitonin-salmon in individual 2 mL
multi-dose vials containing 200 International Units per mL.
4
CONTRAINDICATIONS
Hypersensitivity to calcitonin-salmon or any of the excipients. Reactions have included anaphylaxis with death,
bronchospasm, and swelling of the tongue or throat [see Warnings and Precautions (5.1)].
5
WARNINGS AND PRECAUTIONS
5.1
Hypersensitivity Reactions
Serious hypersensitivity reactions have been reported in patients receiving Miacalcin injection, e.g., bronchospasm,
swelling of the tongue or throat, anaphylactic shock, and death due to anaphylaxis. Appropriate medical support and
monitoring measures should be readily available when Miacalcin injection is administered. If anaphylaxis or other severe
hypersensitivity/allergic reactions occur, initiate appropriate treatment [see Contraindications (4)].
For patients with suspected hypersensitivity to calcitonin-salmon, skin testing should be considered prior to treatment
utilizing a dilute, sterile solution of Miacalcin injection. Healthcare providers may wish to refer patients who require skin
testing to an allergist. A detailed skin testing protocol is available from the Medical Services Department of Novartis
Pharmaceuticals Corporation.
5.2
Hypocalcemia
Hypocalcemia associated with tetany (i.e., muscle cramps, twitching) and seizure activity has been reported with
Miacalcin injection therapy. Hypocalcemia must be corrected before initiating therapy. Other disorders affecting mineral
metabolism (such as vitamin D deficiency) should also be effectively treated. In patients at risk for hypocalcemia,
provisions for parenteral calcium administration should be available during the first several administrations of calcitonin
salmon and serum calcium and symptoms of hypocalcemia should be monitored. Use of Miacalcin injection for the
treatment of Paget’s disease or postmenopausal osteoporosis is recommended in conjunction with an adequate intake of
calcium and vitamin D [see Dosage and Administration (2.5)].
5.3
Malignancy
In a meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray or investigational oral
formulations), the overall incidence of malignancies reported was higher among calcitonin-salmon-treated patients (4.1%)
compared with placebo-treated patients (2.9%). This suggests an increased risk of malignancies in calcitonin-salmon
treated patients compared to placebo-treated patients. It is not possible to exclude an increased risk when calcitonin
salmon is administered long-term subcutaneously, intramuscularly, or intravenously. The benefits for the individual
patient should be carefully considered against possible risks [see Adverse Reactions (6.1)].
5.4
Antibody Formation
Circulating antibodies to calcitonin-salmon have been reported with Miacalcin injection. The possibility of antibody
formation should be considered in any patient with an initial response to Miacalcin injection who later stops responding to
treatment [see Adverse Reactions (6.3)].
5.5
Urine Sediment Abnormalities
Coarse granular casts and casts containing renal tubular epithelial cells were reported in young adult volunteers at bed rest
who were given injectable calcitonin-salmon to study the effect of immobilization on osteoporosis. There was no other
evidence of renal abnormality and the urine sediment normalized after calcitonin-salmon was stopped. Periodic
examinations of urine sediment should be considered.
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
•
Hypersensitivity Reactions, including anaphylaxis [see Warnings and Precautions (5.1)]
Reference ID: 3696059
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Hypocalcemia [see Warnings and Precautions (5.2)]
•
Malignancy [see Warnings and Precautions (5.3)]
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 safety of calcitonin-salmon injection was assessed in open-label trials several months to two years in duration. The
most common adverse reactions are discussed below.
Nausea: Nausea with or without vomiting has been noted in about 10% of patients treated with calcitonin-salmon. It is
most evident when treatment is first initiated and tends to decrease or disappear with continued administration.
Dermatologic Reactions: Local inflammatory reactions at the site of subcutaneous or intramuscular injection have been
reported in about 10% of patients. Flushing of face or hands occurred in about 2%–5% of patients. Skin rashes and
pruritus of the ear lobes have also been reported.
Other Adverse Reactions: Nocturia, feverish sensation, pain in the eyes, poor appetite, abdominal pain, pedal edema,
and salty taste have been reported in patients treated with calcitonin-salmon injection.
Malignancy
A meta-analysis of 21 randomized, controlled clinical trials with calcitonin-salmon (nasal spray or investigational oral
formulations) was conducted to assess the risk of malignancies in calcitonin-salmon-treated patients compared to placebo-
treated patients. The trials in the meta-analysis ranged in duration from 6 months to 5 years and included a total of 10883
patients (6151 treated with calcitonin-salmon and 4732 treated with placebo). The overall incidence of malignancies
reported in these 21 trials was higher among calcitonin-salmon-treated patients (254/6151 or 4.1%) compared with
placebo-treated patients (137/4732 or 2.9%). Findings were similar when analyses were restricted to the 18 nasal spray
only trials [calcitonin-salmon 122/2712 (4.5%); placebo 30/1309 (2.3%)].
The meta-analysis results suggest an increased risk of overall malignancies in calcitonin-salmon-treated patients compared
to placebo-treated patients when all 21 trials are included and when the analysis is restricted to the 18 nasal spray only
trials (see Table 1). It is not possible to exclude an increased risk when calcitonin-salmon is administered by the
subcutaneous, intramuscular, or intravenous route because these routes of administration were not investigated in the
meta-analysis. The increased malignancy risk seen with the meta-analysis was heavily influenced by a single large 5-year
trial, which had an observed risk difference of 3.4% [95% CI (0.4%, 6.5%)]. Imbalances in risks were still observed when
analyses excluded basal cell carcinoma (see Table 1); the data were not sufficient for further analyses by type of
malignancy. A mechanism for these observations has not been identified. Although a definitive causal relationship
between calcitonin-salmon use and malignancies cannot be established from this meta-analysis, the benefits for the
individual patient should be carefully evaluated against all possible risks [see Warnings and Precautions (5.3)].
Table 1: Risk Difference for Malignancies in Calcitonin-Salmon-Treated Patients Compared with Placebo-Treated
Patients
Patients
Malignancies
Risk Difference1
(%)
95% Confidence Interval2 (%)
All (nasal spray + oral)
All
1.0
(0.3, 1.6)
All (nasal spray + oral)
Excluding basal cell
carcinoma
0.5
(-0.1, 1.2)
All (nasal spray only)
All
1.4
(0.3, 2.6)
All (nasal spray only)
Excluding basal cell
carcinoma
0.8
(-0.2, 1.8)
1 The overall adjusted risk difference is the difference between the percentage of patients who had any malignancy (or malignancy excluding
basal cell carcinoma) in calcitonin-salmon and placebo treatment groups, using the Mantel-Haenszel (MH) fixed-effect method. A risk
difference of 0 is suggestive of no difference in malignancy risks between the treatment groups.
2 The corresponding 95% confidence interval for the overall adjusted risk difference also based on MH fixed-effect method.
Reference ID: 3696059
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2
Postmarketing Experience
Because postmarketing adverse 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 following adverse reactions have been reported during post-approval use of Miacalcin injection.
Allergic / Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving
calcitonin-salmon injection, e.g., bronchospasm, swelling of the tongue or throat, anaphylactic shock, and death due to
anaphylaxis.
Skin and subcutaneous tissue disorders: Urticaria
Hypocalcemia: Hypocalcemia with tetany (i.e. muscle cramps, twitching) and seizure activity have been reported.
Body as a Whole: influenza-like symptoms, fatigue, edema (facial, peripheral, and generalized)
Musculoskeletal: arthralgia, musculoskeletal pain
Cardiovascular: hypertension
Gastrointestinal: abdominal pain, diarrhea
Urinary System: polyuria
Nervous System: dizziness, headache, paresthesia, tremor
Vision: visual disturbance
6.3
Immunogenicity
Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of
Miacalcin may trigger the development of anti-calcitonin antibodies. Circulating antibodies to calcitonin-salmon after 2
18 months of treatment have been reported in about one-half of the patients with Paget’s disease in whom antibody studies
were done. In some cases, high antibody titers are found; these patients usually will have a loss of response to treatment
[see Warnings and Precautions (5.4)].
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the
observed incidence of a positive antibody test result may be influenced by several factors, including assay methodology,
sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons,
comparison of antibodies among different calcitonin-salmon products may be misleading.
7
DRUG INTERACTIONS
No formal drug interaction studies have been performed with Miacalcin injection.
Concomitant use of calcitonin-salmon and lithium may lead to a reduction in plasma lithium concentrations due to
increased urinary clearance of lithium. The dose of lithium may require adjustment.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C:
Risk Summary
There are no adequate and well-controlled studies in pregnant women. Miacalcin injection should be used during
pregnancy only if the potential benefit justifies the use as compared with potential risks to the patient and fetus. Based on
animal data, Miacalcin is predicted to have low probability of increasing the risk of adverse developmental outcomes
above background risk.
Animal Data
Calcitonin-salmon has been shown to cause a decrease in fetal birth weights in rabbits when given by subcutaneous
injection in doses 4-18 times the parenteral dose recommended for human use (of 54 International Units/m2).
No embryo/fetal toxicities related to Miacalcin were reported from maternal subcutaneous daily doses in rats up to 80
International Units /kg/day from gestation day 6 to 15.
Reference ID: 3696059
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. No studies have been conducted to assess the impact of
Miacalcin on milk production in humans, its presence in human breast milk, or its effects on the breastfed child. Because
many drugs are excreted in human milk, caution should be exercised when Miacalcin is administered to a nursing woman.
Calcitonin has been shown to inhibit lactation in rats.
8.4
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5
Geriatric Use
Clinical studies of Miacalcin injection did not include sufficient numbers of subjects aged 65 years and older 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.
10
OVERDOSAGE
The pharmacologic actions of Miacalcin injection suggest that hypocalcemic tetany could occur in overdose. Therefore,
provisions for parenteral administration of calcium should be available for the treatment of overdose.
A dose of calcitonin-salmon l000 International Units subcutaneously may produce nausea and vomiting. Doses of 32
International Units per kg per day for 1–2 days demonstrate no other adverse effects. Data on chronic high-dose
administration are insufficient to assess toxicity.
11
DESCRIPTION
Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the
ultimobranchial gland of birds and fish.
Miacalcin (calcitonin-salmon) injection, synthetic is a synthetic polypeptide of 32 amino acids in the same linear sequence
that is found in calcitonin of salmon origin. This is shown by the following graphic formula: graphic formula
It is provided in sterile solution for subcutaneous or intramuscular injection. Each milliliter contains: calcitonin-salmon
200 International Units.
Inactive Ingredients (per mL): acetic acid, USP, 2.25 mg; phenol, USP, 5.0 mg; sodium acetate trihydrate, USP, 2.0 mg;
sodium chloride, USP, 7.5 mg; water for injection, USP.
The activity of Miacalcin injection is stated in International Units based on bioassay in comparison with the International
Reference Preparation of calcitonin-salmon for Bioassay, distributed by the National Institute for Biological Standards
and Control, Holly Hill, London.
Reference ID: 3696059
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
Calcitonin-salmon is a calcitonin receptor agonist. Calcitonin-salmon acts primarily on bone, but direct renal effects and
actions on the gastrointestinal tract are also recognized. Calcitonin-salmon appears to have actions essentially identical to
calcitonins of mammalian origin, but its potency per mg is greater and it has a longer duration of action.
The actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated,
although calcitonin receptors have been discovered in osteoclasts and osteoblasts.
12.2
Pharmacodynamics
Bone
Single injections of calcitonin-salmon caused a marked transient inhibition of the ongoing bone resorptive process. With
prolonged use, there is a persistent, smaller decrease in the rate of bone resorption. Histologically, this is associated with a
decreased number of osteoclasts and an apparent decrease in their resorptive activity.
In healthy adults, who have a relatively low rate of bone resorption, the administration of exogenous calcitonin-salmon
results in decreases in serum calcium within the limits of the normal range. In healthy children and in patients whose bone
resorption is more rapid, decreases in serum calcium are more pronounced in response to calcitonin-salmon.
Kidney
Studies with injectable calcitonin-salmon show increases in the excretion of filtered phosphate, calcium, and sodium by
decreasing their tubular reabsorption.
Gastrointestinal Tract
Some evidence from studies with injectable preparations suggests that calcitonin-salmon may have effects on the
gastrointestinal tract. Short-term administration of injectable calcitonin-salmon results in marked transient decreases in the
volume and acidity of gastric juice and in the volume and the trypsin and amylase content of pancreatic juice. Whether
these effects continue to be elicited after each injection of calcitonin-salmon during chronic therapy has not been
investigated.
12.3
Pharmacokinetics
The absolute bioavailability of calcitonin-salmon is approximately 66% and 71% after intramuscular or subcutaneous
injection, respectively. After subcutaneous administration, peak plasma levels are reached in approximately 23
minutes. The terminal half-life is approximately 58 minutes for intramuscular administration and 59 to 64 minutes for
subcutaneous administration. The apparent volume of distribution is 0.15––0.3 L/kg.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
The incidence of pituitary adenomas was increased in rats after one and two years of subcutaneous exposure to synthetic
calcitonin-salmon. The significance of this finding to humans is unknown because pituitary adenomas are very common in
rats as they age, the pituitary adenomas did not transform into metastatic tumors, there were no other clear treatment-
related neoplasms, and synthetic calcitonin-salmon related neoplasms were not observed in mice after two years of
dosing.
Rat findings:
The only clear neoplastic finding in rats dosed subcutaneously with calcitonin-salmon was an increase in the incidence of
pituitary adenomas in male Fisher 344 rats and female Sprague Dawley rats after one year of dosing and male Sprague
Dawley rats dosed for one and two years. In female Sprague Dawley rats, the incidence of pituitary adenomas after two
years was high in all treatment groups (between 80% and 92% including the control groups) such that a treatment-related
effect could not be distinguished from natural background incidence. The lowest dose in male Sprague Dawley rats that
developed an increased incidence of pituitary adenomas after two years of dosing (1.7 International Units/kg/day) is
approximately 1/6th of the maximum recommended subcutaneous dose in humans (100 International Units/day) based on
body surface area conversion between rats and humans. The findings suggest that calcitonin-salmon reduced the latency
period for development of non-functioning pituitary adenomas.
Reference ID: 3696059
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Mouse findings:
No carcinogenicity potential was evident in male or female mice dosed subcutaneously for two years with synthetic
calcitonin-salmon at doses up to 800 International Units/kg/day. The 800 International Units/kg/day dose is approximately
39 times the maximum recommended subcutaneous dose in humans (100 International Units/day) based on body surface
area conversion between mice and humans.
Mutagenesis
Synthetic calcitonin-salmon tested negative for mutagenicity using Salmonella typhimurium (5 strains) and Escherichia
coli (2 strains), with and without rat liver metabolic activation, and was not clastogenic in a chromosome aberration test in
Chinese Hamster V79 cells. There was no evidence that calcitonin-salmon was clastogenic in the in vivo mouse
micronucleus test.
Fertility
Effects of calcitonin-salmon on fertility have not been assessed in animals.
CLINICAL STUDIES
14.1
Paget’s Disease of Bone
The trials used for the basis of approval for calcitonin-salmon injection for treatment of Paget’s disease of bone were
conducted in patients with moderate to severe disease characterized by polyostotic involvement with elevated serum
alkaline phosphatase and urinary hydroxyproline excretion. In open-label clinical trials of several months to two years
duration with historical controls, biochemical abnormalities were substantially improved (more than 30% reduction) in
about 2/3 of patients studied and bone pain was improved in a similar fraction. A small number of documented instances
of reversal of neurologic deficits have occurred, including improvement in the basilar compression syndrome, and
improvement of spinal cord and spinal nerve lesions. There is too little experience to predict the likelihood of
improvement of any given neurologic lesion. Hearing loss is improved infrequently (4 of 29 patients studied by
audiometry). Patients with increased cardiac output due to extensive Paget’s disease of bone have had measured decreases
in cardiac output while receiving calcitonin-salmon. The number of treated patients in this category is too small to predict
how likely such a result will be.
There is no evidence that the prophylactic use of calcitonin-salmon is beneficial in asymptomatic patients.
14.2
Hypercalcemia
In four open-label clinical trials enrolling 53 patients, calcitonin-salmon has been shown to lower elevated serum calcium
levels of patients with carcinoma (with or without metastases), multiple myeloma, and primary hyperparathyroidism
(lesser response). These patients were treated with calcitonin-salmon only when other methods of lowering serum calcium
(hydration, oral phosphate, corticosteroids) were unsuccessful or unsuitable. With patients’ pre-therapy serum calcium
levels as controls, reduction in serum calcium was evident within 1–2 hours of administration. The peak effect occurred
within 24–48 hours of injection and administration of calcitonin-salmon every 12 hours maintained a hypocalcemic effect
for approximately 5–8 days, the time period evaluated for most patients in the clinical trials. The average reduction of 8
hour post-injection serum calcium was approximately 9% (2–3 mg/dL). Patients with higher values of serum calcium
tended to show greater reductions during calcitonin-salmon treatment.
14.3
Postmenopausal Osteoporosis
The trials used for the basis of approval for calcitonin-salmon injection for treatment of postmenopausal osteoporosis
were two randomized, open-label, 2-year studies in postmenopausal women 50–74 years of age with total body calcium
<85% of expected normal, and vertebral osteopenia (by x-ray criteria) and/or at least one atraumatic compression fracture.
The primary efficacy endpoint was total body calcium measured by neutron activation analysis. Patients were randomized
to calcitonin-salmon injection 100 International Units daily (subcutaneously or intramuscularly) at bedtime, or control. All
subjects received daily supplements of 1200 mg calcium carbonate and 400 International Units of vitamin D.
In both studies, total body calcium increased from baseline with calcitonin-salmon therapy at 1 year, followed by a trend
to decreasing total body calcium (still above baseline) at 2 years.
Thoracic and lumbar spine X-rays (AP/lateral) were obtained yearly. For the two studies combined (34 calcitonin-salmon
and 35 control subjects), in the first year there was a total of 6 new vertebral compression fractures in the calcitonin
salmon group and 5 in the control group. In the second year there were 7 new fractures in each group.
Reference ID: 3696059
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No evidence currently exists to indicate whether Miacalcin injection decreases the risk of osteoporotic fracture. A
controlled study, which was prematurely discontinued, failed to demonstrate any benefit of calcitonin-salmon on fracture
rate.
No adequate controlled trials have examined the effect of calcitonin-salmon injection on vertebral bone mineral density
beyond 1 year of treatment. Therefore, the minimum effective dose of Miacalcin injection for prevention of vertebral bone
mineral density loss has not been established.
In clinical studies of postmenopausal osteoporosis, bone biopsy and radial bone mass assessments at baseline and after 26
months of daily injectable calcitonin-salmon indicate that calcitonin therapy results in the formation of normal bone.
16
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Miacalcin (calcitonin-salmon) injection, synthetic is available as a sterile solution in individual 2 mL multi-dose vials
containing 200 International Units per mL .......................NDC 0078-0149-23
Storage and Handling
Store in refrigerator between 2°C–8°C (36°F–46°F).
17
PATIENT COUNSELING INFORMATION
• Instruct patients and other persons who may administer Miacalcin injection in sterile injection technique. Also instruct
patients to dispose of needles properly [see Dosage and Administration (2.4)].
• Inform patients of the potential increase in risk of malignancy [see Warnings and Precautions (5.3)].
• Advise patients with postmenopausal osteoporosis or Paget’s disease of bone to maintain an adequate calcium (at least
1000 mg elemental calcium per day) and vitamin D (at least 400 International Units per day) intake [see Dosage and
Administration (2.5)].
• Instruct patients to seek emergency medical help or go to the nearest hospital emergency room right away if they
develop any signs or symptoms of a serious allergic reaction [see Warnings and Precautions (5.1)].
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2015-XX
Month Year
Reference ID: 3696059
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:21.778854
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017808s036lbl.pdf', 'application_number': 17808, 'submission_type': 'SUPPL ', 'submission_number': 36}
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Page 3
CAPSULES, ORAL SUSPENSION
and SUPPOSITORIES
INDOCIN®
(INDOMETHACIN)
Cardiovascular Risk
• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
myocardial infarction, and stroke, which can be fatal. This risk may increase with
duration of use. Patients with cardiovascular disease or risk factors for cardiovascular
disease may be at a greater risk (See WARNING).
• INDOCIN is contraindicated for the treatment of peri-operative pain in the setting of
coronary artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including
bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.
These events can occur at any time during use and without warning symptoms. Elderly
patients are at greater risk for serious gastrointestinal events (See WARNINGS).
DESCRIPTION
INDOCIN* (Indomethacin) cannot be considered a simple analgesic and should not be used in
conditions other than those recommended under INDICATIONS.
INDOCIN is supplied in three dosage forms. Capsules INDOCIN for oral administration contain
either 25 mg or 50 mg of indomethacin and the following inactive ingredients: colloidal silicon
dioxide, FD&C Blue 1, FD&C Red 3, gelatin, lactose, lecithin, magnesium stearate, and titanium
dioxide. Suspension INDOCIN for oral use contains 25 mg of indomethacin per 5 mL, alcohol 1%, and
sorbic acid 0.1% added as a preservative and the following inactive ingredients: antifoam AF
emulsion, flavors, purified water, sodium hydroxide or hydrochloric acid to adjust pH, sorbitol
solution, and tragacanth. Suppositories INDOCIN for rectal use contain 50 mg of indomethacin and the
following inactive ingredients: butylated hydroxyanisole, butylated hydroxytoluene, edetic acid,
glycerin, polyethylene glycol 3350, polyethylene glycol 8000 and sodium chloride. Indomethacin is a
non-steroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-
methoxy-2-methyl-1H-indole-3-acetic acid. Indomethacin is practically insoluble in water and
sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and
decomposes in strong alkali. The suspension has a pH of 4.0-5.0. The structural formula is:
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1988, 2005 MERCK & CO., Inc.
All rights reserved
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NDA 16-059/S-096, 17-814/S-039, 18-332/S-029
Page 4
CLINICAL PHARMACOLOGY
INDOCIN is a non-steroidal drug with anti-inflammatory drug (NSAID) that exhibits, antipyretic
and analgesic properties. Its mode of action, like that of other anti-inflammatory drugs, is not known.
However, its therapeutic action is not due to pituitary-adrenal stimulation.
INDOCIN is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached
during therapy which have been demonstrated to have an effect in vivo as well. Prostaglandins
sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.
Moreover, prostaglandins are known to be among the mediators of inflammation. Since indomethacin
is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins
in peripheral tissues.
INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long-term use
in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying
disease.
INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and
reduction of fever, swelling and tenderness. Improvement in patients treated with INDOCIN for
rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints
involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time;
and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN may
enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of
rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients
followed very closely for any possible adverse effects.
Indomethacin has been reported to diminish basal and CO2 stimulated cerebral blood flow in
healthy volunteers following acute oral and intravenous administration. In one study after one week of
treatment with orally administered indomethacin, this effect on basal cerebral blood flow had
disappeared. The clinical significance of this effect has not been established.
Capsules INDOCIN have been found effective in relieving the pain, reducing the fever, swelling,
redness, and tenderness of acute gouty arthritis — see INDICATIONS AND USAGE.
Following single oral doses of Capsules INDOCIN 25 mg or 50 mg, indomethacin is readily
absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2
hours. Orally administered Capsules INDOCIN are virtually 100% bioavailable, with 90% of the dose
absorbed within 4 hours. A single 50 mg dose of Oral Suspension INDOCIN was found to be
bioequivalent to a 50 mg INDOCIN capsule when each was administered with food.
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin
undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be
about 4.5 hours. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma
concentrations of indomethacin are an average 1.4 times those following the first dose.
The rate of absorption is more rapid from the rectal suppository than from Capsules INDOCIN.
Ordinarily, therefore, the total amount absorbed from the suppository would be expected to be at least
equivalent to the capsule. In controlled clinical trials, however, the amount of indomethacin absorbed
was found to be somewhat less (80-90%) than that absorbed from Capsules INDOCIN. This is
probably because some subjects did not retain the material from the suppository for the one hour
necessary to assure complete absorption. Since the suppository dissolves rather quickly rather than
melting slowly, it is seldom recovered in recognizable form if the patient retains the suppository for
more than a few minutes.
Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-
desbenzoyl metabolites, all in the unconjugated form. About 60 percent of an oral dosage is recovered
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Page 5
in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent is
recovered in feces (1.5 percent as indomethacin).
About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic
plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta.
In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was
significantly higher in the group receiving Capsules INDOCIN than in the group taking Suppositories
INDOCIN or placebo.
In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis,
however, the incidence of upper gastrointestinal adverse effects with Suppositories or Capsules
INDOCIN was comparable. The incidence of lower gastrointestinal adverse effects was greater in the
suppository group.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of INDOCIN and other treatment options before
deciding to use INDOCIN. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
Indomethacin has been found effective in active stages of the following:
1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease.
2. Moderate to severe ankylosing spondylitis.
3. Moderate to severe osteoarthritis.
4. Acute painful shoulder (bursitis and/or tendinitis).
5. Acute gouty arthritis.
INDOCIN may enable the reduction of steroid dosage in patients receiving steroids for the more
severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and
the patients followed very closely for any possible adverse effects.
The use of INDOCIN in conjunction with aspirin or other salicylates is not recommended.
Controlled clinical studies have shown that the combined use of INDOCIN and aspirin does not
produce any greater therapeutic effect than the use of INDOCIN alone. Furthermore, in one of these
clinical studies, the incidence of gastrointestinal side effects was significantly increased with combined
therapy (see PRECAUTIONS, Drug Interactions).
CONTRAINDICATIONS
INDOCIN is contraindicated in patients with known hypersensitivity to indomethacin or the excipients
(see DESCRIPTION).
INDOCIN should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid
reactions to NSAIDs have been reported in such patients (see WARNINGS,
Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS, Preexisting Asthma).
INDOCIN is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Suppositories INDOCIN are contraindicated in patients with a history of proctitis or recent rectal
bleeding.
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NDA 16-059/S-096, 17-814/S-039, 18-332/S-029
Page 6
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar
risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To
minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they
occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first
10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke
(see CONTRAINDICATIONS).
Hypertension
NSAIDs, including INDOCIN, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including INDOCIN, should be used with caution in patients with hypertension. Blood
pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout
the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. INDOCIN should be
used with caution in patients with fluid retention or heart failure.
In a study of patients with severe heart failure and hyponatremia, INDOCIN was associated with
significant deterioration of circulatory hemodynamics, presumably due to inhibition of prostaglandin
dependent compensatory mechanisms.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including INDOCIN, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large
intestine, which can be fatal. These serious adverse events can occur at any time, with or without
warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious
upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or
perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in
about 2-4% of patients treated for one year. These trends continue with longer duration of use,
increasing the likelihood of developing a serious GI event at some time during the course of therapy.
However, even short-term therapy is not without risk.
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Page 7
Rarely, in patients taking INDOCIN, intestinal ulceration has been associated with stenosis and
obstruction. Gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing
sigmoid lesions (diverticulum, carcinoma, etc.) have occurred. Increased abdominal pain in ulcerative
colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur
rarely.
NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed
compared to patients with neither of these risk factors. Other factors that increase the risk for GI
bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor
general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients
and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should
include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk
patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-
inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily,
in renal blood flow, which may precipitate over renal decompensation. Patients at greatest risk of this
reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics
and ACE inhibitors, patients with volume depletion, and the elderly. Discontinuation of NSAID
therapy is usually followed by recovery to the pretreatment state.
Caution should be used when initiating the treatment with INDOCIN in patients with considerable
dehydration. It is advisable to rehydrate patients first and then start therapy with INDOCIN. Caution is
also recommended in patients with preexisting kidney disease.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of
INDOCIN, even in some patients without renal impairment. In patients with normal renal function,
these effects have been attributed to a hyporeninemic-hypoaldosteronism state (see PRECAUTIONS,
Drug Interactions).
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of INDOCIN in patients
with advanced renal disease. Therefore, treatment with INDOCIN is not recommended in these
patients with advanced renal disease. If INDOCIN therapy must be initiated, close monitoring of the
patient’s renal function is advisable.
Since INDOCIN is eliminated primarily by the kidneys, patients with significantly impaired renal
function should be closely monitored; a lower daily dosage should be anticipated to avoid excessive
drug accumulation.
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Page 8
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known
prior exposure to INDOCIN. INDOCIN should not be given to patients with the aspirin triad. This
symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal
polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including INDOCIN, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms
of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
Pregnancy
Teratogenic Effects. Pregnancy Category C.
INDOCIN is not recommended for use in pregnant women, since safety for use has not
been established.
Teratogenic studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0
mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day considered secondary to the
decreased average fetal weights, no increase in fetal malformations was observed as
compared with control groups. Other studies in mice reported in the literature using higher
doses (5 to 15 mg/kg/day) have described maternal toxicity and death, increased fetal
resorptions, and fetal malformations. Comparable studies in rodents using high doses of
aspirin have shown similar maternal and fetal effects. However, animal reproduction studies
are not always predictive of human response. There are no adequate and well-controlled
studies in pregnant women.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal
cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late
pregnancy) should be avoided.
The known effects of indomethacin and other drugs of this class on the human fetus during
the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally,
tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus
postnatally which may be resistant to medical management; myocardial degenerative
changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction
or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure,
oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing
enterocolitis.
In rats and mice, 4.0 mg/kg/day given during the last three days of gestation caused a
decrease in maternal weight gain and some maternal and fetal deaths. An increased
incidence of neuronal necrosis in the diencephalon in the live-born fetuses was observed. At
2.0 mg/kg/day, no increase in neuronal necrosis was observed as compared to the control
groups. Administration of 0.5 or 4.0 mg/kg/day during the first three days of life did not cause
an increase in neuronal necrosis at either dose level.
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Page 9
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an
increased incidence of dystocia, delayed parturition, and decreased pup survival occurred.
The effects of INDOCIN on labor and delivery in pregnant women are unknown.
Use in Nursing Mothers
INDOCIN is excreted in the milk of lactating mothers. INDOCIN is not recommended for
use in nursing mothers.
Pregnancy
In late pregnancy, as with other NSAIDs, INDOCIN should be avoided because it may cause
premature closure of the ductus arteriosus.
Ocular Effects:
Corneal deposits and retinal disturbances, including those of the macula, have been observed in
some patients who had received prolonged therapy with INDOCIN. The prescribing physician should
be alert to the possible association between the changes noted and INDOCIN. It is advisable to
discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and
warrants a thorough ophthalmological examination. Since these changes may be asymptomatic,
ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged.
Central Nervous System Effects:
INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism,
and should be used with considerable caution in patients with these conditions. If severe CNS adverse
reactions develop, INDOCIN should be discontinued.
INDOCIN may cause drowsiness; therefore, patients should be cautioned about engaging in
activities requiring mental alertness and motor coordination, such as driving a car. INDOCIN may also
cause headache. Headache which persists despite dosage reduction requires cessation of therapy with
INDOCIN.
PRECAUTIONS
General
INDOCIN cannot be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to
discontinue corticosteroids.
The pharmacological activity of INDOCIN in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs
including INDOCIN. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more
times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials
with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal
fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been
reported.
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Page 10
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver
test has occurred, should be evaluated for evidence of the development of a more severe hepatic
reaction while on therapy with INDOCIN. If clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), INDOCIN should be
discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including INDOCIN. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including INDOCIN, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some
patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and
reversible. Patients receiving INDOCIN who may be adversely affected by alterations in platelet
function, such as those with coagulation disorders or patients receiving anticoagulants, should be
carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs
has been reported in such aspirin-sensitive patients, INDOCIN should not be administered to patients
with this form of aspirin sensitivity and should be used with caution in patients with preexisting
asthma.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be
encouraged to read the NSAID Medication Guide that accompanies each prescription
dispensed.
1. INDOCIN, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which
may result in hospitalization and even death. Although serious CV events can occur without
warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any
indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see
WARNINGS, CARDIOVASCULAR EFFECTS).
2. INDOCIN, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such
as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI
tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for
the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when
observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and
hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
3. INDOCIN, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis,
SJS, and TEN, which may result in hospitalizations and even death. Although serious skin
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Page 11
reactions may occur without warning, patients should be alert for the signs and symptoms of skin
rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for
medical advice when observing any indicative signs or symptoms. Patients should be advised to
stop the drug immediately if they develop any type of rash and contact their physicians as soon as
possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed to seek
immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, INDOCIN should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, INDOCIN should be discontinued.
Drug Interactions
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and
angiotensin II antagonists. INDOCIN can reduce the antihypertensive effects of captopril and losartan.
These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-
inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co-
administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further
deterioration of renal function, including possible acute renal failure, which is usually reversible.
Aspirin
When INDOCIN is administered with aspirin, its protein binding is reduced, although the clearance
of free INDOCIN is not altered. The clinical significance of this interaction is not known.
The use of INDOCIN in conjunction with aspirin or other salicylates is not recommended.
Controlled clinical studies have shown that the combined use of INDOCIN and aspirin does not
produce any greater therapeutic effect than the use of INDOCIN alone. In a clinical study of the
combined use of INDOCIN and aspririn, the incidence of gastrointestinal side effects was significantly
increased with combined therapy.; however, as with other NSAIDs, concomitant administration of
indomethacin and aspirin is not generally recommended because of the potential of increased adverse
effects.
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Page 12
In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of
aspirin per day decreases indomethacin blood levels approximately 20%.
Beta-adrenoceptor blocking agents
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal anti-
inflammatory drugs including INDOCIN has been reported. Therefore, when using these blocking
agents to treat hypertension, patients should be observed carefully in order to confirm that the desired
therapeutic effect has been obtained.
Cyclosporine
Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been
associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of
renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal
function should be carefully monitored.
Diflunisal
In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal
clearance and significantly increased the plasma levels of indomethacin. In some patients, combined
use of INDOCIN and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore,
diflunisal and INDOCIN should not be used concomitantly.
Digoxin
INDOCIN given concomitantly with digoxin has been reported to increase the serum concentration
and prolong the half-life of digoxin. Therefore, when INDOCIN and digoxin are used concomitantly,
serum digoxin levels should be closely monitored.
Diuretics
In some patients, the administration of INDOCIN can reduce the diuretic, natriuretic, and
antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. This response has been
attributed to inhibition of renal prostaglandin synthesis.
INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced
by furosemide administration, or salt or volume depletion. These facts should be considered when
evaluating plasma renin activity in hypertensive patients.
It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN
resulted in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene
should not be administered together.
INDOCIN and potassium-sparing diuretics each may be associated with increased serum potassium
levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium kinetics and
renal function should be considered when these agents are administered concurrently.
Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms
involving inhibition of prostaglandin synthesis by INDOCIN.
During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal
failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%.
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Page 13
Capsules INDOCIN 50 mg t.i.d. produced a clinically relevant elevation of plasma lithium and
reduction in renal lithium clearance in psychiatric patients and normal subjects with steady state
plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis.
As a consequence, when NSAIDs and lithium are given concomitantly, the patient should be carefully
observed for signs of lithium toxicity. (Read circulars for lithium preparations before use of such
concomitant therapy.) In addition, the frequency of monitoring serum lithium concentration should be
increased at the outset of such combination drug treatment.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney
slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used
when NSAIDs are administered concomitantly with methotrexate.
NSAIDs
The concomitant use of INDOCIN with other NSAIDs is not recommended due to the increased
possibility of gastrointestinal toxicity, with little or no increase in efficacy.
Oral anticoagulants
Clinical studies have shown that INDOCIN does not influence the hypoprothrombinemia produced
by anticoagulants. However, when any additional drug, including INDOCIN, is added to the treatment
of patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin
time. In post-marketing experience, bleeding has been reported in patients on concomitant treatment
with anticoagulants and INDOCIN. Caution should be exercised when INDOCIN and anticoagulants
are administered concomitantly. The effects of warfarin and NSAIDs on GI bleeding are synergistic,
such that users of both drugs together have a risk of serious GI bleeding higher than users of either
drug alone.
Probenecid
When INDOCIN is given to patients receiving probenecid, the plasma levels of indomethacin are
likely to be increased. Therefore, a lower total daily dosage of INDOCIN may produce a satisfactory
therapeutic effect. When increases in the dose of INDOCIN are made, they should be made carefully
and in small increments.
Drug/Laboratory Test Interactions
False-negative results in the dexamethasone suppression test (DST) in patients being treated with
INDOCIN have been reported. Thus, results of the DST should be interpreted with caution in these
patients.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day, indomethacin had no
tumorigenic effect.
Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic
studies in the rat (dosing period 73-110 weeks) and the mouse (dosing period 62-88 weeks) at doses up
to 1.5 mg/kg/day.
Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames test and E. coli
with or without metabolic activation) and a series of in vivo tests including the host-mediated assay,
sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.
Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two
generation reproduction study or a two litter reproduction study in rats.
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Page 14
Pregnancy
Teratogenic Effects. Pregnancy Category C.
Teratogenic studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day.
Except for retarded fetal ossification at 4 mg/kg/day considered secondary to the decreased average
fetal weights, no increase in fetal malformations was observed as compared with control groups. Other
studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day) have described
maternal toxicity and death, increased fetal resorptions, and fetal malformations. Comparable studies
in rodents using high doses of aspirin have shown similar maternal and fetal effects. However, animal
reproduction studies are not always predictive of human response. There are no adequate and well-
controlled studies in pregnant women.
INDOCIN should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
The known effects of indomethacin and other drugs of this class on the human fetus during the third
trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence,
and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to
medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding,
intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in
prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and
increased risk of necrotizing enterocolitis.
In rats and mice, 4.0 mg/kg/day given during the last three days of gestation caused a decrease in
maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis
in the diencephalon in the live-born fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal
necrosis was observed as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day
during the first three days of life did not cause an increase in neuronal necrosis at either dose level.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an
increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects
of INDOCIN on labor and delivery in pregnant women are unknown.
Use in Nursing Mothers
INDOCIN is excreted in the milk of lactating mothers. INDOCIN is not recommended for use in
nursing mothers.
Pediatric Use
Safety and effectiveness in pediatric patients 14 years of age and younger has not been established.
INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless
toxicity or lack of efficacy associated with other drugs warrants the risk.
In experience with more than 900 pediatric patients reported in the literature or to the manufacturer
who were treated with Capsules INDOCIN, side effects in pediatric patients were comparable to those
reported in adults. Experience in pediatric patients has been confined to the use of Capsules INDOCIN.
If a decision is made to use indomethacin for pediatric patients two years of age or older, such
patients should be monitored closely and periodic assessment of liver function is recommended. There
have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis,
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Page 15
including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 2 1 mg/kg/day
given in divided doses. Maximum daily dosage should not exceed 4 mg/kg/day or 150-200 mg/day,
whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level
required to control symptoms, or the drug should be discontinued.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since
advancing age appears to increase the possibility of adverse reactions (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation and DOSAGE AND
ADMINISTRATION). Elderly patients seem to tolerate ulceration or bleeding less well than other
individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
Indomethacin may cause confusion or, rarely, psychosis (see ADVERSE REACTIONS);
physicians should remain alert to the possibility of such adverse effects in the elderly.
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 WARNINGS, Renal Effects).
ADVERSE REACTIONS
In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was
significantly higher in the group receiving Capsules INDOCIN than in the group taking Suppositories
INDOCIN or placebo.
In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis,
however, the incidence of upper gastrointestinal adverse effects with Suppositories or Capsules
INDOCIN was comparable. The incidence of lower gastrointestinal adverse effects was greater in the
suppository group.
The adverse reactions for Capsules INDOCIN listed in the following table have been arranged into
two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1)
was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients).
The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary
reports since marketing. The probability of a causal relationship exists between INDOCIN and these
adverse reactions, some of which have been reported only rarely.
The adverse reactions reported with Capsules INDOCIN may occur with use of the suppositories. In
addition, rectal irritation and tenesmus have been reported in patients who have received the
suppositories.
The adverse reactions reported with Capsules INDOCIN may also occur with use of the suspension.
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Page 16
Incidence greater
than 1%
Incidence less
than 1%
GASTROINTESTINAL
nausea** with or without
vomiting
dyspepsia** (including
indigestion, heartburn
and epigastric pain)
diarrhea
abdominal distress or
pain
constipation
anorexia
bloating (includes
distension)
flatulence
peptic ulcer
gastroenteritis
rectal bleeding
proctitis
single or multiple
ulcerations, including
perforation and
hemorrhage of the
esophagus,
stomach, duodenum
or small and large
intestines
intestinal ulceration
associated with
stenosis and
obstruction
gastrointestinal bleeding
without obvious ulcer
formation and
perforation of pre-
existing sigmoid lesions
(diverticulum,
carcinoma, etc.)
development of
ulcerative colitis and
regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice
(some fatal cases have
been reported)
intestinal strictures
(diaphragms)
CENTRAL NERVOUS SYSTEM
headache (11.7%)
dizziness**
vertigo
somnolence
depression and fatigue
(including malaise and
listlessness)
anxiety (includes
nervousness)
muscle weakness
involuntary muscle
movements
insomnia
muzziness
psychic disturbances
including psychotic
episodes
mental confusion
drowsiness
light-headedness
syncope
paresthesia
aggravation of epilepsy
and parkinsonism
depersonalization
coma
peripheral neuropathy
convulsion
dysarthria
SPECIAL SENSES
tinnitus
ocular — corneal
deposits and retinal
disturbances,
including those of the
macula, have been
reported in some
patients on prolonged
therapy with INDOCIN
blurred vision
diplopia
hearing disturbances,
deafness
CARDIOVASCULAR
none
hypertension
hypotension
tachycardia
chest pain
congestive heart failure
arrhythmia; palpitations
METABOLIC
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none
edema
weight gain
fluid retention
flushing or sweating
hyperglycemia
glycosuria
hyperkalemia
INTEGUMENTARY
none
pruritus
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson
syndrome
erythema multiforme
toxic epidermal necrolysis
HEMATOLOGIC
none
leukopenia
bone marrow depression
anemia secondary to
obvious or occult
gastrointestinal
bleeding
aplastic anemia
hemolytic anemia
agranulocytosis
thrombocytopenic purpura
disseminated intravascular
coagulation
HYPERSENSITIVITY
none
acute anaphylaxis
acute respiratory distress
rapid fall in blood
pressure resembling a
shock-like state
angioedema
dyspnea
asthma
purpura
angiitis
pulmonary edema
fever
GENITOURINARY
none
hematuria
vaginal bleeding
proteinuria
nephrotic syndrome
interstitial nephritis
BUN elevation
renal insufficiency,
including renal failure
MISCELLANEOUS
none
epistaxis
breast changes,
including enlargement
and tenderness, or
gynecomastia
** Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than
3% of the patients are unmarked.)
Causal relationship unknown: Other reactions have been reported but occurred under circumstances
where a causal relationship could not be established. However, in these rarely reported events, the
possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting
information to physicians:
Cardiovascular: Thrombophlebitis
Hematologic: Although there have been several reports of leukemia, the supporting information is
weak
Genitourinary: Urinary frequency.
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A
β hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory
agents, including indomethacin, sometimes with fatal outcome (see also PRECAUTIONS, General).
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OVERDOSAGE
The following symptoms may be observed following overdosage: nausea, vomiting, intense
headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of
paresthesias, numbness, and convulsions.
Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if
the ingestion is recent. If vomiting has not occurred spontaneously, the patient should be induced to
vomit with syrup of ipecac. If the patient is unable to vomit, gastric lavage should be performed. Once
the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the
condition of the patient, close medical observation and nursing care may be required. The patient
should be followed for several days because gastrointestinal ulceration and hemorrhage have been
reported as adverse reactions of indomethacin. Use of antacids may be helpful.
The oral LD50 of indomethacin in mice and rats (based on 14 day mortality response) was 50 and
12 mg/kg, respectively.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of INDOCIN and other treatment options before
deciding to use INDOCIN. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with INDOCIN, the dose and frequency should be
adjusted to suit an individual patient’s needs.
INDOCIN is available as 25 and 50 mg Capsules INDOCIN, Oral Suspension INDOCIN,
containing 25 mg of indomethacin per 5 mL, and 50 mg Suppositories INDOCIN for rectal use.
Adverse reactions appear to correlate with the size of the dose of INDOCIN in most patients but not
all. Therefore, every effort should be made to determine the smallest effective dosage for the
individual patient.
Always give Capsules INDOCIN or Oral Suspension INDOCIN with food, immediately after
meals, or with antacids to reduce gastric irritation.
Pediatric Use
INDOCIN ordinarily should not be prescribed for pediatric patients 14 years of age and under (see
PRECAUTIONS, Pediatric Use).
Adult Use
Dosage Recommendations for Active Stages of the Following:
1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe
ankylosing spondylitis; and moderate to severe osteoarthritis.
Suggested Dosage:
Capsules INDOCIN 25 mg b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 or
by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is
obtained or until a total daily dose of 150-200 mg is reached. DOSES ABOVE THIS AMOUNT
GENERALLY DO NOT INCREASE THE EFFECTIVENESS OF THE DRUG.
In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up
to a maximum of 100 mg, of the total daily dose at bedtime, either orally or by rectal suppositories,
may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of
chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by
50 mg daily.
If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated
dose and OBSERVE THE PATIENT CLOSELY.
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Page 19
If severe adverse reactions occur, STOP THE DRUG. After the acute phase of the disease is under
control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the
smallest effective dose or the drug is discontinued.
Careful instructions to, and observations of, the individual patient are essential to the prevention of
serious, irreversible, including fatal, adverse reactions.
As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be
used with greater care in the elderly (see PRECAUTIONS, Geriatric Use).
2. Acute painful shoulder (bursitis and/or tendinitis).
Initial Dose:
75-150 mg daily in 3 or 4 divided doses.
The drug should be discontinued after the signs and symptoms of inflammation have been
controlled for several days. The usual course of therapy is 7-14 days.
3. Acute gouty arthritis.
Suggested Dosage:
Capsules INDOCIN 50 mg t.i.d. until pain is tolerable. The dose should then be rapidly reduced to
complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours.
Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5
days.
HOW SUPPLIED
No. 3316 — Capsules INDOCIN, 25 mg are opaque blue and white capsules, coded INDOCIN and
MSD 25. They are supplied as follows:
NDC 0006-0025-68 bottles of 100
NDC 0006-0025-82 bottles of 1000.
No. 3317 — Capsules INDOCIN, 50 mg are opaque blue and white capsules, coded INDOCIN and
MSD 50. They are supplied as follows:
NDC 0006-0050-68 bottles of 100.
No. 3376 — Oral Suspension INDOCIN, 25 mg per 5 mL, is an off-white suspension with a
pineapple coconut mint flavor. It is supplied as follows:
NDC 0006-3376-66 in bottles of 237 mL.
No. 3354 — Suppositories INDOCIN, 50 mg each, are white, opaque, rectal suppositories and are
supplied as follows:
NDC 0006-0150-30, boxes of 30.
Storage
Store Oral Suspension INDOCIN below 30°C (86°F). Avoid temperatures above 50°C (122°F).
Protect from freezing.
Store Suppositories INDOCIN below 30°C (86°F). Avoid transient temperatures above 40°C
(104°F).
Suppositories INDOCIN® are distributed by:
Manufactured by:
MERCK SHARP & DOHME
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Page 20
(Italia) S.p.A.
27100 — Pavia, Italy
Capsules and Oral Suspension INDOCIN® are distributed and manufactured by:
Issued July 2005
Printed in USA
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
• with longer use of NSAID medicines
• in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time
during treatment. Ulcers and bleeding:
• can happen without warning symptoms
• may cause death
The chance of a person getting an ulcer or bleeding increases with:
• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health
NSAID medicines should only be used:
• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed
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What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical
conditions such as:
• different types of arthritis
• menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID
medicine
• for pain right before or after heart bypass surgery
Tell your healthcare provider:
• about all your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each
other and cause serious side effects. Keep a list of your medicines to show to your
healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their
pregnancy.
• if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma
Other side effects include:
• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• slurred speech
• chest pain
• swelling of the face or throat
• weakness in one part or side of your body
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Page 22
Stop your NSAID medicine and call your healthcare provider right away if you have any
of the following symptoms:
• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel
movement or it is black and sticky
like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands
and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can
cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach
and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter).
Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac
(copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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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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/
---------------------
Bob Rappaport
1/26/2006 10:17:56 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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2025-02-12T13:44:21.827939
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018332s029_017814s039_016059s096lbl.pdf', 'application_number': 17814, 'submission_type': 'SUPPL ', 'submission_number': 39}
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11,068
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
INDOCIN® SUPPOSITORIES safely and effectively. See full prescribing
information for INDOCIN.
INDOCIN (indomethacin) Suppositories, for rectal use
Initial U.S. Approval: 1965
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
See full prescribing information for complete boxed warning.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased
risk of serious cardiovascular thrombotic events, including myocardial
infarction and stroke, which can be fatal. This risk may occur early in
treatment and may increase with duration of use (5.1)
INDOCIN is contraindicated in the setting of coronary artery bypass
graft (CABG) surgery (4, 5.1)
NSAIDs cause an increased risk of serious gastrointestinal (GI)
adverse events including bleeding, ulceration, and perforation of the
stomach or intestines, which can be fatal. These events can occur at
any time during use and without warning symptoms. Elderly patients
and patients with a prior history of peptic ulcer disease and/or GI
bleeding are at greater risk for serious GI events (5.2)
RECENT MAJOR CHANGES
Boxed Warning
5/2016
Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016
Warnings and Precautions, Heart Failure and Edema (5.5)
5/2016
INDICATIONS AND USAGE
INDOCIN is a nonsteroidal anti-inflammatory drug indicated for:
Moderate to severe rheumatoid arthritis including acute flares of chronic
disease
Moderate to severe ankylosing spondylitis
Moderate to severe osteoarthritis
Acute painful shoulder (bursitis and/or tendinitis)
Acute gouty arthritis (1)
DOSAGE AND ADMINISTRATION
Use the lowest effective dosage for shortest duration consistent with
individual patient treatment goals (2.1)
INDOCIN suppositories 50 mg can be substituted for indomethacin
capsules, USP; however, there will be significant differences between the
two dosage regimens in indomethacin blood levels (12.3)
The dosage for moderate to severe rheumatoid arthritis including acute
flares of chronic disease; moderate to severe ankylosing spondylitis; and
moderate to severe osteoarthritis is indomethacin capsules, USP 25 mg
two or three times a day (2.3)
The dosage for acute painful shoulder (bursitis and/or tendinitis) is
indomethacin capsules, USP 75-150 mg daily in 3 or 4 divided doses (2.4)
The dosage for acute gouty arthritis is indomethacin capsules, USP 50 mg
three times a day (2.5)
INDOCIN Suppositories are not for oral or intravaginal use
DOSAGE FORMS AND STRENGTHS
INDOCIN (indomethacin) Suppositories: 50 mg (3)
CONTRAINDICATIONS
Known hypersensitivity to indomethacin or any components of the drug
product (4)
History of asthma, urticaria, or other allergic-type reactions after taking
aspirin or other NSAIDs (4)
In the setting of CABG surgery (4)
In patients with a history of proctitis or recent rectal bleeding (4)
WARNINGS AND PRECAUTIONS
Hepatotoxicity: Inform patients of warning signs and symptoms of
hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if
clinical signs and symptoms of liver disease develop (5.3)
Hypertension: Patients taking some antihypertensive medications may have
impaired response to these therapies when taking NSAIDs. Monitor blood
pressure (5.4, 7)
Heart Failure and Edema: Avoid use of INDOCIN in patients with severe
heart failure unless benefits are expected to outweigh risk of worsening
heart failure (5.5)
Renal Toxicity: Monitor renal function in patients with renal or hepatic
impairment, heart failure, dehydration, or hypovolemia. Avoid use of
INDOCIN in patients with advanced renal disease unless benefits are
expected to outweigh risk of worsening renal function (5.6)
Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction
occurs (5.7)
Exacerbation of Asthma Related to Aspirin Sensitivity: INDOCIN is
contraindicated in patients with aspirin-sensitive asthma. Monitor patients
with preexisting asthma (without aspirin sensitivity) (5.8)
Serious Skin Reactions: Discontinue INDOCIN at first appearance of skin
rash or other signs of hypersensitivity (5.9)
Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant
women starting at 30 weeks gestation (5.10, 8.1)
Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
any signs or symptoms of anemia (5.11, 7)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 3%) are headache, dizziness,
dyspepsia, and nausea. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Iroko
Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
DRUG INTERACTIONS
Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
Monitor patients for bleeding who are concomitantly taking INDOCIN
with drugs that interfere with hemostasis. Concomitant use of INDOCIN
and analgesic doses of aspirin is not generally recommended (7)
ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers:
Concomitant use with INDOCIN may diminish the antihypertensive effect
of these drugs. Monitor blood pressure (7)
ACE Inhibitors and ARBs: Concomitant use with INDOCIN in elderly,
volume depleted, or those with renal impairment may result in deterioration
of renal function. In such high risk patients, monitor for signs of worsening
renal function (7)
Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide
diuretics. Monitor patients to assure diuretic efficacy including
antihypertensive effects (7)
Digoxin: Concomitant use with INDOCIN can increase serum
concentration and prolong half-life of digoxin. Monitor serum digoxin
levels (7)
USE IN SPECIFIC POPULATIONS
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases
the risk of premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)
Infertility: NSAIDs are associated with reversible infertility. Consider
withdrawal of INDOCIN in women who have difficulties conceiving (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised 5/2016
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Instructions
2.2
Suppository Dosing Instructions
2.3
Moderate to severe rheumatoid arthritis including acute
flares of chronic disease; moderate to severe ankylosing
spondylitis; and moderate to severe osteoarthritis
2.4
Acute painful shoulder (bursitis and/or tendinitis)
2.5
Acute Gouty Arthritis
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Cardiovascular Thrombotic Events
5.2
Gastrointestinal Bleeding, Ulceration, and Perforation
5.3
Hepatotoxicity
5.4
Hypertension
5.5
Heart Failure and Edema
5.6
Renal Toxicity and Hyperkalemia
5.7
Anaphylactic Reactions
5.8
Exacerbation of Asthma Related to Aspirin Sensitivity
5.9
Serious Skin Reactions
5.10
Premature Closure of Fetal Ductus Arteriosus
5.11
Hematologic Toxicity
5.12
Masking of Inflammation and Fever
5.13
Laboratory Monitoring
5.14
Central Nervous System Effects
5.15
Ocular Effects
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.2
Lactation
8.3
Females and Males of Reproductive Potential
8.4
Pediatric Use
8.5
Geriatric Use
10
OVERDOSAGE
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
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing
information are not listed.
Reference ID: 3928090
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: RISK OF SERIOUS CARDIOVASCULAR AND
GASTROINTESTINAL EVENTS
Cardiovascular Thrombotic Events
• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious
cardiovascular thrombotic events, including myocardial infarction and stroke,
which can be fatal. This risk may occur early in treatment and may increase with
duration of use [see Warnings and Precautions (5.1)].
• INDOCIN is contraindicated in the setting of coronary artery bypass graft (CABG)
surgery [see Contraindications (4) and Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which
can be fatal. These events can occur at any time during use and without warning
symptoms. Elderly patients and patients with a prior history of peptic ulcer disease
and/or GI bleeding are at greater risk for serious GI events [see Warnings and
Precautions (5.2)].
1
INDICATIONS AND USAGE
INDOCIN Suppository is indicated for:
Moderate to severe rheumatoid arthritis including acute flares of chronic disease
Moderate to severe ankylosing spondylitis
Moderate to severe osteoarthritis
Acute painful shoulder (bursitis and/or tendinitis)
Acute gouty arthritis
2
DOSAGE AND ADMINISTRATION
2.1
General Dosing Instructions
Carefully consider the potential benefits and risks of INDOCIN and other treatment options
before deciding to use INDOCIN. Use the lowest effective dosage for the shortest duration
consistent with individual patient treatment goals [see Warnings and Precautions (5)].
After observing the response to initial therapy with indomethacin, the dose and frequency
should be adjusted to suit an individual patient’s needs.
Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore,
every effort should be made to determine the lowest effective dosage for the individual
patient.
SUPPOSITORIES: INDOCIN Suppositories are available as 50 mg suppositories for
rectal use only. INDOCIN Suppositories are not for oral or intravaginal use.
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2
Suppository Dosing Instructions
THIS SECTION PREDOMINANTLY MAKES REFERENCE TO INDOMETHACIN
CAPSULE, USP ORAL DOSAGE FOR GUIDANCE IN USING SUPPOSITORIES.
INDOCIN suppositories 50 mg can be substituted for indomethacin capsules, USP;
however, there will be significant differences between the two dosage regimens in
indomethacin blood levels [see Clinical Pharmacology (12.3)].
Oral dosage recommendations for active stages of the following:
2.3 Moderate to severe rheumatoid arthritis including acute flares of
chronic disease; moderate to severe ankylosing spondylitis; and
moderate to severe osteoarthritis
Indomethacin capsules, USP 25 mg twice a day. or three times a day. If this is well tolerated,
increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at
weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 -
200 mg is reached. Doses above this amount generally do not increase the effectiveness of the
drug.
In patients who have persistent night pain and/or morning stiffness, the giving of a large
portion, up to a maximum of 100 mg, of the total daily dose at bedtime, either orally or by
rectal suppositories, may be helpful in affording relief. The total daily dose should not exceed
200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the
dosage by 25 mg or, if required, by 50 mg daily.
If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a
tolerated dose and observe the patient closely.
If severe adverse reactions occur, stop the drug. After the acute phase of the disease is under
control, an attempt to reduce the daily dose should be made repeatedly until the patient is
receiving the smallest effective dose or the drug is discontinued.
Careful instructions to, and observations of, the individual patient are essential to the
prevention of serious, irreversible, including fatal, adverse reactions.
As advancing years appear to increase the possibility of adverse reactions, INDOCIN should
be used with greater care in the elderly. [see Use in Specific Populations (8.5)]
2.4 Acute painful shoulder (bursitis and/or tendinitis)
Indomethacin capsules, USP 75-150 mg daily in 3 or 4 divided doses.
The drug should be discontinued after the signs and symptoms of inflammation have been
controlled for several days. The usual course of therapy is 7-14 days.
2.5 Acute Gouty Arthritis
Indomethacin capsules, USP 50 mg three times a day. Until pain is tolerable. The dose should
then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been
reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and
swelling gradually disappears in 3 to 5 days.
Reference ID: 3928090
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
INDOCIN Suppositories : 50 mg of indomethacin. White and opaque.
4
CONTRAINDICATIONS
INDOCIN is contraindicated in the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to
indomethacin or any components of the drug product [see Warnings and Precautions
(5.7, 5.9)]
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other
NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported
in such patients [see Warnings and Precautions (5.7, 5.8)]
In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and
Precautions (5.1)]
In patients with a history of proctitis or recent rectal bleeding
5
WARNINGS AND PRECAUTIONS
5.1 Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years
duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,
including myocardial infarction (MI) and stroke, which can be fatal. Based on available data,
it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative
increase in serious CV thrombotic events over baseline conferred by NSAID use appears to
be similar in those with and without known CV disease or risk factors for CV disease.
However, patients with known CV disease or risk factors had a higher absolute incidence of
excess serious CV thrombotic events, due to their increased baseline rate. Some observational
studies found that this increased risk of serious CV thrombotic events began as early as the
first weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the
lowest effective dose for the shortest duration possible. Physicians and patients should remain
alert for the development of such events, throughout the entire treatment course, even in the
absence of previous CV symptoms. Patients should be informed about the symptoms of
serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and
an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events
[see Warnings and Precautions (5.2)].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in
the first 10–14 days following CABG surgery found an increased incidence of myocardial
infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see
Contraindications (4)].
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that
patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction,
CV-related death, and all-cause mortality beginning in the first week of treatment. In this
same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in
NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
patients. Although the absolute rate of death declined somewhat after the first year post-MI,
the increased relative risk of death in NSAID users persisted over at least the next four years
of follow-up.
Avoid the use of INDOCIN in patients with a recent MI unless the benefits are expected to
outweigh the risk of recurrent CV thrombotic events. If INDOCIN is used in patients with a
recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach,
small intestine, or large intestine, which can be fatal. These serious adverse events can occur
at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one
in five patients who develop a serious upper GI adverse event on NSAID therapy is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in
approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated
for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had
a greater than 10-fold increased risk for developing a GI bleed compared to patients without
these risk factors. Other factors that increase the risk of GI bleeding in patients treated with
NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids,
aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of
alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI
events occurred in elderly or debilitated patients. Additionally, patients with advanced liver
disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the
increased risk of bleeding. For such patients, as well as those with active GI bleeding,
consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID
therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment,
and discontinue INDOCIN until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor
patients more closely for evidence of GI bleeding [see Drug Interactions (7)].
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.3 Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been
reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare,
sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis,
and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients
treated with NSAIDs including indomethacin.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like"
symptoms). If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue INDOCIN
immediately, and perform a clinical evaluation of the patient.
5.4 Hypertension
NSAIDs, including INDOCIN, can lead to new onset of hypertension or worsening of
preexisting hypertension, either of which may contribute to the increased incidence of CV
events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or
loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug
Interactions (7)].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the
course of therapy.
5.5 Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized
controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart
failure in COX-2 selective-treated patients and nonselective NSAID-treated patients
compared to placebo-treated patients. In a Danish National Registry study of patients with
heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with
NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to
treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor
blockers [ARBs]) [see Drug Interactions (7)].
Avoid the use of INDOCIN in patients with severe heart failure unless the benefits are
expected to outweigh the risk of worsening heart failure. If INDOCIN is used in patients with
severe heart failure, monitor patients for signs of worsening heart failure.
5.6 Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal
injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a
compensatory role in the maintenance of renal perfusion. In these patients, administration of
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
an NSAID may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients
at greatest risk of this reaction are those with impaired renal function, dehydration,
hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or
ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to
the pretreatment state.
No information is available from controlled clinical studies regarding the use of INDOCIN in
patients with advanced renal disease. The renal effects of INDOCIN may hasten the
progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating INDOCIN.
Monitor renal function in patients with renal or hepatic impairment, heart failure,
dehydration, or hypovolemia during use of INDOCIN [see Drug Interactions (7)]. Avoid the
use of INDOCIN in patients with advanced renal disease unless the benefits are expected to
outweigh the risk of worsening renal function. If INDOCIN is used in patients with advanced
renal disease, monitor patients for signs of worsening renal function.
It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a
maintenance schedule of indomethacin resulted in reversible acute renal failure in two of
four healthy volunteers. Indomethacin and triamterene should not be administered together.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with
use of NSAIDs, even in some patients without renal impairment. In patients with normal
renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism
state.
Both indomethacin and potassium-sparing diuretics may be associated with increased serum
potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on
potassium levels and renal function should be considered when these agents are administered
concurrently.
5.7 Anaphylactic Reactions
Indomethacin has been associated with anaphylactic reactions in patients with and without
known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see
Contraindications (4) and Warnings and Precautions (5.8)].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may
include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal
bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity
between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
INDOCIN is contraindicated in patients with this form of aspirin sensitivity [see
Contraindications (4)]. When INDOCIN is used in patients with preexisting asthma (without
known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.9 Serious Skin Reactions
NSAIDs, including indomethacin, can cause serious skin adverse reactions such as
exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis
(TEN), which can be fatal. These serious events may occur without warning. Inform patients
about the signs and symptoms of serious skin reactions, and to discontinue the use of
INDOCIN at the first appearance of skin rash or any other sign of hypersensitivity.
INDOCIN is contraindicated in patients with previous serious skin reactions to NSAIDs [see
Contraindications (4)].
5.10 Premature Closure of Fetal Ductus Arteriosus
Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of
NSAIDs, including INDOCIN, in pregnant women starting at 30 weeks of gestation (third
trimester) [see Use in Specific Populations (8.1)].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood
loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated
with INDOCIN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including INDOCIN, may increase the risk of bleeding events. Co-morbid
conditions, such as coagulation disorders, or concomitant use of warfarin, other
anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and
serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these
patients for signs of bleeding [see Drug Interactions (7)].
5.12 Masking of Inflammation and Fever
The pharmacological activity of INDOCIN in reducing inflammation, and possibly fever,
may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning
symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC
and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].
5.14 Central Nervous System Effects
INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and
parkinsonism, and should be used with considerable caution in patients with these conditions.
Discontinue INDOCIN if severe CNS adverse reactions develop.
INDOCIN may cause drowsiness; therefore, caution patients about engaging in activities
requiring mental alertness and motor coordination, such as driving a car. Indomethacin may
also cause headache. Headache which persists despite dosage reduction requires cessation of
therapy with INDOCIN.
5.15
Ocular Effects
Corneal deposits and retinal disturbances, including those of the macula, have been observed
in some patients who had received prolonged therapy with INDOCIN. Be alert to the
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
possible association between the changes noted and INDOCIN. It is advisable to discontinue
therapy if such changes are observed. Blurred vision may be a significant symptom and
warrants a thorough ophthalmological examination. Since these changes may be
asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients
receiving prolonged therapy. INDOCIN is not indicated for long-term treatment.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
Hepatotoxicity [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Heart Failure and Edema [see Warnings and Precautions (5.5)]
Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
Anaphylactic Reactions [see Warnings and Precautions (5.7)]
Serious Skin Reactions [see Warnings and Precautions (5.9)]
Hematologic Toxicity [see Warnings and Precautions (5.11)]
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.
In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities
was significantly higher in the group receiving INDOCIN Capsules than in the group taking
INDOCIN Suppositories or placebo.
In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis,
however, the incidence of upper gastrointestinal adverse effects with INDOCIN
Suppositories or Capsules was comparable. The incidence of lower gastrointestinal adverse
effects was greater in the suppository group.
The adverse reactions for INDOCIN Capsules listed in the following table have been
arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%.
The incidence for group (1) was obtained from 33 double-blind controlled clinical trials
reported in the literature (1,092 patients). The incidence for group (2) was based on reports in
clinical trials, in the literature, and on voluntary reports since marketing. The probability of a
causal relationship exists between INDOCIN and these adverse reactions, some of which
have been reported only rarely.
The adverse reactions reported with INDOCIN Capsules may occur with use of the
suppositories. In addition, rectal irritation and tenesmus have been reported in patients who
have received the suppositories.
Table 1
Summary of Adverse Reactions for INDOCIN Capsules
Incidence greater than 1%
Incidence less than 1%
GASTROINTESTINAL
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Incidence greater than 1%
Incidence less than 1%
nausea * with or
without vomiting
dyspepsia * (including
indigestion, heartburn and
epigastric pain)
diarrhea
abdominal distress or pain
constipation
anorexia
bloating (includes distension)
flatulence
peptic ulcer
gastroenteritis
rectal bleeding
proctitis
single or multiple ulcerations,
including perforation and hemorrhage
of the esophagus, stomach,
duodenum or small and large
intestines
intestinal ulceration associated with
stenosis and obstruction
gastrointestinal bleeding without
obvious ulcer formation and
perforation of preexisting
sigmoid lesions (diverticulum,
carcinoma, etc.) development
of ulcerative colitis and
regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice
(some fatal cases have been
reported)
intestinal strictures
(diaphragms)
CENTRAL NERVOUS SYSTEM
headache (11.7%)
dizziness *
vertigo
somnolence
depression and fatigue
(including malaise and
listlessness)
anxiety (includes nervousness)
muscle weakness
involuntary muscle movements
insomnia
muzziness
psychic disturbances including
psychotic episodes
mental confusion
drowsiness
light-headedness
syncope
paresthesia
aggravation of epilepsy and
parkinsonism
depersonalization
coma
peripheral neuropathy
convulsion
dysarthria
SPECIAL SENSES
tinnitus
ocular — corneal deposits and retinal
disturbances, including those of
the macula, have been reported in
some patients on prolonged therapy with
INDOCIN
blurred vision
diplopia
hearing disturbances, deafness
CARDIOVASCULAR
None
hypertension
hypotension
tachycardia
chest pain
congestive heart failure
arrhythmia; palpitations
METABOLIC
None
edema
weight gain
fluid retention
flushing or sweating
hyperglycemia
glycosuria
hyperkalemia
INTEGUMENTARY
none
pruritus
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson syndrome
erythema multiforme
toxic epidermal necrolysis
HEMATOLOGIC
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Incidence greater than 1%
Incidence less than 1%
None
leukopenia
bone marrow depression
anemia secondary to obvious or occult
gastrointestinal bleeding
aplastic anemia
hemolytic anemia
agranulocytosis
thrombocytopenic purpura
disseminated intravascular
coagulation
HYPERSENSITIVITY
None
acute anaphylaxis
acute respiratory distress
rapid fall in blood pressure resembling
a shock-like state
angioedema
dyspnea
asthma
purpura
angiitis
pulmonary edema
fever
GENITOURINARY
None
hematuria
vaginal bleeding
proteinuria
nephrotic syndrome
interstitial nephritis
BUN elevation
renal insufficiency, including renal
failure
MISCELLANEOUS
None
epistaxis
breast changes, including enlargement
and tenderness, or gynecomastia
* Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than 3% of the
patients are unmarked.)
Causal relationship unknown: Other reactions have been reported but occurred under
circumstances where a causal relationship could not be established. However, in these rarely
reported events, the possibility cannot be excluded. Therefore, these observations are being
listed to serve as alerting information to physicians:
Cardiovascular: Thrombophlebitis
Hematologic: Although there have been several reports of leukemia, the supporting
information is weak
Genitourinary: Urinary frequency
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with
Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal
anti-inflammatory agents, including indomethacin, sometimes with fatal outcome
7
DRUG INTERACTIONS
See Table 2 for clinically significant drug interactions with indomethacin.
Table 2
Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact:
Indomethacin and anticoagulants such as warfarin have a synergistic effect on
bleeding. The concomitant use of indomethacin and anticoagulants have an increased
risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and
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cohort epidemiological studies showed that concomitant use of drugs that interfere
with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than
an NSAID alone.
Intervention:
Monitor patients with concomitant use of INDOCIN with anticoagulants (e.g.,
warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors
(SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding
[see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic
doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs
alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated
with a significantly increased incidence of GI adverse reactions as compared to use of
the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:
Concomitant use of INDOCIN and analgesic doses of aspirin is not generally
recommended because of the increased risk of bleeding [see Warnings and Precautions
(5.11)].
INDOCIN is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme
(ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including
propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or
have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs
may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Intervention:
During concomitant use of INDOCIN and ACE-inhibitors, ARBs, or beta-blockers,
monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of INDOCIN and ACE-inhibitors or ARBs in patients who
are elderly, volume-depleted, or have impaired renal function, monitor for signs of
worsening renal function [see Warnings and Precautions (5.6)].
When these drugs are administered concomitantly, patients should be adequately
hydrated. Assess renal function at the beginning of the concomitant treatment and
periodically thereafter.
Diuretics
Clinical Impact:
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced
the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some
patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin
synthesis.
It has been reported that the addition of triamterene to a maintenance schedule of
INDOCIN resulted in reversible acute renal failure in two of four healthy volunteers.
INDOCIN and triamterene should not be administered together.
Both INDOCIN and potassium-sparing diuretics may be associated with increased
serum potassium levels. The potential effects of INDOCIN and potassium-sparing
diuretics on potassium levels and renal function should be considered when these agents
are administered concurrently.
Intervention:
Indomethacin and triamterene should not be administered together.
During concomitant use of INDOCIN with diuretics, observe patients for signs of
worsening renal function, in addition to assuring diuretic efficacy including
antihypertensive effects.
Be aware that indomethacin and potassium-sparing diuretics may both be associated
with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
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Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the
serum concentration and prolong the half-life of digoxin.
Intervention: During concomitant use of INDOCIN and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
NSAIDs have produced elevations in plasma lithium levels and reductions in renal
lithium clearance. The mean minimum lithium concentration increased 15%, and the
renal clearance decreased by approximately 20%. This effect has been attributed to
NSAID inhibition of renal prostaglandin synthesis.
Intervention: During concomitant use of INDOCIN and lithium, monitor patients for signs of lithium
toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate
toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of INDOCIN and methotrexate, monitor patients for
methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of INDOCIN and cyclosporine may increase cyclosporine’s
nephrotoxicity.
Intervention: During concomitant use of INDOCIN and cyclosporine, monitor patients for signs of
worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal,
salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see
Warnings and Precautions (5.2)].
Combined use with diflunisal may be particularly hazardous because diflunisal causes
significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)].
In some patients, combined use of indomethacin and diflunisal has been associated with
fatal gastrointestinal hemorrhage.
Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially
diflunisal, is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of INDOCIN and pemetrexed may increase the risk of pemetrexed
associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing
information).
Intervention:
During concomitant use of INDOCIN and pemetrexed, in patients with renal
impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for
myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be
avoided for a period of two days before, the day of, and two days following
administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs
with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs
should interrupt dosing for at least five days before, the day of, and two days following
pemetrexed administration.
Probenecid
Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of
indomethacin are likely to be increased.
Reference ID: 3928090
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During the concomitant use of INDOCIN and probenecid, a lower total daily dosage of
Intervention: indomethacin may produce a satisfactory therapeutic effect. When increases in the dose
of indomethacin are made, they should be made carefully and in small increments.
Effects on Laboratory Tests
INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA
induced by furosemide administration, or salt or volume depletion. These facts should be
considered when evaluating plasma renin activity in hypertensive patients.
False-negative results in the dexamethasone suppression test (DST) in patients being treated
with indomethacin have been reported. Thus, results of the DST should be interpreted with
caution in these patients.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Use of NSAIDs, including INDOCIN, during the third trimester of pregnancy increases the
risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including
INDOCIN, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of INDOCIN in pregnant women.
Data from observational studies regarding potential embryofetal risks of NSAID use in
women in the first or second trimesters of pregnancy are inconclusive. In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure, have a
background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal
reproduction studies retarded fetal ossification was observed with administration of
indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively,
the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant
mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and
fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the
last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1
and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins
have been shown to have an important role in endometrial vascular permeability, blastocyst
implantation, and decidualization. In animal studies, administration of prostaglandin
synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation
loss.
Clinical Considerations
Labor or Delivery
There are no studies on the effects of INDOCIN during labor or delivery. In animal studies,
NSAIDs, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition,
and increase the incidence of stillbirth.
Reference ID: 3928090
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Data
Animal data
Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and
4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and
0.2 times [rats] the MRHD on a mg/m2 basis, respectively) considered secondary to the
decreased average fetal weights, no increase in fetal malformations was observed as
compared with control groups. Other studies in mice reported in the literature using higher
doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m2 basis) have described maternal
toxicity and death, increased fetal resorptions, and fetal malformations. Comparable studies
in rodents using high doses of aspirin have shown similar maternal and fetal effects.
In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1
times the MRHD on a mg/m2 basis) during the last 3 days of gestation was associated with an
increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however
no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control
groups (0.1 times and 0.05 times the MRHD on a mg/m2 basis). Administration of 0.5 or 4.0
mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal
necrosis at either dose level.
8.2 Lactation
Risk Summary
Based on available published clinical data, indomethacin may be present in human milk. The
developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for INDOCIN and any potential adverse effects on the breastfed infant
from the INDOCIN or from the underlying maternal condition.
Data
In one study, levels of indomethacin in breast milk were below the sensitivity of the assay
(<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally
daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average
concentration present in breast milk was estimated to be 0.27% of the maternal weight-
adjusted dose. In another study indomethacin levels were measured in breast milk of eight
postpartum women using doses of 75 mg daily and the results were used to calculate an
estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was
less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This
is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for
treatment of patent ductus arteriosus.
8.3 Females and Males of Reproductive Potential
Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including
INDOCIN, may delay or prevent rupture of ovarian follicles, which has been associated with
reversible infertility in some women. Published animal studies have shown that
administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-
mediated follicular rupture required for ovulation. Small studies in women treated with
NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs,
including INDOCIN, in women who have difficulties conceiving or who are undergoing
investigation of infertility.
Reference ID: 3928090
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8.4 Pediatric Use
Safety and effectiveness in pediatric patients 14 years of age and younger has not been
established.
INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless
toxicity or lack of efficacy associated with other drugs warrants the risk.
In experience with more than 900 pediatric patients reported in the literature or to the
manufacturer who were treated with INDOCIN Capsules, side effects in pediatric patients
were comparable to those reported in adults. Experience in pediatric patients has been
confined to the use of INDOCIN Capsules.
If a decision is made to use indomethacin for pediatric patients two years of age or older,
such patients should be monitored closely and periodic assessment of liver function is
recommended. There have been cases of hepatotoxicity reported in pediatric patients with
juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a
suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage
should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less. Limited data are
available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day,
whichever is less. As symptoms subside, the total daily dosage should be reduced to the
lowest level required to control symptoms, or the drug should be discontinued.
8.5 Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated
serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated
benefit for the elderly patient outweighs these potential risks, start dosing at the low end of
the dosing range, and monitor patients for adverse effects [see Warnings and Precautions
(5.1, 5.2, 5.3, 5.6, 5.13)].
Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.1)];
physicians should remain alert to the possibility of such adverse effects in the elderly.
Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and
the risk of adverse reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function, use
caution in this patient population, and it may be useful to monitor renal function [see Clinical
Pharmacology (12.3)].
10 OVERDOSAGE
Symptoms following acute NSAID overdosages have been typically limited to lethargy,
drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with
supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure,
respiratory depression, and coma have occurred, but were rare [see Warnings and
Precautions (5.1, 5.2, 5.4, 5.6)].
Manage patients with symptomatic and supportive care following an NSAID overdosage.
There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams
in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in
symptomatic patients seen within four hours of ingestion or in patients with a large
Reference ID: 3928090
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overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine,
hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1
800-222-1222).
11 DESCRIPTION
INDOCIN (indomethacin) Suppositories is a nonsteroidal anti-inflammatory drug, available
as a suppository containing 50 mg of indomethacin administered for rectal use. The chemical
name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular
weight is 357.8. Its molecular formula is C19H16ClNO4 , and it has the following chemical
structure. structural formula
Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and
sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic
media and decomposes in strong alkali.
The inactive ingredients in INDOCIN Suppositories include: butylated hydroxyanisole,
butylated hydroxytoluene, edetic acid, glycerin, polyethylene glycol 3350, polyethylene
glycol 8000 and sodium chloride. INDOCIN Suppositories, 50 mg each, are white, opaque,
rectal suppositories.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Indomethacin has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of INDOCIN, like that of other NSAIDs, is not completely
understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin
concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize
afferent nerves and potentiate the action of bradykinin in inducing pain in animal models.
Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of
prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in
peripheral tissues.
Reference ID: 3928090
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12.3 Pharmacokinetics
Absorption
Following single oral doses of INDOCIN Capsules 25 mg or 50 mg, indomethacin is readily
absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at
about 2 hours. Orally administered INDOCIN Capsules are virtually 100% bioavailable, with
90% of the dose absorbed within 4 hours. With a typical therapeutic regimen of 25 or 50 mg
three times a day, the steady-state plasma concentrations of indomethacin are an average
1.4 times those following the first dose.
The rate of absorption is more rapid from the rectal suppository than from INDOCIN
Capsules. Ordinarily, therefore, the total amount absorbed from the suppository would be
expected to be at least equivalent to the capsule. In controlled clinical trials, however, the
amount of indomethacin absorbed was found to be somewhat less (80-90%) than that
absorbed from INDOCIN Capsules. This is probably because some subjects did not retain the
material from the suppository for the one hour necessary to assure complete absorption. Since
the suppository dissolves rather quickly rather than melting slowly, it is seldom recovered in
recognizable form if the patient retains the suppository for more than a few minutes.
Distribution
Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of
therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain
barrier and the placenta, and appears in breast milk.
Elimination
Metabolism
Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and
desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation
of glucuronide conjugates of each metabolite and of indomethacin are formed.
Excretion
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral
dose is recovered in urine as drug and metabolites (26% as indomethacin and its
glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life
of indomethacin is estimated to be about 4.5 hours.
Specific Populations
Pediatric: The pharmacokinetics of INDOCIN has not been investigated in pediatric
patients.
Race: Pharmacokinetic differences due to race have not been identified.
Hepatic Impairment: The pharmacokinetics of INDOCIN has not been investigated in
patients with hepatic impairment.
Renal Impairment: The pharmacokinetics of INDOCIN has not been investigated in
patients with renal impairment [see Warnings and Precautions (5.6)].
Reference ID: 3928090
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Drug Interaction Studies
Aspirin:
In a study in normal volunteers, it was found that chronic concurrent administration of 3.6
g of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug
Interactions (7)].
When NSAIDs were administered with aspirin, the protein binding of NSAIDs were
reduced, although the clearance of free NSAID was not altered. The clinical significance
of this interaction is not known. See Table 2 for clinically significant drug interactions of
NSAIDs with aspirin [see Drug Interactions (7)].
Diflunisal:
In normal volunteers receiving indomethacin, the administration of diflunisal decreased
the renal clearance and significantly increased the plasma levels of indomethacin [see
Drug Interactions (7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.05 times the
MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced
no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat
(dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to
1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m2 basis,
respectively).
Mutagenesis
Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in
vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and
the micronucleus test in mice.
Impairment of Fertility
Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two
generation reproduction study (0.01 times the MRHD on a mg/m2 basis) or a two litter
reproduction study in rats (0.02 times the MRHD on a mg/m2 basis).
14 CLINICAL STUDIES
INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long-
term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
INDOCIN affords relief of symptoms; it does not alter the progressive course of the
underlying disease.
INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain,
and reduction of fever, swelling and tenderness. Improvement in patients treated with
INDOCIN for rheumatoid arthritis has been demonstrated by a reduction in joint swelling,
average number of joints involved, and morning stiffness; by increased mobility as
demonstrated by a decrease in walking time; and by improved functional capability as
demonstrated by an increase in grip strength. INDOCIN may enable the reduction of steroid
Reference ID: 3928090
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For current labeling information, please visit https://www.fda.gov/drugsatfda
dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In
such instances the steroid dosage should be reduced slowly and the patients followed very
closely for any possible adverse effects.
16 HOW SUPPLIED/STORAGE AND HANDLING
INDOCIN (indomethacin) Suppositories, 50 mg each, are white, opaque, rectal
suppositories.
NDC 0006-0150-30, boxes of 30.
Storage
Store below 30°C (86°F). Avoid transient temperatures above 40°C (104°F).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that
accompanies each prescription dispensed. Inform patients, families, or their caregivers of the
following information before initiating therapy with INDOCIN and periodically during the
course of ongoing therapy. INDOCIN Suppositories are for rectal use only. Advise patients
not to use INDOCIN Suppositories orally or intra-vaginally.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including
chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these
symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain,
dyspepsia, melena, and hematemesis to their health care provider. In the setting of
concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased
risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like”
symptoms). If these occur, instruct patients to stop INDOCIN and seek immediate medical
therapy [see Warnings and Precautions (5.3)].
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of
breath, unexplained weight gain, or edema and to contact their healthcare provider if such
symptoms occur [see Warnings and Precautions (5.5)].
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of
the face or throat). Instruct patients to seek immediate emergency help if these occur [see
Contraindications (4) and Warnings and Precautions (5.7)].
Serious Skin Reactions
Advise patients to stop INDOCIN immediately if they develop any type of rash and to
contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)].
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including
INDOCIN, may be associated with a reversible delay in ovulation [see Use in Specific
Populations (8.3)].
Fetal Toxicity
Inform pregnant women to avoid use of INDOCIN and other NSAIDs starting at 30 weeks
gestation because of the risk of the premature closing of the fetal ductus arteriosus [see
Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of INDOCIN with other NSAIDs or salicylates (e.g.,
diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity,
and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug
Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter”
medications for treatment of colds, fever, or insomnia.
Use of NSAIDs and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with INDOCIN until they talk to
their healthcare provider [see Drug Interactions (7)].
Manufactured for and Distributed by:
Iroko Pharmaceuticals, LLC
Philadelphia, PA 19112
Issued: May/2016
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?
NSAIDs can cause serious side effects, including:
Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment
and may increase:
o with increasing doses of NSAIDs
o with longer use of NSAIDs
Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)."
Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may
have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.
Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the
mouth to the stomach), stomach and intestines:
o anytime during use
o without warning symptoms
o that may cause death
The risk of getting an ulcer or bleeding increases with:
o past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs
o taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs”
o increasing doses of NSAIDs
o longer use of NSAIDs
o smoking
o drinking alcohol
o older age
o poor health
o advanced liver disease
o bleeding problems
NSAIDs should only be used:
o exactly as prescribed
o at the lowest dose possible for your treatment
o for the shortest time needed
What are NSAIDs?
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions
such as different types of arthritis, menstrual cramps, and other types of short-term pain.
Who should not take NSAIDs?
Do not take NSAIDs:
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.
right before or after heart bypass surgery.
Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:
have liver or kidney problems
have high blood pressure
have asthma
are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking
NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.
are breastfeeding or plan to breast feed.
Tell your healthcare provider about all of the medicines you take, including prescription or over-the
counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with
each other and cause serious side effects. Do not start taking any new medicine without talking to your
healthcare provider first.
What are the possible side effects of NSAIDs?
NSAIDs can cause serious side effects, including:
See “What is the most important information I should know about medicines called Nonsteroidal Anti-
inflammatory Drugs (NSAIDs)?”
new or worse high blood pressure
heart failure
liver problems including liver failure
kidney problems including kidney failure
low red blood cells (anemia)
Reference ID: 3928090
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
life-threatening skin reactions
life-threatening allergic reactions
Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea,
vomiting, and dizziness.
Get emergency help right away if you get any of the following symptoms:
shortness of breath or trouble breathing
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat
Stop taking your NSAID and call your healthcare provider right away if you get any of the following
symptoms:
nausea
more tired or weaker than usual
diarrhea
itching
your skin or eyes look yellow
indigestion or stomach pain
flu-like symptoms
vomit blood
there is blood in your bowel movement or
it is black and sticky like tar
unusual weight gain
skin rash or blisters with fever
swelling of the arms, legs, hands and
feet
If you take too much of your NSAID, call your healthcare provider or get medical help right away.
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or
pharmacist about NSAIDs.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Other information about NSAIDs
Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in
the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare
provider before using over-the-counter NSAIDs for more than 10 days.
General information about the safe and effective use of NSAIDs
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the
same symptoms that you have. It may harm them.
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist
or healthcare provider for information about NSAIDs that is written for health professionals.
Manufactured for and Distributed by:
Iroko Pharmaceuticals, LLC
One Kew Place 150 Rouse Boulevard
Philadelphia, PA 19112
For more information, go to www.iroko.com or call 1-877-757-0676
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued or Revised:May 2016
Reference ID: 3928090
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/2016/017814s041s042lbl.pdf', 'application_number': 17814, 'submission_type': 'SUPPL ', 'submission_number': 41}
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11,069
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1
HALOG OINTMENT
(Halcinonide Ointment, USP) 0.1%
For Topical Use Only.
Not For Ophthalmic Use.
DESCRIPTION
The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-
inflammatory and antipruritic agents. The steroids in this class include halcinonide.
Halcinonide is designated chemically as 21-Chloro-9-fluoro-11β,16α, 17-trihydroxy-
pregn-4-ene-3,20-dione cyclic 16,17-acetal with acetone. Graphic formula:
C24H32ClFO5, MW 454.96, CAS-3093-35-4
Each gram of 0.1% HALOG OINTMENT (Halcinonide Ointment, USP) contains 1 mg
halcinonide in Plastibase (Plasticized Hydrocarbon Gel), a mineral oil and polyethylene
gel base, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1450,
and polyethylene glycol 6000 distearate with butylated hydroxytoluene as an antioxidant.
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear.
Various laboratory methods, including vasoconstrictor assays, are used to compare and
predict potencies and/or clinical efficacies of the topical corticosteroids. There is some
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
evidence to suggest that a recognizable correlation exists between vasoconstrictor
potency and therapeutic efficacy in man.
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.
Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or
other disease processes in the skin increase percutaneous absorption. Occlusive dressings
substantially increase the percutaneous absorption of topical corticosteroids. Thus,
occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant
dermatoses (see DOSAGE AND ADMINISTRATION).
Once absorbed through the skin, topical corticosteroids are handled through
pharmacokinetic pathways 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.
INDICATIONS AND USAGE
HALOG OINTMENT (Halcinonide Ointment, USP) 0.1% is indicated for the relief of
the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
CONTRAINDICATIONS
Topical corticosteroids are contraindicated in those patients with a history of
hypersensitivity to any of the components of the preparations.
PRECAUTIONS
General
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.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Conditions which augment systemic absorption include the application of the more potent
steroids, use over large surface areas, prolonged use, and the addition of occlusive
dressings.
Therefore, patients receiving a large dose of any potent topical steroid applied to a large
surface area or under an occlusive dressing should be evaluated periodically for evidence
of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests,
and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the
body temperature occurs, an attempt should be made to withdraw the drug, to reduce the
frequency of application, substitute a less potent steroid, or use a sequential approach
when utilizing the occlusive technique.
Recovery of HPA axis function and thermal homeostasis are generally prompt and
complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid
withdrawal may occur, requiring supplemental systemic corticosteroids. Occasionally, a
patient may develop a sensitivity reaction to a particular occlusive dressing material or
adhesive and a substitute material may be necessary.
Children may absorb proportionally larger amounts of topical corticosteroids and thus be
more susceptible to systemic toxicity (see PRECAUTIONS: Pediatric Use).
If irritation develops, topical corticosteroids should be discontinued and appropriate
therapy instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or
antibacterial agent should be instituted. If a favorable response does not occur promptly,
the corticosteroid should be discontinued until the infection has been adequately
controlled.
This preparation is not for ophthalmic use.
Information for the Patient
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 dermatologic use
only. Avoid contact with the eyes.
2) Patients should be advised not to use this medication for any disorder other than for
which it was prescribed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
3) The treated skin area should not be bandaged or otherwise covered or wrapped as to
be occlusive unless directed by the physician.
4) Patients should report any signs of local adverse reactions especially under occlusive
dressing.
5) Parents of pediatric patients should be advised not to use tight-fitting diapers or
plastic pants on a child being treated in the diaper area, as these garments may
constitute occlusive dressings.
Laboratory Tests
A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating HPA
axis suppression.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential
or the effect on fertility of topical corticosteroids.
Studies to determine mutagenicity with prednisolone and hydrocortisone showed
negative results.
Pregnancy
Teratogenic Effects: Category C
Corticosteroids are generally teratogenic in laboratory animals when administered
systemically at relatively low dosage levels. The more potent corticosteroids have been
shown to be teratogenic after dermal application in laboratory animals. There are no
adequate and well-controlled studies in pregnant women on teratogenic effects from
topically applied corticosteroids. Therefore, topical corticosteroids should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus. Drugs of
this class should not be used extensively on pregnant patients, in large amounts, or for
prolonged periods of time.
Nursing Mothers
It is not known whether topical administration of corticosteroids could result in sufficient
systemic absorption to produce detectable quantities in breast milk. Systemically
administered corticosteroids are secreted into breast milk in quantities not likely to have
a deleterious effect on the infant. Nevertheless, caution should be exercised when topical
corticosteroids are 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
5
Pediatric Use
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 area to body weight ratio.
HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been
reported in children receiving topical corticosteroids. Manifestations of adrenal
suppression in children include linear growth retardation, delayed weight gain, low
plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of
intracranial hypertension include bulging fontanelles, headaches, and bilateral
papilledema.
Administration of topical corticosteroids to children should be limited to the least amount
compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may
interfere with the growth and development of children.
Geriatric Use
Clinical studies of 0.1% HALOG OINTMENT did not include sufficient numbers of
patients aged 65 years and over to determine whether they respond differently from
younger patients. 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.
ADVERSE REACTIONS
The following local adverse reactions are reported infrequently with topical
corticosteroids, but may occur more frequently with the use of occlusive dressings
(reactions are listed in an approximate decreasing order of occurrence): burning, itching,
irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation,
perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary
infection, skin atrophy, striae, and miliaria.
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce
systemic effects (see PRECAUTIONS: General).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
DOSAGE AND ADMINISTRATION
Apply a thin film of 0.1% HALOG OINTMENT (Halcinonide Ointment, USP) to the
affected area two to three times daily.
Occlusive Dressing Technique
Occlusive dressings may be used for the management of psoriasis or other recalcitrant
conditions. Apply a thin film of ointment to the lesion, cover with a pliable nonporous
film, and seal the edges. If needed, additional moisture may be provided by covering the
lesion with a dampened clean cotton cloth before the nonporous film is applied or by
briefly wetting the affected area with water immediately prior to applying the medication.
The frequency of changing dressings is best determined on an individual basis. It may be
convenient to apply HALOG OINTMENT under an occlusive dressing in the evening
and to remove the dressing in the morning (i.e., 12-hour occlusion). When utilizing the
12-hour occlusion regimen, additional ointment should be applied, without occlusion,
during the day. Reapplication is essential at each dressing change.
If an infection develops, the use of occlusive dressings should be discontinued and
appropriate antimicrobial therapy instituted.
HOW SUPPLIED
HALOG OINTMENT (Halcinonide Ointment, USP) 0.1% is supplied as tubes
containing 15 g (NDC 0003-0248-15), 30 g (NDC 0003-0248-20), and 60 g (NDC 0003-
0248-30); and jars containing 240 g (NDC 0003-0248-40) of ointment.
Storage
Store at room temperature; avoid excessive heat (104º F).
Westwood-Squibb Pharmaceuticals, Inc.
A Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
J4105D
1077520A2
Revised April 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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2025-02-12T13:44:22.062959
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17824s024lbl.pdf', 'application_number': 17824, 'submission_type': 'SUPPL ', 'submission_number': 24}
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11,070
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LODOSYN
®
(CARBIDOPA)
TABLETS
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are being
treated with levodopa, the two drugs should be given at the same time, starting with no
more than 20 to 25% of the previous daily dosage of levodopa when given without
LODOSYN (Carbidopa). At least twelve hours should elapse between the last dose of
levodopa and initiation of therapy with LODOSYN (Carbidopa) and levodopa. See the
WARNINGS and DOSAGE AND ADMINISTRATION sections before initiating
therapy.
DESCRIPTION
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline
compound, slightly soluble in water, with a molecular weight of 244.3. It is designated
chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid
monohydrate. Its empirical formula is C10H14N2O4•H2O and its structural formula is: structural formula
LODOSYN (Carbidopa) tablets contain 25 mg of carbidopa. Inactive ingredients are
cellulose,FD&C Yellow 6, magnesium stearate and starch.
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular
weight of 226.3.
CLINICAL PHARMACOLOGY
Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal
nervous system affecting the mobility and control of the skeletal muscular system. Its
characteristic features include resting tremor, rigidity, and bradykinetic movements.
Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.
Reference ID: 3458203
Mechanism of Action
Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of
dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment
of Parkinson’s disease apparently because it does not cross the blood-brain barrier.
However, levodopa, the metabolic precursor of dopamine, does cross the blood- brain barrier,
and presumably is converted to dopamine in the brain. This is thought to be the mechanism
whereby levodopa relieves symptoms of Parkinson’s disease.
Pharmacodynamics
When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral
tissues so that only a small portion of a given dose is transported unchanged to the central
nervous system. For this reason, large doses of levodopa are required for adequate
therapeutic effect and these may often be accompanied by nausea and other adverse
reactions, some of which are attributable to dopamine formed in extracerebral tissues.
The incidence of levodopa-induced nausea and vomiting is less when LODOSYN is used with
levodopa than when levodopa is used without LODOSYN. In many patients, this reduction
in nausea and vomiting will permit more rapid dosage titration.
Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been
demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does
not appear to cross the blood-brain barrier readily and does not affect the metabolism of
levodopa within the central nervous system at doses of carbidopa that are recommended for
maximum effective inhibition of peripheral decarboxylation of levodopa.
Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues,
administration of carbidopa with levodopa makes more levodopa available for transport to the
brain. However, since levodopa and carbidopa compete with certain amino acids for transport
across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients
on a high protein diet.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75%
and, when administered with levodopa, increases both plasma levels and the plasma half-life of
levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
In clinical pharmacologic studies, simultaneous administration of separate tablets of
Reference ID: 3458203
carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the
excretion of dopamine when compared to the two drugs administered at separate times.
Supplemental pyridoxine (vitamin B6) can be given to patients when they are receiving
LODOSYN and levodopa concomitantly or the fixed combination carbidopa-levodopa or
carbidopa-levodopa extended release. Previous reports in the medical literature cautioned that
high doses of vitamin B6 should not be taken by patients on levodopa therapy
alone because exogenously administered pyridoxine would enhance the metabolism of levodopa
to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral
decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of
pyridoxine.
Carbidopa is combined with levodopa in carbidopa-levodopa and carbidopa-levodopa
extended release tablets.
INDICATIONS AND USAGE
LODOSYN is indicated for use with carbidopa-levodopa or with levodopa in the treatment of
the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic
parkinsonism, and symptomatic parkinsonism, which may follow injury to the nervous system
by carbon monoxide intoxication and/or manganese intoxication.
LODOSYN is for use with carbidopa-levodopa in patients for whom the dosage of
carbidopa-levodopa provides less than adequate daily dosage (usually 70 mg daily) of
carbidopa.
LODOSYN is for use with levodopa in the occasional patient whose dosage requirement of
carbidopa and levodopa necessitates separate titration of each medication.
LODOSYN is used with carbidopa-levodopa or with levodopa to permit the administration
of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration,
and with a somewhat smoother response. However, patients with markedly irregular (“on-off”)
responses to levodopa have not been shown to benefit from the addition of carbidopa.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, supplemental
pyridoxine (vitamin B6), can be given to patients when they are receiving carbidopa and
levodopa concomitantly or as carbidopa-levodopa.
Although the administration of LODOSYN permits control of parkinsonism and Parkinson’s
disease with much lower doses of levodopa, there is no conclusive evidence at present that
Reference ID: 3458203
this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration,
and providing a somewhat smoother response to levodopa.
Certain patients who responded poorly to levodopa alone have improved when carbidopa and
levodopa were given concurrently. This was most likely due to decreased peripheral
decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral
nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.
In deciding whether to give LODOSYN with carbidopa-levodopa or with levodopa to
patients who have nausea and/or vomiting, the physician should be aware that, while many
patients may be expected to improve, some may not. Since one cannot predict which patients
are likely to improve, this can only be determined by a trial of therapy. It should be further
noted that in controlled trials comparing carbidopa and levodopa with levodopa alone, about
half the patients with nausea and/or vomiting on levodopa alone improved spontaneously
despite being retained on the same dose of levodopa during the controlled portion of the
trial.
CONTRAINDICATIONS
LODOSYN is contraindicated in patients with known hypersensitivity to any component of this
drug.
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with
levodopa or carbidopa-levodopa combination products with or without LODOSYN. These
inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa.
Carbidopa-levodopa or levodopa may be administered concomitantly with the manufacturer’s
recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline
HCl) (see PRECAUTIONS, Drug Interactions).
Levodopa or carbidopa-levodopa products, with or without LODOSYN, are contra- indicated in
patients with narrow-angle glaucoma.
WARNINGS
LODOSYN (Carbidopa) has no antiparkinsonian effect when given alone. It is indicated
for use with carbidopa-levodopa or levodopa. LODOSYN (Carbidopa) does not decrease
adverse reactions due to central effects of levodopa.
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are
being treated with levodopa alone, the two drugs should be given at the same time.
Reference ID: 3458203
At least twelve hours should elapse between the last dose of levodopa and initiation of
therapy with LODOSYN (Carbidopa) and levodopa in combination. Start with no more
than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when
given without LODOSYN (Carbidopa). See the DOSAGE AND ADMINISTRATION
section before initiating therapy.
The addition of LODOSYN with levodopa or carbidopa-levodopa reduces the peripheral
effects (nausea, vomiting) due to decarboxylation of levodopa; however, LODOSYN does
not decrease the adverse reactions due to the central effects of levodopa. Because
LODOSYN permits more levodopa to reach the brain and more dopamine to be formed,
certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary
movements), may occur at lower dosages and sooner with levodopa in combination with
LODOSYN than with levodopa alone.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have
reported suddenly falling asleep without prior warning of sleepiness while engaged in activities
of daily living (includes operation of motor vehicles). Some of these episodes resulted in
automobile accidents. Although many of these patients reported somnolence while on
dopaminergic medications, some did perceive that they had no warning signs, such as excessive
drowsiness, and believed that they were alert immediately prior to the event. Some patients
reported these events one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing
pre-existing somnolence, although some patients may not give such a history. For this reason,
prescribers should continually reassess patients for drowsiness or sleepiness especially since
some of the events occur after the start of treatment. Prescribers should be aware that patients
may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or
sleepiness during specific activities. Patients who have already experienced somnolence or an
episode of sudden sleep onset should not participate in these activities during treatment with
LODOSYN when taking it with other carbidopa-levodopa products.
Reference ID: 3458203
Before initiating treatment with LODOSYN, advise patients about the potential to develop
drowsiness and ask specifically about factors that may increase the risk for somnolence with
LODOSYN such as the use of concomitant sedating medications and the presence of sleep
disorders. Consider discontinuing LODOSYN in patients who report significant daytime
sleepiness or episodes of falling asleep during activities that require active participation (e.g.,
conversations, eating, etc.). If treatment with LODOSYN continues, patients should be advised
not to drive and to avoid other potentially dangerous activities that might result in harm if the
patients become somnolent. There is insufficient information to establish that dose reduction
will eliminate episodes of falling asleep while engaged in activities of daily living.
Hyperpyrexia and Confusion:
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have
been reported in association with dose reductions or withdrawal of certain antiparkinsonian
agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release.
Therefore, patients should be observed carefully when the dosage of levodopa or carbidopa
levodopa is reduced abruptly or discontinued, especially if the patient is receiving
neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered
consciousness, mental status changes; other disturbances, such as autonomic dysfunction,
tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as
creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum
myoglobin, have been reported.
The early diagnosis of this condition is important for the appropriate management of these
patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses
(e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the
clinical presentation includes both serious medical illness and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
Reference ID: 3458203
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical
monitoring and 2) treatment of any concomitant serious medical problems for which specific
treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants,
such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has
not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and
renal function are recommended during extended concomitant therapy with LODOSYN and
levodopa, or with LODOSYN and carbidopa-levodopa or any combination of these drugs.
Impulse Control/Compulsive Behaviors
Postmarketing reports suggest that patients treated with anti-Parkinson medications can
experience intense urges to gamble, increased sexual urges, intense urges to spend money
uncontrollably, binge eating, and other intense urges. Patients may be unable to control these
urges while taking one or more of the medications that are used for the treatment of Parkinson’s
disease and that increase central dopaminergic tone, including Lodosyn taken with levodopa and
carbidopa. In some cases, although not all, these urges were reported to have stopped when the
dose of anti-Parkinson medications was reduced or discontinued. Because patients may not
recognize these behaviors as abnormal it is important for prescribers to specifically ask patients
or their caregivers about the development of new or increased gambling urges, sexual urges,
uncontrolled spending or other urges while being treated with Lodosyn. Physicians should
consider dose reduction or stopping Lodosyn or levodopa if a patient develops such urges while
taking Lodosyn with carbidopa/levodopa.
Hallucinations/Psychotic-Like Behavior
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Hallucinations and psychotic like behavior have been reported with dopaminergic medications.
In general, hallucinations present shortly after the initiation of therapy and may be responsive to
dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser
extent sleep disorder (insomnia) and excessive dreaming. LODOSYN when taken with
carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking
and behavior may present with one or more symptoms, including paranoid ideation, delusions,
hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation,
and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with LODOSYN and
carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain
medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and
may decrease the effectiveness of LODOSYN.
Dyskinesia
LODOSYN (Carbidopa) may potentiate the dopaminergic side effects of levodopa and may
cause or exacerbate preexisting dyskinesia.
Depression
Patients treated with LODOSYN and carbidopa-levodopa should be observed carefully for the
development of depression with concomitant suicidal tendencies.
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2
to approximately 6-fold higher) of developing melanoma than the general population. Whether
the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used
to treat Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas
frequently and on a regular basis when using LODOSYN tablets for Parkinson’s disease.
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Ideally, periodic skin examinations should be performed by appropriately qualified individuals
(e.g., dermatologists).
Information for Patients
It is important that LODOSYN with levodopa be taken at regular intervals according to the
schedule outlined by the health care provider. Caution patients not to change the prescribed
dosage regimen and not to add any additional antiparkinson medications, including other
carbidopa-levodopa preparations without first consulting a physician.
Advise patients that sometimes a ‘wearing-off’ effect may occur at the end of the dosing interval.
Tell patients to notify the prescriber if such response poses a problem to lifestyle.
Patients should be advised that occasionally dark color (red, brown, or black) may appear in
saliva, urine, or sweat after ingestion of LODOSYN and levodopa. Although the color appears to
be clinically insignificant, garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity
also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in
multivitamin tablets) may also reduce the amount of levodopa available in the body. The above
factors may reduce the clinical effectiveness of the LODOSYN and levodopa therapy.
Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases
without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Advise patients to exercise caution while driving or operating machinery and that if
they have experience somnolence and/or sudden sleep onset, they must refrain from these
activities. (See WARNINGS, Falling Asleep During Activities of Daily Living and Somnolence
General.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment
Reference ID: 3458203
of Parkinson’s disease, including LODOSYN and levodopa. Although it is not proven that the
medications caused these events, these urges were reported to have stopped in some cases when
the dose was reduced or the medication was stopped. Prescribers should ask patients about the
development of new or increased gambling urges, sexual urges, or other intense urges while
taking LODOSYN and levodopa. Physicians should consider dose reduction or stopping
Lodosyn and levodopa if a patient develops such urges while taking Lodosyn with
carbidopa/levodopa (See PRECAUTIONS, Impulse Control/Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as
alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin.
Abnormalities in blood urea nitrogen and positive Coombs test have also been reported.
Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during
concomitant administration of carbidopa and levodopa than with levodopa alone.
Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for
urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will
not be altered by boiling the urine specimen. False-negative tests may result with the use of
glucose-oxidase methods of testing for glucosuria.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with
LODOSYN (Carbidopa) given with levodopa or carbidopa-levodopa fixed dose combination
products.
Symptomatic postural hypotension has occurred when LODOSYN, given with levodopa or
carbidopa-levodopa combination products, was added to the treatment of a patient
receiving antihypertensive drugs. Therefore, when therapy with LODOSYN, given with or
without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of
the antihypertensive drug may be required.
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For patients receiving monoamine oxidase inhibitors (Type A or B), see
CONTRAINDICATIONS. Concomitant therapy with selegiline or rasigiline and
LODOSYN and carbidopa-levodopa may be associated with severe orthostatic hypotension
not attributable to carbidopa-levodopa alone (see CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia,
resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa
preparations.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and
isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of
levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and
papaverine. Patients taking these drugs with LODOSYN and levodopa or carbidopa-levodopa
combination products should be carefully observed for loss of therapeutic response
LODOSYN and iron salts or multi vitamins containing iron salts should be co administered
with caution. Iron salts c a n f or m c he l a t e s w i t h l e vod opa a nd c a r bi dopa a nd
c ons e que nt l y reduce the bioavailability of carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing
gastric emptying, metoclopramide may also adversely affect disease control by its
dopamine receptor antagonistic properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There were no significant differences between treated and control rats with respect to
mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135
mg/kg/day. Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were
given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia
was seen when compared to concurrent controls.
Mutagenesis
Mutagenicity studies have not been performed with either carbidopa or the combination of
carbidopa and levodopa.
Fertility
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Carbidopa had no effect on the mating performance, fertility, or survival of the young when
administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a
moderate decrease in body weight gain in males.
The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100
mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive
performance, or the growth and survival of the young.
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies with LODOSYN
in pregnant women. It has been reported from individual cases that levodopa crosses the
human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in
fetal tissue appeared to be minimal. LODOSYN should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the
mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral
anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum
recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by
the concomitant administration of carbidopa.
Nursing Mothers
It is not known whether carbidopa is excreted in human milk. Because many drugs are
excreted in human milk, and because of their potential for serious adverse reactions 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 nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established, and use of the drug
in patients below the age of 18 is not recommended.
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Geriatric Use
Clinical studies of LODOSYN did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other 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
concomitant disease and other drug therapy.
ADVERSE REACTIONS
Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the
recommended doses. The only adverse reactions that have been observed have been with
concomitant use of carbidopa with other drugs such as levodopa, and with carbidopa
levodopa combination products.
When LODOSYN is administered concomitantly with levodopa or carbidopa-levodopa
combination products, the most common adverse reactions have included dyskinesias such
as choreiform, dystonic, and other involuntary movements, and nausea. Other adverse reactions
reported with LODOSYN when administered concomitantly with levodopa alone or
carbidopa-levodopa combination products were psychotic episodes including delusions,
hallucinations, and paranoid ideation, depression with or without development of suicidal
tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with
concomitant use of LODOSYN and levodopa has not been established.
The following other adverse reactions have been reported with levodopa and carbidopa
levodopa combination products. These same adverse reactions may also occur when
LODOSYN is administered with these products.
Body as a Whole: abdominal pain and distress, asthenia, chest pain, fatigue.
Cardiovascular: cardiac irregularities, hypertension, myocardial infarction, hypotension
including orthostatic hypotension, palpitation, phlebitis, syncope.
Gastrointestinal: anorexia, bruxism, burning sensation of the tongue, constipation, dark
saliva, development of duodenal ulcer, diarrhea, dry mouth, dyspepsia, dysphagia,
flatulence, gastrointestinal bleeding, gastrointestinal pain, heartburn, hiccups, sialorrhea, taste
alterations, vomiting.
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Hematologic: hemolytic and non-hemolytic anemia, leukopenia, thrombocytopenia,
agranulocytosis.
Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions
(including pemphigus-like reactions).
Metabolic: edema, weight gain, weight loss.
Musculoskeletal: back pain, leg pain, muscle cramps, shoulder pain.
Nervous System/Psychiatric: Psychotic episodes including delusions, hallucinations and
paranoid ideation, neuroleptic malignant syndrome (NMS, see WARNINGS), bradykinetic
episodes (“on-off” phenomenon), confusion, agitation, dizziness, somnolence, dream
abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without
development of suicidal tendencies, dementia, pathological gambling, increased libido including
hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal
relationship with LODOSYN and levodopa, has not been established.
Respiratory: upper respiratory infection, dyspnea, pharyngeal pain, cough.
Skin: flushing, increased sweating, malignant melanoma (see also CONTRAINDICATIONS),
rash, alopecia, dark sweat.
Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital: dark urine, priapism, urinary frequency, urinary incontinence, urinary retention,
urinary tract infection.
Laboratory Tests: abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic
dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs test; elevated serum glucose;
decreased hemoglobin and hematocrit; decreased white blood cell count and serum
potassium; increased serum creatinine and uric acid; white blood cells, bacteria and blood in
the urine; protein and glucose in the urine.
Miscellaneous: bizarre breathing patterns, faintness, hoarseness, hot flashes, malaise,
neuroleptic malignant syndrome, sense of stimulation.
OVERDOSAGE
No reports of overdose with LODOSYN have been received. Management of overdosage with
carbidopa is the same as that with levodopa or carbidopa-levodopa preparations.
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In the event of overdosage, general supportive measures should be employed, along with
immediate gastric lavage. Intravenous fluids should be administered judiciously, and an
adequate airway maintained. Electrocardiographic monitoring should be instituted and the
patient carefully observed for the development of arrhythmias; if required, appropriate
antiarrhythmic therapy should be given. The possibility that the patient may have taken other
drugs as well as LODOSYN should be taken into consideration. To date, no experience has
been reported with dialysis; hence, its value in overdosage is not known. Pyridoxine is not
effective in reversing the actions of LODOSYN.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a
significant proportion of rats and mice given single oral doses of levodopa of approximately
1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are
expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die
after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with
levodopa increases the dose at which a significant proportion of mice are expected to die to
3360 mg/kg.
DOSAGE AND ADMINISTRATION
Whether given with carbidopa-levodopa or with levodopa, the optimal daily dose of
LODOSYN must be determined by careful titration. Most patients respond to a 1:10
proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or
more a day. The maximum daily dosage of carbidopa should not exceed 200 mg, since
clinical experience with larger dosages is limited. If the patient is taking carbidopa-levodopa,
the amount of carbidopa in carbidopa-levodopa should be considered when calculating the
total amount of LODOSYN to be administered each day.
Patients Receiving Carbidopa-Levodopa Who
Require Additional Carbidopa
Some patients taking carbidopa-levodopa may not have adequate reduction in nausea and
vomiting when the dosage of carbidopa is less than 70 mg a day, and the dosage of levodopa
is less than 700 mg a day. When these patients are taking carbidopa-levodopa, 25 mg of
LODOSYN may be given with the first dose of carbidopa-levodopa each day. Additional
doses of 12.5 mg or 25 mg may be given during the day with each dose of carbidopa
levodopa. LODOSYN may be given with any dose carbidopa-levodopa as required for
optimum therapeutic response. The maximum daily dosage of carbidopa, given as LODOSYN
and as carbidopa- levodopa), should not exceed 200 mg.
Patients Requiring Individual Titration of Carbidopa and
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Levodopa Dosage
Although carbidopa-levodopa is the most frequently used of carbidopa and levodopa
administration, there may be an occasional patient who requires individually titrated doses of
these two drugs. In these patients, LODOSYN (carbidopa) should be initiated at a dosage
of 25 mg three or four times a day. The two drugs should be given at the same time,
starting with no more than one-fifth (20%) to one-fourth (25%) of the previous or
recommended daily dosage of levodopa when given without LODOSYN (Carbidopa). In
patients already receiving levodopa therapy, at least twelve hours should elapse between
the last dose of levodopa and initiation of therapy with LODOSYN (Carbidopa) and
levodopa. A convenient way to initiate therapy in these patients is in the morning
following a night when the patient has not taken levodopa for at least twelve hours.
Health care providers who prescribe separate doses of LODOSYN and levodopa should be
thoroughly familiar with the directions for use of each drug.
Dosage Adjustment
Dosage of LODOSYN may be adjusted by adding or omitting one-half or one tablet a day.
Because both therapeutic and adverse responses occur more rapidly with combined therapy
than when only levodopa is given, patients should be monitored closely during the dose
adjustment period. Specifically, involuntary movements will occur more rapidly when
LODOSYN and levodopa are given concomitantly than when levodopa is given without
LODOSYN. The occurrence of involuntary movements may require dosage reduction.
Blepharospasm may be a useful early sign of excess dosage in some patients.
Current evidence indicates other standard antiparkinsonian drugs may be continued while
carbidopa and levodopa are being administered. However, the dosage of such other
standard antiparkinsonian drugs may require adjustment.
Interruption of Therapy
Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and
withdrawal of carbidopa-Levodopa) or carbidopa-levodopa Extended Release. Patients should
be observed carefully if abrupt reduction or discontinuation of carbidopa-levodopa or
carbidopa-levodopa Extended-Release is required, especially if the patient is receiving
neuroleptics. (See WARNINGS.)
If general anesthesia is required, therapy may be continued as long as the patient is
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permitted to take fluids and medication by mouth. When therapy is interrupted temporarily,
the patient should be observed for symptoms resembling NMS, and the usual daily dosage
may be resumed as soon as the patient is able to take medication orally.
HOW SUPPLIED
Tablets LODOSYN, 25 mg, are orange, round, compressed tablets that are scored and coded
711 on one side and LODOSYN on the other.
They are supplied as follows:
NDC 0056-0511-68 bottles of 100.
Storage
Store at 25°C (77°F), excursions permitted to 15–30°C (59–86°F).
Manufactured in Canada by:
Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7
Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA
Rev. 2/2014
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11,071
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LODOSYN
®
(CARBIDOPA)
TABLETS
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are being
treated with levodopa, the two drugs should be given at the same time, starting with no
more than 20 to 25% of the previous daily dosage of levodopa when given without
LODOSYN (Carbidopa). At least twelve hours should elapse between the last dose of
levodopa and initiation of therapy with LODOSYN (Carbidopa) and levodopa. See the
WARNINGS and DOSAGE AND ADMINISTRATION sections before initiating
therapy.
DESCRIPTION
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline
compound, slightly soluble in water, with a molecular weight of 244.3. It is designated
chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid
monohydrate. Its empirical formula is C10H14N2O4•H2O and its structural formula is: structural formula
LODOSYN (Carbidopa) tablets contain 25 mg of carbidopa. Inactive ingredients are
cellulose,FD&C Yellow 6, magnesium stearate and starch.
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular
weight of 226.3.
CLINICAL PHARMACOLOGY
Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal
nervous system affecting the mobility and control of the skeletal muscular system. Its
characteristic features include resting tremor, rigidity, and bradykinetic movements.
Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.
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Mechanism of Action
Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of
dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment
of Parkinson’s disease apparently because it does not cross the blood-brain barrier.
However, levodopa, the metabolic precursor of dopamine, does cross the blood- brain barrier,
and presumably is converted to dopamine in the brain. This is thought to be the mechanism
whereby levodopa relieves symptoms of Parkinson’s disease.
Pharmacodynamics
When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral
tissues so that only a small portion of a given dose is transported unchanged to the central
nervous system. For this reason, large doses of levodopa are required for adequate
therapeutic effect and these may often be accompanied by nausea and other adverse
reactions, some of which are attributable to dopamine formed in extracerebral tissues.
The incidence of levodopa-induced nausea and vomiting is less when LODOSYN is used with
levodopa than when levodopa is used without LODOSYN. In many patients, this reduction
in nausea and vomiting will permit more rapid dosage titration.
Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been
demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does
not appear to cross the blood-brain barrier readily and does not affect the metabolism of
levodopa within the central nervous system at doses of carbidopa that are recommended for
maximum effective inhibition of peripheral decarboxylation of levodopa.
Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues,
administration of carbidopa with levodopa makes more levodopa available for transport to the
brain. However, since levodopa and carbidopa compete with certain amino acids for transport
across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients
on a high protein diet.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75%
and, when administered with levodopa, increases both plasma levels and the plasma half-life of
levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
In clinical pharmacologic studies, simultaneous administration of separate tablets of
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carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the
excretion of dopamine when compared to the two drugs administered at separate times.
Supplemental pyridoxine (vitamin B6) can be given to patients when they are receiving
LODOSYN and levodopa concomitantly or the fixed combination carbidopa-levodopa or
carbidopa-levodopa extended release. Previous reports in the medical literature cautioned that
high doses of vitamin B6 should not be taken by patients on levodopa therapy
alone because exogenously administered pyridoxine would enhance the metabolism of levodopa
to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral
decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of
pyridoxine.
Carbidopa is combined with levodopa in carbidopa-levodopa and carbidopa-levodopa
extended release tablets.
INDICATIONS AND USAGE
LODOSYN is indicated for use with carbidopa-levodopa or with levodopa in the treatment of
the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic
parkinsonism, and symptomatic parkinsonism, which may follow injury to the nervous system
by carbon monoxide intoxication and/or manganese intoxication.
LODOSYN is for use with carbidopa-levodopa in patients for whom the dosage of
carbidopa-levodopa provides less than adequate daily dosage (usually 70 mg daily) of
carbidopa.
LODOSYN is for use with levodopa in the occasional patient whose dosage requirement of
carbidopa and levodopa necessitates separate titration of each medication.
LODOSYN is used with carbidopa-levodopa or with levodopa to permit the administration
of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration,
and with a somewhat smoother response. However, patients with markedly irregular (“on-off”)
responses to levodopa have not been shown to benefit from the addition of carbidopa.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, supplemental
pyridoxine (vitamin B6), can be given to patients when they are receiving carbidopa and
levodopa concomitantly or as carbidopa-levodopa.
Although the administration of LODOSYN permits control of parkinsonism and Parkinson’s
disease with much lower doses of levodopa, there is no conclusive evidence at present that
Reference ID: 3458203
this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration,
and providing a somewhat smoother response to levodopa.
Certain patients who responded poorly to levodopa alone have improved when carbidopa and
levodopa were given concurrently. This was most likely due to decreased peripheral
decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral
nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.
In deciding whether to give LODOSYN with carbidopa-levodopa or with levodopa to
patients who have nausea and/or vomiting, the physician should be aware that, while many
patients may be expected to improve, some may not. Since one cannot predict which patients
are likely to improve, this can only be determined by a trial of therapy. It should be further
noted that in controlled trials comparing carbidopa and levodopa with levodopa alone, about
half the patients with nausea and/or vomiting on levodopa alone improved spontaneously
despite being retained on the same dose of levodopa during the controlled portion of the
trial.
CONTRAINDICATIONS
LODOSYN is contraindicated in patients with known hypersensitivity to any component of this
drug.
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with
levodopa or carbidopa-levodopa combination products with or without LODOSYN. These
inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa.
Carbidopa-levodopa or levodopa may be administered concomitantly with the manufacturer’s
recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline
HCl) (see PRECAUTIONS, Drug Interactions).
Levodopa or carbidopa-levodopa products, with or without LODOSYN, are contra- indicated in
patients with narrow-angle glaucoma.
WARNINGS
LODOSYN (Carbidopa) has no antiparkinsonian effect when given alone. It is indicated
for use with carbidopa-levodopa or levodopa. LODOSYN (Carbidopa) does not decrease
adverse reactions due to central effects of levodopa.
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are
being treated with levodopa alone, the two drugs should be given at the same time.
Reference ID: 3458203
At least twelve hours should elapse between the last dose of levodopa and initiation of
therapy with LODOSYN (Carbidopa) and levodopa in combination. Start with no more
than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when
given without LODOSYN (Carbidopa). See the DOSAGE AND ADMINISTRATION
section before initiating therapy.
The addition of LODOSYN with levodopa or carbidopa-levodopa reduces the peripheral
effects (nausea, vomiting) due to decarboxylation of levodopa; however, LODOSYN does
not decrease the adverse reactions due to the central effects of levodopa. Because
LODOSYN permits more levodopa to reach the brain and more dopamine to be formed,
certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary
movements), may occur at lower dosages and sooner with levodopa in combination with
LODOSYN than with levodopa alone.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have
reported suddenly falling asleep without prior warning of sleepiness while engaged in activities
of daily living (includes operation of motor vehicles). Some of these episodes resulted in
automobile accidents. Although many of these patients reported somnolence while on
dopaminergic medications, some did perceive that they had no warning signs, such as excessive
drowsiness, and believed that they were alert immediately prior to the event. Some patients
reported these events one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing
pre-existing somnolence, although some patients may not give such a history. For this reason,
prescribers should continually reassess patients for drowsiness or sleepiness especially since
some of the events occur after the start of treatment. Prescribers should be aware that patients
may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or
sleepiness during specific activities. Patients who have already experienced somnolence or an
episode of sudden sleep onset should not participate in these activities during treatment with
LODOSYN when taking it with other carbidopa-levodopa products.
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Before initiating treatment with LODOSYN, advise patients about the potential to develop
drowsiness and ask specifically about factors that may increase the risk for somnolence with
LODOSYN such as the use of concomitant sedating medications and the presence of sleep
disorders. Consider discontinuing LODOSYN in patients who report significant daytime
sleepiness or episodes of falling asleep during activities that require active participation (e.g.,
conversations, eating, etc.). If treatment with LODOSYN continues, patients should be advised
not to drive and to avoid other potentially dangerous activities that might result in harm if the
patients become somnolent. There is insufficient information to establish that dose reduction
will eliminate episodes of falling asleep while engaged in activities of daily living.
Hyperpyrexia and Confusion:
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have
been reported in association with dose reductions or withdrawal of certain antiparkinsonian
agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release.
Therefore, patients should be observed carefully when the dosage of levodopa or carbidopa
levodopa is reduced abruptly or discontinued, especially if the patient is receiving
neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered
consciousness, mental status changes; other disturbances, such as autonomic dysfunction,
tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as
creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum
myoglobin, have been reported.
The early diagnosis of this condition is important for the appropriate management of these
patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses
(e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the
clinical presentation includes both serious medical illness and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
Reference ID: 3458203
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical
monitoring and 2) treatment of any concomitant serious medical problems for which specific
treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants,
such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has
not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and
renal function are recommended during extended concomitant therapy with LODOSYN and
levodopa, or with LODOSYN and carbidopa-levodopa or any combination of these drugs.
Impulse Control/Compulsive Behaviors
Postmarketing reports suggest that patients treated with anti-Parkinson medications can
experience intense urges to gamble, increased sexual urges, intense urges to spend money
uncontrollably, binge eating, and other intense urges. Patients may be unable to control these
urges while taking one or more of the medications that are used for the treatment of Parkinson’s
disease and that increase central dopaminergic tone, including Lodosyn taken with levodopa and
carbidopa. In some cases, although not all, these urges were reported to have stopped when the
dose of anti-Parkinson medications was reduced or discontinued. Because patients may not
recognize these behaviors as abnormal it is important for prescribers to specifically ask patients
or their caregivers about the development of new or increased gambling urges, sexual urges,
uncontrolled spending or other urges while being treated with Lodosyn. Physicians should
consider dose reduction or stopping Lodosyn or levodopa if a patient develops such urges while
taking Lodosyn with carbidopa/levodopa.
Hallucinations/Psychotic-Like Behavior
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Hallucinations and psychotic like behavior have been reported with dopaminergic medications.
In general, hallucinations present shortly after the initiation of therapy and may be responsive to
dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser
extent sleep disorder (insomnia) and excessive dreaming. LODOSYN when taken with
carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking
and behavior may present with one or more symptoms, including paranoid ideation, delusions,
hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation,
and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with LODOSYN and
carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain
medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and
may decrease the effectiveness of LODOSYN.
Dyskinesia
LODOSYN (Carbidopa) may potentiate the dopaminergic side effects of levodopa and may
cause or exacerbate preexisting dyskinesia.
Depression
Patients treated with LODOSYN and carbidopa-levodopa should be observed carefully for the
development of depression with concomitant suicidal tendencies.
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2
to approximately 6-fold higher) of developing melanoma than the general population. Whether
the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used
to treat Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas
frequently and on a regular basis when using LODOSYN tablets for Parkinson’s disease.
Reference ID: 3458203
Ideally, periodic skin examinations should be performed by appropriately qualified individuals
(e.g., dermatologists).
Information for Patients
It is important that LODOSYN with levodopa be taken at regular intervals according to the
schedule outlined by the health care provider. Caution patients not to change the prescribed
dosage regimen and not to add any additional antiparkinson medications, including other
carbidopa-levodopa preparations without first consulting a physician.
Advise patients that sometimes a ‘wearing-off’ effect may occur at the end of the dosing interval.
Tell patients to notify the prescriber if such response poses a problem to lifestyle.
Patients should be advised that occasionally dark color (red, brown, or black) may appear in
saliva, urine, or sweat after ingestion of LODOSYN and levodopa. Although the color appears to
be clinically insignificant, garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity
also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in
multivitamin tablets) may also reduce the amount of levodopa available in the body. The above
factors may reduce the clinical effectiveness of the LODOSYN and levodopa therapy.
Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases
without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Advise patients to exercise caution while driving or operating machinery and that if
they have experience somnolence and/or sudden sleep onset, they must refrain from these
activities. (See WARNINGS, Falling Asleep During Activities of Daily Living and Somnolence
General.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment
Reference ID: 3458203
of Parkinson’s disease, including LODOSYN and levodopa. Although it is not proven that the
medications caused these events, these urges were reported to have stopped in some cases when
the dose was reduced or the medication was stopped. Prescribers should ask patients about the
development of new or increased gambling urges, sexual urges, or other intense urges while
taking LODOSYN and levodopa. Physicians should consider dose reduction or stopping
Lodosyn and levodopa if a patient develops such urges while taking Lodosyn with
carbidopa/levodopa (See PRECAUTIONS, Impulse Control/Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as
alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin.
Abnormalities in blood urea nitrogen and positive Coombs test have also been reported.
Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during
concomitant administration of carbidopa and levodopa than with levodopa alone.
Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for
urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will
not be altered by boiling the urine specimen. False-negative tests may result with the use of
glucose-oxidase methods of testing for glucosuria.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with
LODOSYN (Carbidopa) given with levodopa or carbidopa-levodopa fixed dose combination
products.
Symptomatic postural hypotension has occurred when LODOSYN, given with levodopa or
carbidopa-levodopa combination products, was added to the treatment of a patient
receiving antihypertensive drugs. Therefore, when therapy with LODOSYN, given with or
without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of
the antihypertensive drug may be required.
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For patients receiving monoamine oxidase inhibitors (Type A or B), see
CONTRAINDICATIONS. Concomitant therapy with selegiline or rasigiline and
LODOSYN and carbidopa-levodopa may be associated with severe orthostatic hypotension
not attributable to carbidopa-levodopa alone (see CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia,
resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa
preparations.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and
isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of
levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and
papaverine. Patients taking these drugs with LODOSYN and levodopa or carbidopa-levodopa
combination products should be carefully observed for loss of therapeutic response
LODOSYN and iron salts or multi vitamins containing iron salts should be co administered
with caution. Iron salts c a n f or m c he l a t e s w i t h l e vod opa a nd c a r bi dopa a nd
c ons e que nt l y reduce the bioavailability of carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing
gastric emptying, metoclopramide may also adversely affect disease control by its
dopamine receptor antagonistic properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There were no significant differences between treated and control rats with respect to
mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135
mg/kg/day. Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were
given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia
was seen when compared to concurrent controls.
Mutagenesis
Mutagenicity studies have not been performed with either carbidopa or the combination of
carbidopa and levodopa.
Fertility
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Carbidopa had no effect on the mating performance, fertility, or survival of the young when
administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a
moderate decrease in body weight gain in males.
The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100
mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive
performance, or the growth and survival of the young.
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies with LODOSYN
in pregnant women. It has been reported from individual cases that levodopa crosses the
human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in
fetal tissue appeared to be minimal. LODOSYN should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the
mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral
anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum
recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by
the concomitant administration of carbidopa.
Nursing Mothers
It is not known whether carbidopa is excreted in human milk. Because many drugs are
excreted in human milk, and because of their potential for serious adverse reactions 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 nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established, and use of the drug
in patients below the age of 18 is not recommended.
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Geriatric Use
Clinical studies of LODOSYN did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other 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
concomitant disease and other drug therapy.
ADVERSE REACTIONS
Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the
recommended doses. The only adverse reactions that have been observed have been with
concomitant use of carbidopa with other drugs such as levodopa, and with carbidopa
levodopa combination products.
When LODOSYN is administered concomitantly with levodopa or carbidopa-levodopa
combination products, the most common adverse reactions have included dyskinesias such
as choreiform, dystonic, and other involuntary movements, and nausea. Other adverse reactions
reported with LODOSYN when administered concomitantly with levodopa alone or
carbidopa-levodopa combination products were psychotic episodes including delusions,
hallucinations, and paranoid ideation, depression with or without development of suicidal
tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with
concomitant use of LODOSYN and levodopa has not been established.
The following other adverse reactions have been reported with levodopa and carbidopa
levodopa combination products. These same adverse reactions may also occur when
LODOSYN is administered with these products.
Body as a Whole: abdominal pain and distress, asthenia, chest pain, fatigue.
Cardiovascular: cardiac irregularities, hypertension, myocardial infarction, hypotension
including orthostatic hypotension, palpitation, phlebitis, syncope.
Gastrointestinal: anorexia, bruxism, burning sensation of the tongue, constipation, dark
saliva, development of duodenal ulcer, diarrhea, dry mouth, dyspepsia, dysphagia,
flatulence, gastrointestinal bleeding, gastrointestinal pain, heartburn, hiccups, sialorrhea, taste
alterations, vomiting.
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Hematologic: hemolytic and non-hemolytic anemia, leukopenia, thrombocytopenia,
agranulocytosis.
Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions
(including pemphigus-like reactions).
Metabolic: edema, weight gain, weight loss.
Musculoskeletal: back pain, leg pain, muscle cramps, shoulder pain.
Nervous System/Psychiatric: Psychotic episodes including delusions, hallucinations and
paranoid ideation, neuroleptic malignant syndrome (NMS, see WARNINGS), bradykinetic
episodes (“on-off” phenomenon), confusion, agitation, dizziness, somnolence, dream
abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without
development of suicidal tendencies, dementia, pathological gambling, increased libido including
hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal
relationship with LODOSYN and levodopa, has not been established.
Respiratory: upper respiratory infection, dyspnea, pharyngeal pain, cough.
Skin: flushing, increased sweating, malignant melanoma (see also CONTRAINDICATIONS),
rash, alopecia, dark sweat.
Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital: dark urine, priapism, urinary frequency, urinary incontinence, urinary retention,
urinary tract infection.
Laboratory Tests: abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic
dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs test; elevated serum glucose;
decreased hemoglobin and hematocrit; decreased white blood cell count and serum
potassium; increased serum creatinine and uric acid; white blood cells, bacteria and blood in
the urine; protein and glucose in the urine.
Miscellaneous: bizarre breathing patterns, faintness, hoarseness, hot flashes, malaise,
neuroleptic malignant syndrome, sense of stimulation.
OVERDOSAGE
No reports of overdose with LODOSYN have been received. Management of overdosage with
carbidopa is the same as that with levodopa or carbidopa-levodopa preparations.
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In the event of overdosage, general supportive measures should be employed, along with
immediate gastric lavage. Intravenous fluids should be administered judiciously, and an
adequate airway maintained. Electrocardiographic monitoring should be instituted and the
patient carefully observed for the development of arrhythmias; if required, appropriate
antiarrhythmic therapy should be given. The possibility that the patient may have taken other
drugs as well as LODOSYN should be taken into consideration. To date, no experience has
been reported with dialysis; hence, its value in overdosage is not known. Pyridoxine is not
effective in reversing the actions of LODOSYN.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a
significant proportion of rats and mice given single oral doses of levodopa of approximately
1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are
expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die
after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with
levodopa increases the dose at which a significant proportion of mice are expected to die to
3360 mg/kg.
DOSAGE AND ADMINISTRATION
Whether given with carbidopa-levodopa or with levodopa, the optimal daily dose of
LODOSYN must be determined by careful titration. Most patients respond to a 1:10
proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or
more a day. The maximum daily dosage of carbidopa should not exceed 200 mg, since
clinical experience with larger dosages is limited. If the patient is taking carbidopa-levodopa,
the amount of carbidopa in carbidopa-levodopa should be considered when calculating the
total amount of LODOSYN to be administered each day.
Patients Receiving Carbidopa-Levodopa Who
Require Additional Carbidopa
Some patients taking carbidopa-levodopa may not have adequate reduction in nausea and
vomiting when the dosage of carbidopa is less than 70 mg a day, and the dosage of levodopa
is less than 700 mg a day. When these patients are taking carbidopa-levodopa, 25 mg of
LODOSYN may be given with the first dose of carbidopa-levodopa each day. Additional
doses of 12.5 mg or 25 mg may be given during the day with each dose of carbidopa
levodopa. LODOSYN may be given with any dose carbidopa-levodopa as required for
optimum therapeutic response. The maximum daily dosage of carbidopa, given as LODOSYN
and as carbidopa- levodopa), should not exceed 200 mg.
Patients Requiring Individual Titration of Carbidopa and
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Levodopa Dosage
Although carbidopa-levodopa is the most frequently used of carbidopa and levodopa
administration, there may be an occasional patient who requires individually titrated doses of
these two drugs. In these patients, LODOSYN (carbidopa) should be initiated at a dosage
of 25 mg three or four times a day. The two drugs should be given at the same time,
starting with no more than one-fifth (20%) to one-fourth (25%) of the previous or
recommended daily dosage of levodopa when given without LODOSYN (Carbidopa). In
patients already receiving levodopa therapy, at least twelve hours should elapse between
the last dose of levodopa and initiation of therapy with LODOSYN (Carbidopa) and
levodopa. A convenient way to initiate therapy in these patients is in the morning
following a night when the patient has not taken levodopa for at least twelve hours.
Health care providers who prescribe separate doses of LODOSYN and levodopa should be
thoroughly familiar with the directions for use of each drug.
Dosage Adjustment
Dosage of LODOSYN may be adjusted by adding or omitting one-half or one tablet a day.
Because both therapeutic and adverse responses occur more rapidly with combined therapy
than when only levodopa is given, patients should be monitored closely during the dose
adjustment period. Specifically, involuntary movements will occur more rapidly when
LODOSYN and levodopa are given concomitantly than when levodopa is given without
LODOSYN. The occurrence of involuntary movements may require dosage reduction.
Blepharospasm may be a useful early sign of excess dosage in some patients.
Current evidence indicates other standard antiparkinsonian drugs may be continued while
carbidopa and levodopa are being administered. However, the dosage of such other
standard antiparkinsonian drugs may require adjustment.
Interruption of Therapy
Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and
withdrawal of carbidopa-Levodopa) or carbidopa-levodopa Extended Release. Patients should
be observed carefully if abrupt reduction or discontinuation of carbidopa-levodopa or
carbidopa-levodopa Extended-Release is required, especially if the patient is receiving
neuroleptics. (See WARNINGS.)
If general anesthesia is required, therapy may be continued as long as the patient is
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permitted to take fluids and medication by mouth. When therapy is interrupted temporarily,
the patient should be observed for symptoms resembling NMS, and the usual daily dosage
may be resumed as soon as the patient is able to take medication orally.
HOW SUPPLIED
Tablets LODOSYN, 25 mg, are orange, round, compressed tablets that are scored and coded
711 on one side and LODOSYN on the other.
They are supplied as follows:
NDC 0056-0511-68 bottles of 100.
Storage
Store at 25°C (77°F), excursions permitted to 15–30°C (59–86°F).
Manufactured in Canada by:
Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7
Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA
Rev. 2/2014
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11,072
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LODOSYN
®
(CARBIDOPA)
TABLETS
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are being
treated with levodopa, the two drugs should be given at the same time, starting with no
more than 20 to 25% of the previous daily dosage of levodopa when given without
LODOSYN (Carbidopa). At least twelve hours should elapse between the last dose of
levodopa and initiation of therapy with LODOSYN (Carbidopa) and levodopa. See the
WARNINGS and DOSAGE AND ADMINISTRATION sections before initiating
therapy.
DESCRIPTION
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline
compound, slightly soluble in water, with a molecular weight of 244.3. It is designated
chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid
monohydrate. Its empirical formula is C10H14N2O4•H2O and its structural formula is: structural formula
LODOSYN (Carbidopa) tablets contain 25 mg of carbidopa. Inactive ingredients are
cellulose,FD&C Yellow 6, magnesium stearate and starch.
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular
weight of 226.3.
CLINICAL PHARMACOLOGY
Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal
nervous system affecting the mobility and control of the skeletal muscular system. Its
characteristic features include resting tremor, rigidity, and bradykinetic movements.
Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.
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Mechanism of Action
Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of
dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment
of Parkinson’s disease apparently because it does not cross the blood-brain barrier.
However, levodopa, the metabolic precursor of dopamine, does cross the blood- brain barrier,
and presumably is converted to dopamine in the brain. This is thought to be the mechanism
whereby levodopa relieves symptoms of Parkinson’s disease.
Pharmacodynamics
When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral
tissues so that only a small portion of a given dose is transported unchanged to the central
nervous system. For this reason, large doses of levodopa are required for adequate
therapeutic effect and these may often be accompanied by nausea and other adverse
reactions, some of which are attributable to dopamine formed in extracerebral tissues.
The incidence of levodopa-induced nausea and vomiting is less when LODOSYN is used with
levodopa than when levodopa is used without LODOSYN. In many patients, this reduction
in nausea and vomiting will permit more rapid dosage titration.
Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been
demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does
not appear to cross the blood-brain barrier readily and does not affect the metabolism of
levodopa within the central nervous system at doses of carbidopa that are recommended for
maximum effective inhibition of peripheral decarboxylation of levodopa.
Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues,
administration of carbidopa with levodopa makes more levodopa available for transport to the
brain. However, since levodopa and carbidopa compete with certain amino acids for transport
across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients
on a high protein diet.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75%
and, when administered with levodopa, increases both plasma levels and the plasma half-life of
levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
In clinical pharmacologic studies, simultaneous administration of separate tablets of
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carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the
excretion of dopamine when compared to the two drugs administered at separate times.
Supplemental pyridoxine (vitamin B6) can be given to patients when they are receiving
LODOSYN and levodopa concomitantly or the fixed combination carbidopa-levodopa or
carbidopa-levodopa extended release. Previous reports in the medical literature cautioned that
high doses of vitamin B6 should not be taken by patients on levodopa therapy
alone because exogenously administered pyridoxine would enhance the metabolism of levodopa
to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral
decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of
pyridoxine.
Carbidopa is combined with levodopa in carbidopa-levodopa and carbidopa-levodopa
extended release tablets.
INDICATIONS AND USAGE
LODOSYN is indicated for use with carbidopa-levodopa or with levodopa in the treatment of
the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic
parkinsonism, and symptomatic parkinsonism, which may follow injury to the nervous system
by carbon monoxide intoxication and/or manganese intoxication.
LODOSYN is for use with carbidopa-levodopa in patients for whom the dosage of
carbidopa-levodopa provides less than adequate daily dosage (usually 70 mg daily) of
carbidopa.
LODOSYN is for use with levodopa in the occasional patient whose dosage requirement of
carbidopa and levodopa necessitates separate titration of each medication.
LODOSYN is used with carbidopa-levodopa or with levodopa to permit the administration
of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration,
and with a somewhat smoother response. However, patients with markedly irregular (“on-off”)
responses to levodopa have not been shown to benefit from the addition of carbidopa.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, supplemental
pyridoxine (vitamin B6), can be given to patients when they are receiving carbidopa and
levodopa concomitantly or as carbidopa-levodopa.
Although the administration of LODOSYN permits control of parkinsonism and Parkinson’s
disease with much lower doses of levodopa, there is no conclusive evidence at present that
Reference ID: 3458203
this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration,
and providing a somewhat smoother response to levodopa.
Certain patients who responded poorly to levodopa alone have improved when carbidopa and
levodopa were given concurrently. This was most likely due to decreased peripheral
decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral
nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.
In deciding whether to give LODOSYN with carbidopa-levodopa or with levodopa to
patients who have nausea and/or vomiting, the physician should be aware that, while many
patients may be expected to improve, some may not. Since one cannot predict which patients
are likely to improve, this can only be determined by a trial of therapy. It should be further
noted that in controlled trials comparing carbidopa and levodopa with levodopa alone, about
half the patients with nausea and/or vomiting on levodopa alone improved spontaneously
despite being retained on the same dose of levodopa during the controlled portion of the
trial.
CONTRAINDICATIONS
LODOSYN is contraindicated in patients with known hypersensitivity to any component of this
drug.
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with
levodopa or carbidopa-levodopa combination products with or without LODOSYN. These
inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa.
Carbidopa-levodopa or levodopa may be administered concomitantly with the manufacturer’s
recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline
HCl) (see PRECAUTIONS, Drug Interactions).
Levodopa or carbidopa-levodopa products, with or without LODOSYN, are contra- indicated in
patients with narrow-angle glaucoma.
WARNINGS
LODOSYN (Carbidopa) has no antiparkinsonian effect when given alone. It is indicated
for use with carbidopa-levodopa or levodopa. LODOSYN (Carbidopa) does not decrease
adverse reactions due to central effects of levodopa.
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are
being treated with levodopa alone, the two drugs should be given at the same time.
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At least twelve hours should elapse between the last dose of levodopa and initiation of
therapy with LODOSYN (Carbidopa) and levodopa in combination. Start with no more
than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when
given without LODOSYN (Carbidopa). See the DOSAGE AND ADMINISTRATION
section before initiating therapy.
The addition of LODOSYN with levodopa or carbidopa-levodopa reduces the peripheral
effects (nausea, vomiting) due to decarboxylation of levodopa; however, LODOSYN does
not decrease the adverse reactions due to the central effects of levodopa. Because
LODOSYN permits more levodopa to reach the brain and more dopamine to be formed,
certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary
movements), may occur at lower dosages and sooner with levodopa in combination with
LODOSYN than with levodopa alone.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have
reported suddenly falling asleep without prior warning of sleepiness while engaged in activities
of daily living (includes operation of motor vehicles). Some of these episodes resulted in
automobile accidents. Although many of these patients reported somnolence while on
dopaminergic medications, some did perceive that they had no warning signs, such as excessive
drowsiness, and believed that they were alert immediately prior to the event. Some patients
reported these events one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing
pre-existing somnolence, although some patients may not give such a history. For this reason,
prescribers should continually reassess patients for drowsiness or sleepiness especially since
some of the events occur after the start of treatment. Prescribers should be aware that patients
may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or
sleepiness during specific activities. Patients who have already experienced somnolence or an
episode of sudden sleep onset should not participate in these activities during treatment with
LODOSYN when taking it with other carbidopa-levodopa products.
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Before initiating treatment with LODOSYN, advise patients about the potential to develop
drowsiness and ask specifically about factors that may increase the risk for somnolence with
LODOSYN such as the use of concomitant sedating medications and the presence of sleep
disorders. Consider discontinuing LODOSYN in patients who report significant daytime
sleepiness or episodes of falling asleep during activities that require active participation (e.g.,
conversations, eating, etc.). If treatment with LODOSYN continues, patients should be advised
not to drive and to avoid other potentially dangerous activities that might result in harm if the
patients become somnolent. There is insufficient information to establish that dose reduction
will eliminate episodes of falling asleep while engaged in activities of daily living.
Hyperpyrexia and Confusion:
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have
been reported in association with dose reductions or withdrawal of certain antiparkinsonian
agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release.
Therefore, patients should be observed carefully when the dosage of levodopa or carbidopa
levodopa is reduced abruptly or discontinued, especially if the patient is receiving
neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered
consciousness, mental status changes; other disturbances, such as autonomic dysfunction,
tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as
creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum
myoglobin, have been reported.
The early diagnosis of this condition is important for the appropriate management of these
patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses
(e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the
clinical presentation includes both serious medical illness and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
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diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical
monitoring and 2) treatment of any concomitant serious medical problems for which specific
treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants,
such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has
not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and
renal function are recommended during extended concomitant therapy with LODOSYN and
levodopa, or with LODOSYN and carbidopa-levodopa or any combination of these drugs.
Impulse Control/Compulsive Behaviors
Postmarketing reports suggest that patients treated with anti-Parkinson medications can
experience intense urges to gamble, increased sexual urges, intense urges to spend money
uncontrollably, binge eating, and other intense urges. Patients may be unable to control these
urges while taking one or more of the medications that are used for the treatment of Parkinson’s
disease and that increase central dopaminergic tone, including Lodosyn taken with levodopa and
carbidopa. In some cases, although not all, these urges were reported to have stopped when the
dose of anti-Parkinson medications was reduced or discontinued. Because patients may not
recognize these behaviors as abnormal it is important for prescribers to specifically ask patients
or their caregivers about the development of new or increased gambling urges, sexual urges,
uncontrolled spending or other urges while being treated with Lodosyn. Physicians should
consider dose reduction or stopping Lodosyn or levodopa if a patient develops such urges while
taking Lodosyn with carbidopa/levodopa.
Hallucinations/Psychotic-Like Behavior
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Hallucinations and psychotic like behavior have been reported with dopaminergic medications.
In general, hallucinations present shortly after the initiation of therapy and may be responsive to
dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser
extent sleep disorder (insomnia) and excessive dreaming. LODOSYN when taken with
carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking
and behavior may present with one or more symptoms, including paranoid ideation, delusions,
hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation,
and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with LODOSYN and
carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain
medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and
may decrease the effectiveness of LODOSYN.
Dyskinesia
LODOSYN (Carbidopa) may potentiate the dopaminergic side effects of levodopa and may
cause or exacerbate preexisting dyskinesia.
Depression
Patients treated with LODOSYN and carbidopa-levodopa should be observed carefully for the
development of depression with concomitant suicidal tendencies.
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2
to approximately 6-fold higher) of developing melanoma than the general population. Whether
the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used
to treat Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas
frequently and on a regular basis when using LODOSYN tablets for Parkinson’s disease.
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Ideally, periodic skin examinations should be performed by appropriately qualified individuals
(e.g., dermatologists).
Information for Patients
It is important that LODOSYN with levodopa be taken at regular intervals according to the
schedule outlined by the health care provider. Caution patients not to change the prescribed
dosage regimen and not to add any additional antiparkinson medications, including other
carbidopa-levodopa preparations without first consulting a physician.
Advise patients that sometimes a ‘wearing-off’ effect may occur at the end of the dosing interval.
Tell patients to notify the prescriber if such response poses a problem to lifestyle.
Patients should be advised that occasionally dark color (red, brown, or black) may appear in
saliva, urine, or sweat after ingestion of LODOSYN and levodopa. Although the color appears to
be clinically insignificant, garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity
also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in
multivitamin tablets) may also reduce the amount of levodopa available in the body. The above
factors may reduce the clinical effectiveness of the LODOSYN and levodopa therapy.
Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases
without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Advise patients to exercise caution while driving or operating machinery and that if
they have experience somnolence and/or sudden sleep onset, they must refrain from these
activities. (See WARNINGS, Falling Asleep During Activities of Daily Living and Somnolence
General.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment
Reference ID: 3458203
of Parkinson’s disease, including LODOSYN and levodopa. Although it is not proven that the
medications caused these events, these urges were reported to have stopped in some cases when
the dose was reduced or the medication was stopped. Prescribers should ask patients about the
development of new or increased gambling urges, sexual urges, or other intense urges while
taking LODOSYN and levodopa. Physicians should consider dose reduction or stopping
Lodosyn and levodopa if a patient develops such urges while taking Lodosyn with
carbidopa/levodopa (See PRECAUTIONS, Impulse Control/Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as
alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin.
Abnormalities in blood urea nitrogen and positive Coombs test have also been reported.
Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during
concomitant administration of carbidopa and levodopa than with levodopa alone.
Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for
urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will
not be altered by boiling the urine specimen. False-negative tests may result with the use of
glucose-oxidase methods of testing for glucosuria.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with
LODOSYN (Carbidopa) given with levodopa or carbidopa-levodopa fixed dose combination
products.
Symptomatic postural hypotension has occurred when LODOSYN, given with levodopa or
carbidopa-levodopa combination products, was added to the treatment of a patient
receiving antihypertensive drugs. Therefore, when therapy with LODOSYN, given with or
without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of
the antihypertensive drug may be required.
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For patients receiving monoamine oxidase inhibitors (Type A or B), see
CONTRAINDICATIONS. Concomitant therapy with selegiline or rasigiline and
LODOSYN and carbidopa-levodopa may be associated with severe orthostatic hypotension
not attributable to carbidopa-levodopa alone (see CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia,
resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa
preparations.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and
isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of
levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and
papaverine. Patients taking these drugs with LODOSYN and levodopa or carbidopa-levodopa
combination products should be carefully observed for loss of therapeutic response
LODOSYN and iron salts or multi vitamins containing iron salts should be co administered
with caution. Iron salts c a n f or m c he l a t e s w i t h l e vod opa a nd c a r bi dopa a nd
c ons e que nt l y reduce the bioavailability of carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing
gastric emptying, metoclopramide may also adversely affect disease control by its
dopamine receptor antagonistic properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There were no significant differences between treated and control rats with respect to
mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135
mg/kg/day. Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were
given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia
was seen when compared to concurrent controls.
Mutagenesis
Mutagenicity studies have not been performed with either carbidopa or the combination of
carbidopa and levodopa.
Fertility
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Carbidopa had no effect on the mating performance, fertility, or survival of the young when
administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a
moderate decrease in body weight gain in males.
The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100
mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive
performance, or the growth and survival of the young.
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies with LODOSYN
in pregnant women. It has been reported from individual cases that levodopa crosses the
human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in
fetal tissue appeared to be minimal. LODOSYN should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the
mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral
anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum
recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by
the concomitant administration of carbidopa.
Nursing Mothers
It is not known whether carbidopa is excreted in human milk. Because many drugs are
excreted in human milk, and because of their potential for serious adverse reactions 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 nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established, and use of the drug
in patients below the age of 18 is not recommended.
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Geriatric Use
Clinical studies of LODOSYN did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other 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
concomitant disease and other drug therapy.
ADVERSE REACTIONS
Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the
recommended doses. The only adverse reactions that have been observed have been with
concomitant use of carbidopa with other drugs such as levodopa, and with carbidopa
levodopa combination products.
When LODOSYN is administered concomitantly with levodopa or carbidopa-levodopa
combination products, the most common adverse reactions have included dyskinesias such
as choreiform, dystonic, and other involuntary movements, and nausea. Other adverse reactions
reported with LODOSYN when administered concomitantly with levodopa alone or
carbidopa-levodopa combination products were psychotic episodes including delusions,
hallucinations, and paranoid ideation, depression with or without development of suicidal
tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with
concomitant use of LODOSYN and levodopa has not been established.
The following other adverse reactions have been reported with levodopa and carbidopa
levodopa combination products. These same adverse reactions may also occur when
LODOSYN is administered with these products.
Body as a Whole: abdominal pain and distress, asthenia, chest pain, fatigue.
Cardiovascular: cardiac irregularities, hypertension, myocardial infarction, hypotension
including orthostatic hypotension, palpitation, phlebitis, syncope.
Gastrointestinal: anorexia, bruxism, burning sensation of the tongue, constipation, dark
saliva, development of duodenal ulcer, diarrhea, dry mouth, dyspepsia, dysphagia,
flatulence, gastrointestinal bleeding, gastrointestinal pain, heartburn, hiccups, sialorrhea, taste
alterations, vomiting.
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Hematologic: hemolytic and non-hemolytic anemia, leukopenia, thrombocytopenia,
agranulocytosis.
Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions
(including pemphigus-like reactions).
Metabolic: edema, weight gain, weight loss.
Musculoskeletal: back pain, leg pain, muscle cramps, shoulder pain.
Nervous System/Psychiatric: Psychotic episodes including delusions, hallucinations and
paranoid ideation, neuroleptic malignant syndrome (NMS, see WARNINGS), bradykinetic
episodes (“on-off” phenomenon), confusion, agitation, dizziness, somnolence, dream
abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without
development of suicidal tendencies, dementia, pathological gambling, increased libido including
hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal
relationship with LODOSYN and levodopa, has not been established.
Respiratory: upper respiratory infection, dyspnea, pharyngeal pain, cough.
Skin: flushing, increased sweating, malignant melanoma (see also CONTRAINDICATIONS),
rash, alopecia, dark sweat.
Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital: dark urine, priapism, urinary frequency, urinary incontinence, urinary retention,
urinary tract infection.
Laboratory Tests: abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic
dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs test; elevated serum glucose;
decreased hemoglobin and hematocrit; decreased white blood cell count and serum
potassium; increased serum creatinine and uric acid; white blood cells, bacteria and blood in
the urine; protein and glucose in the urine.
Miscellaneous: bizarre breathing patterns, faintness, hoarseness, hot flashes, malaise,
neuroleptic malignant syndrome, sense of stimulation.
OVERDOSAGE
No reports of overdose with LODOSYN have been received. Management of overdosage with
carbidopa is the same as that with levodopa or carbidopa-levodopa preparations.
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In the event of overdosage, general supportive measures should be employed, along with
immediate gastric lavage. Intravenous fluids should be administered judiciously, and an
adequate airway maintained. Electrocardiographic monitoring should be instituted and the
patient carefully observed for the development of arrhythmias; if required, appropriate
antiarrhythmic therapy should be given. The possibility that the patient may have taken other
drugs as well as LODOSYN should be taken into consideration. To date, no experience has
been reported with dialysis; hence, its value in overdosage is not known. Pyridoxine is not
effective in reversing the actions of LODOSYN.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a
significant proportion of rats and mice given single oral doses of levodopa of approximately
1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are
expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die
after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with
levodopa increases the dose at which a significant proportion of mice are expected to die to
3360 mg/kg.
DOSAGE AND ADMINISTRATION
Whether given with carbidopa-levodopa or with levodopa, the optimal daily dose of
LODOSYN must be determined by careful titration. Most patients respond to a 1:10
proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or
more a day. The maximum daily dosage of carbidopa should not exceed 200 mg, since
clinical experience with larger dosages is limited. If the patient is taking carbidopa-levodopa,
the amount of carbidopa in carbidopa-levodopa should be considered when calculating the
total amount of LODOSYN to be administered each day.
Patients Receiving Carbidopa-Levodopa Who
Require Additional Carbidopa
Some patients taking carbidopa-levodopa may not have adequate reduction in nausea and
vomiting when the dosage of carbidopa is less than 70 mg a day, and the dosage of levodopa
is less than 700 mg a day. When these patients are taking carbidopa-levodopa, 25 mg of
LODOSYN may be given with the first dose of carbidopa-levodopa each day. Additional
doses of 12.5 mg or 25 mg may be given during the day with each dose of carbidopa
levodopa. LODOSYN may be given with any dose carbidopa-levodopa as required for
optimum therapeutic response. The maximum daily dosage of carbidopa, given as LODOSYN
and as carbidopa- levodopa), should not exceed 200 mg.
Patients Requiring Individual Titration of Carbidopa and
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Levodopa Dosage
Although carbidopa-levodopa is the most frequently used of carbidopa and levodopa
administration, there may be an occasional patient who requires individually titrated doses of
these two drugs. In these patients, LODOSYN (carbidopa) should be initiated at a dosage
of 25 mg three or four times a day. The two drugs should be given at the same time,
starting with no more than one-fifth (20%) to one-fourth (25%) of the previous or
recommended daily dosage of levodopa when given without LODOSYN (Carbidopa). In
patients already receiving levodopa therapy, at least twelve hours should elapse between
the last dose of levodopa and initiation of therapy with LODOSYN (Carbidopa) and
levodopa. A convenient way to initiate therapy in these patients is in the morning
following a night when the patient has not taken levodopa for at least twelve hours.
Health care providers who prescribe separate doses of LODOSYN and levodopa should be
thoroughly familiar with the directions for use of each drug.
Dosage Adjustment
Dosage of LODOSYN may be adjusted by adding or omitting one-half or one tablet a day.
Because both therapeutic and adverse responses occur more rapidly with combined therapy
than when only levodopa is given, patients should be monitored closely during the dose
adjustment period. Specifically, involuntary movements will occur more rapidly when
LODOSYN and levodopa are given concomitantly than when levodopa is given without
LODOSYN. The occurrence of involuntary movements may require dosage reduction.
Blepharospasm may be a useful early sign of excess dosage in some patients.
Current evidence indicates other standard antiparkinsonian drugs may be continued while
carbidopa and levodopa are being administered. However, the dosage of such other
standard antiparkinsonian drugs may require adjustment.
Interruption of Therapy
Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and
withdrawal of carbidopa-Levodopa) or carbidopa-levodopa Extended Release. Patients should
be observed carefully if abrupt reduction or discontinuation of carbidopa-levodopa or
carbidopa-levodopa Extended-Release is required, especially if the patient is receiving
neuroleptics. (See WARNINGS.)
If general anesthesia is required, therapy may be continued as long as the patient is
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permitted to take fluids and medication by mouth. When therapy is interrupted temporarily,
the patient should be observed for symptoms resembling NMS, and the usual daily dosage
may be resumed as soon as the patient is able to take medication orally.
HOW SUPPLIED
Tablets LODOSYN, 25 mg, are orange, round, compressed tablets that are scored and coded
711 on one side and LODOSYN on the other.
They are supplied as follows:
NDC 0056-0511-68 bottles of 100.
Storage
Store at 25°C (77°F), excursions permitted to 15–30°C (59–86°F).
Manufactured in Canada by:
Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7
Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA
Rev. 2/2014
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11,073
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LODOSYN
®
(CARBIDOPA)
TABLETS
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are being
treated with levodopa, the two drugs should be given at the same time, starting with no
more than 20 to 25% of the previous daily dosage of levodopa when given without
LODOSYN (Carbidopa). At least twelve hours should elapse between the last dose of
levodopa and initiation of therapy with LODOSYN (Carbidopa) and levodopa. See the
WARNINGS and DOSAGE AND ADMINISTRATION sections before initiating
therapy.
DESCRIPTION
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline
compound, slightly soluble in water, with a molecular weight of 244.3. It is designated
chemically as (–)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene) propanoic acid
monohydrate. Its empirical formula is C10H14N2O4•H2O and its structural formula is: structural formula
LODOSYN (Carbidopa) tablets contain 25 mg of carbidopa. Inactive ingredients are
cellulose,FD&C Yellow 6, magnesium stearate and starch.
Tablet content is expressed in terms of anhydrous carbidopa which has a molecular
weight of 226.3.
CLINICAL PHARMACOLOGY
Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal
nervous system affecting the mobility and control of the skeletal muscular system. Its
characteristic features include resting tremor, rigidity, and bradykinetic movements.
Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.
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Mechanism of Action
Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of
dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment
of Parkinson’s disease apparently because it does not cross the blood-brain barrier.
However, levodopa, the metabolic precursor of dopamine, does cross the blood- brain barrier,
and presumably is converted to dopamine in the brain. This is thought to be the mechanism
whereby levodopa relieves symptoms of Parkinson’s disease.
Pharmacodynamics
When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral
tissues so that only a small portion of a given dose is transported unchanged to the central
nervous system. For this reason, large doses of levodopa are required for adequate
therapeutic effect and these may often be accompanied by nausea and other adverse
reactions, some of which are attributable to dopamine formed in extracerebral tissues.
The incidence of levodopa-induced nausea and vomiting is less when LODOSYN is used with
levodopa than when levodopa is used without LODOSYN. In many patients, this reduction
in nausea and vomiting will permit more rapid dosage titration.
Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been
demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does
not appear to cross the blood-brain barrier readily and does not affect the metabolism of
levodopa within the central nervous system at doses of carbidopa that are recommended for
maximum effective inhibition of peripheral decarboxylation of levodopa.
Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues,
administration of carbidopa with levodopa makes more levodopa available for transport to the
brain. However, since levodopa and carbidopa compete with certain amino acids for transport
across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients
on a high protein diet.
Pharmacokinetics
Carbidopa reduces the amount of levodopa required to produce a given response by about 75%
and, when administered with levodopa, increases both plasma levels and the plasma half-life of
levodopa, and decreases plasma and urinary dopamine and homovanillic acid.
In clinical pharmacologic studies, simultaneous administration of separate tablets of
Reference ID: 3458203
carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the
excretion of dopamine when compared to the two drugs administered at separate times.
Supplemental pyridoxine (vitamin B6) can be given to patients when they are receiving
LODOSYN and levodopa concomitantly or the fixed combination carbidopa-levodopa or
carbidopa-levodopa extended release. Previous reports in the medical literature cautioned that
high doses of vitamin B6 should not be taken by patients on levodopa therapy
alone because exogenously administered pyridoxine would enhance the metabolism of levodopa
to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral
decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of
pyridoxine.
Carbidopa is combined with levodopa in carbidopa-levodopa and carbidopa-levodopa
extended release tablets.
INDICATIONS AND USAGE
LODOSYN is indicated for use with carbidopa-levodopa or with levodopa in the treatment of
the symptoms of idiopathic Parkinson’s disease (paralysis agitans), postencephalitic
parkinsonism, and symptomatic parkinsonism, which may follow injury to the nervous system
by carbon monoxide intoxication and/or manganese intoxication.
LODOSYN is for use with carbidopa-levodopa in patients for whom the dosage of
carbidopa-levodopa provides less than adequate daily dosage (usually 70 mg daily) of
carbidopa.
LODOSYN is for use with levodopa in the occasional patient whose dosage requirement of
carbidopa and levodopa necessitates separate titration of each medication.
LODOSYN is used with carbidopa-levodopa or with levodopa to permit the administration
of lower doses of levodopa with reduced nausea and vomiting, more rapid dosage titration,
and with a somewhat smoother response. However, patients with markedly irregular (“on-off”)
responses to levodopa have not been shown to benefit from the addition of carbidopa.
Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, supplemental
pyridoxine (vitamin B6), can be given to patients when they are receiving carbidopa and
levodopa concomitantly or as carbidopa-levodopa.
Although the administration of LODOSYN permits control of parkinsonism and Parkinson’s
disease with much lower doses of levodopa, there is no conclusive evidence at present that
Reference ID: 3458203
this is beneficial other than in reducing nausea and vomiting, permitting more rapid titration,
and providing a somewhat smoother response to levodopa.
Certain patients who responded poorly to levodopa alone have improved when carbidopa and
levodopa were given concurrently. This was most likely due to decreased peripheral
decarboxylation of levodopa rather than to a primary effect of carbidopa on the peripheral
nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa.
In deciding whether to give LODOSYN with carbidopa-levodopa or with levodopa to
patients who have nausea and/or vomiting, the physician should be aware that, while many
patients may be expected to improve, some may not. Since one cannot predict which patients
are likely to improve, this can only be determined by a trial of therapy. It should be further
noted that in controlled trials comparing carbidopa and levodopa with levodopa alone, about
half the patients with nausea and/or vomiting on levodopa alone improved spontaneously
despite being retained on the same dose of levodopa during the controlled portion of the
trial.
CONTRAINDICATIONS
LODOSYN is contraindicated in patients with known hypersensitivity to any component of this
drug.
Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with
levodopa or carbidopa-levodopa combination products with or without LODOSYN. These
inhibitors must be discontinued at least two weeks prior to initiating therapy with levodopa.
Carbidopa-levodopa or levodopa may be administered concomitantly with the manufacturer’s
recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline
HCl) (see PRECAUTIONS, Drug Interactions).
Levodopa or carbidopa-levodopa products, with or without LODOSYN, are contra- indicated in
patients with narrow-angle glaucoma.
WARNINGS
LODOSYN (Carbidopa) has no antiparkinsonian effect when given alone. It is indicated
for use with carbidopa-levodopa or levodopa. LODOSYN (Carbidopa) does not decrease
adverse reactions due to central effects of levodopa.
When LODOSYN (Carbidopa) is to be given to carbidopa-naive patients who are
being treated with levodopa alone, the two drugs should be given at the same time.
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At least twelve hours should elapse between the last dose of levodopa and initiation of
therapy with LODOSYN (Carbidopa) and levodopa in combination. Start with no more
than one-fifth (20%) to one-fourth (25%) of the previous daily dosage of levodopa when
given without LODOSYN (Carbidopa). See the DOSAGE AND ADMINISTRATION
section before initiating therapy.
The addition of LODOSYN with levodopa or carbidopa-levodopa reduces the peripheral
effects (nausea, vomiting) due to decarboxylation of levodopa; however, LODOSYN does
not decrease the adverse reactions due to the central effects of levodopa. Because
LODOSYN permits more levodopa to reach the brain and more dopamine to be formed,
certain adverse central nervous system (CNS) effects, e.g., dyskinesias (involuntary
movements), may occur at lower dosages and sooner with levodopa in combination with
LODOSYN than with levodopa alone.
Falling Asleep During Activities of Daily Living and Somnolence
Patients taking carbidopa-levodopa products alone or with other dopaminergic drugs have
reported suddenly falling asleep without prior warning of sleepiness while engaged in activities
of daily living (includes operation of motor vehicles). Some of these episodes resulted in
automobile accidents. Although many of these patients reported somnolence while on
dopaminergic medications, some did perceive that they had no warning signs, such as excessive
drowsiness, and believed that they were alert immediately prior to the event. Some patients
reported these events one year after the initiation of treatment.
Falling asleep while engaged in activities of daily living usually occurs in patients experiencing
pre-existing somnolence, although some patients may not give such a history. For this reason,
prescribers should continually reassess patients for drowsiness or sleepiness especially since
some of the events occur after the start of treatment. Prescribers should be aware that patients
may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or
sleepiness during specific activities. Patients who have already experienced somnolence or an
episode of sudden sleep onset should not participate in these activities during treatment with
LODOSYN when taking it with other carbidopa-levodopa products.
Reference ID: 3458203
Before initiating treatment with LODOSYN, advise patients about the potential to develop
drowsiness and ask specifically about factors that may increase the risk for somnolence with
LODOSYN such as the use of concomitant sedating medications and the presence of sleep
disorders. Consider discontinuing LODOSYN in patients who report significant daytime
sleepiness or episodes of falling asleep during activities that require active participation (e.g.,
conversations, eating, etc.). If treatment with LODOSYN continues, patients should be advised
not to drive and to avoid other potentially dangerous activities that might result in harm if the
patients become somnolent. There is insufficient information to establish that dose reduction
will eliminate episodes of falling asleep while engaged in activities of daily living.
Hyperpyrexia and Confusion:
Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have
been reported in association with dose reductions or withdrawal of certain antiparkinsonian
agents such as levodopa, carbidopa-levodopa, or carbidopa-levodopa extended-release.
Therefore, patients should be observed carefully when the dosage of levodopa or carbidopa
levodopa is reduced abruptly or discontinued, especially if the patient is receiving
neuroleptics.
NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia.
Neurological findings, including muscle rigidity, involuntary movements, altered
consciousness, mental status changes; other disturbances, such as autonomic dysfunction,
tachycardia, tachypnea, sweating, hyper- or hypotension; laboratory findings, such as
creatine phosphokinase elevation, leukocytosis, myoglobinuria, and increased serum
myoglobin, have been reported.
The early diagnosis of this condition is important for the appropriate management of these
patients. Considering NMS as a possible diagnosis and ruling out other acute illnesses
(e.g., pneumonia, systemic infection, etc.) is essential. This may be especially complex if the
clinical presentation includes both serious medical illness and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
Reference ID: 3458203
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system (CNS) pathology.
The management of NMS should include: 1) intensive symptomatic treatment and medical
monitoring and 2) treatment of any concomitant serious medical problems for which specific
treatments are available. Dopamine agonists, such as bromocriptine, and muscle relaxants,
such as dantrolene, are often used in the treatment of NMS; however, their effectiveness has
not been demonstrated in controlled studies.
PRECAUTIONS
General
As with levodopa alone, periodic evaluations of hepatic, hematopoietic, cardiovascular, and
renal function are recommended during extended concomitant therapy with LODOSYN and
levodopa, or with LODOSYN and carbidopa-levodopa or any combination of these drugs.
Impulse Control/Compulsive Behaviors
Postmarketing reports suggest that patients treated with anti-Parkinson medications can
experience intense urges to gamble, increased sexual urges, intense urges to spend money
uncontrollably, binge eating, and other intense urges. Patients may be unable to control these
urges while taking one or more of the medications that are used for the treatment of Parkinson’s
disease and that increase central dopaminergic tone, including Lodosyn taken with levodopa and
carbidopa. In some cases, although not all, these urges were reported to have stopped when the
dose of anti-Parkinson medications was reduced or discontinued. Because patients may not
recognize these behaviors as abnormal it is important for prescribers to specifically ask patients
or their caregivers about the development of new or increased gambling urges, sexual urges,
uncontrolled spending or other urges while being treated with Lodosyn. Physicians should
consider dose reduction or stopping Lodosyn or levodopa if a patient develops such urges while
taking Lodosyn with carbidopa/levodopa.
Hallucinations/Psychotic-Like Behavior
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Hallucinations and psychotic like behavior have been reported with dopaminergic medications.
In general, hallucinations present shortly after the initiation of therapy and may be responsive to
dose reduction in levodopa. Hallucinations may be accompanied by confusion and to a lesser
extent sleep disorder (insomnia) and excessive dreaming. LODOSYN when taken with
carbidopa-levodopa may have similar effects on thinking and behavior. This abnormal thinking
and behavior may present with one or more symptoms, including paranoid ideation, delusions,
hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation,
and delirium.
Ordinarily, patients with a major psychotic disorder should not be treated with LODOSYN and
carbidopa-levodopa, because of the risk of exacerbating psychosis. In addition, certain
medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and
may decrease the effectiveness of LODOSYN.
Dyskinesia
LODOSYN (Carbidopa) may potentiate the dopaminergic side effects of levodopa and may
cause or exacerbate preexisting dyskinesia.
Depression
Patients treated with LODOSYN and carbidopa-levodopa should be observed carefully for the
development of depression with concomitant suicidal tendencies.
Melanoma
Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2
to approximately 6-fold higher) of developing melanoma than the general population. Whether
the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used
to treat Parkinson’s disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas
frequently and on a regular basis when using LODOSYN tablets for Parkinson’s disease.
Reference ID: 3458203
Ideally, periodic skin examinations should be performed by appropriately qualified individuals
(e.g., dermatologists).
Information for Patients
It is important that LODOSYN with levodopa be taken at regular intervals according to the
schedule outlined by the health care provider. Caution patients not to change the prescribed
dosage regimen and not to add any additional antiparkinson medications, including other
carbidopa-levodopa preparations without first consulting a physician.
Advise patients that sometimes a ‘wearing-off’ effect may occur at the end of the dosing interval.
Tell patients to notify the prescriber if such response poses a problem to lifestyle.
Patients should be advised that occasionally dark color (red, brown, or black) may appear in
saliva, urine, or sweat after ingestion of LODOSYN and levodopa. Although the color appears to
be clinically insignificant, garments may become discolored.
The patient should be advised that a change in diet to foods that are high in protein may delay the
absorption of levodopa and may reduce the amount taken up in the circulation. Excessive acidity
also delays stomach emptying thus delaying the absorption of levodopa. Iron salts (such as in
multivitamin tablets) may also reduce the amount of levodopa available in the body. The above
factors may reduce the clinical effectiveness of the LODOSYN and levodopa therapy.
Alert patients to the possibility of sudden onset of sleep during daily activities, in some cases
without awareness or warning signs, when they are taking dopaminergic agents, including
levodopa. Advise patients to exercise caution while driving or operating machinery and that if
they have experience somnolence and/or sudden sleep onset, they must refrain from these
activities. (See WARNINGS, Falling Asleep During Activities of Daily Living and Somnolence
General.)
There have been reports of patients experiencing intense urges to gamble, increased sexual urges,
and other intense urges, and the inability to control these urges while taking one or more of the
medications that increase central dopaminergic tone and that are generally used for the treatment
Reference ID: 3458203
of Parkinson’s disease, including LODOSYN and levodopa. Although it is not proven that the
medications caused these events, these urges were reported to have stopped in some cases when
the dose was reduced or the medication was stopped. Prescribers should ask patients about the
development of new or increased gambling urges, sexual urges, or other intense urges while
taking LODOSYN and levodopa. Physicians should consider dose reduction or stopping
Lodosyn and levodopa if a patient develops such urges while taking Lodosyn with
carbidopa/levodopa (See PRECAUTIONS, Impulse Control/Compulsive Behaviors).
Laboratory Tests
Abnormalities in laboratory tests may include elevations of liver function tests such as
alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, and bilirubin.
Abnormalities in blood urea nitrogen and positive Coombs test have also been reported.
Commonly, levels of blood urea nitrogen, creatinine, and uric acid are lower during
concomitant administration of carbidopa and levodopa than with levodopa alone.
Levodopa and carbidopa-levodopa combination products may cause a false-positive reaction for
urinary ketone bodies when a test tape is used for determination of ketonuria. This reaction will
not be altered by boiling the urine specimen. False-negative tests may result with the use of
glucose-oxidase methods of testing for glucosuria.
Drug Interactions
Caution should be exercised when the following drugs are administered concomitantly with
LODOSYN (Carbidopa) given with levodopa or carbidopa-levodopa fixed dose combination
products.
Symptomatic postural hypotension has occurred when LODOSYN, given with levodopa or
carbidopa-levodopa combination products, was added to the treatment of a patient
receiving antihypertensive drugs. Therefore, when therapy with LODOSYN, given with or
without levodopa or carbidopa-levodopa combination products, is started, dosage adjustment of
the antihypertensive drug may be required.
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For patients receiving monoamine oxidase inhibitors (Type A or B), see
CONTRAINDICATIONS. Concomitant therapy with selegiline or rasigiline and
LODOSYN and carbidopa-levodopa may be associated with severe orthostatic hypotension
not attributable to carbidopa-levodopa alone (see CONTRAINDICATIONS).
There have been rare reports of adverse reactions, including hypertension and dyskinesia,
resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa
preparations.
Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and
isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of
levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and
papaverine. Patients taking these drugs with LODOSYN and levodopa or carbidopa-levodopa
combination products should be carefully observed for loss of therapeutic response
LODOSYN and iron salts or multi vitamins containing iron salts should be co administered
with caution. Iron salts c a n f or m c he l a t e s w i t h l e vod opa a nd c a r bi dopa a nd
c ons e que nt l y reduce the bioavailability of carbidopa and levodopa.
Although metoclopramide may increase the bioavailability of levodopa by increasing
gastric emptying, metoclopramide may also adversely affect disease control by its
dopamine receptor antagonistic properties.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There were no significant differences between treated and control rats with respect to
mortality or neoplasia in a 96-week study of carbidopa at oral doses of 25, 45, or 135
mg/kg/day. Combinations of carbidopa and levodopa (10-20, 10-50, 10-100 mg/kg/day) were
given orally to rats for 106 weeks. No effect on mortality or incidence and type of neoplasia
was seen when compared to concurrent controls.
Mutagenesis
Mutagenicity studies have not been performed with either carbidopa or the combination of
carbidopa and levodopa.
Fertility
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Carbidopa had no effect on the mating performance, fertility, or survival of the young when
administered orally to rats at doses of 30, 60, or 120 mg/kg/day. The highest dose caused a
moderate decrease in body weight gain in males.
The administration of carbidopa-levodopa at dose levels of 10-20, 10-50, or 10-100
mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive
performance, or the growth and survival of the young.
Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies with LODOSYN
in pregnant women. It has been reported from individual cases that levodopa crosses the
human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in
fetal tissue appeared to be minimal. LODOSYN should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Carbidopa, at doses as high as 120 mg/kg/day, was without teratogenic effects in the
mouse or rabbit. In the rabbit, but not in the mouse, carbidopa-levodopa produced visceral
anomalies, similar to those seen with levodopa alone, at approximately 7 times the maximum
recommended human dose. The teratogenic effect of levodopa in rabbits was unchanged by
the concomitant administration of carbidopa.
Nursing Mothers
It is not known whether carbidopa is excreted in human milk. Because many drugs are
excreted in human milk, and because of their potential for serious adverse reactions 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 nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established, and use of the drug
in patients below the age of 18 is not recommended.
Reference ID: 3458203
Geriatric Use
Clinical studies of LODOSYN did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other 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
concomitant disease and other drug therapy.
ADVERSE REACTIONS
Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the
recommended doses. The only adverse reactions that have been observed have been with
concomitant use of carbidopa with other drugs such as levodopa, and with carbidopa
levodopa combination products.
When LODOSYN is administered concomitantly with levodopa or carbidopa-levodopa
combination products, the most common adverse reactions have included dyskinesias such
as choreiform, dystonic, and other involuntary movements, and nausea. Other adverse reactions
reported with LODOSYN when administered concomitantly with levodopa alone or
carbidopa-levodopa combination products were psychotic episodes including delusions,
hallucinations, and paranoid ideation, depression with or without development of suicidal
tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with
concomitant use of LODOSYN and levodopa has not been established.
The following other adverse reactions have been reported with levodopa and carbidopa
levodopa combination products. These same adverse reactions may also occur when
LODOSYN is administered with these products.
Body as a Whole: abdominal pain and distress, asthenia, chest pain, fatigue.
Cardiovascular: cardiac irregularities, hypertension, myocardial infarction, hypotension
including orthostatic hypotension, palpitation, phlebitis, syncope.
Gastrointestinal: anorexia, bruxism, burning sensation of the tongue, constipation, dark
saliva, development of duodenal ulcer, diarrhea, dry mouth, dyspepsia, dysphagia,
flatulence, gastrointestinal bleeding, gastrointestinal pain, heartburn, hiccups, sialorrhea, taste
alterations, vomiting.
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Hematologic: hemolytic and non-hemolytic anemia, leukopenia, thrombocytopenia,
agranulocytosis.
Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous lesions
(including pemphigus-like reactions).
Metabolic: edema, weight gain, weight loss.
Musculoskeletal: back pain, leg pain, muscle cramps, shoulder pain.
Nervous System/Psychiatric: Psychotic episodes including delusions, hallucinations and
paranoid ideation, neuroleptic malignant syndrome (NMS, see WARNINGS), bradykinetic
episodes (“on-off” phenomenon), confusion, agitation, dizziness, somnolence, dream
abnormalities including nightmares, insomnia, paresthesia, headache, depression with or without
development of suicidal tendencies, dementia, pathological gambling, increased libido including
hypersexuality, impulse control symptoms. Convulsions also have occurred; however, a causal
relationship with LODOSYN and levodopa, has not been established.
Respiratory: upper respiratory infection, dyspnea, pharyngeal pain, cough.
Skin: flushing, increased sweating, malignant melanoma (see also CONTRAINDICATIONS),
rash, alopecia, dark sweat.
Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils.
Urogenital: dark urine, priapism, urinary frequency, urinary incontinence, urinary retention,
urinary tract infection.
Laboratory Tests: abnormalities in alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic
dehydrogenase, bilirubin, blood urea nitrogen (BUN), Coombs test; elevated serum glucose;
decreased hemoglobin and hematocrit; decreased white blood cell count and serum
potassium; increased serum creatinine and uric acid; white blood cells, bacteria and blood in
the urine; protein and glucose in the urine.
Miscellaneous: bizarre breathing patterns, faintness, hoarseness, hot flashes, malaise,
neuroleptic malignant syndrome, sense of stimulation.
OVERDOSAGE
No reports of overdose with LODOSYN have been received. Management of overdosage with
carbidopa is the same as that with levodopa or carbidopa-levodopa preparations.
Reference ID: 3458203
In the event of overdosage, general supportive measures should be employed, along with
immediate gastric lavage. Intravenous fluids should be administered judiciously, and an
adequate airway maintained. Electrocardiographic monitoring should be instituted and the
patient carefully observed for the development of arrhythmias; if required, appropriate
antiarrhythmic therapy should be given. The possibility that the patient may have taken other
drugs as well as LODOSYN should be taken into consideration. To date, no experience has
been reported with dialysis; hence, its value in overdosage is not known. Pyridoxine is not
effective in reversing the actions of LODOSYN.
Based on studies in which high doses of levodopa and/or carbidopa were administered, a
significant proportion of rats and mice given single oral doses of levodopa of approximately
1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are
expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die
after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with
levodopa increases the dose at which a significant proportion of mice are expected to die to
3360 mg/kg.
DOSAGE AND ADMINISTRATION
Whether given with carbidopa-levodopa or with levodopa, the optimal daily dose of
LODOSYN must be determined by careful titration. Most patients respond to a 1:10
proportion of carbidopa and levodopa, provided the daily dosage of carbidopa is 70 mg or
more a day. The maximum daily dosage of carbidopa should not exceed 200 mg, since
clinical experience with larger dosages is limited. If the patient is taking carbidopa-levodopa,
the amount of carbidopa in carbidopa-levodopa should be considered when calculating the
total amount of LODOSYN to be administered each day.
Patients Receiving Carbidopa-Levodopa Who
Require Additional Carbidopa
Some patients taking carbidopa-levodopa may not have adequate reduction in nausea and
vomiting when the dosage of carbidopa is less than 70 mg a day, and the dosage of levodopa
is less than 700 mg a day. When these patients are taking carbidopa-levodopa, 25 mg of
LODOSYN may be given with the first dose of carbidopa-levodopa each day. Additional
doses of 12.5 mg or 25 mg may be given during the day with each dose of carbidopa
levodopa. LODOSYN may be given with any dose carbidopa-levodopa as required for
optimum therapeutic response. The maximum daily dosage of carbidopa, given as LODOSYN
and as carbidopa- levodopa), should not exceed 200 mg.
Patients Requiring Individual Titration of Carbidopa and
Reference ID: 3458203
Levodopa Dosage
Although carbidopa-levodopa is the most frequently used of carbidopa and levodopa
administration, there may be an occasional patient who requires individually titrated doses of
these two drugs. In these patients, LODOSYN (carbidopa) should be initiated at a dosage
of 25 mg three or four times a day. The two drugs should be given at the same time,
starting with no more than one-fifth (20%) to one-fourth (25%) of the previous or
recommended daily dosage of levodopa when given without LODOSYN (Carbidopa). In
patients already receiving levodopa therapy, at least twelve hours should elapse between
the last dose of levodopa and initiation of therapy with LODOSYN (Carbidopa) and
levodopa. A convenient way to initiate therapy in these patients is in the morning
following a night when the patient has not taken levodopa for at least twelve hours.
Health care providers who prescribe separate doses of LODOSYN and levodopa should be
thoroughly familiar with the directions for use of each drug.
Dosage Adjustment
Dosage of LODOSYN may be adjusted by adding or omitting one-half or one tablet a day.
Because both therapeutic and adverse responses occur more rapidly with combined therapy
than when only levodopa is given, patients should be monitored closely during the dose
adjustment period. Specifically, involuntary movements will occur more rapidly when
LODOSYN and levodopa are given concomitantly than when levodopa is given without
LODOSYN. The occurrence of involuntary movements may require dosage reduction.
Blepharospasm may be a useful early sign of excess dosage in some patients.
Current evidence indicates other standard antiparkinsonian drugs may be continued while
carbidopa and levodopa are being administered. However, the dosage of such other
standard antiparkinsonian drugs may require adjustment.
Interruption of Therapy
Sporadic cases of hyperpyrexia and confusion have been associated with dose reductions and
withdrawal of carbidopa-Levodopa) or carbidopa-levodopa Extended Release. Patients should
be observed carefully if abrupt reduction or discontinuation of carbidopa-levodopa or
carbidopa-levodopa Extended-Release is required, especially if the patient is receiving
neuroleptics. (See WARNINGS.)
If general anesthesia is required, therapy may be continued as long as the patient is
Reference ID: 3458203
permitted to take fluids and medication by mouth. When therapy is interrupted temporarily,
the patient should be observed for symptoms resembling NMS, and the usual daily dosage
may be resumed as soon as the patient is able to take medication orally.
HOW SUPPLIED
Tablets LODOSYN, 25 mg, are orange, round, compressed tablets that are scored and coded
711 on one side and LODOSYN on the other.
They are supplied as follows:
NDC 0056-0511-68 bottles of 100.
Storage
Store at 25°C (77°F), excursions permitted to 15–30°C (59–86°F).
Manufactured in Canada by:
Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7
Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA
Rev. 2/2014
Reference ID: 3458203
|
custom-source
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2025-02-12T13:44:22.448879
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/017830s014s016s017s018s019s030lbl.pdf', 'application_number': 17830, 'submission_type': 'SUPPL ', 'submission_number': 30}
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11,077
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REGLAN - metoclopramide tablet
Alaven Pharmaceutical LLC
----------
reglan tablets (metoclopramide tablets, USP)
Rx Only
WARNING
TARDIVE DYSKINESIA
Treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder
that is often irreversible. The risk of developing tardive dyskinesia increases with duration of
treatment and total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or symptoms
of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In some patients,
symptoms may lessen or resolve after metoclopramide treatment is stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare
cases where therapeutic benefit is thought to outweigh the risk of developing tardive
dyskinesia.
See WARNINGS
DESCRIPTION
For oral administration, reglan tablets (metoclopramide tablets, USP) 10 mg are white, scored,
capsule-shaped tablets engraved REGLAN on one side and SP 10 on the opposite side.
Each tablet contains:
Metoclopramide base .................................................. 10 mg
(as the monohydrochloride monohydrate)
Inactive Ingredients
Magnesium Stearate, Mannitol, Microcrystalline Cellulose, Stearic Acid.
reglan tablets (metoclopramide tablets, USP) 5 mg are green, elliptical-shaped tablets engraved
REGLAN 5 on one side and SP on the opposite side.
Each tablet contains:
Metoclopramide base .................................................... 5 mg
(as the monohydrochloride monohydrate)
Inactive Ingredients
Corn starch, D&C Yellow 10 Aluminum Lake, FD&C Blue 1 Aluminum Lake, Lactose, Microcrystalline
Cellulose, Silicon Dioxide, Stearic Acid.
Metoclopramide hydrochloride is a white crystalline, odorless substance, freely soluble in water.
Chemically, it is 4-amino-5- chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide
monohydrochloride monohydrate. Its molecular formula is C
H
CIN O •HCl•H O. Its molecular
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22
3
2
2
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weight is 354.3.
CLINICAL PHARMACOLOGY
Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric,
biliary, or pancreatic secretions. Its mode of action is unclear. It seems to sensitize tissues to the
action of acetylcholine. The effect of metoclopramide on motility is not dependent on intact vagal
innervation, but it can be abolished by anticholinergic drugs.
Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions, relaxes
the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum
resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the
lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder.
In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter pressure), single
oral doses of metoclopramide produce dose-related increases in LESP. Effects begin at about 5 mg
and increase through 20 mg (the largest dose tested). The increase in LESP from a 5 mg dose lasts
about 45 minutes and that of 20 mg lasts between 2 and 3 hours. Increased rate of stomach emptying
has been observed with single oral doses of 10 mg.
The antiemetic properties of metoclopramide appear to be a result of its antagonism of central and
peripheral dopamine receptors. Dopamine produces nausea and vomiting by stimulation of the
medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the CTZ by
agents like l-dopa or apomorphine which are known to increase dopamine levels or to possess
dopamine-like effects. Metoclopramide also abolishes the slowing of gastric emptying caused by
apomorphine.
Like the phenothiazines and related drugs, which are also dopamine antagonists, metoclopramide
produces sedation and may produce extrapyramidal reactions, although these are comparatively rare
(see WARNINGS). Metoclopramide inhibits the central and peripheral effects of apomorphine,
induces release of prolactin and causes a transient increase in circulating aldosterone levels, which
may be associated with transient fluid retention.
The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an intravenous
dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes following an oral
dose; pharmacological effects persist for 1 to 2 hours.
Pharmacokinetics
Metoclopramide is rapidly and well absorbed. Relative to an intravenous dose of 20 mg, the absolute
oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a crossover study of 18
subjects. Peak plasma concentrations occur at about 1 to 2 hr after a single oral dose. Similar time to
peak is observed after individual doses at steady state.
In a single dose study of 12 subjects, the area under the drug concentration-time curve increases
linearly with doses from 20 to 100 mg. Peak concentrations increase linearly with dose; time to peak
concentrations remains the same; whole body clearance is unchanged; and the elimination rate
remains the same. The average elimination half-life in individuals with normal renal function is 5 to 6
hr. Linear kinetic processes adequately describe the absorption and elimination of metoclopramide.
Chemical Structure
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Approximately 85% of the radioactivity of an orally administered dose appears in the urine within 72
hr. Of the 85% eliminated in the urine, about half is present as free or conjugated metoclopramide.
The drug is not extensively bound to plasma proteins (about 30%). The whole body volume of
distribution is high (about 3.5 L/kg) which suggests extensive distribution of drug to the tissues.
Renal impairment affects the clearance of metoclopramide. In a study with patients with varying
degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction in
plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life. The
kinetics of metoclopramide in the presence of renal impairment remained linear however. The
reduction in clearance as a result of renal impairment suggests that adjustment downward of
maintenance dosage should be done to avoid drug accumulation.
In pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous
administration are highly variable and a concentration-effect relationship has not been established.
There are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide in
adults and the pediatric population are similar. Although there are insufficient data to support the
efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux (GER) or
cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been studied in these
patient populations.
In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with GER received
metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The mean peak plasma
concentration of metoclopramide after the tenth dose was 2-fold (56.8 μg/L) higher compared to that
observed after the first dose (29 μg/L) indicating drug accumulation with repeated dosing. After the
tenth dose, the mean time to reach peak concentrations (2.2 hr), half-life (4.1 hr), clearance (0.67
L/h/kg), and volume of distribution (4.4 L/kg) of metoclopramide were similar to those observed after
the first dose. In the youngest patient (age, 3.5 weeks), metoclopramide half-life after the first and the
tenth dose (23.1 and 10.3 hr, respectively) was significantly longer compared to other infants due to
reduced clearance. This may be attributed to immature hepatic and renal systems at birth.
Single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were
administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (mean age, 11.7
years; range, 7 to 14 yr) for prophylaxis of cytotoxic-induced vomiting. The metoclopramide plasma
concentrations extrapolated to time zero ranged from 65 to 395 μg/L (mean, 152 μg/L). The mean
elimination half-life, clearance, and volume of distribution of metoclopramide were 4.4 hr (range, 1.7
to 8.3 hr), 0.56 L/h/kg (range, 0.12 to 1.20 L/h/kg), and 3.0 L/kg (range, 1.0 to 4.8 L/kg), respectively.
In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received 4 to 5 intravenous
infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control emesis. After the last
dose, the peak serum concentrations of metoclopramide ranged from 1060 to 5680 μg/L. The mean
Adult Pharmacokinetic Data
Parameter
Value
Vd (L/kg)
~ 3.5
Plasma Protein Binding
~ 30%
t
(hr)
5 to 6
Oral Bioavailability
80%±15.5%
1/2
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elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hr (range, 2.0
to 12.5 hr), 0.37 L/h/kg (range, 0.10 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to 5.50 L/kg),
respectively.
INDICATIONS AND USAGE
The use of reglan tablets is recommended for adults only. Therapy should not exceed 12 weeks in
duration.
Symptomatic Gastroesophageal Reflux
reglan tablets are indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic,
documented gastroesophageal reflux who fail to respond to conventional therapy.
The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn with
less observed effect on nocturnal symptoms. If symptoms are confined to particular situations, such
as following the evening meal, use of metoclopramide as single doses prior to the provocative
situation should be considered, rather than using the drug throughout the day. Healing of esophageal
ulcers and erosions has been endoscopically demonstrated at the end of a 12-week trial using doses
of 15 mg q.i.d. As there is no documented correlation between symptoms and healing of esophageal
lesions, patients with documented lesions should be monitored endoscopically.
Diabetic Gastroparesis (Diabetic Gastric Stasis)
reglan tablets (metoclopramide tablets, USP) is indicated for the relief of symptoms associated with
acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying
(e.g., nausea, vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond to
reglan within different time intervals. Significant relief of nausea occurs early and continues to
improve over a three-week period. Relief of vomiting and anorexia may precede the relief of
abdominal fullness by one week or more.
CONTRAINDICATIONS
Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be
dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or
perforation.
Metoclopramide is contraindicated in patients with pheochromocytoma because the drug may cause
a hypertensive crisis, probably due to release of catecholamines from the tumor. Such hypertensive
crises may be controlled by phentolamine.
Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug.
Metoclopramide should not be used in epileptics or patients receiving other drugs which are likely to
cause extrapyramidal reactions, since the frequency and severity of seizures or extrapyramidal
reactions may be increased.
WARNINGS
Mental depression has occurred in patients with and without prior history of depression. Symptoms
have ranged from mild to severe and have included suicidal ideation and suicide. Metoclopramide
should be given to patients with a prior history of depression only if the expected benefits outweigh
the potential risks.
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Extrapyramidal symptoms, manifested primarily as acute dystonic reactions, occur in approximately 1
in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of metoclopramide. These
usually are seen during the first 24 to 48 hours of treatment with metoclopramide, occur more
frequently in pediatric patients and adult patients less than 30 years of age and are even more
frequent at higher doses. These symptoms may include involuntary movements of limbs and facial
grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus,
or dystonic reactions resembling tetanus. Rarely, dystonic reactions may present as stridor and
dyspnea, possibly due to laryngospasm. If these symptoms should occur, inject 50 mg
diphenhydramine hydrochloride intramuscularly, and they usually will subside. Benztropine mesylate,
1 to 2 mg intramuscularly, may also be used to reverse these reactions.
Parkinsonian-like symptoms have occurred, more commonly within the first 6 months after beginning
treatment with metoclopramide, but occasionally after longer periods. These symptoms generally
subside within 2 to 3 months following discontinuance of metoclopramide. Patients with preexisting
Parkinson's disease should be given metoclopramide cautiously, if at all, since such patients may
experience exacerbation of parkinsonian symptoms when taking metoclopramide.
Tardive Dyskinesia
(see Boxed Warnings)
Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and
disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities.
Although the risk of TD with metoclopramide has not been extensively studied, one published study
reported a TD prevalence of 20% among patients treated for at least 12 weeks. Treatment with
metoclopramide for longer than 12 weeks should be avoided in all but rare cases where therapeutic
benefit is thought to outweigh the risk of developing TD.
Although the risk of developing TD in the general population may be increased among the elderly,
women, and diabetics, it is not possible to predict which patients will develop metoclopramide-
induced TD. Both the risk of developing TD and the likelihood that TD will become irreversible
increase with duration of treatment and total cumulative dose.
Metoclopramide should be discontinued in patients who develop signs or symptoms of TD. There is
no known effective treatment for established cases of TD, although in some patients, TD may remit,
partially or completely, within several weeks to months after metoclopramide is withdrawn.
Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby masking the
underlying disease process. The effect of this symptomatic suppression upon the long-term course of
TD is unknown. Therefore, metoclopramide should not be used for the symptomatic control of TD.
Neuroleptic Malignant Syndrome (NMS)
There have been rare reports of an uncommon but potentially fatal symptom complex sometimes
referred to as Neuroleptic Malignant Syndrome (NMS) associated with metoclopramide. Clinical
manifestations of NMS include hyperthermia, muscle rigidity, altered consciousness, and evidence of
autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac
arrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is
important to identify cases where the clinical presentation includes both serious medical illness (e.g.,
pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and
symptoms (EPS). Other important considerations in the differential diagnosis include central
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anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever and primary central nervous
system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of metoclopramide and other
drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical
monitoring, and 3) treatment of any concomitant serious medical problems for which specific
treatments are available. Bromocriptine and dantrolene sodium have been used in treatment of NMS,
but their effectiveness have not been established (see ADVERSE REACTIONS).
PRECAUTIONS
General
In one study in hypertensive patients, intravenously administered metoclopramide was shown to
release catecholamines; hence, caution should be exercised when metoclopramide is used in
patients with hypertension.
Because metoclopramide produces a transient increase in plasma aldosterone, certain patients,
especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid retention
and volume overload. If these side effects occur at any time during metoclopramide therapy, the drug
should be discontinued.
Adverse reactions, especially those involving the nervous system, may occur after stopping the use of
reglan . A small number of patients may experience a withdrawal period after stopping reglan that
could include dizziness, nervousness, and/or headaches.
Information for Patients
The use of reglan is recommended for adults only. Metoclopramide may impair the mental and/or
physical abilities required for the performance of hazardous tasks such as operating machinery or
driving a motor vehicle. The ambulatory patient should be cautioned accordingly.
For additional information, patients should be instructed to see the Medication Guide for reglan
tablets.
Drug Interactions
The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs
and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with
alcohol, sedatives, hypnotics, narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines in patients with essential hypertension
suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase
inhibitors.
Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas
the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g.,
acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).
Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients.
Exogenously administered insulin may begin to act before food has left the stomach and lead to
hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the
intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
A 77-week study was conducted in rats with oral doses up to about 40 times the maximum
recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation persists
during chronic administration. Tissue culture experiments indicate that approximately one-third of
human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the
prescription of metoclopramide is contemplated in a patient with previously detected breast cancer.
Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been
reported with prolactin-elevating drugs, the clinical significance of elevated serum prolactin levels is
unknown for most patients. An increase in mammary neoplasms has been found in rodents after
chronic administration of prolactin-stimulating neuroleptic drugs and metoclopramide. Neither clinical
studies nor epidemiologic studies conducted to date, however, have shown an association between
chronic administration of these drugs and mammary tumorigenesis; the available evidence is too
limited to be conclusive at this time.
An Ames mutagenicity test performed on metoclopramide was negative.
Pregnancy Category B
Reproduction studies performed in rats, mice and rabbits by the I.V., I.M., S.C., and oral routes at
maximum levels ranging from 12 to 250 times the human dose have demonstrated no impairment of
fertility or significant harm to the fetus due to metoclopramide. 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
Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide is
administered to a nursing mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established (see OVERDOSAGE).
Care should be exercised in administering metoclopramide to neonates since prolonged clearance
may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY -
Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b reductase
which, in combination with the aforementioned pharmacokinetic factors, make neonates more
susceptible to methemoglobinemia (see OVERDOSAGE).
The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients. Dystonias
and other extrapyramidal reactions associated with metoclopramide are more common in the
pediatric population than in adults. (See WARNINGS and ADVERSE REACTIONS - Extrapyramidal
Reactions.)
Geriatric Use
Clinical studies of reglan did not include sufficient numbers of subjects aged 65 and over to
determine whether elderly subjects respond differently from younger subjects.
The risk of developing parkinsonian-like side effects increases with ascending dose. Geriatric patients
should receive the lowest dose of reglan
that is effective. If parkinsonian-like symptoms develop in a
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geriatric patient receiving reglan , reglan
should generally be discontinued before initiating any
specific anti-parkinsonian agents (see WARNINGS and DOSAGE AND ADMINISTRATION – For the
Relief of Symptomatic Gastroesophageal Reflux).
The elderly may be at greater risk for tardive dyskinesia (see WARNINGS – Tardive Dyskinesia).
Sedation has been reported in reglan users. Sedation may cause confusion and manifest as over-
sedation in the elderly (see CLINICAL PHARMACOLOGY, PRECAUTIONS – Information for Patients
and ADVERSE REACTIONS – CNS Effects).
reglan 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 (see DOSAGE AND ADMINISTRATION – Use
in Patients with Renal or Hepatic Impairment).
For these reasons, 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 renal function, concomitant
disease, or other drug therapy in the elderly (see DOSAGE AND ADMINISTRATION – For the Relief
of Symptomatic Gastroesophageal Reflux and Use in Patients with Renal or Hepatic Impairment).
Other Special Populations
Patients with NADH-cytochrome b reductase deficiency are at an increased risk of developing
methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In patients
with G6PD deficiency who experience metoclopramide- induced methemoglobinemia, methylene blue
treatment is not recommended (see OVERDOSAGE).
ADVERSE REACTIONS
In general, the incidence of adverse reactions correlates with the dose and duration of
metoclopramide administration. The following reactions have been reported, although in most
instances, data do not permit an estimate of frequency:
CNS Effects
Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients receiving the
most commonly prescribed dosage of 10 mg q.i.d. (see PRECAUTIONS). Insomnia, headache,
confusion, dizziness, or mental depression with suicidal ideation (see WARNINGS) occur less
frequently. The incidence of drowsiness is greater at higher doses. There are isolated reports of
convulsive seizures without clearcut relationship to metoclopramide. Rarely, hallucinations have been
reported.
Extrapyramidal Reactions (EPS)
Acute dystonic reactions, the most common type of EPS associated with metoclopramide, occur in
approximately 0.2% of patients (1 in 500) treated with 30 to 40 mg of metoclopramide per day.
Symptoms include involuntary movements of limbs, facial grimacing, torticollis, oculogyric crisis,
rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like reactions),
and, rarely, stridor and dyspnea possibly due to laryngospasm; ordinarily these symptoms are readily
reversed by diphenhydramine (see WARNINGS).
Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask-like facies
(see WARNINGS).
Tardive dyskinesia most frequently is characterized by involuntary movements of the tongue, face,
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mouth, or jaw, and sometimes by involuntary movements of the trunk and/or extremities; movements
may be choreoathetotic in appearance (see WARNINGS).
Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness, and insomnia,
as well as inability to sit still, pacing, foot tapping. These symptoms may disappear spontaneously or
respond to a reduction in dosage.
Neuroleptic Malignant Syndrome
Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This potentially fatal
syndrome is comprised of the symptom complex of hyperthermia, altered consciousness, muscular
rigidity, and autonomic dysfunction (see WARNINGS).
Endocrine Disturbances
Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see
PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see CLINICAL
PHARMACOLOGY).
Cardiovascular
Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute
congestive heart failure and possible AV block (see CONTRAINDICATIONS and PRECAUTIONS).
Gastrointestinal
Nausea and bowel disturbances, primarily diarrhea.
Hepatic
Rarely, cases of hepatotoxicity, characterized by such findings as jaundice and altered liver function
tests, when metoclopramide was administered with other drugs with known hepatotoxic potential.
Renal
Urinary frequency and incontinence.
Hematologic
A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut relationship to
metoclopramide. Methemoglobinemia, in adults and especially with overdosage in neonates (see
OVERDOSAGE). Sulfhemoglobinemia in adults.
Allergic Reactions
A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma.
Rarely, angioneurotic edema, including glossal or laryngeal edema.
Miscellaneous
Visual disturbances. Porphyria.
OVERDOSAGE
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Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions.
Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic properties may be helpful
in controlling the extrapyramidal reactions. Symptoms are self-limiting and usually disappear within 24
hours.
Hemodialysis removes relatively little metoclopramide, probably because of the small amount of the
drug in blood relative to tissues. Similarly, continuous ambulatory peritoneal dialysis does not remove
significant amounts of drug. It is unlikely that dosage would need to be adjusted to compensate for
losses through dialysis. Dialysis is not likely to be an effective method of drug removal in overdose
situations.
Unintentional overdose due to misadministration has been reported in infants and children with the
use of metoclopramide oral solution. While there was no consistent pattern to the reports associated
with these overdoses, events included seizures, extrapyramidal reactions, and lethargy.
Methemoglobinemia has occurred in premature and full-term neonates who were given overdoses of
metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously for 1 to 3 or more days).
Methemoglobinemia can be reversed by the intravenous administration of methylene blue. However,
methylene blue may cause hemolytic anemia in patients with G6PD deficiency, which may be fatal
(see PRECAUTIONS – Other Special Populations).
DOSAGE AND ADMINISTRATION
Therapy with reglan tablets should not exceed 12 weeks in duration.
For the Relief of Symptomatic Gastroesophageal Reflux
Administer from 10 mg to 15 mg reglan (metoclopramide hydrochloride, USP) orally up to q.i.d. 30
minutes before each meal and at bedtime, depending upon symptoms being treated and clinical
response (see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). If symptoms occur
only intermittently or at specific times of the day, use of metoclopramide in single doses up to 20 mg
prior to the provoking situation may be preferred rather than continuous treatment. Occasionally,
patients (such as elderly patients) who are more sensitive to the therapeutic or adverse effects of
metoclopramide will require only 5 mg per dose.
Experience with esophageal erosions and ulcerations is limited, but healing has thus far been
documented in one controlled trial using q.i.d. therapy at 15 mg/dose, and this regimen should be
used when lesions are present, so long as it is tolerated (see ADVERSE REACTIONS). Because of
the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy
directed at esophageal lesions is best guided by endoscopic evaluation.
Therapy longer than 12 weeks has not been evaluated and cannot be recommended.
For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric Stasis)
Administer 10 mg of metoclopramide 30 minutes before each meal and at bedtime for two to eight
weeks, depending upon response and the likelihood of continued well-being upon drug
discontinuation.
The initial route of administration should be determined by the severity of the presenting symptoms. If
only the earliest manifestations of diabetic gastric stasis are present, oral administration of reglan
may be initiated. However, if severe symptoms are present, therapy should begin with
metoclopramide injection (consult labeling of the injection prior to initiating parenteral administration).
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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
Administration of metoclopramide injection up to 10 days may be required before symptoms subside,
at which time oral administration may be instituted. Since diabetic gastric stasis is frequently
recurrent, reglan therapy should be reinstituted at the earliest manifestation.
Use in Patients with Renal or Hepatic Impairment
Since metoclopramide is excreted principally through the kidneys, in those patients whose creatinine
clearance is below 40 mL/min, therapy should be initiated at approximately one-half the
recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may
be increased or decreased as appropriate.
See OVERDOSAGE section for information regarding dialysis.
Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe use
has been described in patients with advanced liver disease whose renal function was normal.
HOW SUPPLIED
Each white, capsule-shaped, scored reglan tablet (metoclopramide tablets, USP) contains 10 mg
metoclopramide base (as the monohydrochloride monohydrate). Available in:
Bottles of 100 tablets (NDC 68220-151-10)
Each green, elliptical-shaped reglan tablet (metoclopramide tablets, USP) contains 5 mg
metoclopramide base (as the monohydrochloride monohydrate). Available in:
Bottles of 100 tablets (NDC 68220-150-10)
Dispense tablets in tight, light-resistant container.
Tablets should be stored at controlled room temperature, between 20°C and 25°C (68°F and 77°F).
Manufactured for:
ALAVEN PHARMACEUTICAL LLC
Marietta, GA 30062
For Medical Inquiries, call toll-free 1-888-317-0001
www.alavenpharm.com
Rev. 07/2009
Medication Guide
REGLAN (REG-lan) Tablets
(metoclopramide tablets)
Read the Medication Guide that comes with REGLAN before you start taking it and each time you get
a refill. There may be new information. If you take another product that contains metoclopramide
(such as REGLAN injection, REGLAN ODT, or metoclopramide oral syrup), you should read the
Medication Guide that comes with that product. Some of the information may be different. This
Medication Guide does not take the place of talking with your doctor about your medical condition or
your treatment.
What is the most important information I should know about REGLAN?
®
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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
REGLAN can cause serious side effects, including:
Abnormal muscle movements called tardive dyskinesia (TD). These movements happen mostly in the
face muscles. You can not control these movements. They may not go away even after stopping
REGLAN. There is no treatment for TD, but symptoms may lessen or go away over time after you
stop taking REGLAN.
Your chances for getting TD go up:
z the longer you take REGLAN and the more REGLAN you take. You should not take REGLAN
for more than 12 weeks.
z if you are older, especially if you are a woman
z if you have diabetes
It is not possible for your doctor to know if you will get TD if you take REGLAN.
Call your doctor right away if you get movements you can not stop or control, such as:
z lip smacking, chewing, or puckering up your mouth
z frowning or scowling
z sticking out your tongue
z blinking and moving your eyes
z shaking of your arms and legs
See the section "What are the possible side effects of REGLAN?" for more information about side
effects.
What is REGLAN?
REGLAN is a prescription medicine used:
z in adults for 4 to 12 weeks to relieve heartburn symptoms with gastroesophageal reflux disease
(GERD) when certain other treatments do not work. REGLAN relieves daytime heartburn and
heartburn after meals. It also helps ulcers in the esophagus to heal.
z to relieve symptoms of slow stomach emptying in people with diabetes. REGLAN helps treat
symptoms such as nausea, vomiting, heartburn, feeling full long after a meal, and loss of
appetite. Not all these symptoms get better at the same time.
It is not known if REGLAN is safe and works in children.
Who should not take REGLAN?
Do not take REGLAN if you:
z have stomach or intestine problems that could get worse with REGLAN, such as bleeding,
blockage or a tear in the stomach or bowel wall
z have an adrenal gland tumor called a pheochromocytoma
z are allergic to REGLAN or anything in it. See the end of this Medication Guide for a list of
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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
ingredients in REGLAN.
z take medicines that can cause uncontrolled movements, such as medicines for mental illness
z have seizures
What should I tell my doctor before taking REGLAN?
Tell your doctor about all your medical conditions, including if you have:
z depression
z Parkinson's disease
z high blood pressure
z kidney problems. Your doctor may start with a lower dose.
z liver problems or heart failure. REGLAN may cause your body to hold fluids.
z diabetes. Your dose of insulin may need to be changed.
z breast cancer
z you are pregnant or plan to become pregnant. It is not known if REGLAN will harm your unborn
baby.
z you are breast-feeding. REGLAN can pass into breast milk and may harm your baby. Talk with
your doctor about the best way to feed your baby if you take REGLAN.
Tell your doctor about all the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements. REGLAN and some other medicines may interact with
each other and may not work as well, or cause possible side effects. Do not start any new medicines
while taking REGLAN until you talk with your doctor.
Especially tell your doctor if you take:
z another medicine that contains metoclopramide, such as REGLAN ODT, or metoclopramide
oral syrup
z a blood pressure medicine
z a medicine for depression, especially an Monoamine Oxidase Inhibitor (MAOI)
z insulin
z a medicine that can make you sleepy, such as anti-anxiety medicine, sleep medicines, and
narcotics.
If you are not sure if your medicine is one listed above, ask your doctor or pharmacist.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when
you get a new medicine.
How should I take REGLAN?
z REGLAN comes as a tablet you take by mouth.
z Take REGLAN exactly as your doctor tells you. Do not change your dose unless your doctor
tells you.
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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
z You should not take REGLAN for more than 12 weeks.
z If you take too much REGLAN, call your doctor or Poison Control Center right away.
What should I avoid while taking REGLAN?
z Do not drink alcohol while taking REGLAN. Alcohol may make some side effects of REGLAN
worse, such as feeling sleepy.
z Do not drive, work with machines, or do dangerous tasks until you know how REGLAN affects
you. REGLAN may cause sleepiness.
What are the possible side effects of REGLAN?
Reglan can cause serious side effects, including:
z Abnormal muscle movements. See "What is the most important information I need to know
about REGLAN?"
z Uncontrolled spasms of your face and neck muscles, or muscles of your body, arms, and legs
(dystonia). These muscle spasms can cause abnormal movements and body positions. These
spasms usually start within the first 2 days of treatment. These spasms happen more often in
children and adults under age 30.
z Depression, thoughts about suicide, and suicide. Some people who take REGLAN become
depressed. You may have thoughts about hurting or killing yourself. Some people who take
Reglan have ended their own lives (suicide).
z Neuroleptic Malignant Syndrome (NMS). NMS is a very rare but very serious condition that can
happen with Reglan. NMS can cause death and must be treated in a hospital. Symptoms of
NMS include: high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and
increased sweating.
z Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving or keeping your
balance. If you already have Parkinson's disease, your symptoms may become worse while you
are receiving REGLAN.
Call your doctor and get medical help right away if you:
z feel depressed or have thoughts about hurting or killing yourself
z have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and increased
sweating
z have muscle movements you cannot stop or control
z have muscle movements that are new or unusual
Common side effects of Reglan include:
z feeling restless, sleepy, tired, dizzy, or exhausted
z headache
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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
z confusion
z trouble sleeping
You may have more side effects the longer you take REGLAN and the more REGLAN you take.
You may still have side effects after stopping REGLAN. You may have symptoms from stopping
(withdrawal) REGLAN such as headaches, and feeling dizzy or nervous.
Tell your doctor about any side effects that bother you or do not go away. These are not all the
possible side effects of REGLAN.
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 REGLAN?
z Keep REGLAN at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
z Keep REGLAN in the bottle it comes in. Keep the bottle closed tightly.
Keep REGLAN and all medicines out of the reach of children.
General information about REGLAN
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do
not use REGLAN for a condition for which it was not prescribed. Do not give REGLAN to other
people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about REGLAN. If you would like
more information, talk with your doctor. You can ask your doctor or pharmacist for information about
REGLAN that is written for health professionals. For more information, go to www.alavenpharm.com
or call 1-888-317-0001.
What are the ingredients in REGLAN?
Active ingredient: metoclopramide
Inactive ingredients:
Manufactured for:
ALAVEN PHARMACEUTICAL LLC
Marietta, GA 30062
For Medical Inquiries, call toll-free 1-888-317-0001
www.alavenpharm.com
Revised July 2009
This Medication Guide has been approved by the U.S. Food and Drug Administration.
REGLAN 10 mg tablets: magnesium stearate, mannitol, microcrystalline cellulose, stearic acid
REGLAN 5 mg tablets: corn starch, D&C yellow 10 aluminum lake, FD&C blue 1 aluminum lake,
lactose, microcrystalline cellulose, silicon dioxide, stearic acid
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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
|
custom-source
|
2025-02-12T13:44:22.738464
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017854s052lbl.pdf', 'application_number': 17854, 'submission_type': 'SUPPL ', 'submission_number': 52}
|
11,075
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s
t
ructu
ral formu
l a
Didronel®
(etidronate disodium)
DESCRIPTION:
Didronel® tablets contain 400 mg of etidronate disodium, the disodium salt of (1
hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also known
as EHDP, regulates bone metabolism. It is a white powder, highly soluble in water, with a
molecular weight of 250 and the following structural formula:
Inactive Ingredients: Each tablet contains magnesium stearate, microcrystalline cellulose,
and starch.
CLINICAL PHARMACOLOGY:
Didronel acts primarily on bone. It can inhibit the formation, growth, and dissolution of
hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium
phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required
to inhibit crystal growth. Both effects increase as the dose increases.
Didronel is not metabolized. The amount of drug absorbed after an oral dose is
approximately 3 percent. In normal subjects, plasma half-life (t 1/2 ) of etidronate, based on
non-compartmental pharmacokinetics is 1 to 6 hours. Within 24 hours, approximately half
the absorbed dose is excreted in urine; the remainder is distributed to bone compartments
from which it is slowly eliminated. Animal studies have yielded bone clearance estimates up
to 165 days. In humans, the residence time on bone may vary due to such factors as
specific metabolic condition and bone type. Unabsorbed drug is excreted intact in the feces.
Preclinical studies indicate etidronate disodium does not cross the blood-brain barrier.
Didronel therapy does not adversely affect serum levels of parathyroid hormone or calcium.
Paget’s Disease: Paget's disease of bone (osteitis deformans) is an idiopathic, progressive
disease characterized by abnormal and accelerated bone metabolism in one or more
bones. Signs and symptoms may include bone pain and/or deformity, neurologic disorders,
elevated cardiac output and other vascular disorders, and increased serum alkaline
phosphatase and/or urinary hydroxyproline levels. Bone fractures are common in patients
with Paget's disease.
Didronel slows accelerated bone turnover (resorption and accretion) in pagetic lesions and,
to a lesser extent, in normal bone. This has been demonstrated histologically,
scintigraphically, biochemically, and through calcium kinetic and balance studies. Reduced
bone turnover is often accompanied by symptomatic improvement, including reduced bone
pain. Also, the incidence of pagetic fractures may be reduced, and elevated cardiac output
and other vascular disorders may be improved by Didronel therapy.
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Heterotopic Ossification: Heterotopic ossification, also referred to as myositis ossificans
(circumscripta, progressiva or traumatica), ectopic calcification, periarticular ossification, or
paraosteoarthropathy, is characterized by metaplastic osteogenesis. It usually presents with
signs of localized inflammation or pain, elevated skin temperature, and redness. When
tissues near joints are involved, functional loss may also be present.
Heterotopic ossification may occur for no known reason as in myositis ossificans
progressiva or may follow a wide variety of surgical, occupational, and sports trauma (for
example, hip arthroplasty, spinal cord injury, head injury, burns, and severe thigh bruises).
Heterotopic ossification has also been observed in non-traumatic conditions (for example,
infections of the central nervous system, peripheral neuropathy, tetanus, biliary cirrhosis,
Peyronie's disease, as well as in association with a variety of benign and malignant
neoplasms).
Clinical trials have demonstrated the efficacy of Didronel in heterotopic ossification
following total hip replacement, or due to spinal cord injury.
--Heterotopic ossification complicating total hip replacement typically develops
radiographically 3 to 8 weeks postoperatively in the pericapsular area of the affected hip
joint. The overall incidence is about 50 percent; about one-third of these cases are
clinically significant.
--Heterotopic ossification due to spinal cord injury typically develops radiographically 1 to
4 months after injury. It occurs below the level of injury, usually at major joints. The
overall incidence is about 40 percent; about one-half of these cases are clinically
significant.
Didronel chemisorbs to calcium hydroxyapatite crystals and their amorphous precursors,
blocking the aggregation, growth, and mineralization of these crystals. This is thought to be
the mechanism by which Didronel prevents or retards heterotopic ossification. There is no
evidence Didronel affects mature heterotopic bone.
INDICATIONS AND USAGE:
Didronel is indicated for the treatment of symptomatic Paget’s disease of bone and in the
prevention and treatment of heterotopic ossification following total hip replacement or due to
spinal cord injury. Didronel is not approved for the treatment of osteoporosis.
Paget’s Disease: Didronel is indicated for the treatment of symptomatic Paget's disease of
bone. Didronel therapy usually arrests or significantly impedes the disease process as
evidenced by:
--Symptomatic relief, including decreased pain and/or increased mobility (experienced
by 3 out of 5 patients).
--Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30
percent or more in 4 out of 5 patients).
--Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and
more lamellar bone formation.
2
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
--Bone scans showing reduced radionuclide uptake at pagetic lesions.
In addition, reductions in pagetically elevated cardiac output and skin temperature have
been observed in some patients.
In many patients, the disease process will be suppressed for a period of at least 1 year
following cessation of therapy. The upper limit of this period has not been determined.
The effects of the Didronel treatment in patients with asymptomatic Paget's disease have
not been studied. However, Didronel treatment of such patients may be warranted if
extensive involvement threatens irreversible neurologic damage, major joints, or major
weight-bearing bones.
Heterotopic Ossification: Didronel is indicated in the prevention and treatment of
heterotopic ossification following total hip replacement or due to spinal cord injury.
Didronel reduces the incidence of clinically important heterotopic bone by about two-thirds.
Among those patients who form heterotopic bone, Didronel retards the progression of
immature lesions and reduces the severity by at least half. Follow-up data (at least 9
months posttherapy) suggest these benefits persist.
In total hip replacement patients, Didronel does not promote loosening of the prosthesis or
impede trochanteric reattachment.
In spinal cord injury patients, Didronel does not inhibit fracture healing or stabilization of the
spine.
CONTRAINDICATIONS:
• Abnormalities of the esophagus which delay esophageal emptying such as stricture
or achalasia.
• Known hypersensitivity to etidronate disodium or in patients with clinically overt
osteomalacia.
WARNINGS:
General: Upper Gastrointestinal Adverse Reactions: Didronel, like other
bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal
mucosa. Because of these possible irritant effects and a potential for worsening of the
underlying disease, caution should be used when Didronel is given to patients with active
upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other
esophageal diseases, gastritis, duodenitis or ulcers).
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal
erosions, occasionally with bleeding and rarely followed by esophageal stricture or
perforation, have been reported in patients receiving treatment with oral bisphosphonates.
In some cases, these have been severe and required hospitalization. Physicians should
therefore be alert to any signs or symptoms signaling a possible esophageal reaction and
patients should be instructed to discontinue Didronel and seek medical attention if they
develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
3
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The risk of severe esophageal adverse experiences appears to be greater in patients who
lie down after taking oral bisphosphonates and/or who fail to swallow it with the
recommended full glass (6 to 8 oz) of water, and/or who continue to take oral
bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore,
it is very important that the full dosing instructions are provided to, and understood by, the
patient (see DOSAGE AND ADMINISTRATION). In patients who cannot comply with dosing
instructions due to mental disability, therapy with Didronel should be used under
appropriate supervision.
There have been post-marketing reports of gastric and duodenal ulcers with oral
bisphosphonate use, some severe and with complications, although no increased risk was
observed in controlled clinical trials.
Paget’s Disease: In Paget's patients the response to therapy may be of slow onset and
continue for months after Didronel therapy is discontinued. Dosage should not be
increased prematurely. A 90-day drug-free interval should be provided between courses of
therapy.
Heterotopic Ossification: No specific warnings.
PRECAUTIONS:
General: Patients should maintain an adequate nutritional status, particularly an adequate
intake of calcium and vitamin D.
Therapy has been withheld from some patients with enterocolitis since diarrhea may be
experienced, particularly at higher doses.
Didronel is not metabolized and is excreted intact via the kidney. Hyperphosphatemia may
occur at doses of 10 to 20 mg/kg/day, apparently as a result of drug-related increases in
tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2 to 4
weeks post therapy. There is no experience to specifically guide treatment in patients with
impaired renal function. Didronel dosage should be reduced when reductions in glomerular
filtration rates are present. Patients with renal impairment should be closely monitored. In
approximately 10 percent of patients in clinical trials of Didronel® I. V. Infusion (etidronate
disodium) for hypercalcemia of malignancy, occasional, mild-to-moderate abnormalities in
renal function (increases of > 0.5 mg/dl serum creatinine) were observed during or
immediately after treatment.
Didronel suppresses bone turnover, and may retard mineralization of osteoid laid down
during the bone accretion process. These effects are dose and time dependent. Osteoid,
which may accumulate noticeably at doses of 10 to 20 mg/kg/day, mineralizes normally post
therapy. In patients with fractures, especially of long bones, it may be advisable to delay or
interrupt treatment until callus is evident.
Osteonecrosis of the jaw (ONJ): ONJ, which can occur spontaneously, is generally
associated with tooth extraction and/or local infection with delayed healing, and has been
reported in patients taking bisphosphonates, including Didronel. Known risk factors for
osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction,
dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example,
chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid
4
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
disorders (for example, periodontal and/or other pre-existing dental disease, anemia,
coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of
exposure to bisphosphonates.
For patients requiring invasive dental procedures, discontinuation of bisphosphonate
treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or
oral surgeon should guide the management plan of each patient based on individual
benefit/risk assessment.
Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should
receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ
may exacerbate the condition. Discontinuation of bisphosphonate therapy should be
considered based on individual benefit/risk assessment.
Musculoskeletal Pain: In postmarketing experience, there have been infrequent reports of
severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking
bisphosphonates (see ADVERSE REACTIONS). 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 medication. A subset had recurrence of symptoms when rechallenged with
the same drug or another bisphosphonate.
Paget’s Disease: In Paget's patients, treatment regimens exceeding the recommended
(see DOSAGE AND ADMINISTRATION) daily maximum dose of 20 mg/kg or continuous
administration of medication for periods greater than 6 months may be associated with
osteomalacia and an increased risk of fracture.
Long bones predominantly affected by lytic lesions, particularly in those patients
unresponsive to Didronel therapy, may be especially prone to fracture.
Patients with predominantly lytic lesions should be monitored radiographically and
biochemically to permit termination of Didronel in those patients unresponsive to treatment.
Drug Interactions: There have been isolated reports of patients experiencing increases in
their prothrombin times when etidronate was added to warfarin therapy. The majority of
these reports concerned variable elevations in prothrombin times without clinically
significant sequelae. Although the relevance of these reports and any mechanism of
coagulation alterations is unclear, patients on warfarin should have their prothrombin time
monitored.
Carcinogenesis: Long-term studies in rats have indicated that Didronel is not
carcinogenic.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In teratology and developmental
toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5 to
20 times the clinical dose), no adverse or teratogenic effects have been observed in the
offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rats when
given at oral dose levels of 300 mg/kg (15 to 60 times the human dose). Other effects on
the offspring (including decreased live births) are at dosages that cause significant toxicity
in the parent generation and are 25 to 200 times the human dose. The skeletal effects are
thought to be the result of the pharmacological effects of the drug on bone.
5
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bisphosphonates are incorporated into the bone matrix, from which they are gradually
released over periods of weeks to years. The amount of bisphosphonate incorporation into
adult bone, and hence, the amount available for release back into the systemic circulation,
is directly related to the dose and duration of bisphosphonate use. There are no data on
fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly
skeletal, 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 studied.
There are no adequate and well-controlled studies in pregnant women. Didronel (etidronate
disodium) should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Nursing Mothers: 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 Didronel is
administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Pediatric patients have been treated with Didronel, at doses recommended for adults, to
prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been
reported infrequently at doses of 10 mg/kg/day and more for prolonged periods approaching
or exceeding a year. The epiphyseal radiologic changes associated with retarded
mineralization of new osteoid and cartilage, and occasional symptoms reported, have been
reversible when medication is discontinued.
Geriatric Use: Clinical studies of Didronel 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, 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. 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 when prescribing this drug therapy. As stated in
PRECAUTIONS, Didronel dosage should be reduced when reductions in glomerular
filtration rates are present. In addition, patients with renal impairment should be closely
monitored.
ADVERSE REACTIONS:
The incidence of gastrointestinal complaints (diarrhea, nausea) is the same for Didronel at
5 mg/kg/day as for placebo, about 1 patient in 15. At 10 to 20 mg/kg/day the incidence may
increase to 2 or 3 in 10. These complaints are often alleviated by dividing the total daily
dose.
Paget’s Disease: In Paget's patients, increased or recurrent bone pain at pagetic sites,
and/or the onset of pain at previously asymptomatic sites has been reported. At 5
mg/kg/day about 1 patient in 10 (versus 1 in 15 in the placebo group) report these
6
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
phenomena. At higher doses the incidence rises to about 2 in 10. When therapy continues,
pain resolves in some patients but persists in others.
Heterotopic Ossification: No specific adverse reactions.
Worldwide Post-Marketing Experience: The worldwide post-marketing experience for
etidronate disodium reflects its use in the following approved indications: Paget's disease,
heterotopic ossification, and hypercalcemia of malignancy. It also reflects the use of
etidronate disodium for osteoporosis where approved in countries outside the US. Other
adverse events that have been reported and were thought to be possibly related to
etidronate disodium include the following: alopecia; arthropathies, including arthralgia and
arthritis; bone fracture; esophagitis; glossitis; hypersensitivity reactions, including
angioedema, follicular eruption, macular rash, maculopapular rash, pruritus, Stevens-
Johnson syndrome, toxic epidermal necrolysis, and urticaria; osteomalacia; neuropsychiatric
events, including amnesia, confusion, depression, and hallucination; and paresthesias.
In patients receiving etidronate disodium, there have been rare reports of agranulocytosis,
pancytopenia, and a report of leukopenia with recurrence on rechallenge. In addition, there
have been rare reports of exacerbation of asthma. Exacerbation of existing peptic ulcer
disease including perforation has been reported rarely.
In osteoporosis clinical trials, headache, gastritis, leg cramps, and arthralgia occurred at a
significantly greater incidence in patients who received etidronate as compared with those
who received placebo.
OVERDOSAGE:
Clinical experience with acute Didronel overdosage is extremely limited. Decreases in
serum calcium following substantial overdosage may be expected in some patients. Signs
and symptoms of hypocalcemia also may occur in some of these patients. Some patients
may develop vomiting. In one event, an 18-year-old female who ingested an estimated
single dose of 4000 to 6000 mg (67 to 100 mg/kg) of Didronel was reported to be mildly
hypocalcemic (7.52 mg/dl) and experienced paresthesia of the fingers. Hypocalcemia
resolved 6 hours after lavage and treatment with intravenous calcium gluconate. A 92-year
old female who accidentally received 1600 mg of etidronate disodium per day for 3.5 days
experienced marked diarrhea and required treatment for electrolyte imbalance. Orally
administered etidronate disodium may cause hematologic abnormalities in some patients
(see ADVERSE REACTIONS).
Etidronate disodium suppresses bone turnover and may retard mineralization of osteoid laid
down during the bone accretion process. These effects are dose and time dependent.
Osteoid which may accumulate noticeably at doses of 10 to 20 mg/kg/day of chronic,
continuous dosing mineralizes normally posttherapy.
Prolonged continuous treatment (chronic overdosage) has been reported to cause nephrotic
syndrome and fracture.
Gastric lavage may remove unabsorbed drug. Standard procedures for treating
hypocalcemia, including the administration of Ca++ intravenously, would be expected to
restore physiologic amounts of ionized calcium and relieve signs and symptoms of
hypocalcemia. Such treatment has been effective.
7
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION:
Didronel should be taken as a single, oral dose. As with other bisphosphonates, it is
recommended that Didronel should be swallowed with a full glass of water (6 to 8 oz).
Patients should not lie down after taking the medication. However, should gastrointestinal
discomfort occur, the dose may be divided. To maximize absorption, patients should avoid
taking the following items within two hours of dosing:
--Food, especially food high in calcium, such as milk or milk products.
--Vitamins with mineral supplements or antacids which are high in metals such as
calcium, iron, magnesium, or aluminum.
Paget’s Disease: Initial Treatment Regimens: 5 to 10 mg/kg/day, not to exceed 6
months, or 11 to 20 mg/kg/day, not to exceed 3 months.
The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months. Doses
above 10 mg/kg/day should be reserved for when 1) lower doses are ineffective or 2) there
is an overriding need to suppress rapid bone turnover (especially when irreversible
neurologic damage is possible) or reduce elevated cardiac output. Doses in excess of 20
mg/kg/day are not recommended.
Retreatment Guidelines: Retreatment should be initiated only after 1) a Didronel-free
period of at least 90 days and 2) there is biochemical, symptomatic or other evidence of
active disease process. It is advisable to monitor patients every 3 to 6 months although
some patients may go drug free for extended periods. Retreatment regimens are the same
as for initial treatment. For most patients the original dose will be adequate for retreatment.
If not, consideration should be given to increasing the dose within the recommended
guidelines.
Heterotopic Ossification: The following treatment regimens have been shown to be
effective:
--Total Hip Replacement Patients: 20 mg/kg/day for 1 month before and 3 months after
surgery (4 months total).
--Spinal Cord Injured Patients: 20 mg/kg/day for 2 weeks followed by 10 mg/kg/day for 10
weeks (12 weeks total). Didronel therapy should begin as soon as medically feasible
following the injury, preferably prior to evidence of heterotopic ossification.
Retreatment has not been studied.
HOW SUPPLIED:
Didronel® (etidronate disodium) is available as 400 mg, white, scored, capsule-shaped
tablets with "N|E" on one face and "406" on the other.
NDC 0430-0406-20
Bottles of 60 tablets
Store at 25° C (77° F); excursions permitted to 15 to 30° C (59 to 86° F)
[see USP Controlled Room Temperature]
8
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
Norwich Pharmaceuticals, Inc.
North Norwich, NY 13814
Marketed by:
Warner Chilcott (US), LLC
Rockaway, NJ 07866
1-800-521-8813
-
Content updated: April 2015
To report SUSPECTED ADVERSE REACTIONS, contact Warner Chilcott at 1-800-521
8813 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. company logo
9
Reference ID: 3728054
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:22.844065
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017831s058lbl.pdf', 'application_number': 17831, 'submission_type': 'SUPPL ', 'submission_number': 58}
|
11,074
|
Procter & Gamble Pharmaceuticals
Revised May 2005
Didronel®
(etidronate disodium)
DESCRIPTION: Didronel tablets contain either 200 mg or 400 mg of etidronate disodium,
the disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral administration. This
compound, also known as EHDP, regulates bone metabolism. It is a white powder, highly
soluble in water, with a molecular weight of 250 and the following structural formula:
H O
P
C
P
OH
O H
O Na
O
O Na
O
C H3
Inactive Ingredients: Each tablet contains magnesium stearate, microcrystalline cellulose,
and starch.
CLINICAL PHARMACOLOGY:
Didronel acts primarily on bone. It can inhibit the formation, growth, and dissolution of
hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium
phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are
required to inhibit crystal growth. Both effects increase as the dose increases.
Didronel is not metabolized. The amount of drug absorbed after an oral dose is
approximately 3%. In normal subjects, plasma half-life (t1/2) of etidronate, based on non-
compartmental pharmacokinetics is 1 to 6 hours. Within 24 hours, approximately half the
absorbed dose is excreted in urine; the remainder is distributed to bone compartments
from which it is slowly eliminated. Animal studies have yielded bone clearance estimates
up to 165 days. In humans, the residence time on bone may vary due to such factors as
specific metabolic condition and bone type. Unabsorbed drug is excreted intact in the
feces. Preclinical studies indicate etidronate disodium does not cross the blood-brain
barrier.
Didronel therapy does not adversely affect serum levels of parathyroid hormone or
calcium.
Paget’s Disease: Paget's disease of bone (osteitis deformans) is an idiopathic,
progressive disease characterized by abnormal and accelerated bone metabolism in one or
more bones. Signs and symptoms may include bone pain and/or deformity, neurologic
disorders, elevated cardiac output and other vascular disorders, and increased serum
alkaline phosphatase and/or urinary hydroxyproline levels. Bone fractures are common in
patients with Paget's disease.
Didronel slows accelerated bone turnover (resorption and accretion) in pagetic lesions
and, to a lesser extent, in normal bone. This has been demonstrated histologically,
scintigraphically, biochemically, and through calcium kinetic and balance studies. Reduced
bone turnover is often accompanied by symptomatic improvement, including reduced bone
pain. Also, the incidence of pagetic fractures may be reduced, and elevated cardiac output
and other vascular disorders may be improved by Didronel therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Didronel (etidronate disodium)
Procter & Gamble Pharmaceuticals
Revised May 2005
2
Heterotopic Ossification: Heterotopic ossification, also referred to as myositis ossificans
(circumscripta, progressiva or traumatica), ectopic calcification, periarticular ossification, or
paraosteoarthropathy, is characterized by metaplastic osteogenesis. It usually presents
with signs of localized inflammation or pain, elevated skin temperature, and redness.
When tissues near joints are involved, functional loss may also be present.
Heterotopic ossification may occur for no known reason as in myositis ossificans
progressiva or may follow a wide variety of surgical, occupational, and sports trauma (e.g.,
hip arthroplasty, spinal cord injury, head injury, burns, and severe thigh bruises).
Heterotopic ossification has also been observed in non-traumatic conditions (e.g.,
infections of the central nervous system, peripheral neuropathy, tetanus, biliary cirrhosis,
Peyronie's disease, as well as in association with a variety of benign and malignant
neoplasms).
Clinical trials have demonstrated the efficacy of Didronel in heterotopic ossification
following total hip replacement, or due to spinal cord injury.
--Heterotopic ossification complicating total hip replacement typically develops
radiographically 3 to 8 weeks postoperatively in the pericapsular area of the affected
hip joint. The overall incidence is about 50%; about one-third of these cases are
clinically significant.
--Heterotopic ossification due to spinal cord injury typically develops radiographically 1
to 4 months after injury. It occurs below the level of injury, usually at major joints. The
overall incidence is about 40%; about one-half of these cases are clinically significant.
Didronel chemisorbs to calcium hydroxyapatite crystals and their amorphous precursors,
blocking the aggregation, growth, and mineralization of these crystals. This is thought to
be the mechanism by which Didronel prevents or retards heterotopic ossification. There is
no evidence Didronel affects mature heterotopic bone.
INDICATIONS AND USAGE: Didronel is indicated for the treatment of symptomatic
Paget’s disease of bone and in the prevention and treatment of heterotopic ossification
following total hip replacement or due to spinal cord injury. Didronel is not approved for
the treatment of osteoporosis.
Paget’s Disease: Didronel is indicated for the treatment of symptomatic Paget's disease
of bone. Didronel therapy usually arrests or significantly impedes the disease process as
evidenced by:
--Symptomatic relief, including decreased pain and/or increased mobility (experienced
by 3 out of 5 patients).
--Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30% or
more in 4 out of 5 patients).
--Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and
more lamellar bone formation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Didronel (etidronate disodium)
Procter & Gamble Pharmaceuticals
Revised May 2005
3
--Bone scans showing reduced radionuclide uptake at pagetic lesions.
In addition, reductions in pagetically elevated cardiac output and skin temperature have
been observed in some patients.
In many patients, the disease process will be suppressed for a period of at least 1 year
following cessation of therapy. The upper limit of this period has not been determined.
The effects of the Didronel treatment in patients with asymptomatic Paget's disease have
not been studied. However, Didronel treatment of such patients may be warranted if
extensive involvement threatens irreversible neurologic damage, major joints, or major
weight-bearing bones.
Heterotopic Ossification: Didronel is indicated in the prevention and treatment of
heterotopic ossification following total hip replacement or due to spinal cord injury.
Didronel reduces the incidence of clinically important heterotopic bone by about two-thirds.
Among those patients who form heterotopic bone, Didronel retards the progression of
immature lesions and reduces the severity by at least half. Follow-up data (at least 9
months posttherapy) suggest these benefits persist.
In total hip replacement patients, Didronel does not promote loosening of the prosthesis or
impede trochanteric reattachment.
In spinal cord injury patients, Didronel does not inhibit fracture healing or stabilization of
the spine.
CONTRAINDICATIONS: Didronel tablets are contraindicated in patients with known
hypersensitivity to etidronate disodium or in patients with clinically overt osteomalacia.
WARNINGS: Paget’s Disease: In Paget's patients the response to therapy may be of
slow onset and continue for months after Didronel therapy is discontinued. Dosage should
not be increased prematurely. A 90-day drug-free interval should be provided between
courses of therapy.
Heterotopic Ossification: No specific warnings.
PRECAUTIONS: General: Patients should maintain an adequate nutritional status,
particularly an adequate intake of calcium and vitamin D.
Therapy has been withheld from some patients with enterocolitis since diarrhea may be
experienced, particularly at higher doses.
Didronel is not metabolized and is excreted intact via the kidney. Hyperphosphatemia may
occur at doses of 10 to 20 mg/kg/day, apparently as a result of drug-related increases in
tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2 to
4 weeks posttherapy. There is no experience to specifically guide treatment in patients
with impaired renal function. Didronel dosage should be reduced when reductions in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Didronel (etidronate disodium)
Procter & Gamble Pharmaceuticals
Revised May 2005
4
glomerular filtration rates are present. Patients with renal impairment should be closely
monitored. In approximately 10% of patients in clinical trials of Didronel® I. V. Infusion
(etidronate disodium) for hypercalcemia of malignancy, occasional, mild-to-moderate
abnormalities in renal function (increases of > 0.5 mg/dl serum creatinine) were observed
during or immediately after treatment.
Didronel suppresses bone turnover, and may retard mineralization of osteoid laid down
during the bone accretion process. These effects are dose and time dependent. Osteoid,
which may accumulate noticeably at doses of 10 to 20 mg/kg/day, mineralizes normally
posttherapy. In patients with fractures, especially of long bones, it may be advisable to
delay or interrupt treatment until callus is evident.
Osteonecrosis, primarily in the jaw, has been reported in patients treated with
bisphosphonates. Most cases have been in cancer patients undergoing dental procedures
such as tooth extraction, but some have occurred in patients with postmenopausal
osteoporosis or other diagnoses. Most reported cases have been in patients treated with
bisphosphonates intravenously but some have been in patients treated orally.
For patients requiring dental procedures, there are no data available to suggest whether
discontinuation of bisphosphonate treatment, prior to the procedure, reduces the risk of
osteonecrosis of the jaw. Clinical judgment should guide the management plan of each
patient based on individual benefit/risk assessment.
Musculoskeletal Pain:
In postmarketing experience, there have been infrequent reports of severe and
occasionally incapacitating bone, joint, and/or muscle pain in patients taking
bisphosphonates (see ADVERSE REACTIONS). 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 medication. A subset had recurrence of symptoms when
rechallenged with the same drug or another bisphosphonate.
Paget’s Disease: In Paget's patients, treatment regimens exceeding the recommended
(see DOSAGE AND ADMINISTRATION) daily maximum dose of 20 mg/kg or continuous
administration of medication for periods greater than 6 months may be associated with
osteomalacia and an increased risk of fracture.
Long bones predominantly affected by lytic lesions, particularly in those patients
unresponsive to Didronel therapy, may be especially prone to fracture.
Patients with predominantly lytic lesions should be monitored radiographically and
biochemically to permit termination of Didronel in those patients unresponsive to
treatment.
Drug Interactions: There have been isolated reports of patients experiencing increases in
their prothrombin times when etidronate was added to warfarin therapy. The majority of
these reports concerned variable elevations in prothrombin times without clinically
significant sequelae. Although the relevance of these reports and any mechanism of
coagulation alterations is unclear, patients on warfarin should have their prothrombin time
monitored.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Didronel (etidronate disodium)
Procter & Gamble Pharmaceuticals
Revised May 2005
5
Carcinogenesis: Long-term studies in rats have indicated that Didronel is not
carcinogenic.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In teratology and
developmental toxicity studies conducted in rats and rabbits treated with dosages of up to
100 mg/kg (5 to 20 times the clinical dose), no adverse or teratogenic effects have been
observed in the offspring. Etidronate disodium has been shown to cause skeletal
abnormalities in rats when given at oral dose levels of 300 mg/kg (15 to 60 times the
human dose). Other effects on the offspring (including decreased live births) are at
dosages that cause significant toxicity in the parent generation and are 25 to 200 times the
human dose. The skeletal effects are thought to be the result of the pharmacological
effects of the drug on bone.
Bisphosphonates are incorporated into the bone matrix, from which they are gradually
released over periods of weeks to years. The amount of bisphosphonate incorporation into
adult bone, and hence, the amount available for release back into the systemic circulation,
is directly related to the dose and duration of bisphosphonate use. There are no data on
fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly
skeletal, 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 studied.
There are no adequate and well-controlled studies in pregnant women. Didronel
(etidronate disodium) should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Nursing Mothers: 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 Didronel is
administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Pediatric patients have been treated with Didronel, at doses recommended for adults, to
prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been
reported infrequently at doses of 10 mg/kg/day and more for prolonged periods
approaching or exceeding a year. The epiphyseal radiologic changes associated with
retarded mineralization of new osteoid and cartilage, and occasional symptoms reported,
have been reversible when medication is discontinued.
Geriatric Use: Clinical studies of Didronel 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, 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. 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 when prescribing this drug therapy. As
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Didronel (etidronate disodium)
Procter & Gamble Pharmaceuticals
Revised May 2005
6
stated in PRECAUTIONS, Didronel dosage should be reduced when reductions in
glomerular filtration rates are present. In addition, patients with renal impairment should be
closely monitored.
ADVERSE REACTIONS: The incidence of gastrointestinal complaints (diarrhea, nausea)
is the same for Didronel at 5 mg/kg/day as for placebo, about 1 patient in 15. At 10 to 20
mg/kg/day the incidence may increase to 2 or 3 in 10. These complaints are often
alleviated by dividing the total daily dose.
Paget’s Disease: In Paget's patients, increased or recurrent bone pain at pagetic sites,
and/or the onset of pain at previously asymptomatic sites has been reported. At 5
mg/kg/day about 1 patient in 10 (versus 1 in 15 in the placebo group) report these
phenomena. At higher doses the incidence rises to about 2 in 10. When therapy
continues, pain resolves in some patients but persists in others.
Heterotopic Ossification: No specific adverse reactions.
Worldwide Postmarketing Experience: The worldwide postmarketing experience for
etidronate disodium reflects its use in the following approved indications: Paget's disease,
heterotopic ossification, and hypercalcemia of malignancy. It also reflects the use of
etidronate disodium for osteoporosis where approved in countries outside the US. Other
adverse events that have been reported and were thought to be possibly related to
etidronate disodium include the following: alopecia; arthropathies, including arthralgia and
arthritis; bone fracture; esophagitis; glossitis; hypersensitivity reactions, including
angioedema, follicular eruption, macular rash, maculopapular rash, pruritus, a single case
of Stevens-Johnson syndrome, and urticaria; osteomalacia; neuropsychiatric events,
including amnesia, confusion, depression, and hallucination; and paresthesias.
In patients receiving etidronate disodium, there have been rare reports of agranulocytosis,
pancytopenia, and a report of leukopenia with recurrence on rechallenge. In addition,
there have been rare reports of exacerbation of asthma. Exacerbation of existing peptic
ulcer disease has been reported in a few patients. In one patient, perforation also
occurred.
In osteoporosis clinical trials, headache, gastritis, leg cramps, and arthralgia occurred at a
significantly greater incidence in patients who received etidronate as compared with those
who received placebo.
OVERDOSAGE: Clinical experience with acute Didronel overdosage is extremely limited.
Decreases in serum calcium following substantial overdosage may be expected in some
patients. Signs and symptoms of hypocalcemia also may occur in some of these patients.
Some patients may develop vomiting. In one event, an 18-year-old female who ingested an
estimated single dose of 4000 to 6000 mg (67 to 100 mg/kg) of Didronel was reported to
be mildly hypocalcemic (7.52 mg/dl) and experienced paresthesia of the fingers.
Hypocalcemia resolved 6 hours after lavage and treatment with intravenous calcium
gluconate. A 92-year-old female who accidentally received 1600 mg of etidronate
disodium per day for 3.5 days experienced marked diarrhea and required treatment for
electrolyte imbalance. Orally administered etidronate disodium may cause hematologic
abnormalities in some patients (see ADVERSE REACTIONS).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Didronel (etidronate disodium)
Procter & Gamble Pharmaceuticals
Revised May 2005
7
Etidronate disodium suppresses bone turnover and may retard mineralization of osteoid
laid down during the bone accretion process. These effects are dose and time dependent.
Osteoid which may accumulate noticeably at doses of 10 to 20 mg/kg/day of chronic,
continuous dosing mineralizes normally posttherapy.
Prolonged continuous treatment (chronic overdosage) has been reported to cause
nephrotic syndrome and fracture.
Gastric lavage may remove unabsorbed drug. Standard procedures for treating
hypocalcemia, including the administration of Ca++ intravenously, would be expected to
restore physiologic amounts of ionized calcium and relieve signs and symptoms of
hypocalcemia. Such treatment has been effective.
DOSAGE AND ADMINISTRATION: Didronel should be taken as a single, oral dose.
However, should gastrointestinal discomfort occur, the dose may be divided. To maximize
absorption, patients should avoid taking the following items within two hours of dosing:
--Food, especially food high in calcium, such as milk or milk products.
--Vitamins with mineral supplements or antacids which are high in metals such as
calcium, iron, magnesium, or aluminum.
Paget’s Disease: Initial Treatment Regimens: 5 to 10 mg/kg/day, not to exceed 6
months, or 11 to 20 mg/kg/day, not to exceed 3 months.
The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months. Doses
above 10 mg/kg/day should be reserved for when 1) lower doses are ineffective or 2) there
is an overriding need to suppress rapid bone turnover (especially when irreversible
neurologic damage is possible) or reduce elevated cardiac output. Doses in excess of 20
mg/kg/day are not recommended.
Retreatment Guidelines: Retreatment should be initiated only after 1) a Didronel-free
period of at least 90 days and 2) there is biochemical, symptomatic or other evidence of
active disease process. It is advisable to monitor patients every 3 to 6 months although
some patients may go drug free for extended periods. Retreatment regimens are the same
as for initial treatment. For most patients the original dose will be adequate for retreatment.
If not, consideration should be given to increasing the dose within the recommended
guidelines.
Heterotopic Ossification: The following treatment regimens have been shown to be
effective:
--Total Hip Replacement Patients: 20 mg/kg/day for 1 month before and 3 months after
surgery (4 months total).
--Spinal Cord Injured Patients: 20 mg/kg/day for 2 weeks followed by 10 mg/kg/day for 10
weeks (12 weeks total). Didronel therapy should begin as soon as medically feasible
following the injury, preferably prior to evidence of heterotopic ossification.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Didronel (etidronate disodium)
Procter & Gamble Pharmaceuticals
Revised May 2005
8
Retreatment has not been studied.
HOW SUPPLIED: Didronel is available as 200-mg, white, rectangular tablets with "P & G"
on one face and "402" on the other.
NDC 0149-0405-60 bottle of 60
400-mg, white, scored, capsule-shaped tablets with "N E" on one face and "406" on the
other.
NDC 0149-0406-60 bottle of 60
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
[see USP Controlled Room Temperature]
Mfg. by: OSG Norwich
Pharmaceuticals, Inc.
North Norwich, NY 13814
Dist. by:
Procter & Gamble Pharmaceuticals,
TM Owner, Cincinnati, OH 45202
REVISED MAY 2005
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 Parks
1/9/2006 07:36:40 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:22.861497
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017831s054lbl.pdf', 'application_number': 17831, 'submission_type': 'SUPPL ', 'submission_number': 54}
|
11,076
|
reglan® tablets (metoclopramide tablets, USP)
Rx Only
WARNING: TARDIVE DYSKINESIA
Treatment with metoclopramide can cause tardive dyskinesia, a serious movement
disorder that is often irreversible. The risk of developing tardive dyskinesia increases
with duration of treatment and total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or
symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In
some patients, symptoms may lessen or resolve after metoclopramide treatment is
stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but
rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive
dyskinesia.
See WARNINGS
DESCRIPTION
For oral administration, reglan® tablets (metoclopramide tablets, USP) 10 mg are white, scored,
capsule-shaped tablets engraved REGLAN on one side and SP 10 on the opposite side.
Each tablet contains:
Metoclopramide base .................................................. 10 mg
(as the monohydrochloride monohydrate)
Inactive Ingredients
Magnesium Stearate, Mannitol, Microcrystalline Cellulose, Stearic Acid.
reglan® tablets (metoclopramide tablets, USP) 5 mg are green, elliptical-shaped tablets
engraved REGLAN 5 on one side and SP on the opposite side.
Each tablet contains:
Metoclopramide base .................................................... 5 mg
(as the monohydrochloride monohydrate)
Inactive Ingredients
Corn starch, D&C Yellow 10 Aluminum Lake, FD&C Blue 1 Aluminum Lake, Lactose,
Microcrystalline Cellulose, Silicon Dioxide, Stearic Acid.
Metoclopramide hydrochloride is a white crystalline, odorless substance, freely soluble in water.
Chemically, it is 4-amino-5- chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide
monohydrochloride monohydrate. Its molecular formula is C14H22CIN3O2•HCl•H2O. Its molecular
weight is 354.3.
REGLAN® - Package Insert
Page 1 of 12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Structural Formula
CLINICAL PHARMACOLOGY
Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating gastric,
biliary, or pancreatic secretions. Its mode of action is unclear. It seems to sensitize tissues to
the action of acetylcholine. The effect of metoclopramide on motility is not dependent on intact
vagal innervation, but it can be abolished by anticholinergic drugs.
Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions,
relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum
and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the
resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the
colon or gallbladder.
In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter pressure),
single oral doses of metoclopramide produce dose-related increases in LESP. Effects begin at
about 5 mg and increase through 20 mg (the largest dose tested). The increase in LESP from a
5 mg dose lasts about 45 minutes and that of 20 mg lasts between 2 and 3 hours. Increased
rate of stomach emptying has been observed with single oral doses of 10 mg.
The antiemetic properties of metoclopramide appear to be a result of its antagonism of central
and peripheral dopamine receptors. Dopamine produces nausea and vomiting by stimulation of
the medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the
CTZ by agents like l-dopa or apomorphine which are known to increase dopamine levels or to
possess dopamine-like effects. Metoclopramide also abolishes the slowing of gastric emptying
caused by apomorphine.
Like the phenothiazines and related drugs, which are also dopamine antagonists,
metoclopramide produces sedation and may produce extrapyramidal reactions, although these
are comparatively rare (see WARNINGS). Metoclopramide inhibits the central and peripheral
effects of apomorphine, induces release of prolactin and causes a transient increase in
circulating aldosterone levels, which may be associated with transient fluid retention.
The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an
intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes
following an oral dose; pharmacological effects persist for 1 to 2 hours.
Pharmacokinetics
Metoclopramide is rapidly and well absorbed. Relative to an intravenous dose of 20 mg, the
absolute oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a crossover
study of 18 subjects. Peak plasma concentrations occur at about 1 to 2 hr after a single oral
dose. Similar time to peak is observed after individual doses at steady state.
In a single dose study of 12 subjects, the area under the drug concentration-time curve
increases linearly with doses from 20 to 100 mg. Peak concentrations increase linearly with
dose; time to peak concentrations remains the same; whole body clearance is unchanged; and
the elimination rate remains the same. The average elimination half-life in individuals with
normal renal function is 5 to 6 hr. Linear kinetic processes adequately describe the absorption
and elimination of metoclopramide.
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Approximately 85% of the radioactivity of an orally administered dose appears in the urine within
72 hr. Of the 85% eliminated in the urine, about half is present as free or conjugated
metoclopramide.
The drug is not extensively bound to plasma proteins (about 30%). The whole body volume of
distribution is high (about 3.5 L/kg) which suggests extensive distribution of drug to the tissues.
Renal impairment affects the clearance of metoclopramide. In a study with patients with varying
degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction
in plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life.
The kinetics of metoclopramide in the presence of renal impairment remained linear however.
The reduction in clearance as a result of renal impairment suggests that adjustment downward
of maintenance dosage should be done to avoid drug accumulation.
Adult Pharmacokinetic Data
Parameter
Value
Vd (L/kg)
Plasma Protein Binding
t1/2 (hr)
Oral Bioavailability
~ 3.5
~ 30%
5 to 6
80%±15.5%
In pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous
administration are highly variable and a concentration-effect relationship has not been
established.
There are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide
in adults and the pediatric population are similar. Although there are insufficient data to support
the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux
(GER) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been
studied in these patient populations.
In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with GER
received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The mean peak
plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8 μg/L) higher
compared to that observed after the first dose (29 μg/L) indicating drug accumulation with
repeated dosing. After the tenth dose, the mean time to reach peak concentrations (2.2 hr), half-
life (4.1 hr), clearance (0.67 L/h/kg), and volume of distribution (4.4 L/kg) of metoclopramide
were similar to those observed after the first dose. In the youngest patient (age, 3.5 weeks),
metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hr, respectively) was
significantly longer compared to other infants due to reduced clearance. This may be attributed
to immature hepatic and renal systems at birth.
Single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were
administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (mean age,
11.7 years; range, 7 to 14 yr) for prophylaxis of cytotoxic-induced vomiting. The metoclopramide
plasma concentrations extrapolated to time zero ranged from 65 to 395 μg/L (mean, 152 μg/L).
The mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.4
hr (range, 1.7 to 8.3 hr), 0.56 L/h/kg (range, 0.12 to 1.20 L/h/kg), and 3.0 L/kg (range, 1.0 to 4.8
L/kg), respectively.
In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received 4 to 5
intravenous infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control
emesis. After the last dose, the peak serum concentrations of metoclopramide ranged from
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1060 to 5680 μg/L. The mean elimination half-life, clearance, and volume of distribution of
metoclopramide were 4.5 hr (range, 2.0 to 12.5 hr), 0.37 L/h/kg (range, 0.10 to 1.24 L/h/kg), and
1.93 L/kg (range, 0.95 to 5.50 L/kg), respectively.
INDICATIONS AND USAGE
The use of reglan® tablets is recommended for adults only. Therapy should not exceed 12
weeks in duration.
Symptomatic Gastroesophageal Reflux
reglan® tablets are indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic,
documented gastroesophageal reflux who fail to respond to conventional therapy.
The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn
with less observed effect on nocturnal symptoms. If symptoms are confined to particular
situations, such as following the evening meal, use of metoclopramide as single doses prior to
the provocative situation should be considered, rather than using the drug throughout the day.
Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of
a 12-week trial using doses of 15 mg q.i.d. As there is no documented correlation between
symptoms and healing of esophageal lesions, patients with documented lesions should be
monitored endoscopically.
Diabetic Gastroparesis (Diabetic Gastric Stasis)
reglan® tablets (metoclopramide tablets, USP) is indicated for the relief of symptoms associated
with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric
emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals, and anorexia)
appear to respond to reglan® within different time intervals. Significant relief of nausea occurs
early and continues to improve over a three-week period. Relief of vomiting and anorexia may
precede the relief of abdominal fullness by one week or more.
CONTRAINDICATIONS
Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be
dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or
perforation.
Metoclopramide is contraindicated in patients with pheochromocytoma because the drug may
cause a hypertensive crisis, probably due to release of catecholamines from the tumor. Such
hypertensive crises may be controlled by phentolamine.
Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug.
Metoclopramide should not be used in epileptics or patients receiving other drugs which are
likely to cause extrapyramidal reactions, since the frequency and severity of seizures or
extrapyramidal reactions may be increased.
WARNINGS
Mental depression has occurred in patients with and without prior history of depression.
Symptoms have ranged from mild to severe and have included suicidal ideation and suicide.
Metoclopramide should be given to patients with a prior history of depression only if the
expected benefits outweigh the potential risks.
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Extrapyramidal symptoms, manifested primarily as acute dystonic reactions, occur in
approximately 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of
metoclopramide. These usually are seen during the first 24 to 48 hours of treatment with
metoclopramide, occur more frequently in pediatric patients and adult patients less than 30
years of age and are even more frequent at higher doses. These symptoms may include
involuntary movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic
protrusion of tongue, bulbar type of speech, trismus, or dystonic reactions resembling tetanus.
Rarely, dystonic reactions may present as stridor and dyspnea, possibly due to laryngospasm. If
these symptoms should occur, inject 50 mg diphenhydramine hydrochloride intramuscularly,
and they usually will subside. Benztropine mesylate, 1 to 2 mg intramuscularly, may also be
used to reverse these reactions.
Parkinsonian-like symptoms have occurred, more commonly within the first 6 months after
beginning treatment with metoclopramide, but occasionally after longer periods. These
symptoms generally subside within 2 to 3 months following discontinuance of metoclopramide.
Patients with preexisting Parkinson’s disease should be given metoclopramide cautiously, if at
all, since such patients may experience exacerbation of parkinsonian symptoms when taking
metoclopramide.
Tardive Dyskinesia (see Boxed Warnings)
Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and
disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities.
Although the risk of TD with metoclopramide has not been extensively studied, one published
study reported a TD prevalence of 20% among patients treated for at least 12 weeks.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare
cases where therapeutic benefit is thought to outweigh the risk of developing TD.
Although the risk of developing TD in the general population may be increased among the
elderly, women, and diabetics, it is not possible to predict which patients will develop
metoclopramide-induced TD. Both the risk of developing TD and the likelihood that TD will
become irreversible increase with duration of treatment and total cumulative dose.
Metoclopramide should be discontinued in patients who develop signs or symptoms of TD.
There is no known effective treatment for established cases of TD, although in some patients,
TD may remit, partially or completely, within several weeks to months after metoclopramide is
withdrawn.
Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby masking the
underlying disease process. The effect of this symptomatic suppression upon the long-term
course of TD is unknown. Therefore, metoclopramide should not be used for the symptomatic
control of TD.
Neuroleptic Malignant Syndrome (NMS)
There have been rare reports of an uncommon but potentially fatal symptom complex
sometimes referred to as Neuroleptic Malignant Syndrome (NMS) associated with
metoclopramide. Clinical manifestations of NMS include hyperthermia, muscle rigidity, altered
consciousness, and evidence of autonomic instability (irregular pulse or blood pressure,
tachycardia, diaphoresis and cardiac arrhythmias).
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The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases where the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug fever
and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of metoclopramide and
other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical
monitoring, and 3) treatment of any concomitant serious medical problems for which specific
treatments are available. Bromocriptine and dantrolene sodium have been used in treatment of
NMS, but their effectiveness have not been established (see ADVERSE REACTIONS).
PRECAUTIONS
General
In one study in hypertensive patients, intravenously administered metoclopramide was shown to
release catecholamines; hence, caution should be exercised when metoclopramide is used in
patients with hypertension.
Because metoclopramide produces a transient increase in plasma aldosterone, certain patients,
especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid
retention and volume overload. If these side effects occur at any time during metoclopramide
therapy, the drug should be discontinued.
Adverse reactions, especially those involving the nervous system, may occur after stopping the
use of reglan®. A small number of patients may experience a withdrawal period after stopping
reglan® that could include dizziness, nervousness, and/or headaches.
Information for Patients
The use of reglan® is recommended for adults only. Metoclopramide may impair the
mental and/or physical abilities required for the performance of hazardous tasks such as
operating machinery or driving a motor vehicle. The ambulatory patient should be
cautioned accordingly.
For additional information, patients should be instructed to see the Medication Guide for
reglan® tablets.
Drug Interactions
The effects of metoclopramide on gastrointestinal motility are antagonized by
anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when
metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines in patients with essential
hypertension suggests that it should be used cautiously, if at all, in patients receiving
monoamine oxidase inhibitors.
Absorption of drugs from the stomach may be diminished (e.g., digoxin) by
metoclopramide, whereas the rate and/or extent of absorption of drugs from the small
bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol,
cyclosporine).
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Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some
patients. Exogenously administered insulin may begin to act before food has left the
stomach and lead to hypoglycemia. Because the action of metoclopramide will influence
the delivery of food to the intestines and thus the rate of absorption, insulin dosage or
timing of dosage may require adjustment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 77-week study was conducted in rats with oral doses up to about 40 times the
maximum recommended human daily dose. Metoclopramide elevates prolactin levels
and the elevation persists during chronic administration. Tissue culture experiments
indicate that approximately one-third of human breast cancers are prolactin-dependent
in vitro, a factor of potential importance if the prescription of metoclopramide is
contemplated in a patient with previously detected breast cancer. Although disturbances
such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported
with prolactin-elevating drugs, the clinical significance of elevated serum prolactin levels
is unknown for most patients. An increase in mammary neoplasms has been found in
rodents after chronic administration of prolactin-stimulating neuroleptic drugs and
metoclopramide. Neither clinical studies nor epidemiologic studies conducted to date,
however, have shown an association between chronic administration of these drugs and
mammary tumorigenesis; the available evidence is too limited to be conclusive at this
time.
An Ames mutagenicity test performed on metoclopramide was negative.
Pregnancy Category B
Reproduction studies performed in rats, mice and rabbits by the I.V., I.M., S.C., and oral
routes at maximum levels ranging from 12 to 250 times the human dose have
demonstrated no impairment of fertility or significant harm to the fetus due to
metoclopramide. 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
Metoclopramide is excreted in human milk. Caution should be exercised when
metoclopramide is administered to a nursing mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established (see
OVERDOSAGE).
Care should be exercised in administering metoclopramide to neonates since prolonged
clearance may produce excessive serum concentrations (see CLINICAL
PHARMACOLOGY - Pharmacokinetics). In addition, neonates have reduced levels of
NADH-cytochrome b5 reductase which, in combination with the aforementioned
pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see
OVERDOSAGE).
The safety profile of metoclopramide in adults cannot be extrapolated to pediatric
patients. Dystonias and other extrapyramidal reactions associated with metoclopramide
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are more common in the pediatric population than in adults. (See WARNINGS and
ADVERSE REACTIONS - Extrapyramidal Reactions.)
Geriatric Use
Clinical studies of reglan® did not include sufficient numbers of subjects aged 65 and
over to determine whether elderly subjects respond differently from younger subjects.
The risk of developing parkinsonian-like side effects increases with ascending dose.
Geriatric patients should receive the lowest dose of reglan® that is effective. If
parkinsonian-like symptoms develop in a geriatric patient receiving reglan®, reglan®
should generally be discontinued before initiating any specific anti-parkinsonian agents
(see WARNINGS and DOSAGE AND ADMINISTRATION – For the Relief of
Symptomatic Gastroesophageal Reflux).
The elderly may be at greater risk for tardive dyskinesia (see WARNINGS – Tardive
Dyskinesia).
Sedation has been reported in reglan® users. Sedation may cause confusion and
manifest as over-sedation in the elderly (see CLINICAL PHARMACOLOGY,
PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – CNS
Effects).
reglan® 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 (see
DOSAGE AND ADMINISTRATION – USE IN PATIENTS WITH RENAL OR HEPATIC
IMPAIRMENT).
For these reasons, 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 renal function, concomitant disease, or other drug therapy in the elderly (see
DOSAGE AND ADMINISTRATION – For the Relief of Symptomatic
Gastroesophageal Reflux and USE IN PATIENTS WITH RENAL OR HEPATIC
IMPAIRMENT).
Other Special Populations
Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of
developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is
administered. In patients with G6PD deficiency who experience metoclopramide-
induced methemoglobinemia, methylene blue treatment is not recommended (see
OVERDOSAGE).
ADVERSE REACTIONS
In general, the incidence of adverse reactions correlates with the dose and duration of
metoclopramide administration. The following reactions have been reported, although in
most instances, data do not permit an estimate of frequency:
CNS Effects
Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients
receiving the most commonly prescribed dosage of 10 mg q.i.d. (see PRECAUTIONS).
Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation
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(see WARNINGS) occur less frequently. The incidence of drowsiness is greater at
higher doses. There are isolated reports of convulsive seizures without clearcut
relationship to metoclopramide. Rarely, hallucinations have been reported.
Extrapyramidal Reactions (EPS)
Acute dystonic reactions, the most common type of EPS associated with
metoclopramide, occur in approximately 0.2% of patients (1 in 500) treated with 30 to 40
mg of metoclopramide per day. Symptoms include involuntary movements of limbs,
facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type
of speech, trismus, opisthotonus (tetanus-like reactions), and, rarely, stridor and
dyspnea possibly due to laryngospasm; ordinarily these symptoms are readily reversed
by diphenhydramine (see WARNINGS).
Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask
like facies (see WARNINGS).
Tardive dyskinesia most frequently is characterized by involuntary movements of the
tongue, face, mouth, or jaw, and sometimes by involuntary movements of the trunk
and/or extremities; movements may be choreoathetotic in appearance (see
WARNINGS).
Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness,
and insomnia, as well as inability to sit still, pacing, foot tapping. These symptoms may
disappear spontaneously or respond to a reduction in dosage.
Neuroleptic Malignant Syndrome
Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This
potentially fatal syndrome is comprised of the symptom complex of hyperthermia,
altered consciousness, muscular rigidity, and autonomic dysfunction (see WARNINGS).
Endocrine Disturbances
Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia
(see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone
(see CLINICAL PHARMACOLOGY).
Cardiovascular
Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention,
acute congestive heart failure and possible AV block (see CONTRAINDICATIONS and
PRECAUTIONS).
Gastrointestinal
Nausea and bowel disturbances, primarily diarrhea.
Hepatic
Rarely, cases of hepatotoxicity, characterized by such findings as jaundice and altered
liver function tests, when metoclopramide was administered with other drugs with
known hepatotoxic potential.
Renal
Urinary frequency and incontinence.
Hematologic
A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut
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relationship to metoclopramide. Methemoglobinemia, in adults and especially with
overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.
Allergic Reactions
A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of
asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.
Miscellaneous
Visual disturbances. Porphyria.
OVERDOSAGE
Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal
reactions. Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic
properties may be helpful in controlling the extrapyramidal reactions. Symptoms are
self-limiting and usually disappear within 24 hours.
Hemodialysis removes relatively little metoclopramide, probably because of the small
amount of the drug in blood relative to tissues. Similarly, continuous ambulatory
peritoneal dialysis does not remove significant amounts of drug. It is unlikely that
dosage would need to be adjusted to compensate for losses through dialysis. Dialysis is
not likely to be an effective method of drug removal in overdose situations.
Unintentional overdose due to misadministration has been reported in infants and
children with the use of metoclopramide oral solution. While there was no consistent
pattern to the reports associated with these overdoses, events included seizures,
extrapyramidal reactions, and lethargy.
Methemoglobinemia has occurred in premature and full-term neonates who were given
overdoses of metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously
for 1 to 3 or more days). Methemoglobinemia can be reversed by the intravenous
administration of methylene blue. However, methylene blue may cause hemolytic
anemia in patients with G6PD deficiency, which may be fatal (see PRECAUTIONS –
Other Special Populations).
DOSAGE AND ADMINISTRATION
Therapy with reglan® tablets should not exceed 12 weeks in duration.
For the Relief of Symptomatic Gastroesophageal Reflux
Administer from 10 mg to 15 mg reglan® (metoclopramide hydrochloride, USP) orally up
to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being
treated and clinical response (see CLINICAL PHARMACOLOGY and INDICATIONS
AND USAGE). If symptoms occur only intermittently or at specific times of the day, use
of metoclopramide in single doses up to 20 mg prior to the provoking situation may be
preferred rather than continuous treatment. Occasionally, patients (such as elderly
patients) who are more sensitive to the therapeutic or adverse effects of
metoclopramide will require only 5 mg per dose.
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Experience with esophageal erosions and ulcerations is limited, but healing has thus far
been documented in one controlled trial using q.i.d. therapy at 15 mg/dose, and this
regimen should be used when lesions are present, so long as it is tolerated (see
ADVERSE REACTIONS). Because of the poor correlation between symptoms and
endoscopic appearance of the esophagus, therapy directed at esophageal lesions is
best guided by endoscopic evaluation.
Therapy longer than 12 weeks has not been evaluated and cannot be recommended.
For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic
Gastric Stasis)
Administer 10 mg of metoclopramide 30 minutes before each meal and at bedtime for
two to eight weeks, depending upon response and the likelihood of continued well-being
upon drug discontinuation.
The initial route of administration should be determined by the severity of the presenting
symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral
administration of reglan® may be initiated. However, if severe symptoms are present,
therapy should begin with metoclopramide injection (consult labeling of the injection
prior to initiating parenteral administration).
Administration of metoclopramide injection up to 10 days may be required before
symptoms subside, at which time oral administration may be instituted. Since diabetic
gastric stasis is frequently recurrent, reglan® therapy should be reinstituted at the
earliest manifestation.
USE IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT
Since metoclopramide is excreted principally through the kidneys, in those patients
whose creatinine clearance is below 40 mL/min, therapy should be initiated at
approximately one-half the recommended dosage. Depending upon clinical efficacy and
safety considerations, the dosage may be increased or decreased as appropriate.
See OVERDOSAGE section for information regarding dialysis.
Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation.
Its safe use has been described in patients with advanced liver disease whose renal
function was normal.
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HOW SUPPLIED
Each white, capsule-shaped, scored reglan® tablet (metoclopramide tablets, USP)
contains 10 mg metoclopramide base (as the monohydrochloride monohydrate).
Available in:
Bottles of 100 tablets (NDC 0091-6701-63)
Each green, elliptical-shaped reglan® tablet (metoclopramide tablets, USP)
contains 5 mg metoclopramide base (as the monohydrochloride monohydrate).
Available in:
Bottles of 100 tablets (NDC 0091-6705-63)
Dispense tablets in tight, light-resistant container.
Tablets should be stored at controlled room temperature, between 20°C and 25°C (68°F
and 77°F). Company logo
Rev. 06/09
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Medication Guide
REGLAN (REG-lan) Tablets
(metoclopramide tablets)
Read the Medication Guide that comes with REGLAN before you start taking it and each time
you get a refill. There may be new information. If you take another product that contains
metoclopramide (such as REGLAN injection, REGLAN ODT, or metoclopramide oral syrup), you
should read the Medication Guide that comes with that product. Some of the information may
be different. This Medication Guide does not take the place of talking with your doctor about
your medical condition or your treatment.
What is the most important information I should know about REGLAN?
REGLAN can cause serious side effects, including:
Abnormal muscle movements called tardive dyskinesia (TD). These movements happen
mostly in the face muscles. You can not control these movements. They may not go away even
after stopping REGLAN. There is no treatment for TD, but symptoms may lessen or go away
over time after you stop taking REGLAN.
Your chances for getting TD go up:
• the longer you take REGLAN and the more REGLAN you take. You should not take
REGLAN for more than 12 weeks.
• if you are older, especially if you are a woman
• if you have diabetes
It is not possible for your doctor to know if you will get TD if you take REGLAN.
Call your doctor right away if you get movements you can not stop or control, such as:
• lip smacking, chewing, or puckering up your mouth
• frowning or scowling
• sticking out your tongue
• blinking and moving your eyes
• shaking of your arms and legs
See the section “What are the possible side effects of REGLAN?” for more information about
side effects.
What is REGLAN?
REGLAN is a prescription medicine used:
• in adults for 4 to 12 weeks to relieve heartburn symptoms with gastroesophageal reflux
disease (GERD) when certain other treatments do not work. REGLAN relieves daytime
heartburn and heartburn after meals. It also helps ulcers in the esophagus to heal.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• to relieve symptoms of slow stomach emptying in people with diabetes. REGLAN helps treat
symptoms such as nausea, vomiting, heartburn, feeling full long after a meal, and loss of
appetite. Not all these symptoms get better at the same time.
It is not known if REGLAN is safe and works in children.
Who should not take REGLAN?
Do not take REGLAN if you:
• have stomach or intestine problems that could get worse with REGLAN, such as bleeding,
blockage or a tear in the stomach or bowel wall
• have an adrenal gland tumor called a pheochromocytoma
• are allergic to REGLAN or anything in it. See the end of this Medication Guide for a list of
ingredients in REGLAN.
• take medicines that can cause uncontrolled movements, such as medicines for mental
illness
• have seizures
What should I tell my doctor before taking REGLAN?
Tell your doctor about all your medical conditions, including if you have:
• depression
• Parkinson’s disease
• high blood pressure
• kidney problems. Your doctor may start with a lower dose.
• liver problems or heart failure. REGLAN may cause your body to hold fluids.
• diabetes. Your dose of insulin may need to be changed.
• breast cancer
• you are pregnant or plan to become pregnant. It is not known if REGLAN will harm your
unborn baby.
• you are breast-feeding. REGLAN can pass into breast milk and may harm your baby. Talk
with your doctor about the best way to feed your baby if you take REGLAN.
Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. REGLAN and some other
medicines may interact with each other and may not work as well, or cause possible side
effects. Do not start any new medicines while taking REGLAN until you talk with your doctor.
Especially tell your doctor if you take:
• another medicine that contains metoclopramide, such as REGLAN ODT, or
metoclopramide oral syrup
• a blood pressure medicine
• a medicine for depression, especially an Monoamine Oxidase Inhibitor (MAOI)
• insulin
• a medicine that can make you sleepy, such an anti-anxiety medicine, sleep medicines,
and narcotics.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If you are not sure if your medicine is one listed above, ask your doctor or pharmacist.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist
when you get a new medicine.
How should I take REGLAN?
• REGLAN comes as a tablet you take by mouth.
• Take REGLAN exactly as your doctor tells you. Do not change your dose unless your
doctor tells you.
• You should not take REGLAN for more than 12 weeks.
• If you take too much REGLAN, call your doctor or Poison Control Center right away.
What should I avoid while taking REGLAN?
• Do not drink alcohol while taking REGLAN. Alcohol may make some side effects of
REGLAN worse, such as feeling sleepy.
• Do not drive, work with machines, or do dangerous tasks until you know how REGLAN
affects you. REGLAN may cause sleepiness.
What are the possible side effects of REGLAN?
Reglan can cause serious side effects, including:
• Abnormal muscle movements. See “What is the most important information I need to
about know REGLAN?”
• Uncontrolled spasms of your face and neck muscles, or muscles of your body,
arms, and legs (dystonia). These muscle spasms can cause abnormal movements and
body positions. These spasms usually start within the first 2 days of treatment. These
spasms happen more often in children and adults under age 30.
• Depression, thoughts about suicide, and suicide. Some people who take REGLAN
become depressed. You may have thoughts about hurting or killing yourself. Some people
who take Reglan have ended their own lives (suicide).
• Neuroleptic Malignant Syndrome (NMS). NMS is a very rare but very serious
condition that can happen with Reglan. NMS can cause death and must be treated in a
hospital. Symptoms of NMS include: high fever, stiff muscles, problems thinking, very fast
or uneven heartbeat, and increased sweating.
• Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving or
keeping your balance. If you already have Parkinson’s disease, your symptoms may
become worse while you are receiving REGLAN.
Call your doctor and get medical help right away if you:
• feel depressed or have thoughts about hurting or killing yourself
• have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and
increased sweating
• have muscle movements you cannot stop or control
• have muscle movements that are new or unusual
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Common side effects of Reglan include:
•
feeling restless, sleepy, tired, dizzy, or exhausted
•
headache
•
confusion
•
trouble sleeping
You may have more side effects the longer you take REGLAN and the more REGLAN you take.
You may still have side effects after stopping REGLAN. You may have symptoms from stopping
(withdrawal) REGLAN such as headaches, and feeling dizzy or nervous.
Tell your doctor about any side effects that bother you or do not go away. These are not all the
possible side effects of REGLAN.
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 REGLAN?
•
Keep REGLAN at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
•
Keep REGLAN in the bottle it comes in. Keep the bottle closed tightly.
Keep REGLAN and all medicines out of the reach of children.
General information about REGLAN
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use REGLAN for a condition for which it was not prescribed. Do not give REGLAN to
other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about REGLAN. If you would
like more information, talk with your doctor. You can ask your doctor or pharmacist for
information about REGLAN that is written for health professionals. For more information, go to
www.alavenpharma.com or call 1-888-317-0001.
What are the ingredients in REGLAN?
Active ingredient: metoclopramide
Inactive ingredients:
REGLAN 10 mg tablets: magnesium stearate, mannitol, microcrystalline cellulose, stearic
acid
REGLAN 5 mg tablets: corn starch, D&C yellow 10 aluminum lake, FD&C blue 1 aluminum
lake, lactose, microcrystalline cellulose, silicon dioxide, stearic acid
Manufactured for
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Alaven Pharmaceutical LLC, Marietta, GA 30062
Revised June 2009
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
REGLAN ODT™
(metoclopramide orally disintegrating tablets)
Rx Only
WARNING: TARDIVE DYSKINESIA
Treatment with metoclopramide can cause tardive dyskinesia, a serious movement
disorder that is often irreversible. The risk of developing tardive dyskinesia increases with
duration of treatment and total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or
symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In
some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare
cases where therapeutic benefit is thought to outweigh the risk of developing tardive
dyskinesia.
See WARNINGS
DESCRIPTION
REGLAN ODT™ (metoclopramide orally disintegrating tablets) is an orally administered
formulation of metoclopramide which disintegrates on the tongue.
Metoclopramide hydrochloride is a white crystalline, odorless substance, freely soluble in water.
Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide
monohydrochloride monohydrate. Its molecular formula is C14H22ClN3O2•HCl•H2O. Its
molecular weight is 354.3. Structural Formula
Each orally disintegrating tablet contains either 5 mg or 10 mg of metoclopramide base (as the
monohydrochloride monohydrate) and the following inactive ingredients: aspartame, colloidal
silicon dioxide, crospovidone, magnesium stearate, mannitol, aminoalkyl methacrylate
copolymer, microcrystalline cellulose, natural and artificial orange flavor and povidone.
REGLAN ODT™ - Package Insert
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CLINICAL PHARMACOLOGY
Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating
gastric, biliary, or pancreatic secretions. Its mode of action is unclear. It seems to sensitize
tissues to the action of acetylcholine. The effect of metoclopramide on motility is not dependent
on intact vagal innervation, but it can be abolished by anticholinergic drugs.
Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions,
relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum
and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the
resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the
colon or gallbladder.
In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter pressure),
single oral doses of metoclopramide produce dose-related increases in LESP. Effects begin at
about 5 mg and increase through 20 mg (the largest dose tested). The increase in LESP from a
5 mg dose lasts about 45 minutes and that of 20 mg lasts between 2 and 3 hours. Increased rate
of stomach emptying has been observed with single oral doses of 10 mg.
The antiemetic properties of metoclopramide appear to be a result of its antagonism of central
and peripheral dopamine receptors. Dopamine produces nausea and vomiting by stimulation of
the medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the
CTZ by agents like l-dopa or apomorphine which are known to increase dopamine levels or to
possess dopamine-like effects. Metoclopramide also abolishes the slowing of gastric emptying
caused by apomorphine.
Like the phenothiazines and related drugs, which are also dopamine antagonists, metoclopramide
produces sedation and may produce extrapyramidal reactions, although these are comparatively
rare (see WARNINGS). Metoclopramide inhibits the central and peripheral effects of
apomorphine, induces release of prolactin and causes a transient increase in circulating
aldosterone levels, which may be associated with transient fluid retention.
The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an
intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes
following an oral dose; pharmacological effects persist for 1 to 2 hours.
Pharmacokinetics
Metoclopramide is rapidly and well absorbed. Relative to an intravenous dose of 20 mg, the
absolute oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a crossover
study of 18 subjects. Peak plasma concentrations occur at about 1 to 2 hr after a single oral dose.
Similar time to peak is observed after individual doses at steady state.
In a single dose study of 12 subjects, the area under the drug concentration-time curve increases
linearly with doses from 20 to 100 mg. Peak concentrations increase linearly with dose; time to
peak concentrations remains the same; whole body clearance is unchanged; and the elimination
rate remains the same. The mean elimination half-life of metoclopramide is approximately 7 hr
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after administration of REGLAN ODT™. Linear kinetic processes adequately describe the
absorption and elimination of metoclopramide.
Approximately 85% of the radioactivity of an orally administered dose appears in the urine
within 72 hr. Of the 85% eliminated in the urine, about half is present as free or conjugated
metoclopramide.
The drug is not extensively bound to plasma proteins (about 30%). The whole body volume of
distribution is high (about 3.5 L/kg) which suggests extensive distribution of drug to the tissues.
Renal impairment affects the clearance of metoclopramide. In a study with patients with varying
degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction
in plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life.
The kinetics of metoclopramide in the presence of renal impairment remained linear however.
The reduction in clearance as a result of renal impairment suggests that adjustment downward of
maintenance dosage should be done to avoid drug accumulation.
Adult Pharmacokinetic Data
Parameter
Value
Vd (L/kg)
~ 3.5
Plasma Protein Binding
~ 30%
t½ (hr)
~ 7
Oral Bioavailability
80% ± 15.5%
In pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous
administration are highly variable and a concentration-effect relationship has not been
established.
There are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide
in adults and the pediatric population are similar. Although there are insufficient data to support
the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux
(GER) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been
studied in these patient populations.
In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with GER
received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The mean peak
plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8 μg/L) higher
compared to that observed after the first dose (29 μg/L) indicating drug accumulation with
repeated dosing. After the tenth dose, the mean time to reach peak concentrations (2.2 hr), half-
life (4.1 hr), clearance (0.67 L/h/kg), and volume of distribution (4.4 L/kg) of metoclopramide
were similar to those observed after the first dose. In the youngest patient (age, 3.5 weeks),
REGLAN ODT™ - Package Insert
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metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hr, respectively) was
significantly longer compared to other infants due to reduced clearance. This may be attributed
to immature hepatic and renal systems at birth.
Single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were
administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (mean age,
11.7 years; range, 7 to 14 yr) for prophylaxis of cytotoxic-induced vomiting. The
metoclopramide plasma concentrations extrapolated to time zero ranged from 65 to 395 μg/L
(mean, 152 μg/L). The mean elimination half-life, clearance, and volume of distribution of
metoclopramide were 4.4 hr (range, 1.7 to 8.3 hr), 0.56 L/h/kg (range, 0.12 to 1.20 L/h/kg), and
3.0 L/kg (range, 1.0 to 4.8 L/kg), respectively.
In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received 4 to 5 intravenous
infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control emesis. After the
last dose, the peak serum concentrations of metoclopramide ranged from 1060 to 5680 μg/L. The
mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hr
(range, 2.0 to 12.5 hr), 0.37 L/h/kg (range, 0.10 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to
5.50 L/kg), respectively.
INDICATIONS AND USAGE
The use of REGLAN ODT™ is recommended for adults only. Therapy should not exceed
12 weeks in duration.
Symptomatic Gastroesophageal Reflux
REGLAN ODT™ is indicated as short-term (4 to 12 weeks) therapy for adults with
symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy.
The principal effect of metoclopramide is on symptoms of postprandial and daytime heartburn
with less observed effect on nocturnal symptoms. If symptoms are confined to particular
situations, such as following the evening meal, use of metoclopramide as single doses prior to
the provocative situation should be considered, rather than using the drug throughout the day.
Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of a
12-week trial using doses of 15 mg four times daily. As there is no documented correlation
between symptoms and healing of esophageal lesions, patients with documented lesions should
be monitored endoscopically.
Diabetic Gastroparesis (Diabetic Gastric Stasis)
REGLAN ODT™ is indicated for the relief of symptoms associated with acute and recurrent
diabetic gastric stasis. The usual manifestations of delayed gastric emptying (e.g., nausea,
vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond to
metoclopramide within different time intervals. Significant relief of nausea occurs early and
continues to improve over a three-week period. Relief of vomiting and anorexia may precede the
relief of abdominal fullness by one week or more.
REGLAN ODT™ - Package Insert
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CONTRAINDICATIONS
Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be
dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or
perforation.
Metoclopramide is contraindicated in patients with pheochromocytoma because the drug may
cause a hypertensive crisis, probably due to release of catecholamines from the tumor. Such
hypertensive crises may be controlled by phentolamine.
Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug.
Metoclopramide should not be used in epileptics or patients receiving other drugs which are
likely to cause extrapyramidal reactions, since the frequency and severity of seizures or
extrapyramidal reactions may be increased.
WARNINGS
Mental depression has occurred in patients with and without prior history of depression.
Symptoms have ranged from mild to severe and have included suicidal ideation and suicide.
Metoclopramide should be given to patients with a prior history of depression only if the
expected benefits outweigh the potential risks.
Extrapyramidal symptoms, manifested primarily as acute dystonic reactions, occur in
approximately 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day of
metoclopramide. These usually are seen during the first 24 to 48 hours of treatment with
metoclopramide, occur more frequently in pediatric patients and adult patients less than 30 years
of age and are even more frequent at higher doses. These symptoms may include involuntary
movements of limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of
tongue, bulbar type of speech, trismus, or dystonic reactions resembling tetanus. Rarely, dystonic
reactions may present as stridor and dyspnea, possibly due to laryngospasm. If these symptoms
should occur, inject 50 mg diphenhydramine hydrochloride intramuscularly, and they usually
will subside. Benztropine mesylate, 1 to 2 mg intramuscularly, may also be used to reverse these
reactions.
Parkinsonian-like symptoms have occurred, more commonly within the first 6 months after
beginning treatment with metoclopramide, but occasionally after longer periods. These
symptoms generally subside within 2 to 3 months following discontinuance of metoclopramide.
Patients with preexisting Parkinson’s disease should be given metoclopramide cautiously, if at
all, since such patients may experience exacerbation of parkinsonian symptoms when taking
metoclopramide.
Tardive Dyskinesia (see Boxed Warnings)
Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and
disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities.
REGLAN ODT™ - Package Insert
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Although the risk of TD with metoclopramide has not been extensively studied, one published
study reported a TD prevalence of 20% among patients treated for at least 12 weeks. Treatment
with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where
therapeutic benefit is thought to outweigh the risk of developing TD.
Although the risk of developing TD in the general population may be increased among the
elderly, women, and diabetics, it is not possible to predict which patients will develop
metoclopramide-induced TD. Both the risk of developing TD and the likelihood that TD will
become irreversible increase with duration of treatment and total cumulative dose.
Metoclopramide should be discontinued in patients who develop signs or symptoms of TD.
There is no known effective treatment for established cases of TD, although in some patients, TD
may remit, partially or completely, within several weeks to months after metoclopramide is
withdrawn.
Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby masking the
underlying disease process. The effect of this symptomatic suppression upon the long-term
course of TD is unknown. Therefore, metoclopramide should not be used for the symptomatic
control of TD.
Neuroleptic Malignant Syndrome (NMS)
There have been rare reports of an uncommon but potentially fatal symptom complex sometimes
referred to as Neuroleptic Malignant Syndrome (NMS) associated with metoclopramide.
Clinical manifestations of NMS include hyperthermia, muscle rigidity, altered consciousness,
and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis
and cardiac arrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases where the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug
fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of metoclopramide and
other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical
monitoring, and 3) treatment of any concomitant serious medical problems for which specific
treatments are available. Bromocriptine and dantrolene sodium have been used in treatment of
NMS, but their effectiveness have not been established (see ADVERSE REACTIONS).
PRECAUTIONS
General
In one study in hypertensive patients, intravenously administered metoclopramide was shown to
release catecholamines; hence, caution should be exercised when metoclopramide is used in
patients with hypertension.
REGLAN ODT™ - Package Insert
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Because metoclopramide produces a transient increase in plasma aldosterone, certain patients,
especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid
retention and volume overload. If these side effects occur at any time during metoclopramide
therapy, the drug should be discontinued.
Adverse reactions, especially those involving the nervous system, may occur after stopping the
use of REGLAN ODT™. A small number of patients may experience a withdrawal period after
stopping REGLAN ODT™ that could include dizziness, nervousness, and/or headaches.
Information for Patients
Patients should be instructed not to remove REGLAN ODT™ orally disintegrating tablets from
the bottle until just prior to dosing. With dry hands, the tablet should be removed from the bottle
and immediately placed on the tongue to disintegrate and be swallowed with the saliva. The
tablet typically disintegrates in about one and one-half minutes. Administration with liquid is
not necessary.
The use of REGLAN ODT™ orally disintegrating tablets is recommended for adults only.
Metoclopramide may impair the mental and/or physical abilities required for the performance of
hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient
should be cautioned accordingly.
For additional information, patients should be instructed to see the Medication Guide for
REGLAN ODT™.
Phenylketonurics
Phenylketonuric patients should be informed that REGLAN ODT™ contains phenylalanine
4.2 mg per 5 mg orally disintegrating tablet and 8.3 mg per 10 mg orally disintegrating tablet.
Drug Interactions
The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic
drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given
with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines in patients with essential hypertension
suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase
inhibitors.
Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide,
whereas the rate and/or extent of absorption of drugs from the small bowel may be increased
(e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).
Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients.
Exogenously administered insulin may begin to act before food has left the stomach and lead to
hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the
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intestines and thus the rate of absorption, insulin dosage or timing of dosage may require
adjustment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 77-week study was conducted in rats with oral doses of metoclopramide up to 40 mg/kg/day
(about 5 times the maximum recommended human dose on surface area basis). Metoclopramide
elevates prolactin levels and the elevation persists during chronic administration. Tissue culture
experiments indicate that approximately one-third of human breast cancers are prolactin-
dependent in vitro, a factor of potential importance if the prescription of metoclopramide is
contemplated in a patient with previously detected breast cancer. Although disturbances such as
galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-
elevating drugs, the clinical significance of elevated serum prolactin levels is unknown for most
patients. An increase in mammary neoplasms has been found in rodents after chronic
administration of prolactin-stimulating neuroleptic drugs and metoclopramide. Neither clinical
studies nor epidemiologic studies conducted to date, however, have shown an association
between chronic administration of these drugs and mammary tumorigenesis; the available
evidence is too limited to be conclusive at this time.
In a rat model for assessing the tumor promotion potential, a two-week oral treatment with
metoclopramide at a dose of 260 mg/kg/day (about 35 times the maximum recommended human
dose on surface area basis) enhanced the tumorigenic effect of N-nitrosodiethylamine.
Metoclopramide was positive in the in vitro Chinese hamster lung cell/HGPRT forward mutation
assay for mutagenic effects and the in vitro human lymphocyte chromosome aberration assay for
clastogenic effects. It was negative in the in vitro Ames mutation assay, the in vitro unscheduled
DNA synthesis (UDS) assay with rat and human hepatocytes and the in vivo rat micronucleus
assay.
Metoclopramide at intramuscular doses up to 20 mg/kg/day in male and female rats (about 3
times the maximum recommended human dose on surface area basis) was found to have no
effect on fertility and reproductive performance.
Pregnancy Teratogenic Effects: Pregnancy Category B
Teratology studies have been performed in rats at oral doses up to 45 mg/kg/day (about 6 times
the maximum recommended human dose on surface area basis), and in rabbits at oral doses up to
45 mg/kg/day (about 12 times the maximum recommended human dose on surface area basis)
and have revealed no evidence of impaired fertility or harm to the fetus due to metoclopramide.
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
Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide
is administered to a nursing mother. Because of the potential for serious adverse reactions in
nursing infants from metoclopramide and because of the potential for tumorigenicity and tumor
promoting potential shown for metoclopramide in rats, a decision should be made whether to
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discontinue nursing or to discontinue the drug, taking into account the importance of the drug to
the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established (see OVERDOSAGE).
Care should be exercised in administering metoclopramide to neonates since prolonged clearance
may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY—
Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5
reductase which, in combination with the aforementioned pharmacokinetic factors, make
neonates more susceptible to methemoglobinemia (see OVERDOSAGE).
The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients.
Dystonias and other extrapyramidal reactions associated with metoclopramide are more common
in the pediatric population than in adults. (See WARNINGS and ADVERSE REACTIONS—
Extrapyramidal Reactions.)
Geriatric Use
Clinical studies of metoclopramide did not include sufficient numbers of subjects aged 65 and
over to determine whether elderly subjects respond differently from younger subjects.
The risk of developing parkinsonian-like side effects increases with ascending dose. Geriatric
patients should receive the lowest dose of REGLAN ODT™ that is effective. If parkinsonian-
like symptoms develop in a geriatric patient receiving REGLAN ODT™, REGLAN ODT™
should generally be discontinued before initiating any specific anti-parkinsonian agents (see
WARNINGS and DOSAGE AND ADMINISTRATION – For the Relief of Symptomatic
Gastroesophageal Reflux).
The elderly may be at greater risk for tardive dyskinesia (see WARNINGS – Tardive
Dyskinesia).
Sedation has been reported in metoclopramide users. Sedation may cause confusion and
manifest as over-sedation in the elderly (see CLINICAL PHARMACOLOGY,
PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – CNS Effects).
Metoclopramide 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 (see DOSAGE
AND ADMINISTRATION – Use in Patients with Renal or Hepatic Impairment).
For these reasons, 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 renal function,
concomitant disease, or other drug therapy in the elderly (see DOSAGE AND
ADMINISTRATION – For the Relief of Symptomatic Gastroesophageal Reflux and Use in
Patients with Renal or Hepatic Impairment).
Other Special Populations
Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing
methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In
REGLAN ODT™ - Package Insert
Page 9 of 14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia,
methylene blue treatment is not recommended (see OVERDOSAGE).
ADVERSE REACTIONS
In general, the incidence of adverse reactions correlates with the dose and duration of
metoclopramide administration. The following reactions have been reported, although in most
instances, data do not permit an estimate of frequency:
CNS Effects
Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients receiving
the most commonly prescribed dosage of 10 mg four times daily. (see PRECAUTIONS).
Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation (see
WARNINGS) occur less frequently. The incidence of drowsiness is greater at higher doses.
There are isolated reports of convulsive seizures without clear-cut relationship to
metoclopramide. Rarely, hallucinations have been reported.
Extrapyramidal Reactions (EPS)
Acute dystonic reactions, the most common type of EPS associated with metoclopramide, occur
in approximately 0.2% of patients (1 in 500) treated with 30 to 40 mg of metoclopramide per
day. Symptoms include involuntary movements of limbs, facial grimacing, torticollis, oculogyric
crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like
reactions), and, rarely, stridor and dyspnea possibly due to laryngospasm; ordinarily these
symptoms are readily reversed by diphenhydramine (see WARNINGS).
Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask-like
facies (see WARNINGS).
Tardive dyskinesia most frequently is characterized by involuntary movements of the tongue,
face, mouth, or jaw, and sometimes by involuntary movements of the trunk and/or extremities;
movements may be choreoathetotic in appearance (see WARNINGS).
Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness, and
insomnia, as well as inability to sit still, pacing, foot tapping. These symptoms may disappear
spontaneously or respond to a reduction in dosage.
Neuroleptic Malignant Syndrome
Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This
potentially fatal syndrome is comprised of the symptom complex of hyperthermia, altered
consciousness, muscular rigidity, and autonomic dysfunction (see WARNINGS).
Endocrine Disturbances
Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see
PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see
CLINICAL PHARMACOLOGY).
Cardiovascular
REGLAN ODT™ - Package Insert
Page 10 of 14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute
congestive heart failure and possible AV block (see CONTRAINDICATIONS and
PRECAUTIONS).
Gastrointestinal
Nausea and bowel disturbances, primarily diarrhea.
Hepatic
Rarely, cases of hepatotoxicity, characterized by such findings as jaundice and altered liver
function tests, when metoclopramide was administered with other drugs with known hepatotoxic
potential.
Renal
Urinary frequency and incontinence.
Hematologic
A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clear-cut
relationship to metoclopramide. Methemoglobinemia, in adults and especially with overdosage
in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.
Allergic Reactions
A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma.
Rarely, angioneurotic edema, including glossal or laryngeal edema.
Miscellaneous
Visual disturbances. Porphyria.
The adverse experience profile seen with REGLAN ODT™ orally disintegrating tablets in 21
healthy subjects, was similar to that seen with Reglan® Tablets.
OVERDOSAGE
Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions.
Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic properties may be
helpful in controlling the extrapyramidal reactions. Symptoms are self-limiting and usually
disappear within 24 hours.
Hemodialysis removes relatively little metoclopramide, probably because of the small amount of
the drug in blood relative to tissues. Similarly, continuous ambulatory peritoneal dialysis does
not remove significant amounts of drug. It is unlikely that dosage would need to be adjusted to
compensate for losses through dialysis. Dialysis is not likely to be an effective method of drug
removal in overdose situations.
Unintentional overdose due to misadministration has been reported in infants and children with
the use of metoclopramide oral solution. While there was no consistent pattern to the reports
associated with these overdoses, events included seizures, extrapyramidal reactions, and
lethargy.
REGLAN ODT™ - Package Insert
Page 11 of 14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Methemoglobinemia has occurred in premature and full-term neonates who were given
overdoses of metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously for 1 to
3 or more days). Methemoglobinemia can be reversed by the intravenous administration of
methylene blue. However, methylene blue may cause hemolytic anemia in patients with G6PD
deficiency, which may be fatal (see PRECAUTIONS – Other Special Populations).
DOSAGE AND ADMINISTRATION
Therapy with REGLAN ODT™ should not exceed 12 weeks in duration.
Instructions for Use/Handling REGLAN ODT™
Just prior to administration, remove the REGLAN ODT™ orally disintegrating tablet from the
bottle with dry hands. The tablet should be removed from the bottle and immediately placed on
the tongue, to disintegrate and be swallowed with the saliva. The tablet typically disintegrates in
about one and one-half minutes. Administration with liquid is not necessary.
For the Relief of Symptomatic Gastroesophageal Reflux
Administer from 10 mg to 15 mg of REGLAN ODT™ orally up to four times daily, 30 minutes
before each meal and at bedtime, depending upon symptoms being treated and clinical response
(see CLINICAL PHARMACOLOGY and INDICATIONS AND USAGE). If symptoms
occur only intermittently or at specific times of the day, use of metoclopramide in single doses
up to 20 mg prior to the provoking situation may be preferred rather than continuous treatment.
Occasionally, patients (such as elderly patients) who are more sensitive to the therapeutic or
adverse effects of metoclopramide will require only 5 mg per dose.
Experience with esophageal erosions and ulcerations is limited, but healing has thus far been
documented in one controlled trial using four times daily therapy at 15 mg/dose, and this
regimen should be used when lesions are present, so long as it is tolerated (see ADVERSE
REACTIONS). Because of the poor correlation between symptoms and endoscopic appearance
of the esophagus, therapy directed at esophageal lesions is best guided by endoscopic evaluation.
Therapy longer than 12 weeks has not been evaluated and cannot be recommended.
For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic Gastric
Stasis)
Administer 10 mg of REGLAN ODT™ 30 minutes before each meal and at bedtime for two to
eight weeks, depending upon response and the likelihood of continued well-being upon drug
discontinuation.
The initial route of administration should be determined by the severity of the presenting
symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral
administration of REGLAN ODT™ may be initiated. However, if severe symptoms are present,
therapy should begin with metoclopramide injection (consult labeling of the injection prior to
initiating parenteral administration).
REGLAN ODT™ - Package Insert
Page 12 of 14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Administration of metoclopramide injection up to 10 days may be required before symptoms
subside, at which time oral administration may be instituted. Since diabetic gastric stasis is
frequently recurrent, REGLAN ODT™ therapy should be reinstituted at the earliest
manifestation.
Use in Patients with Renal or Hepatic Impairment
Since metoclopramide is excreted principally through the kidneys, in those patients whose
creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half
the recommended dosage. Depending upon clinical efficacy and safety considerations, the
dosage may be increased or decreased as appropriate.
See OVERDOSAGE section for information regarding dialysis.
Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe
use has been described in patients with advanced liver disease whose renal function was normal.
HOW SUPPLIED
REGLAN ODT™ (metoclopramide orally disintegrating tablets) 5 mg base (as the
monohydrochloride monohydrate) are white, round, flat-faced, orange-flavored and engraved
“SP331” on one side and “5” on the other side. They are supplied as follows:
Bottles of 100
NDC 0091-3331-01
REGLAN ODT™ (metoclopramide orally disintegrating tablets) 10 mg base (as the
monohydrochloride monohydrate) are white, round, flat-faced, orange-flavored and engraved
“SP332”on the one side and “10” on the other side. They are supplied as follows:
Bottles of 100
NDC 0091-3332-01
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See
USP Controlled Room Temperature]. Protect from moisture.
Dispense in a tight, light-resistant container as defined in the USP/NF.
Manufactured for: Company logo
Milwaukee, WI 53201, USA
By: CIMA LABS INC.®
Eden Prairie, MN 55344, USA
REGLAN ODT™ uses CIMA LABS INC® U.S. Patent Nos. 6,024,981 and 6,221,392.
REGLAN ODT™ - Package Insert
Page 13 of 14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reglan® is a registered trademark of SRZ Properties, Inc.
Rev. 06/09
REGLAN ODT™ - Package Insert
Page 14 of 14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medication Guide
REGLAN ODT (REG-lan Oh-dee-tee)
(metoclopramide orally disintegrating tablets)
Read the Medication Guide that comes with REGLAN ODT before you start taking it and each
time you get a refill. There may be new information. If you take another product that contains
metoclopramide (such as REGLAN tablets, REGLAN injection, or metoclopramide oral syrup),
you should read the Medication Guide that comes with that product. Some of the information
may be different. This Medication Guide does not take the place of talking with your doctor
about your medical condition or your treatment.
What is the most important information I should know about REGLAN ODT?
REGLAN ODT can cause serious side effects, including:
Abnormal muscle movements called tardive dyskinesia (TD). These movements happen
mostly in the face muscles. You can not control these movements. They may not go away even
after stopping REGLAN ODT. There is no treatment for TD, but symptoms may lessen or go
away over time after you stop taking REGLAN ODT.
Your chances for getting TD go up:
• the longer you take REGLAN ODT and the more REGLAN ODT you take. You should not
take REGLAN ODT for more than 12 weeks.
• if you are older, especially if you are a woman
• if you have diabetes.
It is not possible for your doctor to know if you will get TD if you take REGLAN ODT.
Call your doctor right away if you get movements you can not stop or control, such as:
• lip smacking, chewing, or puckering up your mouth
• frowning or scowling
• sticking out your tongue
• blinking and moving your eyes
• shaking of your arms and legs
See the section “What are the possible side effects of REGLAN ODT?” for more information
about side effects.
What is REGLAN ODT?
REGLAN ODT is a prescription medicine used:
• in adults for 4 to 12 weeks to relieve heartburn symptoms with gastroesophageal reflux
disease (GERD) when certain other treatments do not work. REGLAN ODT relieves daytime
heartburn and heartburn after meals. It also helps ulcers in the esophagus to heal.
• to relieve symptoms of slow stomach emptying in people with diabetes. REGLAN ODT helps
treat symptoms such as nausea, vomiting, heartburn, feeling full long after a meal, and loss
of appetite. Not all these symptoms get better at the same time.
It is not known if REGLAN ODT is safe and works in children.
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 REGLAN ODT?
Do not take REGLAN ODT if you:
• have stomach or intestine problems that could get worse with REGLAN ODT, such as
bleeding, blockage, or a tear in the stomach or bowel wall
• have an adrenal gland tumor called a pheochromocytoma
• are allergic to REGLAN ODT or anything in it. See the end of this Medication Guide for a list
of ingredients in REGLAN ODT.
• take medicines that can cause uncontrolled movements, such as medicines for mental
illness have seizures
What should I tell my doctor before taking REGLAN ODT?
Tell your doctor about all your medical conditions, including if you have:
• depression
• Parkinson’s disease
• high blood pressure
• kidney problems. Your doctor may start with a lower dose.
• liver problems or heart failure. REGLAN ODT may cause your body to hold fluids.
• diabetes. Your dose of insulin may need to be changed.
• breast cancer
• phenylketonuria. REGLAN ODT contains aspartame.
• you are pregnant or plan to become pregnant. It is not known if REGLAN ODT will harm
your unborn baby.
• you are breast-feeding. REGLAN ODT can pass into breast milk and may harm your baby.
Talk with your doctor about the best way to feed your baby if you take REGLAN ODT.
Tell your doctor about all the medicines you take including, prescription and non
prescription medicines, vitamins, and herbal supplements. REGLAN ODT and some
other medicines may interact with each other and may not work as well, or cause possible side
effects. Do not start any new medicines while taking REGLAN ODT until you talk with your
doctor.
Especially tell your doctor if you take:
• another medicine that contains metoclopramide, such as REGLAN tablets, or
metoclopramide oral syrup.
• a blood pressure medicine
• a medicine for depression, especially an Monoamine Oxidase Inhibitor (MAOI)
• insulin
• a medicine that can make you sleepy, such an anti-anxiety medicine, sleep medicines,
and narcotics.
If you are not sure if your medicine is one listed above, ask your doctor or pharmacist.
Know the medicines you take. Keep a list of them and show it your doctor and pharmacist when
you get a new medicine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
How should I take REGLAN ODT?
• REGLAN ODT comes as a tablet that melts in your mouth.
• Take REGLAN ODT exactly as your doctor tells you. Do not change your dose unless your
doctor tells you.
• You should not take REGLAN ODT for more than 12 weeks.
• To take REGLAN ODT:
• Leave the tablet in the bottle until you are ready to take it.
• Use dry hands to take out a tablet. If your hands are wet, the tablets will melt.
• Put the tablet on your tongue right away. Let it melt and then swallow. You do not
need water to take REGLAN ODT.
•
If you take too much REGLAN ODT, call your doctor or Poison Control Center right away.
What should I avoid while taking REGLAN ODT?
• Do not drink alcohol while taking REGLAN ODT. Alcohol may make some side effects of
REGLAN ODT worse, such as feeling sleepy.
• Do not drive, work with machines, or do dangerous tasks until you know how REGLAN
ODT affects you. REGLAN ODT may cause sleepiness.
What are the possible side effects of REGLAN ODT?
Reglan ODT can cause serious side effects, including:
• Abnormal muscle movements. See “What is the most important information I should
know about REGLAN ODT?”
• Uncontrolled spasm of your face and neck muscles, or muscles of your body,
arms, and legs (dystonia). These muscle spasms can cause abnormal movements and
body positions. These spasms usually start within the first 2 days of treatment. These
spasms happen more often in children and adults under age 30.
• Depression, thoughts about suicide, and suicide. Some people who take REGLAN
ODT become depressed. You may have thoughts about hurting or killing yourself. Some
people who take REGLAN ODT have ended their own lives (suicide).
• Neuroleptic Malignant Syndrome (NMS). NMS is a rare but very serious condition
that can happen with REGLAN ODT. NMS can cause death and must be treated in a
hospital. Symptoms of NMS include: high fever, stiff muscles, problems thinking, very fast
or uneven heartbeat, and increased sweating.
• Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving or
keeping your balance. If you already have Parkinson’s disease, your symptoms may
become worse while you are receiving REGLAN ODT.
Call your doctor and get medical help right away if you:
• feel depressed or have thoughts about hurting or killing yourself
• have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and
increased sweating
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
have muscle movements you can not stop or control
•
have muscle movements that are new or unusual
Common side effects include:
•
feeling restless, sleepy, tired, dizzy, or exhausted
•
headache
•
confusion
•
trouble sleeping
You may have more side effects the longer you take REGLAN ODT and the more REGLAN ODT
you take.
You may still have side effects after you stop REGLAN ODT. You may have symptoms from
stopping (withdrawal) REGLAN ODT such as headaches, and feeling dizzy or nervous.
Tell your doctor about any side effects that bother you or do not go away. These are not all
the possible side effects of REGLAN ODT.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–
800–FDA-1088.
How do I store REGLAN ODT?
•
Keep REGLAN ODT at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
•
Keep REGLAN ODT in the bottle it comes in. Keep the bottle closed tightly.
•
Keep REGLAN ODT dry so it does not melt.
Keep REGLAN ODT and all medicines out of the reach of children.
General information about REGLAN ODT
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use REGLAN ODT for a condition for which it was not prescribed. Do not give REGLAN
ODT to other people even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about REGLAN ODT. If you
would like more information, talk with your doctor. You can ask your doctor or pharmacist for
information about REGLAN ODT that is written for health professionals. For more information go
to www.alavenpharma.com or call 1-888-317-0001.
What are the ingredients in REGLAN ODT?
Active ingredient: metoclopramide
Inactive ingredients: aspartame, colloidal silicon dioxide, crospovidone, magnesium stearate,
mannitol, aminoalkyl methacrylate copolymer, microcrystalline cellulose, natural and artificial
orange flavor, povidone
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured for
Alaven Pharmaceutical LLC, Marietta, GA 30062
Revised June 2009
This Medication Guide has been approved by the U.S. Food and Drug Administration.
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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2025-02-12T13:44:22.960566
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017854s051,021793s004lbl.pdf', 'application_number': 17854, 'submission_type': 'SUPPL ', 'submission_number': 51}
|
11,078
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reglan® tablets (metoclopramide tablets, USP)
Rx Only
WARNING: TARDIVE DYSKINESIA
Treatment with metoclopramide can cause tardive dyskinesia, a serious
movement disorder that is often irreversible. The risk of developing tardive
dyskinesia increases with duration of treatment and total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or
symptoms of tardive dyskinesia. There is no known treatment for tardive
dyskinesia. In some patients, symptoms may lessen or resolve after
metoclopramide treatment is stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in
all but rare cases where therapeutic benefit is thought to outweigh the risk of
developing tardive dyskinesia.
See WARNINGS
DESCRIPTION
For oral administration, reglan® tablets (metoclopramide tablets, USP) 10 mg are white,
scored, capsule-shaped tablets engraved “REGLAN” on one side and “ANI 10” on the
opposite side.
Each tablet contains:
Metoclopramide base .................................................. 10 mg
(as the monohydrochloride monohydrate)
Inactive Ingredients
Magnesium Stearate, Mannitol, Microcrystalline Cellulose, Stearic Acid.
reglan® tablets (metoclopramide tablets, USP) 5 mg are green, elliptical-shaped tablets
engraved “REGLAN” over “5” on one side and “ANI” on the opposite side.
Each tablet contains:
Metoclopramide base .................................................... 5 mg
(as the monohydrochloride monohydrate)
Inactive Ingredients
Corn starch, D&C Yellow 10 Aluminum Lake, FD&C Blue 1 Aluminum Lake, Lactose,
Microcrystalline Cellulose, Silicon Dioxide, Stearic Acid.
Metoclopramide hydrochloride is a white crystalline, odorless substance, freely soluble in
water. Chemically, it is 4-amino-5- chloro-N-[2-(diethylamino)ethyl]-2-methoxy
Reference ID: 3018416
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
benzamide monohydrochloride monohydrate. Its molecular formula is
C14H22ClN3O2•HCl•H2O. Its molecular weight is 354.3.
CLINICAL PHARMACOLOGY
Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating
gastric, biliary, or pancreatic secretions. Its mode of action is unclear. It seems to
sensitize tissues to the action of acetylcholine. The effect of metoclopramide on motility
is not dependent on intact vagal innervation, but it can be abolished by anticholinergic
drugs.
Metoclopramide increases the tone and amplitude of gastric (especially antral)
contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis
of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal
transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any,
effect on the motility of the colon or gallbladder.
In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter
pressure), single oral doses of metoclopramide produce dose-related increases in LESP.
Effects begin at about 5 mg and increase through 20 mg (the largest dose tested). The
increase in LESP from a 5 mg dose lasts about 45 minutes and that of 20 mg lasts
between 2 and 3 hours. Increased rate of stomach emptying has been observed with
single oral doses of 10 mg.
The antiemetic properties of metoclopramide appear to be a result of its antagonism of
central and peripheral dopamine receptors. Dopamine produces nausea and vomiting by
stimulation of the medullary chemoreceptor trigger zone (CTZ), and metoclopramide
blocks stimulation of the CTZ by agents like l-dopa or apomorphine which are known to
increase dopamine levels or to possess dopamine-like effects. Metoclopramide also
abolishes the slowing of gastric emptying caused by apomorphine.
Like the phenothiazines and related drugs, which are also dopamine antagonists,
metoclopramide produces sedation and may produce extrapyramidal reactions, although
these are comparatively rare (see WARNINGS). Metoclopramide inhibits the central and
peripheral effects of apomorphine, induces release of prolactin and causes a transient
increase in circulating aldosterone levels, which may be associated with transient fluid
retention.
The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an
intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60
minutes following an oral dose; pharmacological effects persist for 1 to 2 hours.
Reference ID: 3018416
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Metoclopramide is rapidly and well absorbed. Relative to an intravenous dose of 20 mg,
the absolute oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a
crossover study of 18 subjects. Peak plasma concentrations occur at about 1 to 2 hr after a
single oral dose. Similar time to peak is observed after individual doses at steady state.
In a single dose study of 12 subjects, the area under the drug concentration-time curve
increases linearly with doses from 20 to 100 mg. Peak concentrations increase linearly
with dose; time to peak concentrations remains the same; whole body clearance is
unchanged; and the elimination rate remains the same. The average elimination half-life
in individuals with normal renal function is 5 to 6 hr. Linear kinetic processes adequately
describe the absorption and elimination of metoclopramide.
Approximately 85% of the radioactivity of an orally administered dose appears in the
urine within 72 hr. Of the 85% eliminated in the urine, about half is present as free or
conjugated metoclopramide.
The drug is not extensively bound to plasma proteins (about 30%). The whole body
volume of distribution is high (about 3.5 L/kg) which suggests extensive distribution of
drug to the tissues.
Renal impairment affects the clearance of metoclopramide. In a study with patients with
varying degrees of renal impairment, a reduction in creatinine clearance was correlated
with a reduction in plasma clearance, renal clearance, non-renal clearance, and increase
in elimination half-life. The kinetics of metoclopramide in the presence of renal
impairment remained linear however. The reduction in clearance as a result of renal
impairment suggests that adjustment downward of maintenance dosage should be done to
avoid drug accumulation.
Adult Pharmacokinetic Data
Parameter
Value
Vd (L/kg)
~ 3.5
Plasma Protein Binding
~ 30%
t1/2 (hr)
5 to 6
Oral Bioavailability
80%±15.5%
In pediatric patients, the pharmacodynamics of metoclopramide following oral and
intravenous administration are highly variable and a concentration-effect relationship has
not been established.
There are insufficient reliable data to conclude whether the pharmacokinetics of
metoclopramide in adults and the pediatric population are similar. Although there are
insufficient data to support the efficacy of metoclopramide in pediatric patients with
symptomatic gastroesophageal reflux (GER) or cancer chemotherapy-related nausea and
vomiting, its pharmacokinetics have been studied in these patient populations.
Reference ID: 3018416
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with
GER received metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The
mean peak plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8
μg/L) higher compared to that observed after the first dose (29 μg/L) indicating drug
accumulation with repeated dosing. After the tenth dose, the mean time to reach peak
concentrations (2.2 hr), half-life (4.1 hr), clearance (0.67 L/h/kg), and volume of
distribution (4.4 L/kg) of metoclopramide were similar to those observed after the first
dose. In the youngest patient (age, 3.5 weeks), metoclopramide half-life after the first and
the tenth dose (23.1 and 10.3 hr, respectively) was significantly longer compared to other
infants due to reduced clearance. This may be attributed to immature hepatic and renal
systems at birth.
Single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were
administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (mean
age, 11.7 years; range, 7 to 14 yr) for prophylaxis of cytotoxic-induced vomiting. The
metoclopramide plasma concentrations extrapolated to time zero ranged from 65 to 395
μg/L (mean, 152 μg/L). The mean elimination half-life, clearance, and volume of
distribution of metoclopramide were 4.4 hr (range, 1.7 to 8.3 hr), 0.56 L/h/kg (range, 0.12
to 1.20 L/h/kg), and 3.0 L/kg (range, 1.0 to 4.8 L/kg), respectively.
In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received 4 to 5
intravenous infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to
control emesis. After the last dose, the peak serum concentrations of metoclopramide
ranged from 1060 to 5680 μg/L. The mean elimination half-life, clearance, and volume of
distribution of metoclopramide were 4.5 hr (range, 2.0 to 12.5 hr), 0.37 L/h/kg (range,
0.10 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to 5.50 L/kg), respectively.
INDICATIONS AND USAGE
The use of reglan® tablets is recommended for adults only. Therapy should not
exceed 12 weeks in duration.
Symptomatic Gastroesophageal Reflux
reglan® tablets are indicated as short-term (4 to 12 weeks) therapy for adults with
symptomatic, documented gastroesophageal reflux who fail to respond to conventional
therapy.
The principal effect of metoclopramide is on symptoms of postprandial and daytime
heartburn with less observed effect on nocturnal symptoms. If symptoms are confined to
particular situations, such as following the evening meal, use of metoclopramide as single
doses prior to the provocative situation should be considered, rather than using the drug
throughout the day. Healing of esophageal ulcers and erosions has been endoscopically
demonstrated at the end of a 12-week trial using doses of 15 mg q.i.d. As there is no
documented correlation between symptoms and healing of esophageal lesions, patients
with documented lesions should be monitored endoscopically.
Diabetic Gastroparesis (Diabetic Gastric Stasis)
reglan® tablets (metoclopramide tablets, USP) is indicated for the relief of symptoms
associated with acute and recurrent diabetic gastric stasis. The usual manifestations of
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delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after
meals, and anorexia) appear to respond to reglan® within different time intervals.
Significant relief of nausea occurs early and continues to improve over a three-week
period. Relief of vomiting and anorexia may precede the relief of abdominal fullness by
one week or more.
CONTRAINDICATIONS
Metoclopramide should not be used whenever stimulation of gastrointestinal motility
might be dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical
obstruction, or perforation.
Metoclopramide is contraindicated in patients with pheochromocytoma because the drug
may cause a hypertensive crisis, probably due to release of catecholamines from the
tumor. Such hypertensive crises may be controlled by phentolamine.
Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the
drug.
Metoclopramide should not be used in epileptics or patients receiving other drugs which
are likely to cause extrapyramidal reactions, since the frequency and severity of seizures
or extrapyramidal reactions may be increased.
WARNINGS
Mental depression has occurred in patients with and without prior history of depression.
Symptoms have ranged from mild to severe and have included suicidal ideation and
suicide. Metoclopramide should be given to patients with a prior history of depression
only if the expected benefits outweigh the potential risks.
Extrapyramidal symptoms, manifested primarily as acute dystonic reactions, occur in
approximately 1 in 500 patients treated with the usual adult dosages of 30 to 40 mg/day
of metoclopramide. These usually are seen during the first 24 to 48 hours of treatment
with metoclopramide, occur more frequently in pediatric patients and adult patients less
than 30 years of age and are even more frequent at higher doses. These symptoms may
include involuntary movements of limbs and facial grimacing, torticollis, oculogyric
crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, or dystonic reactions
resembling tetanus. Rarely, dystonic reactions may present as stridor and dyspnea,
possibly due to laryngospasm. If these symptoms should occur, inject 50 mg
diphenhydramine hydrochloride intramuscularly, and they usually will subside.
Benztropine mesylate, 1 to 2 mg intramuscularly, may also be used to reverse these
reactions.
Parkinsonian-like symptoms have occurred, more commonly within the first 6 months
after beginning treatment with metoclopramide, but occasionally after longer periods.
These symptoms generally subside within 2 to 3 months following discontinuance of
metoclopramide. Patients with preexisting Parkinson’s disease should be given
metoclopramide cautiously, if at all, since such patients may experience exacerbation of
parkinsonian symptoms when taking metoclopramide.
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Tardive Dyskinesia
(See Boxed Warnings)
Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially
irreversible and disfiguring disorder characterized by involuntary movements of the face,
tongue, or extremities. The risk of developing tardive dyskinesia increases with the
duration of treatment and the total cumulative dose. An analysis of utilization of patterns
showed that about 20% of patients who used metoclopramide took it longer than 12
weeks. Treatment with metoclopramide for longer than the recommended 12 weeks
should be avoided in all but rare cases where therapeutic benefit is thought to outweigh
the risk of developing TD.
Although the risk of developing TD in the general population may be increased among
the elderly, women, and diabetics, it is not possible to predict which patients will develop
metoclopramide-induced TD. Both the risk of developing TD and the likelihood that TD
will become irreversible increase with duration of treatment and total cumulative dose.
Metoclopramide should be discontinued in patients who develop signs and symptoms of
TD. There is no known effective treatment for established cases of TD, although in some
patients, TD may remit, partially or completely, within several weeks to months after
metoclopramide is withdrawn.
Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby
masking the underlying disease process. The effect of this symptomatic suppression upon
the long-term course of TD is unknown. Therefore, metoclopramide should not be used
for the symptomatic control of TD.
Neuroleptic Malignant Syndrome (NMS)
There have been rare reports of an uncommon but potentially fatal symptom complex
sometimes referred to as Neuroleptic Malignant Syndrome (NMS) associated with
metoclopramide. Clinical manifestations of NMS include hyperthermia, muscle rigidity,
altered consciousness, and evidence of autonomic instability (irregular pulse or blood
pressure, tachycardia, diaphoresis and cardiac arrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases where the clinical presentation includes both
serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or
inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity, heat
stroke, malignant hyperthermia, drug fever and primary central nervous system (CNS)
pathology.
The management of NMS should include 1) immediate discontinuation of
metoclopramide and other drugs not essential to concurrent therapy, 2) intensive
symptomatic treatment and medical monitoring, and 3) treatment of any concomitant
serious medical problems for which specific treatments are available. Bromocriptine and
dantrolene sodium have been used in treatment of NMS, but their effectiveness have not
been established (see ADVERSE REACTIONS).
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PRECAUTIONS
General
In one study in hypertensive patients, intravenously administered metoclopramide was
shown to release catecholamines; hence, caution should be exercised when
metoclopramide is used in patients with hypertension.
Because metoclopramide produces a transient increase in plasma aldosterone, certain
patients, especially those with cirrhosis or congestive heart failure, may be at risk of
developing fluid retention and volume overload. If these side effects occur at any time
during metoclopramide therapy, the drug should be discontinued.
Adverse reactions, especially those involving the nervous system, may occur after
stopping the use of reglan®. A small number of patients may experience a withdrawal
period after stopping reglan® that could include dizziness, nervousness, and/or headaches.
Information for Patients
The use of reglan® is recommended for adults only. Metoclopramide may impair the
mental and/or physical abilities required for the performance of hazardous tasks such as
operating machinery or driving a motor vehicle. The ambulatory patient should be
cautioned accordingly.
For additional information, patients should be instructed to see the Medication Guide for
reglan® tablets.
Drug Interactions
The effects of metoclopramide on gastrointestinal motility are antagonized by
anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when
metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines in patients with essential
hypertension suggests that it should be used cautiously, if at all, in patients receiving
monoamine oxidase inhibitors.
Absorption of drugs from the stomach may be diminished (e.g., digoxin) by
metoclopramide, whereas the rate and/or extent of absorption of drugs from the small
bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol,
cyclosporine).
Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some
patients. Exogenously administered insulin may begin to act before food has left the
stomach and lead to hypoglycemia. Because the action of metoclopramide will influence
the delivery of food to the intestines and thus the rate of absorption, insulin dosage or
timing of dosage may require adjustment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 77-week study was conducted in rats with oral doses up to about 40 times the
maximum recommended human daily dose. Metoclopramide elevates prolactin levels and
the elevation persists during chronic administration. Tissue culture experiments indicate
that approximately one-third of human breast cancers are prolactin-dependent in vitro, a
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factor of potential importance if the prescription of metoclopramide is contemplated in a
patient with previously detected breast cancer. Although disturbances such as
galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with
prolactin-elevating drugs, the clinical significance of elevated serum prolactin levels is
unknown for most patients. An increase in mammary neoplasms has been found in
rodents after chronic administration of prolactin-stimulating neuroleptic drugs and
metoclopramide. Neither clinical studies nor epidemiologic studies conducted to date,
however, have shown an association between chronic administration of these drugs and
mammary tumorigenesis; the available evidence is too limited to be conclusive at this
time.
An Ames mutagenicity test performed on metoclopramide was negative.
Pregnancy Category B
Reproduction studies performed in rats, mice and rabbits by the I.V., I.M., S.C., and oral
routes at maximum levels ranging from 12 to 250 times the human dose have
demonstrated no impairment of fertility or significant harm to the fetus due to
metoclopramide. 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
Metoclopramide is excreted in human milk. Caution should be exercised when
metoclopramide is administered to a nursing mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established (see
OVERDOSAGE).
Care should be exercised in administering metoclopramide to neonates since prolonged
clearance may produce excessive serum concentrations (see CLINICAL
PHARMACOLOGY - Pharmacokinetics). In addition, neonates have reduced levels of
NADH-cytochrome b5 reductase which, in combination with the aforementioned
pharmacokinetic factors, make neonates more susceptible to methemoglobinemia (see
OVERDOSAGE).
The safety profile of metoclopramide in adults cannot be extrapolated to pediatric
patients. Dystonias and other extrapyramidal reactions associated with metoclopramide
are more common in the pediatric population than in adults. (See WARNINGS and
ADVERSE REACTIONS - Extrapyramidal Reactions.)
Geriatric Use
Clinical studies of reglan® did not include sufficient numbers of subjects aged 65 and
over to determine whether elderly subjects respond differently from younger subjects.
The risk of developing parkinsonian-like side effects increases with ascending dose.
Geriatric patients should receive the lowest dose of reglan® that is effective. If
parkinsonian-like symptoms develop in a geriatric patient receiving reglan®, reglan®
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should generally be discontinued before initiating any specific anti-parkinsonian agents
(see WARNINGS and DOSAGE AND ADMINISTRATION – For the Relief of
Symptomatic Gastroesophageal Reflux).
The elderly may be at greater risk for tardive dyskinesia (see WARNINGS – Tardive
Dyskinesia).
Sedation has been reported in reglan® users. Sedation may cause confusion and manifest
as over-sedation in the elderly (see CLINICAL PHARMACOLOGY,
PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – CNS
Effects).
reglan® 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 (see
DOSAGE AND ADMINISTRATION – Use in Patients with Renal or Hepatic
Impairment).
For these reasons, 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
renal function, concomitant disease, or other drug therapy in the elderly (see DOSAGE
AND ADMINISTRATION – For the Relief of Symptomatic Gastroesophageal
Reflux and Use in Patients with Renal or Hepatic Impairment).
Other Special Populations
Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of
developing methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is
administered. In patients with G6PD deficiency who experience metoclopramide-
induced methemoglobinemia, methylene blue treatment is not recommended (see
OVERDOSAGE).
ADVERSE REACTIONS
In general, the incidence of adverse reactions correlates with the dose and duration of
metoclopramide administration. The following reactions have been reported, although in
most instances, data do not permit an estimate of frequency:
CNS Effects
Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients
receiving the most commonly prescribed dosage of 10 mg q.i.d. (see PRECAUTIONS).
Insomnia, headache, confusion, dizziness, or mental depression with suicidal ideation
(see WARNINGS) occur less frequently. The incidence of drowsiness is greater at
higher doses. There are isolated reports of convulsive seizures without clearcut
relationship to metoclopramide. Rarely, hallucinations have been reported.
Extrapyramidal Reactions (EPS)
Acute dystonic reactions, the most common type of EPS associated with metoclopramide,
occur in approximately 0.2% of patients (1 in 500) treated with 30 to 40 mg of
metoclopramide per day. Symptoms include involuntary movements of limbs, facial
grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of
Reference ID: 3018416
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speech, trismus, opisthotonus (tetanus-like reactions), and, rarely, stridor and dyspnea
possibly due to laryngospasm; ordinarily these symptoms are readily reversed by
diphenhydramine (see WARNINGS).
Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask
like facies (see WARNINGS).
Tardive dyskinesia most frequently is characterized by involuntary movements of the
tongue, face, mouth, or jaw, and sometimes by involuntary movements of the trunk
and/or extremities; movements may be choreoathetotic in appearance (see
WARNINGS).
Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness, and
insomnia, as well as inability to sit still, pacing, foot tapping. These symptoms may
disappear spontaneously or respond to a reduction in dosage.
Neuroleptic Malignant Syndrome
Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This
potentially fatal syndrome is comprised of the symptom complex of hyperthermia, altered
consciousness, muscular rigidity, and autonomic dysfunction (see WARNINGS).
Endocrine Disturbances
Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia
(see PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone
(see CLINICAL PHARMACOLOGY).
Cardiovascular
Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention,
acute congestive heart failure and possible AV block (see CONTRAINDICATIONS
and PRECAUTIONS).
Gastrointestinal
Nausea and bowel disturbances, primarily diarrhea.
Hepatic
Rarely, cases of hepatotoxicity, characterized by such findings as jaundice and altered
liver function tests, when metoclopramide was administered with other drugs with known
hepatotoxic potential.
Renal
Urinary frequency and incontinence.
Hematologic
A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clearcut
relationship to metoclopramide. Methemoglobinemia, in adults and especially with
overdosage in neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.
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Allergic Reactions
A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of
asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.
Miscellaneous
Visual disturbances. Porphyria.
OVERDOSAGE
Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal
reactions. Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic
properties may be helpful in controlling the extrapyramidal reactions. Symptoms are self-
limiting and usually disappear within 24 hours.
Hemodialysis removes relatively little metoclopramide, probably because of the small
amount of the drug in blood relative to tissues. Similarly, continuous ambulatory
peritoneal dialysis does not remove significant amounts of drug. It is unlikely that dosage
would need to be adjusted to compensate for losses through dialysis. Dialysis is not likely
to be an effective method of drug removal in overdose situations.
Unintentional overdose due to misadministration has been reported in infants and
children with the use of metoclopramide oral solution. While there was no consistent
pattern to the reports associated with these overdoses, events included seizures,
extrapyramidal reactions, and lethargy.
Methemoglobinemia has occurred in premature and full-term neonates who were given
overdoses of metoclopramide (1 to 4 mg/kg/day orally, intramuscularly or intravenously
for 1 to 3 or more days). Methemoglobinemia can be reversed by the intravenous
administration of methylene blue. However, methylene blue may cause hemolytic anemia
in patients with G6PD deficiency, which may be fatal (see PRECAUTIONS – Other
Special Populations).
DOSAGE AND ADMINISTRATION
Therapy with reglan® tablets should not exceed 12 weeks in duration.
For the relief of Symptomatic Gastroesophageal Reflux
Administer from 10 mg to 15 mg reglan® (metoclopramide hydrochloride, USP) orally up
to q.i.d. 30 minutes before each meal and at bedtime, depending upon symptoms being
treated and clinical response (see CLINICAL PHARMACOLOGY and
INDICATIONS AND USAGE). If symptoms occur only intermittently or at specific
times of the day, use of metoclopramide in single doses up to 20 mg prior to the
provoking situation may be preferred rather than continuous treatment. Occasionally,
patients (such as elderly patients) who are more sensitive to the therapeutic or adverse
effects of metoclopramide will require only 5 mg per dose.
Experience with esophageal erosions and ulcerations is limited, but healing has thus far
been documented in one controlled trial using q.i.d. therapy at 15 mg/dose, and this
regimen should be used when lesions are present, so long as it is tolerated (see
ADVERSE REACTIONS). Because of the poor correlation between symptoms and
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endoscopic appearance of the esophagus, therapy directed at esophageal lesions is best
guided by endoscopic evaluation.
Therapy longer than 12 weeks has not been evaluated and cannot be recommended.
For the Relief of Symptoms Associated with Diabetic Gastroparesis
(Diabetic Gastric Stasis)
Administer 10 mg of metoclopramide 30 minutes before each meal and at bedtime for
two to eight weeks, depending upon response and the likelihood of continued well-being
upon drug discontinuation.
The initial route of administration should be determined by the severity of the presenting
symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral
administration of reglan® may be initiated. However, if severe symptoms are present,
therapy should begin with metoclopramide injection (consult labeling of the injection
prior to initiating parenteral administration).
Administration of metoclopramide injection up to 10 days may be required before
symptoms subside, at which time oral administration may be instituted. Since diabetic
gastric stasis is frequently recurrent, reglan® therapy should be reinstituted at the earliest
manifestation.
Use in Patients with Renal or Hepatic Impairment
Since metoclopramide is excreted principally through the kidneys, in those patients
whose creatinine clearance is below 40 mL/min, therapy should be initiated at
approximately one-half the recommended dosage. Depending upon clinical efficacy and
safety considerations, the dosage may be increased or decreased as appropriate.
See OVERDOSAGE section for information regarding dialysis.
Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation.
Its safe use has been described in patients with advanced liver disease whose renal
function was normal.
HOW SUPPLIED
Each white, capsule-shaped, scored reglan® tablet (metoclopramide tablets, USP)
contains 10 mg metoclopramide base (as the monohydrochloride monohydrate).
Available in:
Bottles of 100 tablets (NDC 62559-166-01)
Each green, elliptical-shaped reglan® tablet (metoclopramide tablets, USP) contains 5 mg
metoclopramide base (as the monohydrochloride monohydrate). Available in :
Bottles of 100 tablets (NDC 62559-165-01)
Dispense tablets in tight, light-resistant container.
Tablets should be stored at controlled room temperature, between 20°C and 25°C (68°F
and 77°F).
Manufactured by:
ANI Pharmaceuticals, Inc.
Baudette, MN 56623
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For Medical Inquiries, call toll free at 1-800-308-6755.
www.anipharmaceuticals.com
PCS 9454
Rev 08/2011
Medication guide
REGLAN (REG-lan) Tablets
(metoclopramide tablets)
Read the Medication Guide that comes with REGLAN before you start taking it and each
time you get a refill. There may be new information. If you take another product that
contains metoclopramide (such as REGLAN injection, REGLAN ODT, or
metoclopramide oral syrup), you should read the Medication Guide that comes with that
product. Some of the information may be different. This Medication Guide does not take
the place of talking with your doctor about your medical condition or your treatment.
What is the most important information I should know about REGLAN?
REGLAN can cause serious side effects, including:
Tardive dyskinesia (abnormal muscle movements). These movements happen mostly
in the face muscles. You can not control these movements. They may not go away even
after stopping REGLAN. There is no treatment for tardive dyskinesia, but symptoms may
lessen or go away over time after you stop taking REGLAN.
Your chances for getting tardive dyskinesia go up:
• the longer you take REGLAN and the more REGLAN you take. You should not
take REGLAN for more than 12 weeks.
• if you are older, especially if you are a woman
• if you have diabetes
It is not possible for your doctor to know if you will get tardive dyskinesia if you take
REGLAN.
Call your doctor right away if you get movements you can not stop or control, such as:
• lip smacking, chewing, or puckering up your mouth
• frowning or scowling
• sticking out your tongue
• blinking and moving your eyes
• shaking of your arms and legs
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See the section "What are the possible side effects of REGLAN?" for more information
about side effects.
What is REGLAN?
REGLAN is a prescription medicine used:
• in adults for 4 to 12 weeks to relieve heartburn symptoms with gastroesophageal
reflux disease (GERD) when certain other treatments do not work. REGLAN
relieves daytime heartburn and heartburn after meals. It also helps ulcers in the
esophagus to heal.
• to relieve symptoms of slow stomach emptying in people with diabetes. REGLAN
helps treat symptoms such as nausea, vomiting, heartburn, feeling full long after a
meal, and loss of appetite. Not all these symptoms get better at the same time.
It is not known if REGLAN is safe and works in children.
Who should not take REGLAN?
Do not take REGLAN if you:
• have stomach or intestine problems that could get worse with REGLAN, such as
bleeding, blockage or a tear in the stomach or bowel wall
• have an adrenal gland tumor called a pheochromocytoma
• are allergic to REGLAN or anything in it. See the end of this Medication Guide
for a list of ingredients in REGLAN.
• take medicines that can cause uncontrolled movements, such as medicines for
mental illness
• have seizures
What should I tell my doctor before taking REGLAN?
Tell your doctor about all your medical conditions, including if you have:
• depression
• Parkinson's disease
• high blood pressure
• kidney problems. Your doctor may start with a lower dose.
• liver problems or heart failure. REGLAN may cause your body to hold fluids.
• diabetes. Your dose of insulin may need to be changed.
• breast cancer
• you are pregnant or plan to become pregnant. It is not known if REGLAN will
harm your unborn baby.
• you are breast-feeding. REGLAN can pass into breast milk and may harm your
baby. Talk with your doctor about the best way to feed your baby if you take
REGLAN.
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Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. REGLAN and some other
medicines may interact with each other and may not work as well, or cause possible side
effects. Do not start any new medicines while taking REGLAN until you talk with your
doctor.
Especially tell your doctor if you take:
• another medicine that contains metoclopramide, such as REGLAN ODT, or
metoclopramide oral syrup
• a blood pressure medicine
• a medicine for depression, especially an Monoamine Oxidase Inhibitor (MAOI)
• insulin
• a medicine that can make you sleepy, such as anti-anxiety medicine, sleep
medicines, and narcotics.
If you are not sure if your medicine is one listed above, ask your doctor or pharmacist.
Know the medicines you take. Keep a list of them and show it to your doctor and
pharmacist when you get a new medicine.
How should I take REGLAN?
• REGLAN comes as a tablet you take by mouth.
• Take REGLAN exactly as your doctor tells you. Do not change your dose unless
your doctor tells you.
• You should not take REGLAN for more than 12 weeks.
• If you take too much REGLAN, call your doctor or Poison Control Center right
away.
What should I avoid while taking REGLAN?
• Do not drink alcohol while taking REGLAN. Alcohol may make some side
effects of REGLAN worse, such as feeling sleepy.
• Do not drive, work with machines, or do dangerous tasks until you know how
REGLAN affects you. REGLAN may cause sleepiness.
What are the possible side effects of REGLAN?
Reglan can cause serious side effects, including:
• Tardive dyskinesia (abnormal muscle movements). See "What is the most
important information I need to know about REGLAN?"
• Uncontrolled spasms of your face and neck muscles, or muscles of your body,
arms, and legs (dystonia). These muscle spasms can cause abnormal movements
Reference ID: 3018416
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and body positions. These spasms usually start within the first 2 days of
treatment. These spasms happen more often in children and adults under age 30.
• Depression, thoughts about suicide, and suicide. Some people who take
REGLAN become depressed. You may have thoughts about hurting or killing
yourself. Some people who take Reglan have ended their own lives (suicide).
• Neuroleptic Malignant Syndrome (NMS). NMS is a very rare but very serious
condition that can happen with Reglan. NMS can cause death and must be treated
in a hospital. Symptoms of NMS include: high fever, stiff muscles, problems
thinking, very fast or uneven heartbeat, and increased sweating.
• Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving
or keeping your balance. If you already have Parkinson's disease, your symptoms
may become worse while you are receiving REGLAN.
Call your doctor and get medical help right away if you:
• feel depressed or have thoughts about hurting or killing yourself
• have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat,
and increased sweating
• have muscle movements you cannot stop or control
• have muscle movements that are new or unusual
Common side effects of Reglan include:
• feeling restless, sleepy, tired, dizzy, or exhausted
• headache
• confusion
• trouble sleeping
You may have more side effects the longer you take REGLAN and the more REGLAN
you take. You may still have side effects after stopping REGLAN. You may have
symptoms from stopping (withdrawal) REGLAN such as headaches, and feeling dizzy or
nervous.
Tell your doctor about any side effects that bother you or do not go away. These are not
all the possible side effects of REGLAN.
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 REGLAN?
• Keep REGLAN at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep REGLAN in the bottle it comes in. Keep the bottle closed tightly.
Keep REGLAN and all medicines out of the reach of children.
Reference ID: 3018416
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General information about REGLAN
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use REGLAN for a condition for which it was not prescribed. Do not give
REGLAN to other people, even if they have the same symptoms that you have. It may
harm them.
This Medication Guide summarizes the most important information about REGLAN. If
you would like more information, talk with your doctor. You can ask your doctor or
pharmacist for information about REGLAN that is written for health professionals. For
more information, go to www.anipharmaceuticals.com or call toll free at 1-800-308
6755.
What are the ingredients in REGLAN?
Active ingredient: metoclopramide
Inactive ingredients:
REGLAN 10 mg tablets: magnesium stearate, mannitol, microcrystalline
cellulose, stearic acid
REGLAN 5 mg tablets: corn starch, D&C yellow 10 aluminum lake, FD&C blue
1 aluminum lake, lactose, microcrystalline cellulose, silicon dioxide, stearic acid
Manufactured by:
ANI Pharmaceuticals, Inc.
Baudette, MN 56623
For Medical Inquiries, call toll-free 1-800-308-6755.
www.anipharmaceuticals.com
PCS 9455
Rev. 08/2011
Revised August 2011
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reference ID: 3018416
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:23.120372
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017854s058lbl.pdf', 'application_number': 17854, 'submission_type': 'SUPPL ', 'submission_number': 58}
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Page 1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Kit for the
Preparation of Technetium Tc 99m Sulfur Colloid Injection.
See full prescribing information for Kit for the Preparation of Technetium
Tc 99m Sulfur Colloid Injection.
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection for
Subcutaneous, Intraperitoneal, Intravenous, and Oral Use.
Initial U.S. Approval: 1978
----------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1) 08/2012
Dosage and Administration (2.1, 2.2, 2.4) 08/2012
---------------------------INDICATIONS AND USAGE---------------------------
Technetium Tc 99m Sulfur Colloid Injection is a radioactive diagnostic agent
indicated (1):
In adults, to assist in the:
localization of lymph nodes draining a primary tumor in patients with
breast cancer or malignant melanoma when used with a hand-held
gamma counter.
evaluation of peritoneo-venous (LeVeen) shunt patency in adults.
In adults and pediatric patients, for:
imaging areas of functioning reticuloendothelial cells in the liver, spleen
and bone marrow.
studies of esophageal transit and gastroesophageal reflux, and detection of
pulmonary aspiration of gastric contents.
----------------------DOSAGE AND ADMINISTRATION------------------------
Minimize Tc99m Sulfur Colloid radiation exposure and measure patient doses
immediately before administration.
Breast cancer or malignant melanoma setting: by subcutaneous injection,
3.7 to 37 MBq (0.1 to 1 mCi in volumes ranging from 0.1 to 1 mL) (2.1).
Peritoneo-venous (LeVeen) shunt setting in adults: (2.1)
o by intraperitoneal injection: 37 to 111 MBq (1 to 3 mCi);
o by percutaneous transtubal injection: 12 to 37 MBq (0.3 to 1 mCi) in
a volume not to exceed 0.5 mL.
Imaging areas of functioning reticuloendothelial cells by intravenous
injection (2.1):
In adults:
o Liver/spleen imaging: 37 to 296 MBq (1 to 8 mCi);
o Bone marrow imaging: 111 to 444 MBq (3 to 12 mCi);
In pediatric patients:
o Liver/spleen imaging in newborns: 7.4 to 18.5 MBq (0.2 to 0.5 mCi);
o Liver/spleen imaging in children: 0.56 to 2.78 MBq (0.015 to 0.075
mCi) per kg of body weight (BW);
o Bone marrow imaging: 1.11 to 5.55 MBq (0.03 to 0.15 mCi) per kg
of BW.
Gastroesophageal and pulmonary aspiration studies by oral route (2.1):
In adults:
o Gastroesophageal studies: 5.55 to 11.1 MBq (0.15 to 0.30 mCi);
o Pulmonary aspiration studies: 11.1 to 18.5 MBq (0.30 to 0.50 mCi).
In pediatric patients:
o 3.7 to 11.1 MBq (0.10 to 0.30 mCi).
---------------------DOSAGE FORMS AND STRENGTHS-------------------
The Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection is
supplied as a package that contains 5 kits. Each kit contains three vials: one
10 mL multi-dose Reaction Vial, a Solution A vial and a Solution B vial. The
vials contain the sterile non-pyrogenic, non-radioactive ingredients necessary
to produce Technetium Tc 99m Sulfur Colloid Injection (3).
----------------------------CONTRAINDICATIONS--------------------------------
None
-----------------------WARNINGS AND PRECAUTIONS------------------------
Anaphylactic reactions including rare fatalities have occurred following
intravenously administered Technetium Tc 99m Sulfur Colloid. Have
resuscitation equipment and personnel immediately available (5.1).
---------------------------ADVERSE REACTIONS----------------------------------
The most frequently reported adverse reactions include rash, urticaria,
anaphylactic shock, and hypotension (6).
To report SUSPECTED ADVERSE REACTIONS, contact
Pharmalucence Inc. at 1-800-221-7554 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
See 17 for PATIENT COUNSELING INFORMATION
Revised 08/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Doses
2.2 Drug Preparation and Administration
2.3 Radiation Dosimetry
2.4 Imaging Considerations
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactic Reactions
5.2 Radiation Risks
5.3 Altered Distribution, Accumulation of Tracer in the Lungs
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
8.6 Females of Reproductive Potential
10 OVERDOSAGE
11 DESCRIPTION
11.1 Physical Characteristics
11.2 External Radiation
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 Tracer Localization to Lymph Nodes in Breast Cancer
14.2 Tracer Localization to Lymph Nodes in Malignant Melanoma
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
_______________________________________________________________________________________________________________________________________
Reference ID: 3173576
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
Technetium Tc 99m Sulfur Colloid Injection is indicated:
In adults, to assist in the:
localization of lymph nodes draining a primary tumor in patients with breast cancer or malignant melanoma when used with a hand-held gamma counter.
evaluation of peritoneo-venous (LeVeen) shunt patency.
In adults and pediatric patients, for imaging:
areas of functioning reticuloendothelial cells in the liver, spleen and bone marrow.
studies of esophageal transit and, gastroesophageal reflux, and detection of pulmonary aspiration of gastric contents.
2
DOSAGE AND ADMINISTRATION
Technetium Tc 99m Sulfur Colloid Injection emits radiation. Use procedures to minimize radiation exposure. Measure patient dose by a suitable radioactivity calibration
system immediately before administration.
2.1 Recommended Doses
Breast cancer or malignant melanoma setting in adults: 3.7 to 37 MBq (0.1 to 1 mCi) in volumes ranging from 0.1 to 1 mL by subcutaneous injection.
Peritoneo-venous (LeVeen) shunt setting in adults: 37 to 111 MBq (1 to 3 mCi) by intraperitoneal injection, or 12 to 37 MBq (0.3 to 1 mCi) in a volume not to exceed
0.5 mL by percutaneous transtubal (efferent limb) injection. Patient repositioning or other measures may be used to help assure uniform mixing of the
radiopharmaceutical with peritoneal fluid.
Imaging areas of functioning reticuloendothelial cells:
In adults:
○ liver/spleen imaging: 37 to 296 MBq (1 to 8 mCi) by intravenous injection;
○ bone marrow imaging: 111 to 444 MBq (3 to 12 mCi) by intravenous injection.
In pediatric patients:
○ liver/spleen imaging in children: 0.56 to 2.78 MBq (0.015 to 0.075 mCi) per kg of body weight (BW) by intravenous injection;
○ liver/spleen imaging in newborns: 7.4 to 18.5 MBq (0.20 MBq to 0.50 mCi) by intravenous injection;
○ bone marrow imaging: 1.11 to 5.55 MBq (0.03 to 0.15 mCi) per kg of BW by intravenous injection.
Gastroesophageal and pulmonary aspiration imaging studies:
In adults:
o gastroesophageal studies: 5.55 to 11.1 MBq (0.15 to 0.30 mCi) by oral administration;
o pulmonary aspiration studies: 11.1 to 18.5 MBq (0.30 to 0.50 mCi) by oral administration.
In pediatric patients:
o gastroesophageal and pulmonary aspiration studies: 3.7 to 11.1 MBq (0.10 to 0.30 mCi) by oral or nasogastric tube administration. For oral administration,
combine the radiopharmaceutical with a milk feeding. For nasogastric tube administration, administer the radiopharmaceutical into the stomach then instill a
normal volume of dextrose or milk feeding.
2.2 Drug Preparation and Administration
The contents of the two Solution vials, the Solution A vial containing the appropriate acidic solution and the Solution B vial containing the appropriate buffer solution,
are intended only for use in the preparation of the Technetium Tc 99m Sulfur Colloid Injection and are not to be directly administered to the patient.
Do not use Sodium Pertechnetate Tc 99m containing oxidants to reconstitute this kit.
The contents of the kit are not radioactive. However, after the Sodium Pertechnetate Tc 99m is added, maintain adequate shielding of the final preparation. Wear
waterproof gloves during the preparation procedure.
Do not use Sodium Pertechnetate Tc 99m containing more than 10 micrograms per mL of aluminum ion because a flocculent precipitate may occur and such a
precipitate may localize in the lung.
The contents of the kit are sterile and non-pyrogenic. This preparation contains no bacteriostatic preservative. Follow the directions carefully and adhere strictly to
aseptic procedures during preparation.
Prepare Technetium Tc 99m Sulfur Colloid Injection by the following aseptic procedure:
1.
Remove the dark brown plastic cap from the Sulfur Colloid multi-dose Reaction Vial and swab the top of the vial closure with alcohol to sterilize the
surface. Complete the radiation label and affix to the vial. Place the vial in an appropriate lead-capped radiation shield labeled and identified.
2. With a sterile shielded syringe, aseptically obtain 1 to 3 mL of a suitable, oxidant-free sterile and non-pyrogenic Sodium Pertechnetate Tc 99m, each milliliter
containing a maximum activity of 18,500 MBq (500 mCi).
3. Aseptically add the Sodium Pertechnetate Tc 99m to the vial.
4. Place a lead cover on the vial shield and dissolve the reagent by gentle swirling.
5. Just before use, remove the red cap from the Solution A vial and swab the top of the vial closure with alcohol to sterilize the surface. Using a sterile needle and
syringe, aseptically withdraw 1.5 mL Solution A from the vial. Aseptically Inject 1.5mL Solution A into the multi-dose Reaction Vial and swirl again.
6.
Transfer the multi-dose Reaction Vial from vial shield and place in a vigorously boiling water bath (water bath should be shielded with 1/8” to 1/4” lead) deep
enough to cover the entire liquid contents of the vial. Keep the vial in the water bath for five minutes.
7. Remove the multi-dose Reaction Vial from the water bath and place in the lead shield and allow to cool for three minutes. Swab the vial closure again with an
antiseptic.
Page 2
Reference ID: 3173576
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For current labeling information, please visit https://www.fda.gov/drugsatfda
8. Just before use, remove the blue cap from the Solution B vial and swab the top of the vial closure with alcohol to sterilize the surface. Using a sterile needle and
syringe, aseptically withdraw 1.5 mL Solution B from the vial. Aseptically Inject 1.5 mL Solution B into the multi-dose Reaction Vial and swirl again.
9. Record time and date of preparation.
10. Allow the preparation to cool to body temperature before use. Maintain adequate shielding of the radioactive colloid preparation at all times.
11. Where appropriate, dilute the preparation with sterile Sodium Chloride Injection to bring the dosage to within the recommended range.
12. Mix the multi-dose Reaction Vial and aseptically withdraw material with a sterile shielded syringe for use within 6 hours of preparation. For optimum results this
time should be minimized. The vial contains no bacteriostatic preservative. Store the reconstituted vial at 20 to 25°C (68 to77°F). Discard vial 6 hours after
reconstitution.
13. Carefully agitate the shielded syringe immediately prior to administration of sulfur colloid to avoid particles aggregation and non-uniform distribution of
radioactivity.
Measure the patient dose by a suitable radioactivity calibration system immediately before administration. Check radiochemical purity before patient administration.
Inspect Technetium Tc 99m Sulfur Colloid Injection visually for particulate matter and discoloration before administration, whenever solution and container permit. Do
not administer the drug if it contains particulate matter or discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance with
applicable regulations.
2.3 Radiation Dosimetry
Subcutaneous injection to assist in lymph node localization
Table 1. Estimated Adult Absorbed Radiation Doses
from Subcutaneous Administration of Technetium Tc
99m Sulfur Colloid Injection (mSv/MBq and rem/mCi)1
Target Organ
mSv/MBq
rem/mCi
Injection Site
9.51
35. 2
Lymph Nodes
0.951
3.52
Liver
0.0028
0.0104
Spleen
0.0017
0.00629
Bone Marrow
0.0019
0.00703
Testes
0.0009
0.0033
Ovaries
0.00018
0.00066
Total Body
0.004
0.0148
1Bergqvist L, Strand S-E, Persson B, et al. Dosimetry in
Lymphoscintigraphy of Tc 99m Antimony Sulfide Colloid,
J Nucl Med, 23: 698-705, 1982.
● Intravenous Injection
Adult Radiation Doses
Table 2. Estimated Adult Absorbed Radiation Doses from Technetium Tc 99m Sulfur Colloid Injection Administration
(mSv/MBq and rem/mCi)2
Diffuse Parenchymal Disease
Target Organ
Normal Liver
Early to Intermediate
Intermediate to Advanced
mSv/MBq
rem/mCi
mSv/MBq
rem/mCi
mSv/MBq
rem/mCi
Liver
0.091
0.338
0.058
0.213
0.044
0.163
Spleen
0.058
0.213
0.074
0.275
0.115
0.425
Bone Marrow
0.008
0.028
0.012
0.045
0.021
0.079
Testes
0.0003
0.001
0.0005
0.002
0.0008
0.003
Ovaries
0.0016
0.006
0.0022
0.008
0.0032
0.012
Total Body
0.005
0.019
0.005
0.019
0.005
0.018
2Modified from Summary of Current Radiation Dose Estimates to Humans with Various Liver Conditions from 99m Tc-Sulfur
Colloid, MIRD Dose Estimate Report No 3, J Nucl Med 16: 108A - 108B, 197
Page 3
Reference ID: 3173576
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Radiation Doses
Table 3A. Estimated Pediatric Absorbed Radiation Doses from Technetium Tc 99m Sulfur Colloid Injection Administration of
1 MBq and 1 mCi for Liver/Spleen and Bone Marrow Imaging (in mSv/MBq and rem/mCi)3
Age
Body Weight
Newborn
3.5 kg
1 year
12.1 kg
5 years
20.3 kg
10 years
33.5 kg
15 years
55 kg
Absorbed Dose
Target Organ
Liver
mSv/MBq
0.86
0.38
0.22
0.18
0.13
rem/mCi
3.2
1.4
0.82
0.67
0.49
Spleen
mSv/MBq
0.76
0.32
0.18
0.13
0.09
rem/mCi
2.8
1.2
0.65
0.49
0.33
Red Marrow
mSv/MBq
0.16
0.05
0.03
0.022
0.01
rem/mCi
0.58
0.18
0.11
0.081
0.036
Ovaries
mSv/MBq
0.04
0.02
0.0103
0.0043
0.0022
rem/mCi
0.14
0.064
0.038
0.016
0.008
Testes
mSv/MBq
0.011
0.006
0.004
0.004
0.001
rem/mCi
0.04
0.021
0.013
0.014
0.002
Total Body
mSv/MBq
0.032
0.026
0.018
0.012
0.006
rem/mCi
0.12
0.096
0.066
0.043
0.022
3from Age-dependent “S” values of Henrichs et al, Berlin 1982, except for the 1-year old. The 1-year old “S” values were taken from phantom
work of the Metabolism and Dosimetry Group at ORNL
Table 3B. Estimated Pediatric Maximum Absorbed Radiation Doses from Administration of the Maximum Recommended Dose
for Technetium Tc 99m Sulfur Colloid Injection (mSv and rem) 3
Age
Body Weight
Newborn
3.5 kg
1 year
12.1 kg
5 years
20.3 kg
10 years
33.5 kg
15 years
55 kg
Maximum
Recommended Dose:
a*
b*
a*
b*
a*
b*
a*
b*
a*
b*
MBq
18.5
22.2
33.3
67.3
55.5
114.7
92.5
186.1
151.7
307.1
mCi
0.5
0.6
0.9
1.82
1.5
3.1
2.5
5.03
4.1
8.3
Maximum Absorbed Dose from Maximum Recommended Dose Administered (mSv and rem)
Target Organ
Liver
mSv
16
19.2
12.6
25.46
12.3
25.42
16.7
33.6
20.1
40.69
rem
1.6
1.92
1.26
2.55
1.23
2.54
1.67
3.36
2.01
4.07
Spleen
mSv
14
16.8
10.8
21.83
9.75
20.15
12.2
24.55
13.5
27.33
rem
1.4
1.68
1.08
2.18
0.98
2.02
1.22
2.45
1.35
2.73
Red Marrow
mSv
2.9
3.48
1.62
3.27
1.65
3.41
2.03
4.08
1.48
3
rem
0.29
0.35
0.16
0.33
0.17
0.34
0.2
0.41
0.15
0.3
Ovaries
mSv
0.7
0.84
0.58
1.17
0.57
1.18
0.4
0.8
0.34
0.69
rem
0.07
0.084
0.058
0.117
0.057
0.118
0.04
0.08
0.034
0.069
Testes
mSv
0.2
0.24
0.19
0.38
0.2
0.41
0.35
0.7
0.09
0.18
rem
0.02
0.024
0.019
0.038
0.02
0.041
0.035
0.07
0.009
0.018
Total Body
mSv
0.6
0.72
0.86
1.74
0.99
2.05
1.07
2.15
0.9
1.82
rem
0.06
0.072
0.086
0.174
0.099
0.205
0.107
0.215
0.09
0.182
*a liver/spleen imaging
*b bone marrow imaging
3.from Age-dependent “S” values of Henrichs et al., Berlin 1982, except for the 1-year old. The 1-year old “S” values were taken from phantom
work of the Metabolism and Dosimetry Group at ORNL
Page 4
Reference ID: 3173576
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Oral Administration
Table 4. Adult Radiation Absorbed Dose from Oral Administration of
1mCi of Technetium Tc99m Sulfur Colloid Injection (mSv/MBq and
rem/mCi)
Target Organ
Assumed
Residence
Time (hr.)
mSv/MBq
rem/mCi
Stomach Wall
1.5
0.038
0.14
Small Intestine
4
0.07
0.26
Upper Large Intestine Wall
13
0.13
0.48
Upper Large Intestine Wall
24
0.089
0.33
Ovaries
-
0.026
0.096
Testes
-
0.001
0.005
Total Body
-
0.005
0.018
Intraperitoneal Injection
Table 5. Adult Absorbed Radiation Dose from Intraperitoneal Injection of 3 mCi of Technetium Tc 99m
Sulfur Colloid (mSv/MBq and rem/mCi)
Target Organ
Shunt Open
Shunt Closed
mSv/MBq
rem/mCi
mSv/MBq
rem/mCi
Liver
0.092
0.34
0.015
0.056
Ovaries and Testes
0.0003 to 0.0016
0.0012 to 0.006
0.015
0.056
Organs in the Peritoneal Cavity
-
-
0.015
0.056
Total Body
0.0049
0.0180
0.005
0.019
Assumptions: Calculations for the absorbed radiation dose are based upon an effective half-time of 3 hours for the
open shunt and 6.02 hours for the closed shunt and an even distribution of the radiopharmaceutical in the peritoneal cavity
with no biological clearance.
Other Exposure Estimates
Table 6. Radiation Doses to Hospital Personnel (µSv/MBq and mrem/mCi)
Technician
Preparation of Drug*
Administered Drug
Target
µSv/MBq
mrem/mCi
µSv/MBq
mrem/mCi
Extremity Dose
0.016
0.0575
0.07
0.25
Whole Body Dose
0.0007
0.0025
0.003
0.0125
*Using shielded vial and syringe
2.4 Imaging Considerations
Breast cancer or malignant melanoma setting in adults:
In clinical studies, patients received injection of Technetium Tc 99m Sulfur Colloid Injection and a concomitant blue dye tracer in order to enhance the ability
to detect lymph nodes. Visual inspection was performed to identify the blue-labeled nodes and a hand held gamma counter was used to identify nodes
concentrating the radiopharmaceutical. Multiple methods were used to detect the concentrated radioactivity within lymph nodes. For example, investigators
used thresholds of background radioactivity to localize nodes containing a minimum of radioactive counts 3 times higher than the background or containing at
least 10 fold higher counts than contiguous nodes.
In clinical studies of patients with malignant melanoma, preoperative lymphoscintigraphy was usually performed using planar imaging techniques to establish
a road map of nodal basins and to facilitate intraoperative identification of lymph nodes. [see Clinical Studies (14)]
Technetium Tc 99m Sulfur Colloid Injection and other tracers may not localize all lymph nodes and the tracers may differ in their extent of lymph node
localization. The lymph node localization of Technetium Tc 99m Sulfur Colloid Injection is dependent upon the underlying patency and structure of the
lymphatic system, the extent of functional reticuloendothelial cells within lymph nodes and the radiopharmaceutical injection technique. Distortion of the
Page 5
Reference ID: 3173576
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
underlying lymphatic system architecture and function by prior surgery, radiation or extensive metastatic disease may result in failure of the
radiopharmaceutical and other tracers to localize lymph nodes. The use of Technetium Tc 99m Sulfur Colloid Injection is intended to supplement palpation,
visual inspection and other procedures important to lymph node localization. [see Clinical Studies (14)]
Peritoneo-venous (LeVeen) shunt setting in adults: Following administration of Technetium Tc 99m Sulfur Colloid Injection into the peritoneal cavity, the
radiopharmaceutical mixes with the peritoneal fluid. Clearance from the peritoneal cavity varies from insignificant, which may occur with complete shunt blockage, to
very rapid clearance with subsequent transfer into the systemic circulation when the shunt is patent. Following transfer into the systemic circulation, the
radiopharmaceutical concentrates within the liver (a target organ). Obtain serial images of both the shunt and liver. An adequate evaluation of the difference between total
blockage of the shunt and partial blockage may not be feasible in all cases. Transperitoneal absorption of sulfur colloid into the systemic circulation may occur, but it
occurs slowly. Therefore, the most definitive scintigraphic evaluation of shunt patency will generally be obtained if there is visualization of both the shunt itself and the
liver and/or spleen within the first three hours post intraperitoneal injection of the radiopharmaceutical.
Imaging areas of functioning reticuloendothelial cells in liver, spleen or bone marrow: Altered biodistribution with lung and soft tissue uptake instead of
reticuloendothelial system has been reported after intravenous injection. The size and physical-chemical properties of the sulfur colloid particles formed from the
components of the kit may determine the biodistribution of the colloid and its uptake by the reticuloendothelial system. Diseases affecting the reticuloendothelial system
may also alter the expected uptake pattern.
Gastroesophageal and pulmonary aspiration imaging studies: To facilitate the imaging of gastroesophageal reflux consider administering Sulfur Colloid by nasogastric
tube.
3 DOSAGE FORMS AND STRENGTHS
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection is supplied in a package that contains 5 kits. All components of a kit are sterile and non-pyrogenic.
Each 10mL multi-dose Reaction Vial contains, in lyophilized form, 2 mg sodium thiosulfate anhydrous, 2.3 mg edetate disodium and 18.1 mg bovine gelatin; each
Solution A vial contains 1.8 mL 0.148 N hydrochloric acid solution and each Solution B vial contains 1.8 mL aqueous solution of 24.6 mg/mL sodium biphosphate
anhydrous and 7.9 mg/mL sodium hydroxide. Included in each 5-kit package are one package insert and 10 radiation labels.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactic reactions
Anaphylactic reactions with bronchospasm, hypotension, urticaria and rare fatalities have occurred following intravenously administered Technetium Tc 99m Sulfur
Colloid Injection. Have emergency resuscitation equipment and personnel immediately available.
5.2 Radiation Risks
Radiation-emitting products, including Technetium Tc 99m Sulfur Colloid Injection, may increase the risk for cancer, especially in pediatric patients. Use the smallest
dose necessary for imaging and ensure safe handling to protect the patient and health care worker. [see Dosage and Administration (2.3)]
5.3 Altered distribution, Accumulation of Tracer in the Lungs
Technetium Tc 99m Sulfur Colloid Injection is physically unstable, and the particles will settle with time or with exposure to polyvalent cations. These larger particles are
likely to be trapped by the pulmonary capillary bed following intravenous injection and result in non-uniform distribution of radioactivity. Agitate the vial adequately
before administration of sulfur colloid to avoid particle aggregation and non-uniform distribution of radioactivity. Discard unused drug after 6 hours from the time of
formulation. [see Dosage and Administration (2.2)]
6
ADVERSE REACTIONS
The most frequently reported adverse reactions, across all categories of use and routes of administration, include rash, allergic reaction, urticaria, anaphylaxis/anaphylactic
shock, and hypotension. Less frequently reported adverse reactions are fatal cardiopulmonary arrest, seizures, dyspnea, bronchospasm, abdominal pain, flushing, nausea,
vomiting, itching, fever, chills, perspiration, numbness, and dizziness. Local injection site reactions, including burning, blanching, erythema, sclerosis, swelling, eschar,
and scarring, have also been reported.
7
DRUG INTERACTIONS
Specific drug-drug interactions have not been studied.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: Technetium Tc 99m crosses the placenta. Among 14 infants born to pregnant patients exposed to Technetium Tc 99m Sulfur Colloid Injection
for lymph node localization, no birth defects were reported following drug exposure. Animal reproduction studies have not been conducted with Technetium Tc 99m
Page 6
Reference ID: 3173576
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sulfur Colloid Injection. Technetium Tc 99m Sulfur Colloid Injection should be given to a pregnant woman only if clearly needed. All radiopharmaceuticals, including
Technetium Tc 99m Sulfur Colloid Injection, have a potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development and the
magnitude of the radiopharmaceutical dose. Assess pregnancy status before administering Technetium Tc 99m Sulfur Colloid Injection to a female of reproductive
potential.
8.3 Nursing Mothers
Technetium Tc 99m is excreted in human milk during lactation. If nursing, patients should express and discard milk for a minimum of 6 hours after administration of
Technetium Tc 99m Sulfur Colloid Injection. Following higher dose procedures [greater than 370 MBq (10 mCi)], patients should minimize close contact with infants
for 6 hours after receiving a Technetium Tc 99m Sulfur Colloid Injection.
8.4 Pediatric Use
The safety and efficacy of Technetium Tc 99m Sulfur Colloid kit in pediatric patients has been shown for the following indications: liver, spleen, and bone marrow
imaging, and gastroesophageal and pulmonary aspiration studies.
8.5 Geriatric Use
Clinical studies of Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects.
8.6 Females of Reproductive Potential
In females of reproductive potential, imaging procedures with Technetium Tc 99m Sulfur Colloid Injection should be performed within ten days following the onset of
menses or a pregnancy test should be performed within 48 hours of the procedure.
10
OVERDOSAGE
The clinical consequences of overdosing with Technetium Tc 99m Sulfur Colloid Injection are not known.
11
DESCRIPTION
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection contains a multi-dose Reaction Vial, a Solution A vial and a Solution B vial which contain the
sterile non-pyrogenic, non-radioactive ingredients necessary to produce Technetium Tc 99m Sulfur Colloid Injection for diagnostic use by subcutaneous, intraperitoneal,
or intravenous injection or by oral administration.
Each 10 mL multi-dose Reaction Vial contains, in lyophilized form 2 mg sodium thiosulfate anhydrous, 2.3 mg edetate disodium and 18.1 mg bovine gelatin; a Solution
A vial contains 1.8 mL of 0.148 N hydrochloric acid solution and a Solution B vial contains 1.8 mL aqueous solution of 24.6 mg/mL sodium biphosphate anhydrous and
7.9 mg/mL sodium hydroxide.
When a solution of sterile and non-pyrogenic Sodium Pertechnetate Tc 99m Injection in isotonic saline is mixed with these components, following the instructions
provided with the kit, Technetium Tc 99m Sulfur Colloid Injection is formed. The product is intended for subcutaneous, intraperitoneal, or intravenous injection or for
oral administration. The precise structure of Technetium Tc 99m Sulfur Colloid Injection is not known at this time.
11.1 Physical Characteristics
Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.4 The principal photon that is useful for detection and imaging studies is listed in
Table 7.
Table 7. Principal Radiation Emission Data4
Radiation
Mean Percent Per
Disintegration
Mean Energy
(keV)
Gamma-2
89.07
140.5
4 Kocher DC: Radioactive decay data tables. DOE/TIC-11026: 108,
11.2 External Radiation
The specific gamma ray constant for Tc 99m is 0.78 R/millicurie-hr at 1cm. The first half-value layer is 0.017 cm of lead (Pb). A range of values for the relative
attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 8. For example, the use of a 0.25 cm
thickness of Pb will attenuate the radiation emitted by a factor of about 1,000.
Page 7
Reference ID: 3173576
1981
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 8. Radiation Attenuation by Lead Shielding
Shield Thickness
(Pb) cm
Coefficient of Attenuation
0.017
0.5
0.08
10-1
0.16
10-2
0.25
10-3
0.33
10-4
To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 9.
Table 9. Physical Decay Chart: Tc 99m, half-life 6.02 hours
Hours
Fraction Remaining
Hours
Fraction Remaining
0*
1.000
6
0.501
1
0.891
7
0.447
2
0.794
8
0.398
3
0.708
9
0.355
4
0.631
10
0.316
5
0.562
11
0.282
-
-
12
0.251
*Calibration time
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Technetium Tc 99m decays by isomeric transition, emitting a photon that can be detected for imaging purposes. [see Description (11.1)]
Following subcutaneous injection, Technetium Tc 99m Sulfur Colloid enters the lymphatic capillaries and is transported with lymph to lymph nodes. However, when
there is massive nodal metastatic involvement, the normal transport to lymph nodes is lost because few normal cells remain in the node. [see Dosage and Administration
(2.4)]
Following intraperitoneal injection, Technetium Tc 99m Sulfur Colloid mixes with the peritoneal fluid; rate of clearance from the cavity allows assessment of the patency
of the shunt. Clearance varies from insignificant, which may occur with complete shunt blockage, to very rapid clearance with subsequent transfer into the systemic
circulation when the shunt is patent.
Following intravenous injection, Technetium Tc 99m Sulfur Colloid is taken up by the reticuloendothelial system (RES), allowing RES rich structures to be imaged.
With oral administration, Technetium Tc 99m Sulfur Colloid is not absorbed accounting for its function in esophageal transit studies, gastroesophageal reflux
scintigraphy, and for the detection of pulmonary aspiration of gastric contents.
12.3 Pharmacokinetics
Following intravenous administration, Technetium Tc 99m Sulfur Colloid Injection is rapidly cleared from the blood by the reticuloendothelial system with a nominal
half-life of approximately 2 1/2 minutes. Uptake of the radioactive colloid by organs of the RES is dependent upon both their relative blood flow rates and the functional
capacity of the phagocytic cells. In the average patient 80 to 90% of the injected colloidal particles are phagocytized by the Kupffer cells of the liver, 5 to 10% by the
spleen and the balance by the bone marrow.
Following oral ingestion, Technetium Tc 99m Sulfur Colloid is distributed primarily through the gastrointestinal tract with elimination primarily through the feces.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies to evaluate the carcinogenicity, mutagenesis, or reproductive toxicity potentials of Technetium Tc 99m Sulfur Colloid have not been conducted.
Page 8
Reference ID: 3173576
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14 CLINICAL STUDIES
14.1 Tracer Localization to Lymph Nodes in Breast Cancer
A systematic review of 43 publications examined procedures that used the injection of Technetium Tc 99m Sulfur Colloid Injection and a blue dye (tracers) to assist
surgeons in the localization of lymph nodes among patients with a primary breast cancer lesion. From these publications, 15 studies were identified for inclusion within a
meta-analysis, based upon the following criteria: prospective design, minimum number of 50 lymph node localization procedures, and paired outcome data available for
both Technetium Tc 99m Sulfur Colloid Injection and blue dye. Within these studies, the number of procedures ranged from 62 to 6,197; in general one procedure
involved a single patient but in some uncommon situations, one patient underwent more than one procedure. The patients received subcutaneous Technetium Tc 99m
Sulfur Colloid Injection doses ranging between 0.1 and 2 mCi. The mean age of patients ranged from 52 to 60 years, and almost all were female. Lymph nodes that
contained radioactivity were generally localized based upon increased counts, in comparison to a background threshold (e.g., nodes containing a minimum of radioactive
counts 3 times higher than background or containing at least 10 fold higher counts than contiguous nodes). Radioactivity was measured using a handheld gamma counter.
Table 10 shows the tracer localization rates where the tracer localization rate (%) is defined as the percentage of procedures which had at least one lymph node containing
the specific tracer. Random effect meta-analytic measures were used for estimating various rates of tracer localization by procedure along with the respective confidence
intervals. The random effect meta-analytical methods take into account the sample size of each study as well as within and between study variability. In general, most
procedures involved the resection of lymph nodes in which a tracer had localized to at least one node. However, in some procedures (estimated at approximately 3.4%)
neither tracer was localized to a resected lymph node. The reports were insufficient to establish the basis for failed tracer localization. [see Dosage and Administration
(2.4)]
Table 10. Tracer Localization by Procedure – Breast Cancer*
Number of
Clinical Studies
Number of
Procedures
BD Present
(%)
SCI Present
(%)
Only BD Present
(%)
Only SCI Present
(%)
Neither
SCI nor BD
Present
(%)
15
9,213
85.1
94.1
3.8
12.1
3.4
95% Confidence Intervals**
81.4, 88.2
91.4, 96.0
2.8, 5.2
9.9, 15.0
2.1, 5.4
BD = blue dye, SCI = Technetium Tc 99m Sulfur Colloid Injection
* Percentage of procedures in which at least one lymph node contained the specific tracer; the percents do not add to 100% due to rounding.
** 95% Confidence Intervals are based on meta-analysis and represent the spread in the individual estimates.
In some of the publications, different methods of Technetium Tc 99m Sulfur Colloid Injection administration were compared: intradermal (ID), subareolar (SA) and
intraparenchymal (IP) methods. Generally, more favorable results were seen using the ID and SA routes, with less favorable results reported when surgeons used the IP
method.
14.2 Tracer Localization to Lymph Nodes in Malignant Melanoma
A systematic review of eight publications examined the use of Technetium Tc 99m Sulfur Colloid and a blue dye (tracers) to assist surgeons in the localization of lymph
nodes among patients with malignant melanoma. A meta-analysis was performed using data from the studies that reported the resected lymph node content of
Technetium Tc 99m Sulfur Colloid Injection and blue dye. Four of the eight publications met this criterion and were included in the meta-analysis. Within these four
studies, the number of reported patients ranged from 12 to 94. The patients received subcutaneous Technetium Tc 99m Sulfur Colloid Injection doses ranging between
0.25 to 2 mCi. The patients were aged 15 to 89 years and most (53 to 70%) were male.
Lymph nodes that contained radioactivity were generally localized based upon increased counts, in comparison to a background threshold (e.g., nodes containing a
minimum of radioactive counts 3 times higher than background). Radioactivity was measured using a handheld gamma counter.
Table 11 shows the tracer localization rates where the tracer localization rate (%) is defined as the percentage of patients who had at least one lymph node containing the
specific tracer. Random effect meta-analytic measures were used for estimating the various rates of tracer localization by patient along with the respective confidence
intervals. The random effect meta-analytical methods take into account the sample size of each study as well as within and between study variability. In general, most
patients had resected lymph nodes that contained at least one of the tracers. However, in some patients (estimated at approximately 1.6%) neither tracer was localized to a
resected lymph node. The reports were insufficient to establish the basis for failed tracer localization. [see Dosage and Administration (2.4)]
Table 11. Tracer Localization by Patient – Malignant Melanoma*
Number of
Clinical Studies
Number of
Patients
BD Present
(%)
SCI Present
(%)
Only BD Present
(%)
Only SCI Present
(%)
Neither
SCI nor BD
Present
(%)
4
249
83.6
96.4
3.2
15.5
1.6
95% Confidence Intervals**
73.4, 90.4
92.0, 98.5
1.4, 6.9
9.6, 24.1
0.4, 6.5
BD = blue dye, SCI = Technetium Tc 99m Sulfur Colloid Injection
* Percentage of patients in which at least one lymph node contained the specific tracer; the percents do not add to 100% due to rounding.
** 95% Confidence Intervals are based on meta-analysis and represent the spread in the individual estimates.
Page 9
Reference ID: 3173576
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
REFERENCES
1. Bergqvist L, Strand S-E, Persson B, et al. Dosimetry in Lymphoscintigraphy of Tc 99m Antimony Sulfide Colloid, J Nucl Med., 23: 698-705, 1982.
2. Summary of Current Radiation Dose Estimates to Humans with Various Liver Conditions from 99m Tc-Sulfur Colloid, MIRD Dose Estimate Report No 3, J
Nucl Med., 16: 108A - 108B, 1975
3. Henrichs K, Kaul A, Roedler HD: Estimation of Age-dependent Internal Dose from Radiopharmaceuticals, Phys Med Biol., 27: 775-784, 1982.
4. Kocher DC: Radioactive Decay Data Tables. DOE/TIC-11026: 108, 1981.
16
HOW SUPPLIED/STORAGE AND HANDLING
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection is supplied in a package that contains 5 kits. All kit components are sterile and non
pyrogenic. Each 10mL multi-dose Reaction Vial contains, in lyophilized form, 2 mg sodium thiosulfate anhydrous, 2.3 mg edetate disodium and 18.1 mg bovine
gelatin; each Solution A vial contains 1.8 mL 0.148 N hydrochloric acid solution and each Solution B vial contains 1.8 mL aqueous solution of 24.6 mg/mL
sodium biphosphate anhydrous and 7.9 mg/mL sodium hydroxide. Included in each 5-kit package are one package insert and 10 radiation labels.
Store the kit at 20-25°C (68-77°F) as packaged and after reconstitution.
This reagent kit for preparation of a radiopharmaceutical is approved for use by persons licensed pursuant to Section 120.547, Code of Massachusetts Regulation
105, or under equivalent license to the U.S. Nuclear Regulatory Commission or an Agreement State.
NDC #45567-0030-1
17
PATIENT COUNSELING INFORMATION
Inform patients they may experience a burning sensation at the injection site.
Inform lactating patients that they should express and discard milk for a minimum of 6 hours following administration of Technetium Tc 99m Sulfur Colloid
Injection.
Manufactured By:
Pharmalucence, Inc.
29 Dunham Road
Billerica, MA 01821
1-800-221-7554
(For International dial: 1-781-275-7120)
PL-000001
Rev. Date 08/2012
Page 10
Reference ID: 3173576
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:23.246031
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017858Orig1s035lbl.pdf', 'application_number': 17858, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
11,079
|
Topicort Emollie
®
nt Cream
(desoximetasone) 0.25%
ollient Cream
FOR DERMATOLOGIC USE ONLY.
OR USE IN EYES.
5% and Topicort® LP
orticosteroid
rily synthetic
Each gram of TOPICORT Emollient Cream 0.25% contains 2.5 mg of Desoximetasone
r USP,
ryl Alcohol NF,
Desoximetasone
Water USP,
il USP, Cetostearyl Alcohol NF,
Aluminum Stearate, Edetate Disodium USP, Lactic Acid USP and Magnesium Stearate.
The chemical name of desoximetasone is Pregna-1, 4-diene-3, 20-dione, 9-fluoro-11,
21-dihydroxy-16-methyl-, (11β, 16α)-. Desoximetasone has the empirical formula
C22H29FO4 and a molecular weight of 376.47.
The CAS Registry Number is 382-67-2. The chemical structure is:
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, anti-pruritic, and vasoconstrictive
actions.
The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear.
Various laboratory methods, including vasoconstrictor assays, are used to compare and
predict potencies and/or clinical efficacies of the topical corticosteroids. There is some
Topicort® LP Em
(desoximetasone) 0.05%
NOT F
Rx Only
DESCRIPTION
Topicort® (desoximetasone) Emollient Cream 0.2
(desoximetasone) Emollient Cream 0.05% contain the active synthetic c
desoximetasone. The topical corticosteroids constitute a class of prima
steroids used as anti-inflammatory and anti-pruritic agents.
in an emollient cream consisting of White Petrolatum USP, Purified Wate
Isopropyl Myristate NF, Lanolin Alcohols NF, Mineral Oil USP, Cetostea
Aluminum Stearate, and Magnesium Stearate.
Each Gram of TOPICORT LP Emollient Cream 0.05% contains 0.5 mg
in an emollient cream consisting of White Petrolatum USP, Purified
Isopropyl Myristate NF, Lanolin Alcohols NF, Mineral O
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
evidence to suggest that a recognizable correlation exists between vasoconstrictor
potency and therapeutic efficacy in man.
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
ation and/or
cesses in the skin increase percutaneous absorption. Occlusive
dressings substantially increase the percutaneous absorption of topical corticosteroids.
ct for treatment of
hrough
pharmacokinetic pathways similar to systemically administered corticosteroids.
rticosteroids are
. Some of the
e bile.
ient Cream
etion in urine
of sensitivity:
Seven days after application, no further radioactivity was
s 15 ± 2 hours (for urine) and
tudies with other similarly
n occurs through
conjugation to form the glucuronide and sulfate ester.
Topicort (desoximetasone) Emollient Cream 0.25% and Topicort® LP
etasone) Emollient Cream 0.05% are indicated for the relief of the
responsive dermatoses.
Topical corticosteroids are contraindicated in those patients with a history of
hypersensitivity to any of the components of the preparation.
WARNINGS
Topicort® (desoximetasone) Emollient Cream 0.25% and Topicort® LP
(desoximetasone) Emollient Cream 0.05% are not for ophthalmic use.
Keep out of reach of children.
occlusive dressings.
Topical corticosteroids can be absorbed from normal intact skin. Inflamm
other disease pro
Thus, occlusive dressings may be a valuable therapeutic adjun
resistant dermatoses.
Once absorbed through the skin, topical corticosteroids are handled t
Corticosteroids are bound to plasma proteins in varying degrees. Co
metabolized primarily in the liver and are then excreted by the kidneys
topical corticosteroids and their metabolites are also excreted into th
Pharmacokinetic studies in men with Topicort® (desoximetasone) Emoll
0.25% with tagged desoximetasone showed a total of 5.2% ± 2.9% excr
(4.1% ± 2.3%) and feces (1.1% ± 0.6%) and no detectable level (limit
0.005 µg/mL) in the blood when it was applied topically on the back followed by
occlusion for 24 hours.
detected in urine or feces. The half-life of the material wa
17 ± 2 hours (for feces) between the third and fifth trial day. S
structured steroids have shown that predominant metabolite reactio
INDICATIONS AND USAGE
®
(desoxim
inflammatory and pruritic manifestations of corticosteroid-
CONTRAINDICATIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General
Systemic absorption of topical corticosteroids has produced reversible hypothalamic-
pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome,
ion of the more
addition of
potent topical
g should be
urinary free
n attempt
ncy of application, or to
erally prompt and
ymptoms of steroid
teroids.
Pediatric patients may absorb proportionally larger amounts of topical corticosteroids
NS - Pediatric
ontinued and
py instituted.
atological infections, the use of an appropriate antifungal or
es not occur
has been
a
I
atient
hyperglycemia, and glucosuria in some patients.
Conditions which augment systemic absorption include the applicat
potent steroids, use over large surface areas, prolonged use, and the
occlusive dressings. Therefore, patients receiving a large dose of a
steroid applied to a large surface area or under an occlusive dressin
evaluated periodically for evidence of HPA axis suppression by using the
cortisol and ACTH stimulation tests. If HPA axis suppression is noted, a
should be made to withdraw the drug, to reduce the freque
substitute a less potent steroid. Recovery of HPA axis function is gen
complete upon discontinuation of the drug. Infrequently, signs and s
withdrawal may occur, requiring supplemental systemic corticos
and thus be more susceptible to systemic toxicity (See PRECAUTIO
Use). If irritation develops, topical corticosteroids should be disc
appropriate thera
In the presence of derm
antibacterial agent should be instituted. If a favorable response do
promptly, the corticosteroid should be discontinued until the infection
dequately controlled.
nformation for the P
ation and
1
n is to be used as directed by the physician. It is for external use
2
rder other than for
skin area should not be bandaged or otherwise covered or wrapped as
especially under
occlusive dressing.
5. Parents of pediatric patients should be advised not to use tight-fitting diapers or
plastic pants on a child being treated in the diaper area, as these garments may
constitute occlusive dressings.
Laboratory Tests
Patients using topical corticosteroids should receive the following inform
instructions:
. This medicatio
only. Avoid contact with the eyes.
. Patients should be advised not to use this medication for any diso
which it was prescribed.
3. The treated
to be occlusive unless directed by the physician.
4. Patients should report any signs of local adverse reactions,
The following tests may be helpful in evaluating the hypothalamic-pituitary-adrenal
(HPA) axis suppression: Urinary free cortisol test and ACTH stimulation test.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic
potential or the effect on fertility of desoximetasone.
Desoximetasone was nonmutagenic in the Ames test.
Pregnancy Category: Teratogenic Effects: Pregnancy Category C
y animals when
steroids have
als.
ice, rats, and
rabbits when given by subcutaneous or dermal routes of administration in doses 3 to 30
0.25% or 15 to
Cream 0.05%.
n on teratogenic
cts from topically applied corticosteroids. Therefore, TOPICORT Emollient Cream
and TOPICORT LP Emollient Cream should be used during pregnancy only if the
s should not be
onged periods of
Corticosteroids have been shown to be teratogenic in laborator
administered systemically at relatively low dosage levels. Some cortico
been shown to be teratogenic after dermal application in laboratory anim
Desoximetasone has been shown to be teratogenic and embryotoxic in m
times the human dose of Topicort® (desoximetasone) Emollient Cream
150 times the human dose of Topicort® LP (desoximetasone) Emollient
There are no adequate and well-controlled studies in pregnant wome
effe
potential benefit justifies the potential risk to the fetus. Drugs of this clas
used extensively on pregnant patients, in large amounts, or for prol
time.
Nursing Mothers
It is not known whether topical administration of corticosteroids could result in sufficient
st milk. Systemically
es not likely to have
exercised when
topical corticosteroids are administered to a nursing woman.
systemic absorption to produce detectable quantities in brea
administered corticosteroids are secreted into breast milk in quantiti
a deleterious effect on the infant. Nevertheless, caution should be
Pediatric Use
Pediatric patients may demonstrate greater susceptibility
corticosteroid-induced HPA axis suppression and Cushing’s syndrome than
mature patients
to topical
because of a larger skin surface area to body weight ratio.
sion have been
anifestations of adrenal
suppression in pediatric patients include linear growth retardation, delayed weight gain,
levels, and absence of response to ACTH stimulation.
s, headaches, and
Administration of topical corticosteroids to pediatric patients should be limited to the
least amount compatible with an effective therapeutic regimen. Chronic corticosteroid
therapy may interfere with the growth and development of pediatric patients.
ADVERSE REACTIONS
The following local adverse reactions are reported infrequently with topical
corticosteroids, but may occur more frequently with the use of occlusive dressings.
HPA axis suppression, Cushing’s syndrome, and interacranial hyperten
reported in pediatric patients receiving topical corticosteroids. M
low plasma cortisol
Manifestations of intracranial hypertension include bulging fontanelle
bilateral papilledema.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These reactions are listed in an approximate decreasing ord
itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions,
hypopigmentation, perioral dermatitis, allerg
er of occurrence: burning,
ic contact dermatitis, maceration of the skin,
ow (0.8%) for
d burning, folliculitis,
ence of adverse reactions was also 0.8% for
®
(desoximetasone) Emollient Cream 0.05% and included pruritus,
OVERDOSAGE
ids can be absorbed in sufficient amounts to produce
D ADMINISTRATION
Emollient Cream to
tly.
Topicort (desoximetasone) Emollient Cream 0.25% is supplied in 15 gram (NDC
tubes.
mollient Cream 0.05% is supplied in 15 gram (NDC
) and 60 gram (NDC 99207-012-60) tubes.
lled room temperature 15° - 30°C (59° - 86°F).
n as of April 1999.
MEDICIS, The Dermatology Company®
Phoenix, AZ 85018
by: Hoechst Marion Roussel Deutschland GmbH,
D-65926 Frankfurt am Main
Made in Germany
Reg TM HOECHST AG
secondary infection, skin atrophy, striae, and miliaria.
In controlled clinical studies the incidence of adverse reactions was l
Topicort® (desoximetasone) Emollient Cream 0.25% and include
and folliculopustular lesions. The incid
Topicort LP
erythema, vesiculation, and burning sensation.
Topically applied corticostero
systemic effects (See Precautions).
DOSAGE AN
Apply a thin film of TOPICORT Emollient Cream or TOPICORT LP
the affected skin areas twice daily. Rub in gen
HOW SUPPLIED
®
99207-011-15) and 60 gram (NDC 99207-011-60)
Topicort® LP (desoximetasone) E
99207-012-15
Store at contro
Prescribing Informatio
Manufactured for:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:23.270035
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/17856slr024,18309slr013_topicort_lbl.pdf', 'application_number': 17856, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
11,082
|
REGLAN Injection (metoclopramide injection, USP)
Rx only
WARNING: TARDIVE DYSKINESIA
Treatment with metoclopramide can cause tardive dyskinesia, a serious movement
disorder that is often irreversible. The risk of developing tardive dyskinesia increases with
duration of treatment and total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or
symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In
some patients, symptoms may lessen or resolve after metoclopramide treatment is
stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but
rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive
dyskinesia. See WARNINGS.
DESCRIPTION
Metoclopramide hydrochloride is a white crystalline, odorless substance, freely soluble in water.
Chemically, it is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamide
monohydrochloride monohydrate. Molecular weight: 354.3. Structural Formula
C14H22ClN3O2•HCl•H2O
REGLAN Injection (metoclopramide injection, USP) is a clear, colorless, sterile solution with a
pH of 4.5-6.5 for intravenous (IV) or intramuscular (IM) administration.
This product is light sensitive. It should be inspected before use and discarded if either color or
particulate is observed.
2 mL single dose vials; 10 mL and 30 mL single dose vials
Each 1 mL contains: Metoclopramide base 5 mg (as the monohydrochloride monohydrate),
Sodium Chloride, USP 8.5 mg, Water for Injection, USP q.s. pH adjusted, when necessary, with
1
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hydrochloric acid and/or sodium hydroxide.
CLINICAL PHARMACOLOGY
Metoclopramide stimulates motility of the upper gastrointestinal tract without stimulating
gastric, biliary, or pancreatic secretions. Its mode of action is unclear. It seems to sensitize
tissues to the action of acetylcholine. The effect of metoclopramide on motility is not dependent
on intact vagal innervation, but it can be abolished by anticholinergic drugs.
Metoclopramide increases the tone and amplitude of gastric (especially antral) contractions,
relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum
and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the
resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the
colon or gallbladder.
In patients with gastroesophageal reflux and low LESP (lower esophageal sphincter pressure),
single oral doses of metoclopramide produce dose-related increases in LESP. Effects begin at
about 5 mg and increase through 20 mg (the largest dose tested). The increase in LESP from a
5 mg dose lasts about 45 minutes and that of 20 mg lasts between 2 and 3 hours. Increased rate
of stomach emptying has been observed with single oral doses of 10 mg.
The antiemetic properties of metoclopramide appear to be a result of its antagonism of central
and peripheral dopamine receptors. Dopamine produces nausea and vomiting by stimulation of
the medullary chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation of the
CTZ by agents like l-dopa or apomorphine which are known to increase dopamine levels or to
possess dopamine-like effects. Metoclopramide also abolishes the slowing of gastric emptying
caused by apomorphine.
Like the phenothiazines and related drugs, which are also dopamine antagonists, metoclopramide
produces sedation and may produce extrapyramidal reactions, although these are comparatively
rare (see WARNINGS). Metoclopramide inhibits the central and peripheral effects of
apomorphine, induces release of prolactin and causes a transient increase in circulating
aldosterone levels, which may be associated with transient fluid retention.
The onset of pharmacological action of metoclopramide is 1 to 3 minutes following an
intravenous dose, 10 to 15 minutes following intramuscular administration, and 30 to 60 minutes
following an oral dose; pharmacological effects persist for 1 to 2 hours.
Pharmacokinetics
Metoclopramide is rapidly and well absorbed. Relative to an intravenous dose of 20 mg, the
absolute oral bioavailability of metoclopramide is 80% ± 15.5% as demonstrated in a crossover
study of 18 subjects. Peak plasma concentrations occur at about 1-2 hr after a single oral dose.
Similar time to peak is observed after individual doses at steady state.
In a single dose study of 12 subjects, the area under the drug concentration-time curve increases
linearly with doses from 20 to 100 mg. Peak concentrations increase linearly with dose; time to
peak concentrations remains the same; whole body clearance is unchanged; and the elimination
rate remains the same. The average elimination half-life in individuals with normal renal
function is 5-6 hr. Linear kinetic processes adequately describe the absorption and elimination of
2
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metoclopramide.
Approximately 85% of the radioactivity of an orally administered dose appears in the urine
within 72 hr. Of the 85% eliminated in the urine, about half is present as free or conjugated
metoclopramide.
The drug is not extensively bound to plasma proteins (about 30%). The whole body volume of
distribution is high (about 3.5 L/kg) which suggests extensive distribution of drug to the tissues.
Renal impairment affects the clearance of metoclopramide. In a study with patients with varying
degrees of renal impairment, a reduction in creatinine clearance was correlated with a reduction
in plasma clearance, renal clearance, non-renal clearance, and increase in elimination half-life.
The kinetics of metoclopramide in the presence of renal impairment remained linear however.
The reduction in clearance as a result of renal impairment suggests that adjustment downward of
maintenance dosage should be done to avoid drug accumulation.
Adult Pharmacokinetic Data
Parameter
Value
Vd (L/kg)
~ 3.5
Plasma Protein Binding
~ 30%
t1/2 (hr)
5-6
Oral Bioavailability
80%±15.5%
In pediatric patients, the pharmacodynamics of metoclopramide following oral and intravenous
administration are highly variable and a concentration-effect relationship has not been
established.
There are insufficient reliable data to conclude whether the pharmacokinetics of metoclopramide
in adults and the pediatric population are similar. Although there are insufficient data to support
the efficacy of metoclopramide in pediatric patients with symptomatic gastroesophageal reflux
(GER) or cancer chemotherapy-related nausea and vomiting, its pharmacokinetics have been
studied in these patient populations.
In an open-label study, six pediatric patients (age range, 3.5 weeks to 5.4 months) with GER
received a metoclopramide 0.15 mg/kg oral solution every 6 hours for 10 doses. The mean peak
plasma concentration of metoclopramide after the tenth dose was 2-fold (56.8 μg/L) higher
compared to that observed after the first dose (29 μg/L) indicating drug accumulation with
repeated dosing. After the tenth dose, the mean time to reach peak concentrations (2.2 hr), half-
life (4.1 hr), clearance (0.67 L/h/kg), and volume of distribution (4.4 L/kg) of metoclopramide
were similar to those observed after the first dose. In the youngest patient (age, 3.5 weeks),
metoclopramide half-life after the first and the tenth dose (23.1 and 10.3 hr, respectively) was
significantly longer compared to other infants due to reduced clearance. This may be attributed
to immature hepatic and renal systems at birth.
Single intravenous doses of metoclopramide 0.22 to 0.46 mg/kg (mean, 0.35 mg/kg) were
administered over 5 minutes to 9 pediatric cancer patients receiving chemotherapy (mean age,
11.7 years; range, 7 to 14 yr) for prophylaxis of cytotoxic-induced vomiting. The
metoclopramide plasma concentrations extrapolated to time zero ranged from 65 to 395 μg/L
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(mean, 152 μg/L). The mean elimination half-life, clearance, and volume of distribution of
metoclopramide were 4.4 hr (range, 1.7 to 8.3 hr), 0.56 L/h/kg (range, 0.12 to 1.20 L/h/kg), and
3.0 L/kg (range, 1.0 to 4.8 L/kg), respectively.
In another study, nine pediatric cancer patients (age range, 1 to 9 yr) received 4 to 5 intravenous
infusions (over 30 minutes) of metoclopramide at a dose of 2 mg/kg to control emesis. After the
last dose, the peak serum concentrations of metoclopramide ranged from 1060 to 5680 μg/L. The
mean elimination half-life, clearance, and volume of distribution of metoclopramide were 4.5 hr
(range, 2.0 to 12.5 hr), 0.37 L/h/kg (range, 0.10 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to
5.50 L/kg), respectively.
Pediatric Pharmacokinetic Studies
Reference
Dose, Route
t1/2
Cl
Vd
Cmax
(hr)
(L/hr/kg)
(L/kg)
(µg/L)
1.
0.35 mg/kg,
4.4±0.56
0.56±0.10
3.0±0.38
152±31
IV over 5 min
(Dose/Cp0)
2.
2 mg/kg
4.5a
0.37a
1.93a
1060 to 5680a
30 min IV
infusion 4-5
times
within 9.5 hours
a. SEM not available.
1. Bateman, DN, et al. Br J Clin Pharmac 15:557-559, 1983.
2. Ford, C. Clin Pharmac Ther 43:196, 1988.
INDICATIONS AND USAGE
Diabetic Gastroparesis (Diabetic Gastric Stasis)
REGLAN (metoclopramide hydrochloride, USP) is indicated for the relief of symptoms
associated with acute and recurrent diabetic gastric stasis.
The Prevention of Nausea and Vomiting Associated with Emetogenic Cancer
Chemotherapy
REGLAN Injection is indicated for the prophylaxis of vomiting associated with emetogenic
cancer chemotherapy.
The Prevention of Postoperative Nausea and Vomiting
REGLAN Injection is indicated for the prophylaxis of postoperative nausea and vomiting in
those circumstances where nasogastric suction is undesirable.
Small Bowel Intubation
REGLAN Injection may be used to facilitate small bowel intubation in adults and pediatric
patients in whom the tube does not pass the pylorus with conventional maneuvers.
Radiological Examination
REGLAN Injection may be used to stimulate gastric emptying and intestinal transit of barium in
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cases where delayed emptying interferes with radiological examination of the stomach and/or
small intestine.
CONTRAINDICATIONS
Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be
dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or
perforation.
Metoclopramide is contraindicated in patients with pheochromocytoma because the drug may
cause a hypertensive crisis, probably due to release of catecholamines from the tumor. Such
hypertensive crises may be controlled by phentolamine.
Metoclopramide is contraindicated in patients with known sensitivity or intolerance to the drug.
Metoclopramide should not be used in epileptics or patients receiving other drugs which are
likely to cause extrapyramidal reactions, since the frequency and severity of seizures or
extrapyramidal reactions may be increased.
WARNINGS
Neuroleptic Malignant Syndrome (NMS)
There have been rare reports of an uncommon but potentially fatal symptom complex sometimes
referred to as Neuroleptic Malignant Syndrome (NMS) associated with metoclopramide. Clinical
manifestations of NMS include hyperthermia, muscle rigidity, altered consciousness, and
evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and
cardiac arrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to identify cases where the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, malignant hyperthermia, drug
fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of metoclopramide and
other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical
monitoring, and 3) treatment of any concomitant serious medical problems for which specific
treatments are available. Bromocriptine and dantrolene sodium have been used in treatment of
NMS, but their effectiveness have not been established (see ADVERSE REACTIONS).
Extrapyramidal Symptoms (EPS)
Acute Dystonic Reactions
Acute dystonic reactions occur in approximately 1 in 500 patients treated with the usual adult
dosages of 30-40 mg/day of metoclopramide. These usually are seen during the first 24-48 hours
of treatment with metoclopramide, occur more frequently in pediatric patients and adult patients
less than 30 years of age and are even more frequent at the higher doses used in prophylaxis of
vomiting due to cancer chemotherapy. These symptoms may include involuntary movements of
limbs and facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar
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type of speech, trismus, or dystonic reactions resembling tetanus. Rarely, dystonic reactions may
present as stridor and dyspnea, possibly due to laryngospasm. If these symptoms should occur,
inject 50 mg Benadryl® (diphenhydramine hydrochloride) intramuscularly, and they usually will
subside. Cogentin® (benztropine mesylate), 1 to 2 mg intramuscularly, may also be used to
reverse these reactions.
Tardive Dyskinesia (see Boxed Warnings)
Treatment with metoclopramide can cause tardive dyskinesia (TD), a potentially irreversible and
disfiguring disorder characterized by involuntary movements of the face, tongue, or extremities.
Although the risk of TD with metoclopramide has not been extensively studied, one published
study reported a TD prevalence of 20% among patients treated for at least 12 weeks. Treatment
with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where
therapeutic benefit is thought to outweigh the risk of developing TD.
Although the risk of developing TD in the general population may be increased among the
elderly, women, and diabetics, it is not possible to predict which patients will develop
metoclopramide-induced TD. Both the risk of developing TD and the likelihood that TD will
become irreversible increase with duration of treatment and total cumulative dose.
Metoclopramide should be discontinued in patients who develop signs or symptoms of TD.
There is no known effective treatment for established cases of TD, although in some patients, TD
may remit, partially or completely, within several weeks to months after metoclopramide is
withdrawn.
Metoclopramide itself may suppress, or partially suppress, the signs of TD, thereby masking the
underlying disease process. The effect of this symptomatic suppression upon the long-term
course of TD is unknown. Therefore, metoclopramide should not be used for the symptomatic
control of TD.
Parkinsonian-like Symptoms
Parkinsonian-like symptoms, including bradykinesia, tremor, cogwheel rigidity, or mask-like
facies, have occurred more commonly within the first 6 months after beginning treatment with
metoclopramide, but occasionally after longer periods. These symptoms generally subside within
2-3 months following discontinuance of metoclopramide. Patients with preexisting Parkinson’s
disease should be given metoclopramide cautiously, if at all, since such patients may experience
exacerbation of parkinsonian symptoms when taking metoclopramide.
Depression
Mental depression has occurred in patients with and without prior history of depression.
Symptoms have ranged from mild to severe and have included suicidal ideation and suicide.
Metoclopramide should be given to patients with a prior history of depression only if the
expected benefits outweigh the potential risks.
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PRECAUTIONS
General
In one study in hypertensive patients, intravenously administered metoclopramide was shown to
release catecholamines; hence, caution should be exercised when metoclopramide is used in
patients with hypertension.
Intravenous injections of undiluted metoclopramide should be made slowly allowing 1 to 2
minutes for 10 mg since a transient but intense feeling of anxiety and restlessness, followed by
drowsiness, may occur with rapid administration.
Because metoclopramide produces a transient increase in plasma aldosterone, certain patients,
especially those with cirrhosis or congestive heart failure, may be at risk of developing fluid
retention and volume overload. If these side effects occur at any time during metoclopramide
therapy, the drug should be discontinued.
Intravenous administration of REGLAN Injection diluted in a parenteral solution should be made
slowly over a period of not less than 15 minutes.
Giving a promotility drug such as metoclopramide theoretically could put increased pressure on
suture lines following a gut anastomosis or closure. This possibility should be considered and
weighed when deciding whether to use metoclopramide or nasogastric suction in the prevention
of postoperative nausea and vomiting.
Information for Patients
A patient Medication Guide is available for REGLAN Injection. 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 printed at the end of this
document.
Metoclopramide may impair the mental and/or physical abilities required for the performance of
hazardous tasks such as operating machinery or driving a motor vehicle. The ambulatory patient
should be cautioned accordingly.
Drug Interactions
The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic
drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given
with alcohol, sedatives, hypnotics, narcotics, or tranquilizers.
The finding that metoclopramide releases catecholamines in patients with essential hypertension
suggests that it should be used cautiously, if at all, in patients receiving monoamine oxidase
inhibitors.
Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide,
whereas the rate and/or extent of absorption of drugs from the small bowel may be increased
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(e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine).
Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients.
Exogenously administered insulin may begin to act before food has left the stomach and lead to
hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the
intestines and thus the rate of absorption, insulin dosage or timing of dosage may require
adjustment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 77-week study was conducted in rats with oral doses up to about 40 times the maximum
recommended human daily dose. Metoclopramide elevates prolactin levels and the elevation
persists during chronic administration. Tissue culture experiments indicate that approximately
one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential
importance if the prescription of metoclopramide is contemplated in a patient with previously
detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia,
and impotence have been reported with prolactin-elevating drugs, the clinical significance of
elevated serum prolactin levels is unknown for most patients. An increase in mammary
neoplasms has been found in rodents after chronic administration of prolactin-stimulating
neuroleptic drugs and metoclopramide. Neither clinical studies nor epidemiologic studies
conducted to date, however, have shown an association between chronic administration of these
drugs and mammary tumorigenesis; the available evidence is too limited to be conclusive at this
time.
An Ames mutagenicity test performed on metoclopramide was negative.
Pregnancy Category B
Reproduction studies performed in rats, mice and rabbits by the IM, IV, subcutaneous (SC), and
oral routes at maximum levels ranging from 12 to 250 times the human dose have demonstrated
no impairment of fertility or significant harm to the fetus due to metoclopramide. 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
Metoclopramide is excreted in human milk. Caution should be exercised when metoclopramide
is administered to a nursing mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established except as stated to
facilitate small bowel intubation (see OVERDOSAGE and DOSAGE AND
ADMINISTRATION).
Care should be exercised in administering metoclopramide to neonates since prolonged clearance
may produce excessive serum concentrations (see CLINICAL PHARMACOLOGY —
Pharmacokinetics). In addition, neonates have reduced levels of NADH-cytochrome b5
reductase which, in combination with the aforementioned pharmacokinetic factors, make
neonates more susceptible to methemoglobinemia (see OVERDOSAGE).
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The safety profile of metoclopramide in adults cannot be extrapolated to pediatric patients.
Dystonias and other extrapyramidal reactions associated with metoclopramide are more common
in the pediatric population than in adults. (See WARNINGS and ADVERSE REACTIONS —
Extrapyramidal Reactions.)
Geriatric Use
Clinical studies of REGLAN did not include sufficient numbers of subjects aged 65 and over to
determine whether elderly subjects respond differently from younger subjects.
The risk of developing parkinsonian-like side effects increases with ascending dose. Geriatric
patients should receive the lowest dose of REGLAN that is effective. If parkinsonian-like
symptoms develop in a geriatric patient receiving REGLAN, REGLAN should generally be
discontinued before initiating any specific anti-parkinsonian agents (see WARNINGS).
The elderly may be at greater risk for tardive dyskinesia (see WARNINGS - Tardive
Dyskinesia).
Sedation has been reported in REGLAN users. Sedation may cause confusion and manifest as
over-sedation in elderly (see CLINICAL PHARMACOLOGY, PRECAUTIONS –
Information for Patients and ADVERSE REACTIONS – CNS Effects).
REGLAN 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 (see DOSAGE AND
ADMINISTRATION - Use in Patients With Renal or Hepatic Impairment).
For these reasons, 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 renal function,
concomitant disease, or other drug therapy in the elderly (see Use in Patients With Renal or
Hepatic Impairment).
Other Special Populations
Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing
methemoglobinemia and/or sulfhemoglobinemia when metoclopramide is administered. In
patients with G6PD deficiency who experience metoclopramide-induced methemoglobinemia,
methylene blue treatment is not recommended (see OVERDOSAGE).
ADVERSE REACTIONS
In general, the incidence of adverse reactions correlates with the dose and duration of
metoclopramide administration. The following reactions have been reported, although in most
instances, data do not permit an estimate of frequency:
CNS Effects
Restlessness, drowsiness, fatigue, and lassitude may occur in patients receiving the
recommended prescribed dosage of REGLAN Injection. Insomnia, headache, confusion,
dizziness, or mental depression with suicidal ideation also may occur (see WARNINGS). In
cancer chemotherapy patients being treated with 1-2 mg/kg per dose, incidence of drowsiness is
about 70%. There are isolated reports of convulsive seizures without clear-cut relationship to
metoclopramide. Rarely, hallucinations have been reported.
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Extrapyramidal Reactions (EPS)
Acute dystonic reactions, the most common type of EPS associated with metoclopramide, occur
in approximately 0.2% of patients (1 in 500) treated with 30 to 40 mg of metoclopramide per
day. In cancer chemotherapy patients receiving 1-2 mg/kg per dose, the incidence is 2% in
patients over the ages of 30-35, and 25% or higher in pediatric patients and adult patients less
than 30 years of age who have not had prophylactic administration of diphenhydramine.
Symptoms include involuntary movements of limbs, facial grimacing, torticollis, oculogyric
crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like
reactions), and, rarely, stridor and dyspnea possibly due to laryngospasm; ordinarily these
symptoms are readily reversed by diphenhydramine (see WARNINGS).
Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask-like
facies (see WARNINGS).
Tardive dyskinesia most frequently is characterized by involuntary movements of the tongue,
face, mouth, or jaw, and sometimes by involuntary movements of the trunk and/or extremities;
movements may be choreoathetotic in appearance (see WARNINGS).
Motor restlessness (akathisia) may consist of feelings of anxiety, agitation, jitteriness, and
insomnia, as well as inability to sit still, pacing, foot tapping. These symptoms may disappear
spontaneously or respond to a reduction in dosage.
Neuroleptic Malignant Syndrome
Rare occurrences of neuroleptic malignant syndrome (NMS) have been reported. This potentially
fatal syndrome is comprised of the symptom complex of hyperthermia, muscular rigidity, altered
consciousness, and autonomic instability (see WARNINGS).
Endocrine Disturbances
Galactorrhea, amenorrhea, gynecomastia, impotence secondary to hyperprolactinemia (see
PRECAUTIONS). Fluid retention secondary to transient elevation of aldosterone (see
CLINICAL PHARMACOLOGY).
Cardiovascular
Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute
congestive heart failure and possible atrioventricular (AV) block (see
CONTRAINDICATIONS and PRECAUTIONS).
Gastrointestinal
Nausea and bowel disturbances, primarily diarrhea.
Hepatic
Rarely, cases of hepatotoxicity, characterized by such findings as jaundice and altered liver
function tests, when metoclopramide was administered with other drugs with known hepatotoxic
potential.
Renal
Urinary frequency and incontinence.
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Hematologic
A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clear-cut
relationship to metoclopramide. Methemoglobinemia in adults and especially with overdosage in
neonates (see OVERDOSAGE). Sulfhemoglobinemia in adults.
Allergic Reactions
A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma.
Rarely, angioneurotic edema, including glossal or laryngeal edema.
Miscellaneous
Visual disturbances. Porphyria.
Transient flushing of the face and upper body, without alterations in vital signs, following high
doses intravenously.
OVERDOSAGE
Symptoms of overdosage may include drowsiness, disorientation and extrapyramidal reactions.
Anticholinergic or antiparkinson drugs or antihistamines with anticholinergic properties may be
helpful in controlling the extrapyramidal reactions. Symptoms are self-limiting and usually
disappear within 24 hours.
Hemodialysis removes relatively little metoclopramide, probably because of the small amount of
the drug in blood relative to tissues. Similarly, continuous ambulatory peritoneal dialysis does
not remove significant amounts of drug. It is unlikely that dosage would need to be adjusted to
compensate for losses through dialysis. Dialysis is not likely to be an effective method of drug
removal in overdose situations.
Unintentional overdose due to misadministration has been reported in infants and children with
the use of REGLAN syrup. While there was no consistent pattern to the reports associated with
these overdoses, events included seizures, extrapyramidal reactions, and lethargy.
Methemoglobinemia has occurred in premature and full-term neonates who were given
overdoses of metoclopramide (1-4 mg/kg/day orally, intramuscularly or intravenously for 1-3 or
more days). Methemoglobinemia can be reversed by the intravenous administration of methylene
blue. However, methylene blue may cause hemolytic anemia in patients with G6PD deficiency,
which may be fatal (see PRECAUTIONS – Other Special Populations).
DOSAGE AND ADMINISTRATION
For the Relief of Symptoms Associated with Diabetic Gastroparesis (Diabetic
Gastric Stasis)
If only the earliest manifestations of diabetic gastric stasis are present, oral administration of
metoclopramide may be initiated. However, if severe symptoms are present, therapy should
begin with REGLAN Injection (IM or IV). Doses of 10 mg may be administered slowly by the
intravenous route over a 1- to 2-minute period.
Administration of REGLAN Injection (metoclopramide injection, USP) up to 10 days may be
required before symptoms subside, at which time oral administration of metoclopramide may be
instituted. The physician should make a thorough assessment of the risks and benefits prior to
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prescribing further metoclopramide treatment.
For the Prevention of Nausea and Vomiting Associated with Emetogenic Cancer
Chemotherapy
Intravenous infusions should be made slowly over a period of not less than 15 minutes, 30
minutes before beginning cancer chemotherapy and repeated every 2 hours for two doses, then
every 3 hours for three doses.
The initial two doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or
dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg per dose
may be adequate.
For doses in excess of 10 mg, REGLAN Injection should be diluted in 50 mL of a parenteral
solution.
The preferred parenteral solution is Sodium Chloride Injection (normal saline), which when
combined with REGLAN Injection, can be stored frozen for up to 4 weeks. REGLAN Injection
is degraded when admixed and frozen with Dextrose-5% in Water. REGLAN Injection diluted in
Sodium Chloride Injection, Dextrose-5% in Water, Dextrose-5% in 0.45% Sodium Chloride,
Ringer’s Injection, or Lactated Ringer’s Injection may be stored up to 48 hours (without
freezing) after preparation if protected from light. All dilutions may be stored unprotected from
light under normal light conditions up to 24 hours after preparation.
If acute dystonic reactions should occur, inject 50 mg Benadryl® (diphenhydramine
hydrochloride) intramuscularly, and the symptoms usually will subside.
For the Prevention of Postoperative Nausea and Vomiting
REGLAN Injection should be given intramuscularly near the end of surgery. The usual adult
dose is 10 mg; however, doses of 20 mg may be used.
To Facilitate Small Bowel Intubation
If the tube has not passed the pylorus with conventional maneuvers in 10 minutes, a single dose
(undiluted) may be administered slowly by the intravenous route over a 1- to 2-minute period.
The recommended single dose is: Pediatric patients above 14 years of age and adults — 10 mg
metoclopramide base. Pediatric patients (6-14 years of age) — 2.5 to 5 mg metoclopramide base;
(under 6 years of age) — 0.1 mg/kg metoclopramide base.
To Aid in Radiological Examinations
In patients where delayed gastric emptying interferes with radiological examination of the
stomach and/or small intestine, a single dose may be administered slowly by the intravenous
route over a 1- to 2-minute period.
For dosage, see intubation above.
Use in Patients With Renal or Hepatic Impairment
Since metoclopramide is excreted principally through the kidneys, in those patients whose
creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half
the recommended dosage. Depending upon clinical efficacy and safety considerations, the
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosage may be increased or decreased as appropriate.
See OVERDOSAGE section for information regarding dialysis.
Metoclopramide undergoes minimal hepatic metabolism, except for simple conjugation. Its safe
use has been described in patients with advanced liver disease whose renal function was normal.
NOTE: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
ADMIXTURES COMPATIBILITIES
REGLAN Injection (metoclopramide injection, USP) is compatible for mixing and injection with
the following dosage forms to the extent indicated below:
Physically and Chemically Compatible Up to 48 Hours
Cimetidine Hydrochloride (SK&F), Mannitol, USP (Abbott), Potassium Acetate, USP (Invenex),
Potassium Phosphate, USP (Invenex).
Physically Compatible Up to 48 Hours
Ascorbic Acid, USP (Abbott), Benztropine Mesylate, USP (MS&D), Cytarabine, USP (Upjohn),
Dexamethasone Sodium Phosphate, USP (ESI, MS&D), Diphenhydramine Hydrochloride, USP
(Parke-Davis), Doxorubicin Hydrochloride, USP (Adria), Heparin Sodium, USP (ESI),
Hydrocortisone Sodium Phosphate (MS&D), Lidocaine Hydrochloride, USP (ESI), Multi-
Vitamin Infusion (must be refrigerated-USV), Vitamin B Complex with Ascorbic Acid (Roche).
Physically Compatible Up to 24 Hours (Do not use if precipitation occurs)
Clindamycin Phosphate, USP (Upjohn), Cyclophosphamide, USP (Mead-Johnson), Insulin, USP
(Lilly).
Conditionally Compatible (Use within one hour after mixing or may be infused
directly into the same running IV line)
Ampicillin Sodium, USP (Bristol), Cisplatin (Bristol), Erythromycin Lactobionate, USP
(Abbott), Methotrexate Sodium, USP (Lederle), Penicillin G Potassium, USP (Squibb),
Tetracycline Hydrochloride, USP (Lederle).
Incompatible (Do Not Mix)
Cephalothin Sodium, USP (Lilly), Chloramphenicol Sodium, USP (Parke-Davis), Sodium
Bicarbonate, USP (Abbott).
HOW SUPPLIED
REGLAN Injection (metoclopramide injection, USP) 5 mg metoclopramide base (as the
monohydrochloride monohydrate) per mL; available in:
2 mL single dose vials in cartons of 25 (NDC 60977-451-01),
10 mL single dose vials in cartons of 25 (NDC 60977-451-02),
30 mL single dose vials in cartons of 25 (NDC 60977-451-03).
Container
Total Contents #
Concentration #
Administration
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2 mL single
10 mg
5 mg/mL
FOR IV or IM
dose vial
ADMINISTRATION
10 mL single
50 mg
5 mg/mL
FOR IV INFUSION ONLY;
dose vial
DILUTE BEFORE USING
30 mL single
150 mg
5 mg/mL
FOR IV INFUSION ONLY;
dose vial
DILUTE BEFORE USING
# Metoclopramide base (as the monohydrochloride monohydrate)
Store vials in carton until used. Do not store open single dose vials for later use, as they contain
no preservative.
This product is light sensitive. It should be inspected before use and discarded if either color or
particulate is observed.
Dilutions may be stored unprotected from light under normal light conditions up to
24 hours after preparation.
REGLAN Injection should be stored at Controlled Room Temperature, 20°-25°C (68°
77°F) [see USP Controlled Room Temperature].
Reglan is a registered trademark of SRZ Properties, Inc.
Baxter and the ESI logo are trademarks of Baxter International, Inc., or its subsidiaries. Company logo
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 933 3030
MLT00066,D
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
REGLAN (Reg-lan)
(metoclopramide)
injection
You or your caregiver should read the Medication Guide before you start receiving
REGLAN injection and before you get another dose of REGLAN injection. There may
be new information. If you take another product that contains metoclopramide (such as
REGLAN tablets, REGLAN ODT, or metoclopramide oral syrup), you should read the
Medication Guide that comes with that product. Some of the information may be
different. This Medication Guide does not take the place of talking to your doctor about
your medical condition or your treatment.
What is the most important information I should know about REGLAN?
REGLAN can cause serious side effects, including:
Abnormal muscle movements called tardive dyskinesia (TD). These movements
happen mostly in the face muscles. You can not control these movements. They may not
go away even after stopping REGLAN. There is no treatment for TD, but symptoms may
lessen or go away over time after you stop taking REGLAN.
Your chances for getting TD go up:
• the longer you take REGLAN and the more REGLAN you take. You should
not take REGLAN for more than 12 weeks.
• if you are older, especially if you are a woman
• if you have diabetes
It is not possible for your doctor to know if you will get TD if you take REGLAN.
Call your doctor right away if you get movements you can not stop or control, such as:
• lip smacking, chewing, or puckering up your mouth
• frowning or scowling
• sticking out your tongue
• blinking and moving your eyes
• shaking of your arms and legs
See the section “What are the possible side effects of REGLAN?” for more information
about side effects.
What is REGLAN?
REGLAN is a prescription medicine used to:
• relieve symptoms of slow stomach emptying in people with diabetes
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• prevent nausea and vomiting that can happen with cancer chemotherapy
• prevent nausea and vomiting that may happen after surgery, if your doctor decides
that you should not be treated with a stomach tube and suction
• help make it easier to insert a tube into the small intestine in both adults and children,
if the tube does not pass into the stomach normally.
• to help empty stomach contents or to help barium move through your intestine, when
you get an X-ray examination of the stomach or small intestine. It is not known if
REGLAN is safe and works in children except when used to help insert a tube into
the small intestine.
Who should not receive REGLAN?
Do not receive REGLAN if you:
• have stomach or intestine problems that could get worse with REGLAN, such as
bleeding, blockage or a tear in your stomach or bowel wall
• have an adrenal gland tumor called pheochromocytoma
• are allergic to REGLAN or anything in it. See the end of this Medication Guide for a
list of ingredients in REGLAN.
• take medicines that can cause uncontrolled movements, such as medicines for mental
illness
• have seizures
What should I tell my doctor before receiving REGLAN?
Tell your doctor about all of your medical conditions, including if you have:
• depression
• Parkinson’s disease
• high blood pressure
• kidney problems. Your doctor may start with a lower dose.
• liver problems or heart failure. REGLAN may cause your body to hold fluids.
• diabetes. Your dose of insulin may need to be changed.
• breast cancer
• you are pregnant or plan to become pregnant. It is not known if REGLAN will harm
your unborn child.
• you are breastfeeding. REGLAN is passed into human milk and may harm your
baby. Talk with your doctor about the best way to feed your baby if you take
REGLAN.
Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins and herbal supplements. REGLAN and some other
medicines can affect each other and may not work as well, or cause possible side effects.
Do not start any new medicines while receiving REGLAN until you talk with your
doctor.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Especially tell your doctor if you take:
• another medicine that contains metoclopramide, such as REGLAN tablets,
REGLAN ODT, or metoclopramide oral syrup
• a blood pressure medicine
• a medicine for depression, especially a Monoamine Oxidase Inhibitor (MAOI)
• insulin
• a medicine that can make you sleepy, such as anti-anxiety medicine, sleep
medicines, and narcotics.
If you are not sure if your medicine is one listed above, ask your doctor or pharmacist.
Know the medicines you take. Keep a list of them and show it to your doctor and
pharmacist when you get a new medicine.
How will I receive REGLAN?
• REGLAN will be given to you by intravenous (IV) infusion into your vein or by
intramuscular (IM) injection into a large muscle. Where and how you receive your
REGLAN injection (IV or IM) will depend on why you are receiving it.
• Certain side effects can happen if REGLAN is given too fast. See the section “What
are the possible side effects of REGLAN?”
• You should not take or receive REGLAN for more than 12 weeks.
What should I avoid while receiving REGLAN?
• Do not drink alcohol while receiving REGLAN. Alcohol may make some side
effects of REGLAN worse, such as feeling sleepy.
• Do not drive, work with machines, or do dangerous tasks until you know how
REGLAN affects you. REGLAN may cause sleepiness.
What are the possible side effects of REGLAN?
REGLAN can cause serious side effects, including:
• Abnormal muscle movements. See the section “What is the most important
information I should know about REGLAN?”
• Uncontrolled spasms of your face and neck muscles, or muscles of your body,
arms, and legs (dystonia). These muscle spasms can cause abnormal movements
and body positions. These spasms usually start within the first 2 days of treatment.
These spasms happen more often in children and adults under age 30.
• Depression, thoughts about suicide, and suicide. Some people who take
REGLAN become depressed. You may have thoughts about hurting or killing
yourself. Some people who take REGLAN have ended their own lives (suicide).
• Neuroleptic Malignant Syndrome (NMS). NMS is a very rare but very serious
condition that can happen with REGLAN. NMS can cause death and must be
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
treated in a hospital. Symptoms of NMS include: high fever, stiff muscles,
problems thinking, very fast or uneven heartbeat, and increased sweating.
• Parkinsonism. Symptoms include slight shaking, body stiffness, trouble moving or
keeping your balance. If you already have Parkinson’s disease, your symptoms
may become worse while you are receiving REGLAN.
Call your doctor and get medical help right away if you:
• feel depressed or have thoughts about hurting or killing yourself
• have high fever, stiff muscles, problems thinking, very fast or uneven heartbeat, and
increased sweating
• have muscle movements you can not stop or control
• have muscle movements that are new or unusual
Common side effects of REGLAN include:
• feeling restless, sleepy, tired, dizzy, or exhausted
• headache
• confusion
• trouble sleeping
Infusion related side effects can happen if REGLAN is given too fast. You may feel
very anxious and restless for a short time, and then become sleepy while you are
receiving a dose of REGLAN. Tell your doctor or nurse right away if this happens.
You may have more side effects the longer you take REGLAN and the more REGLAN
you take.
Tell your doctor about any side effects that bother you or do not go away. These are not
all the possible side effects of REGLAN.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
General information about REGLAN
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide.
This Medication Guide summarizes the most important information about REGLAN. If
you would like more information about REGLAN, talk with your doctor. You can ask
your doctor or pharmacist for information about REGLAN that is written for healthcare
professionals. For more information, call Baxter Healthcare at 1-800-933-3030.
What are the ingredients in REGLAN?
Active ingredient: metoclopramide
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Inactive ingredients: sodium chloride, water, hydrochloric acid or sodium hydroxide
Revised June 2009
Manufactured by:
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
This Medication Guide has been approved by the U.S. Food and Drug Administration.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:23.375197
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017862s061lbl.pdf', 'application_number': 17862, 'submission_type': 'SUPPL ', 'submission_number': 61}
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Page 1 of 10
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Kit for the
Preparation of Technetium Tc 99m Sulfur Colloid Injection safely and effectively.
See full prescribing information for Kit for the Preparation of Technetium
Tc 99m Sulfur Colloid Injection.
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection for
Subcutaneous, Intraperitoneal, Intravenous, and Oral Use.
Initial U.S. Approval: 1978
o
----------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1) 07/2011
Dosage and Administration (2) 07/2011
---------------------------INDICATIONS AND USAGE---------------------------
Technetium Tc 99m Sulfur Colloid Injection is a diagnostic
radiopharmaceutical indicated (1):
In adults, to assist in the:
•
localization of lymph nodes draining a primary tumor in patients with
breast cancer when used with a hand-held gamma counter.
•
evaluation of peritoneo-venous (LeVeen) shunt patency in adults.
In adults and pediatric patients, for:
• imaging areas of functioning reticuloendothelial cells in the liver, spleen
and bone marrow.
• studies of esophageal transit and gastroesophageal reflux, and detection of
pulmonary aspiration of gastric contents.
----------------------DOSAGE AND ADMINISTRATION------------------------
Technetium Tc 99m Sulfur Colloid Injection emits radiation. Use procedures
to minimize radiation exposure. Measure patient doses by a suitable
radioactivity calibration system immediately before administration.
• Breast cancer setting: by subcutaneous injection, 3.7 to 37 MBq (0.1 to
1 mCi in volumes ranging from 0.1 to 1 mL) (2.1).
• Peritoneo-venous (LeVeen) shunt setting in adults: (2.1)
o by intraperitoneal injection: 37 to 111 MBq (1 to 3 mCi);
o by percutaneous transtubal injection: 12 to 37 MBq (0.3 to 1 mCi) in
a volume not to exceed 0.5 mL.
• Imaging areas of functioning reticuloendothelial cells by intravenous
injection (2.1):
In adults:
o Liver/spleen imaging: 37 to 296 MBq (1 to 8 mCi);
o Bone marrow imaging: 111 to 444 MBq (3 to 12 mCi);
In pediatric patients:
• Gastroesophageal and pulmonary aspiration studies by oral administration
(2.1):
In adults:
o Gastroesophageal studies: 5.55 to 11.1 MBq (0.15 to 0.30 mCi);
Pulmonary aspiration studies: 11.1 to 18.5 MBq (0.30 to 0.50 mCi).
In pediatric patients:
o 3.7 to 11.1 MBq (0.10 to 0.30 mCi).
---------------------DOSAGE FORMS AND STRENGTHS-------------------
The Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection is
supplied as a package that contains 5 kits. Each kit contains three vials: one
10 mL multi-dose Reaction Vial, a Solution A vial and a Solution B vial. The
vials contain the sterile non-pyrogenic, non-radioactive ingredients necessary
to produce Technetium Tc 99m Sulfur Colloid Injection (3).
----------------------------CONTRAINDICATIONS--------------------------------
None
-----------------------WARNINGS AND PRECAUTIONS------------------------
Anaphylactic reactions with bronchospasm, hypotension, urticaria and rare
fatalities have occurred following intravenously administered Technetium Tc
99m Sulfur Colloid. Have emergency resuscitation equipment and personnel
immediately available (5.1).
---------------------------ADVERSE REACTIONS----------------------------------
The most frequently reported adverse reactions include rash, urticaria,
anaphylactic shock, and hypotension. Less frequently reported reactions are
fatal cardiopulmonary arrest, seizures, dyspnea, bronchospasm, abdominal
pain, flushing, nausea, vomiting, itching, fever, chills, perspiration, numbness,
dizziness and injection site reactions.(6)
To report SUSPECTED ADVERSE REACTIONS, contact Pharmalucence
Inc. at 1-800-221-7554 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
-------------------------USE IN SPECIFIC POPULATIONS----------------------
•
Pregnancy: use only if clearly needed (8.1).
•
Nursing Mothers: express and discard milk for a minimum of 6 hours
following injection (8.3).
See 17 for PATIENT COUNSELING INFORMATION
Revised: 07/2011
o Liver/spleen imaging in newborns: 7.4 to 18.5 MBq (0.2 to 0.5 mCi);
o Liver/spleen imaging in children: 0.56 to 2.78 MBq (0.015 to 0.075 mCi)
per kg of body weight (BW);
o Bone marrow imaging: 1.11 to 5.55 MBq (0.03 to 0.15 mCi) per kg of BW.
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Doses
2.2 Drug Preparation and Administration
2.3 Radiation Dosimetry
2.4 Imaging Considerations
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactic Reactions
5.2 Radiation Risks
5.3 Altered Distribution, Accumulation of Tracer in the Lungs
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
8.6 Females of Reproductive Potential
10 OVERDOSAGE
11 DESCRIPTION
11.1 Physical Characteristics
11.2 External Radiation
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 Tracer Localization to Lymph Nodes in Breast Cancer
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 2977567
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
Technetium Tc 99m Sulfur Colloid Injection is indicated:
In adults, to assist in the:
• localization of lymph nodes draining a primary tumor in patients with breast cancer when used with a hand-held gamma counter.
• evaluation of peritoneo-venous (LeVeen) shunt patency.
In adults and pediatric patients, for imaging:
• areas of functioning reticuloendothelial cells in the liver, spleen and bone marrow.
• studies of esophageal transit and, gastroesophageal reflux, and detection of pulmonary aspiration of gastric contents.
2
DOSAGE AND ADMINISTRATION
Technetium Tc 99m Sulfur Colloid Injection emits radiation. Use procedures to minimize radiation exposure. Measure patient dose by a suitable radioactivity calibration
system immediately before administration.
2.1 Recommended Doses
• Breast cancer setting in adults: 3.7 to 37 MBq (0.1 to 1 mCi) in volumes ranging from 0.1 to 1 mL by subcutaneous injection.
• Peritoneo-venous (LeVeen) shunt setting in adults: 37 to 111 MBq (1 to 3 mCi) by intraperitoneal injection, or 12 to 37 MBq (0.3 to 1 mCi) in a volume not to exceed
0.5 mL by percutaneous transtubal (efferent limb) injection. Patient repositioning or other measures may be used to help assure uniform mixing of the
radiopharmaceutical with peritoneal fluid.
• Imaging areas of functioning reticuloendothelial cells:
In adults:
○ liver/spleen imaging: 37 to 296 MBq (1 to 8 mCi) by intravenous injection;
○ bone marrow imaging: 111 to 444 MBq (3 to 12 mCi) by intravenous injection.
In pediatric patients:
○ liver/spleen imaging in children: 0.56 to 2.78 MBq (0.015 to 0.075 mCi) per kg of body weight (BW) by intravenous injection;
○ liver/spleen imaging in newborns: 7.4 to 18.5 MBq (0.20 MBq to 0.50 mCi) by intravenous injection;
○ bone marrow imaging: 1.11 to 5.55 MBq (0.03 to 0.15 mCi) per kg of BW by intravenous injection.
• Gastroesophageal and pulmonary aspiration imaging studies:
In adults:
o gastroesophageal studies: 5.55 to 11.1 MBq (0.15 to 0.30 mCi) by oral administration;
o pulmonary aspiration studies: 11.1 to 18.5 MBq (0.30 to 0.50 mCi) by oral administration.
In pediatric patients:
o gastroesophageal and pulmonary aspiration studies: 3.7 to 11.1 MBq (0.10 to 0.30 mCi) by oral or nasogastric tube administration. For oral administration,
combine the radiopharmaceutical with a milk feeding. For nasogastric tube administration, administer the radiopharmaceutical into the stomach then instill a
normal volume of dextrose or milk feeding.
2.2 Drug Preparation and Administration
• The contents of the two Solution vials, the Solution A vial containing the appropriate acidic solution and the Solution B vial containing the appropriate buffer solution,
are intended only for use in the preparation of the Technetium Tc 99m Sulfur Colloid Injection and are not to be directly administered to the patient.
• Do not use Sodium Pertechnetate Tc 99m containing oxidants to reconstitute this kit.
• The contents of the kit are not radioactive. However, after the Sodium Pertechnetate Tc 99m is added, maintain adequate shielding of the final preparation. Wear
waterproof gloves during the preparation procedure.
• Do not use Sodium Pertechnetate Tc 99m containing more than 10 micrograms per mL of aluminum ion because a flocculent precipitate may occur and such a
precipitate may localize in the lung.
• The contents of the kit are sterile and non-pyrogenic. This preparation contains no bacteriostatic preservative. Follow the directions carefully and adhere strictly to
aseptic procedures during preparation.
Prepare Technetium Tc 99m Sulfur Colloid Injection by the following aseptic procedure:
1.
Remove the dark brown plastic cap from the Sulfur Colloid multi-dose Reaction Vial and swab the top of the vial closure with alcohol to sterilize the
surface. Complete the radiation label and affix to the vial. Place the vial in an appropriate lead-capped radiation shield labeled and identified.
2. With a sterile shielded syringe, aseptically obtain 1 to 3 mL of a suitable, oxidant-free sterile and non-pyrogenic Sodium Pertechnetate Tc 99m, each milliliter
containing a maximum activity of 18,500 MBq (500 mCi).
3. Aseptically add the Sodium Pertechnetate Tc 99m to the vial.
4. Place a lead cover on the vial shield and dissolve the reagent by gentle swirling.
5. Just before use, remove the red cap from the Solution A vial and swab the top of the vial closure with alcohol to sterilize the surface. Using a sterile needle and
syringe, aseptically withdraw 1.5 mL Solution A from the vial. Aseptically Inject 1.5mL Solution A into the multi-dose Reaction Vial and swirl again.
6.
Transfer the multi-dose Reaction Vial from vial shield and place in a vigorously boiling water bath (water bath should be shielded with 1/8” to 1/4” lead) deep
enough to cover the entire liquid contents of the vial. Keep the vial in the water bath for five minutes.
Page 2 of 10
Reference ID: 2977567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7. Remove the multi-dose Reaction Vial from the water bath and place in the lead shield and allow to cool for three minutes. Swab the vial closure again with an
antiseptic.
8. Just before use, remove the blue cap from the Solution B vial and swab the top of the vial closure with alcohol to sterilize the surface. Using a sterile needle and
syringe, aseptically withdraw 1.5 mL Solution B from the vial. Aseptically Inject 1.5 mL Solution B into the multi-dose Reaction Vial and swirl again.
9. Record time and date of preparation.
10. Allow the preparation to cool to body temperature before use. Maintain adequate shielding of the radioactive colloid preparation at all times.
11. Where appropriate, dilute the preparation with sterile Sodium Chloride Injection to bring the dosage to within the recommended range.
12. Mix the multi-dose Reaction Vial and aseptically withdraw material with a sterile shielded syringe for use within 6 hours of preparation. For optimum results this
time should be minimized. The vial contains no bacteriostatic preservative. Store the reconstituted vial at 20 to 25°C (68 to77°F). Discard vial 6 hours after
reconstitution.
Measure the patient dose by a suitable radioactivity calibration system immediately before administration. Check radiochemical purity before patient administration.
Inspect Technetium Tc 99m Sulfur Colloid Injection visually for particulate matter and discoloration before administration, whenever solution and container permit. Do
not administer the drug if it contains particulate matter or discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance with
applicable regulations.
2.3 Radiation Dosimetry
• Subcutaneous injection to assist in lymph node localization
Table 1. Estimated Adult Absorbed Radiation Doses
from Subcutaneous Administration of Technetium Tc
99m Sulfur Colloid Injection (mSv/MBq and rem/mCi)1
Target Organ
mSv/MBq
rem/mCi
Injection Site
9.51
35. 2
Lymph Nodes
0.951
3.52
Liver
0.0028
0.0104
Spleen
0.0017
0.00629
Bone Marrow
0.0019
0.00703
Testes
0.0009
0.0033
Ovaries
0.00018
0.00066
Total Body
0.004
0.0148
1Bergqvist L, Strand S-E, Persson B, et al. Dosimetry in
Lymphoscintigraphy of Tc 99m Antimony Sulfide Colloid,
J Nucl Med, 23: 698-705, 1982.
● Intravenous Injection
Adult Radiation Doses
Table 2. Estimated Adult Absorbed Radiation Doses from Technetium Tc 99m Sulfur Colloid Injection Administration
(mSv/MBq and rem/mCi)2
Diffuse Parenchymal Disease
Target Organ
Normal Liver
Early to Intermediate
Intermediate to Advanced
mSv/MBq
rem/mCi
mSv/MBq
rem/mCi
mSv/MBq
rem/mCi
Liver
0.091
0.338
0.058
0.213
0.044
0.163
Spleen
0.058
0.213
0.074
0.275
0.115
0.425
Bone Marrow
0.008
0.028
0.012
0.045
0.021
0.079
Testes
0.0003
0.001
0.0005
0.002
0.0008
0.003
Ovaries
0.0016
0.006
0.0022
0.008
0.0032
0.012
Total Body
0.005
0.019
0.005
0.019
0.005
0.018
2Modified from Summary of Current Radiation Dose Estimates to Humans with Various Liver Conditions from 99m Tc-Sulfur
Colloid, MIRD Dose Estimate Report No 3, J Nucl Med 16: 108A - 108B, 197
Page 3 of 10
Reference ID: 2977567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Radiation Doses
Table 3A. Estimated Pediatric Absorbed Radiation Doses from Technetium Tc 99m Sulfur Colloid Injection Administration of
1 MBq and 1 mCi for Liver/Spleen and Bone Marrow Imaging (in mSv/MBq and rem/mCi)3
Age
Body Weight
Newborn
3.5 kg
1 year
12.1 kg
5 years
20.3 kg
10 years
33.5 kg
15 years
55 kg
Absorbed Dose
Target Organ
Liver
mSv/MBq
0.86
0.38
0.22
0.18
0.13
rem/mCi
3.2
1.4
0.82
0.67
0.49
Spleen
mSv/MBq
0.76
0.32
0.18
0.13
0.09
rem/mCi
2.8
1.2
0.65
0.49
0.33
Red Marrow
mSv/MBq
0.16
0.05
0.03
0.022
0.01
rem/mCi
0.58
0.18
0.11
0.081
0.036
Ovaries
mSv/MBq
0.04
0.02
0.0103
0.0043
0.0022
rem/mCi
0.14
0.064
0.038
0.016
0.008
Testes
mSv/MBq
0.011
0.006
0.004
0.004
0.001
rem/mCi
0.04
0.021
0.013
0.014
0.002
Total Body
mSv/MBq
0.032
0.026
0.018
0.012
0.006
rem/mCi
0.12
0.096
0.066
0.043
0.022
3from Age-dependent “S” values of Henrichs et al, Berlin 1982, except for the 1-year old. The 1-year old “S” values were taken from phantom
work of the Metabolism and Dosimetry Group at ORNL
Table 3B. Estimated Pediatric Maximum Absorbed Radiation Doses from Administration of the Maximum Recommended Dose
for Technetium Tc 99m Sulfur Colloid Injection (mSv and rem) 3
Age
Body Weight
Newborn
3.5 kg
1 year
12.1 kg
5 years
20.3 kg
10 years
33.5 kg
15 years
55 kg
Maximum
Recommended Dose:
a*
b*
a*
b*
a*
b*
a*
b*
a*
b*
MBq
18.5
22.2
33.3
67.3
55.5
114.7
92.5
186.1
151.7
307.1
mCi
0.5
0.6
0.9
1.82
1.5
3.1
2.5
5.03
4.1
8.3
Maximum Absorbed Dose from Maximum Recommended Dose Administered (mSv and rem)
Target Organ
Liver
mSv
16
19.2
12.6
25.46
12.3
25.42
16.7
33.6
20.1
40.69
rem
1.6
1.92
1.26
2.55
1.23
2.54
1.67
3.36
2.01
4.07
Spleen
mSv
14
16.8
10.8
21.83
9.75
20.15
12.2
24.55
13.5
27.33
rem
1.4
1.68
1.08
2.18
0.98
2.02
1.22
2.45
1.35
2.73
Red Marrow
mSv
2.9
3.48
1.62
3.27
1.65
3.41
2.03
4.08
1.48
3
rem
0.29
0.35
0.16
0.33
0.17
0.34
0.2
0.41
0.15
0.3
Ovaries
mSv
0.7
0.84
0.58
1.17
0.57
1.18
0.4
0.8
0.34
0.69
rem
0.07
0.084
0.058
0.117
0.057
0.118
0.04
0.08
0.034
0.069
Testes
mSv
0.2
0.24
0.19
0.38
0.2
0.41
0.35
0.7
0.09
0.18
rem
0.02
0.024
0.019
0.038
0.02
0.041
0.035
0.07
0.009
0.018
Total Body
mSv
0.6
0.72
0.86
1.74
0.99
2.05
1.07
2.15
0.9
1.82
rem
0.06
0.072
0.086
0.174
0.099
0.205
0.107
0.215
0.09
0.182
*a liver/spleen imaging
*b bone marrow imaging
3.from Age-dependent “S” values of Henrichs et al., Berlin 1982, except for the 1-year old. The 1-year old “S” values were taken from phantom
work of the Metabolism and Dosimetry Group at ORNL
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•
Oral Administration
Table 4. Adult Radiation Absorbed Dose from Oral Administration of
1mCi of Technetium Tc99m Sulfur Colloid Injection (mSv/MBq and
rem/mCi)
Target Organ
Assumed
Residence
Time (hr.)
mSv/MBq
rem/mCi
Stomach Wall
1.5
0.038
0.14
Small Intestine
4
0.07
0.26
Upper Large Intestine Wall
13
0.13
0.48
Upper Large Intestine Wall
24
0.089
0.33
Ovaries
-
0.026
0.096
Testes
-
0.001
0.005
Total Body
-
0.005
0.018
•
Intraperitoneal Injection
Table 5. Adult Absorbed Radiation Dose from Intraperitoneal Injection of 3 mCi of Technetium Tc 99m
Sulfur Colloid (mSv/MBq and rem/mCi)
Target Organ
Shunt Open
Shunt Closed
mSv/MBq
rem/mCi
mSv/MBq
rem/mCi
Liver
0.092
0.34
0.015
0.056
Ovaries and Testes
0.0003 to 0.0016
0.0012 to 0.006
0.015
0.056
Organs in the Peritoneal Cavity
-
-
0.015
0.056
Total Body
0.0049
0.0180
0.005
0.019
Assumptions: Calculations for the absorbed radiation dose are based upon an effective half-time of 3 hours for the
open shunt and 6.02 hours for the closed shunt and an even distribution of the radiopharmaceutical in the peritoneal cavity
with no biological clearance.
•
Other Exposure Estimates
Table 6. Radiation Doses to Hospital Personnel (µSv/MBq and mrem/mCi)
Technician
Preparation of Drug*
Administered Drug
Target
µSv/MBq
mrem/mCi
µSv/MBq
mrem/mCi
Extremity Dose
0.016
0.0575
0.07
0.25
Whole Body Dose
0.0007
0.0025
0.003
0.0125
*Using shielded vial and syringe
2.4 Imaging Considerations
Breast cancer setting in adults:
•
In clinical studies, patients received injection of Technetium Tc 99m Sulfur Colloid Injection and a concomitant blue dye tracer in order to enhance the ability
to detect lymph nodes. Visual inspection was performed to identify the blue-labeled nodes and a hand held gamma counter was used to identify nodes
concentrating the radiopharmaceutical. Multiple methods were used to detect the concentrated radioactivity within lymph nodes. For example, investigators
used thresholds of background radioactivity to localize nodes containing a minimum of radioactive counts 3 times higher than the background or containing at
least 10 fold higher counts than contiguous nodes.
•
Technetium Tc 99m Sulfur Colloid Injection and other tracers may not localize all lymph nodes and the tracers may differ in their extent of lymph node
localization. The lymph node localization of Technetium Tc 99m Sulfur Colloid Injection is dependent upon the underlying patency and structure of the
lymphatic system, the extent of functional reticuloendothelial cells within lymph nodes and the radiopharmaceutical injection technique. Distortion of the
underlying lymphatic system architecture and function by prior surgery, radiation or extensive metastatic disease may result in failure of the
radiopharmaceutical and other tracers to localize lymph nodes. The use of Technetium Tc 99m Sulfur Colloid Injection is intended to supplement palpation,
visual inspection and other procedures important to lymph node localization. [see Clinical Studies (14)]
Peritoneo-venous (LeVeen) shunt setting in adults: Following administration of Technetium Tc 99m Sulfur Colloid Injection into the peritoneal cavity, the
radiopharmaceutical mixes with the peritoneal fluid. Clearance from the peritoneal cavity varies from insignificant, which may occur with complete shunt blockage, to
very rapid clearance with subsequent transfer into the systemic circulation when the shunt is patent. Following transfer into the systemic circulation, the
radiopharmaceutical concentrates within the liver (a target organ). Obtain serial images of both the shunt and liver. An adequate evaluation of the difference between total
blockage of the shunt and partial blockage may not be feasible in all cases. Transperitoneal absorption of sulfur colloid into the systemic circulation may occur, but it
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occurs slowly. Therefore, the most definitive scintigraphic evaluation of shunt patency will generally be obtained if there is visualization of both the shunt itself and the
liver and/or spleen within the first three hours post intraperitoneal injection of the radiopharmaceutical.
Imaging areas of functioning reticuloendothelial cells in liver, spleen or bone marrow: Altered biodistribution with lung and soft tissue uptake instead of
reticuloendothelial system has been reported after intravenous injection. The size and physical-chemical properties of the sulfur colloid particles formed from the
components of the kit may determine the biodistribution of the colloid and its uptake by the reticuloendothelial system. Diseases affecting the reticuloendothelial system
may also alter the expected uptake pattern.
Gastroesophageal and pulmonary aspiration imaging studies: To facilitate the imaging of gastroesophageal reflux consider administering Sulfur Colloid by nasogastric
tube.
3 DOSAGE FORMS AND STRENGTHS
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection is supplied in a package that contains 5 kits. All components of a kit are sterile and non-pyrogenic.
Each 10mL multi-dose Reaction Vial contains, in lyophilized form, 2 mg sodium thiosulfate anhydrous, 2.3 mg edetate disodium and 18.1 mg bovine gelatin; each
Solution A vial contains 1.8 mL 0.148 N hydrochloric acid solution and each Solution B vial contains 1.8 mL aqueous solution of 24.6 mg/mL sodium biphosphate
anhydrous and 7.9 mg/mL sodium hydroxide. Included in each 5-kit package are one package insert and 10 radiation labels.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Anaphylactic reactions
Anaphylactic reactions with bronchospasm, hypotension, urticaria and rare fatalities have occurred following intravenously administered Technetium Tc 99m Sulfur
Colloid Injection. Have emergency resuscitation equipment and personnel immediately available.
5.2 Radiation Risks
Radiation-emitting products, including Technetium Tc 99m Sulfur Colloid Injection, may increase the risk for cancer, especially in pediatric patients. Use the smallest
dose necessary for imaging and ensure safe handling to protect the patient and health care worker. [see Dosage and Administration (2.3)].
5.3 Altered distribution, Accumulation of Tracer in the Lungs
Technetium Tc 99m Sulfur Colloid Injection is physically unstable, and the particles will settle with time or with exposure to polyvalent cations. These larger particles are
likely to be trapped by the pulmonary capillary bed following intravenous injection and result in non-uniform distribution of radioactivity. Agitate the vial adequately
before administration of sulfur colloid to avoid particle aggregation and non-uniform distribution of radioactivity. Discard unused drug after 6 hours from the time of
formulation. [see Dosage and Administration (2.2)]
6
ADVERSE REACTIONS
The most frequently reported adverse reactions, across all categories of use and routes of administration, include rash, allergic reaction, urticaria, anaphylaxis/anaphylactic
shock, and hypotension. Less frequently reported adverse reactions are fatal cardiopulmonary arrest, seizures, dyspnea, bronchospasm, abdominal pain, flushing, nausea,
vomiting, itching, fever, chills, perspiration, numbness, and dizziness. Local injection site reactions, including burning, blanching, erythema, sclerosis, swelling, eschar,
and scarring, have also been reported.
7
DRUG INTERACTIONS
Specific drug-drug interactions have not been studied.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: There are no adequate or well-controlled studies of Technetium Tc 99m Sulfur Colloid Injection in pregnant women, but Technetium Tc 99m
crosses the placenta. Among 14 infants born to pregnant patients exposed to Technetium Tc 99m Sulfur Colloid Injection for lymph node localization, no birth defects
were reported following drug exposure. No reproduction and development studies in animals have been performed. Technetium Tc 99m Sulfur Colloid Injection should
be given to a pregnant woman only if clearly needed.
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8.3 Nursing Mothers
Technetium Tc 99m is excreted in human milk during lactation. If nursing, patients should express and discard milk for a minimum of 6 hours after administration of
Technetium Tc 99m Sulfur Colloid Injection. Following higher dose procedures [greater than 370 MBq (10 mCi)], patients should minimize close contact with infants
for 6 hours after receiving a Technetium Tc 99m Sulfur Colloid Injection.
8.4 Pediatric Use
The safety and efficacy of Technetium Tc 99m Sulfur Colloid kit in pediatric patients has been shown for the following indications: liver, spleen, and bone marrow
imaging, and gastroesophageal and pulmonary aspiration studies.
8.5 Geriatric Use
Clinical studies of Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects.
8.6 Females of Reproductive Potential
In females of reproductive potential, imaging procedures with Technetium Tc 99m Sulfur Colloid Injection should be performed within ten days following the onset of
menses or a pregnancy test should be performed within 48 hours of the procedure.
10
OVERDOSAGE
The clinical consequences of overdosing with Technetium Tc 99m Sulfur Colloid Injection are not known.
11
DESCRIPTION
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection contains a multi-dose Reaction Vial, a Solution A vial and a Solution B vial which contain the
sterile non-pyrogenic, non-radioactive ingredients necessary to produce Technetium Tc 99m Sulfur Colloid Injection for diagnostic use by subcutaneous, intraperitoneal,
or intravenous injection or by oral administration.
Each 10 mL multi-dose Reaction Vial contains, in lyophilized form 2 mg sodium thiosulfate anhydrous, 2.3 mg edetate disodium and 18.1 mg bovine gelatin; a Solution
A vial contains 1.8 mL of 0.148 N hydrochloric acid solution and a Solution B vial contains 1.8 mL aqueous solution of 24.6 mg/mL sodium biphosphate anhydrous and
7.9 mg/mL sodium hydroxide.
When a solution of sterile and non-pyrogenic Sodium Pertechnetate Tc 99m Injection in isotonic saline is mixed with these components, following the instructions
provided with the kit, Technetium Tc 99m Sulfur Colloid Injection is formed. The product is intended for subcutaneous, intraperitoneal, or intravenous injection or for
oral administration. The precise structure of Technetium Tc 99m Sulfur Colloid Injection is not known at this time.
11.1 Physical Characteristics
Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.4 The principal photon that is useful for detection and imaging studies is listed in
Table 7.
Table 7. Principal Radiation Emission Data4
Radiation
Mean Percent Per
Disintegration
Mean Energy
(keV)
Gamma-2
89.07
140.5
4 Kocher DC: Radioactive decay data tables. DOE/TIC-11026: 108,
1981
11.2 External Radiation
The specific gamma ray constant for Tc 99m is 0.78 R/millicurie-hr at 1cm. The first half-value layer is 0.017 cm of lead (Pb). A range of values for the relative
attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 8. For example, the use of a 0.25 cm
thickness of Pb will attenuate the radiation emitted by a factor of about 1,000.
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Table 8. Radiation Attenuation by Lead Shielding
Shield Thickness
(Pb) cm
Coefficient of Attenuation
0.017
0.5
0.08
10-1
0.16
10-2
0.25
10-3
0.33
10-4
To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 9.
Table 9. Physical Decay Chart: Tc 99m, half-life 6.02 hours
Hours
Fraction Remaining
Hours
Fraction Remaining
0*
1.000
6
0.501
1
0.891
7
0.447
2
0.794
8
0.398
3
0.708
9
0.355
4
0.631
10
0.316
5
0.562
11
0.282
-
-
12
0.251
*Calibration time
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Technetium Tc 99m decays by isomeric transition, emitting a photon that can be detected for imaging purposes.[see Description (11.1)]
Following subcutaneous injection, Technetium Tc 99m Sulfur Colloid enters the lymphatic capillaries and is transported with lymph to lymph nodes. However, when
there is massive nodal metastatic involvement, the normal transport to lymph nodes is lost because few normal cells remain in the node.[see Dosage and Administration
(2.4)]
Following intraperitoneal injection, Technetium Tc 99m Sulfur Colloid mixes with the peritoneal fluid; rate of clearance from the cavity allows assessment of the patency
of the shunt. Clearance varies from insignificant, which may occur with complete shunt blockage, to very rapid clearance with subsequent transfer into the systemic
circulation when the shunt is patent.
Following intravenous injection, Technetium Tc 99m Sulfur Colloid is taken up by the reticuloendothelial system (RES), allowing RES rich structures to be imaged.
With oral administration, Technetium Tc 99m Sulfur Colloid is not absorbed accounting for its function in esophageal transit studies, gastroesophageal reflux
scintigraphy, and for the detection of pulmonary aspiration of gastric contents.
12.3 Pharmacokinetics
Following intravenous administration, Technetium Tc 99m Sulfur Colloid Injection is rapidly cleared from the blood by the reticuloendothelial system with a nominal
half-life of approximately 2 1/2 minutes. Uptake of the radioactive colloid by organs of the RES is dependent upon both their relative blood flow rates and the functional
capacity of the phagocytic cells. In the average patient 80 to 90% of the injected collodial particles are phagocytized by the Kupffer cells of the liver, 5 to 10% by the
spleen and the balance by the bone marrow.
Following oral ingestion, Technetium Tc 99m Sulfur Colloid is distributed primarily through the gastrointestinal tract with elimination primarily through the feces.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term animal studies have been performed to evaluate carcinogenic potential or whether Technetium Tc 99m Sulfur Colloid affects fertility in males or females.
Mutagenesis studies have not been conducted.
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14 CLINICAL STUDIES
14.1 Tracer Localization to Lymph Nodes in Breast Cancer
A systematic review of 43 publications examined procedures that used the injection of Technetium Tc 99m Sulfur Colloid Injection and a blue dye (tracers) to assist
surgeons in the localization of lymph nodes among patients with a primary breast cancer lesion. From these publications, 15 studies were identified for inclusion within a
meta-analysis, based upon the following criteria: prospective design, minimum number of 50 lymph node localization procedures, and paired outcome data available for
both Technetium Tc 99m Sulfur Colloid Injection and blue dye. Within these studies, the number of procedures ranged from 62 to 6,197; in general one procedure
involved a single patient but in some uncommon situations, one patient underwent more than one procedure. The patients received subcutaneous Technetium Tc 99m
Sulfur Colloid Injection doses ranging between 0.1 and 2 mCi. The mean age of patients ranged from 52 to 60 years, and almost all were female. Lymph nodes that
contained radioactivity were generally localized based upon increased counts, in comparison to a background threshold (e.g., nodes containing a minimum of radioactive
counts 3 times higher than background or containing at least 10 fold higher counts than contiguous nodes). Radioactivity was measured using a handheld gamma counter.
Random effect meta-analytic measures were used for estimating various rates of tracer localization by procedure and respective confidence intervals for blue dye and
Technetium Tc 99m Sulfur Colloid Injection. Table 10 summarizes the percentage of procedures in which at least one of the resected lymph nodes contained a tracer
(radiopharmaceutical and/or blue dye) as well as the percentage of procedures in which none of the resected nodes contained a tracer. In general, most procedures
involved the resection of lymph nodes in which a tracer had localized to at least one node. However, in some procedures (estimated at approximately 3.4%) neither tracer
was localized to a resected lymph node. The reports were insufficient to establish the basis for failed tracer localization. [see Dosage and Administration (2.4)]
Table 10. Tracer Localization by Procedure*
Number of
Clinical Studies
Number of
Procedures
BD Present
SCI Present
Only BD Present
Only SCI
Present
Neither
SCI nor BD Present
15
9,213
85.1%
94.1%
3.8%
12.1%
3.4%
95% Confidence Intervals
81.4, 88.2
91.4, 96.0
2.8, 5.2
9.9, 14.98
2.1, 5.4
*Percentage of procedures in which at least one lymph node contained the specific tracer; the percents do not add to 100% due to rounding.
BD = blue dye, SCI = Technetium Tc 99m Sulfur Colloid Injection
In some of the publications, different methods of Technetium Tc 99m Sulfur Colloid Injection administration were compared: intradermal (ID), subareolar (SA) and
intraparenchymal (IP) methods. Generally, more favorable results were seen using the ID and SA routes, with less favorable results reported when surgeons used the IP
method.
15
REFERENCES
1. Bergqvist L, Strand S-E, Persson B, et al. Dosimetry in Lymphoscintigraphy of Tc 99m Antimony Sulfide Colloid, J Nucl Med., 23: 698-705, 1982.
2. Summary of Current Radiation Dose Estimates to Humans with Various Liver Conditions from 99m Tc-Sulfur Colloid, MIRD Dose Estimate Report No 3, J
Nucl Med., 16: 108A - 108B, 1975
3. Henrichs et al. Estimation of age-dependent internal dose from radiopharmaceuticals, Phys. Med. Biol., 27: 775-784, 1982.
4. Kocher DC: Radioactive decay data tables. DOE/TIC-11026: 108, 1981.
16
HOW SUPPLIED/STORAGE AND HANDLING
Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection is supplied in a package that contains 5 kits. All kit components are sterile and non
pyrogenic. Each 10mL multi-dose Reaction Vial contains, in lyophilized form, 2 mg sodium thiosulfate anhydrous, 2.3 mg edetate disodium and 18.1 mg bovine
gelatin; each Solution A vial contains 1.8 mL 0.148 N hydrochloric acid solution and each Solution B vial contains 1.8 mL aqueous solution of 24.6 mg/mL
sodium biphosphate anhydrous and 7.9 mg/mL sodium hydroxide. Included in each 5-kit package are one package insert and 10 radiation labels.
Store the kit at 20-25°C (68-77°F) as packaged and after reconstitution.
This reagent kit for preparation of a radiopharmaceutical is approved for use by persons licensed pursuant to Section 120.547, Code of Massachusetts Regulation
105, or under equivalent license to the U.S. Nuclear Regulatory Commission or an Agreement State.
NDC #45567-0030-1
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17
PATIENT COUNSELING INFORMATION
Inform patients they may experience a burning sensation at the injection site.
Inform lactating patients that they should express and discard milk for a minimum of 6 hours following administration of Technetium Tc 99m Sulfur Colloid
Injection.
Manufactured By:
Pharmalucence, Inc.
10 DeAngelo Drive
Bedford, MA 01730
1-800-221-7554
(For International dial: 1-781-275-7120)
RM 2A-067
Rev. Date 7/2011
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|
custom-source
|
2025-02-12T13:44:23.445654
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017858Orig1s034lbl.pdf', 'application_number': 17858, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,085
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
TRANSDERM SCOP safely and effectively. See full prescribing
information for TRANSDERM SCOP.
Transderm Scōp (scopolamine) transdermal system patch
Initial U.S. Approval: 1979
----------------------------INDICATIONS AND USAGE---------------------
Transderm Scōp is an anticholinergic agent indicated in adults for
the prevention of nausea and vomiting associated with:
Motion Sickness (1.1)
Post Operative Nausea and Vomiting (PONV) (1.2)
-------------------------DOSAGE AND ADMINISTRATION--------------
DO NOT cut the patch. Apply ONE patch in the postauricular area
to prevent:
Apply 4 hrs before antiemetic effect is required- for use
up to 3 days (2.1)
Motion Sickness For use longer than 3 days, remove current patch and
place new patch behind other ear (2.2)
Post Operative
Apply evening before scheduled surgery (2.1)
Nausea and
For cesarean section, apply 1 hour prior to surgery (2.1)
Vomiting (PONV) Discard 24 hrs after surgery (2.2)
-------------------------DOSAGE FORMS AND STRENGTHS------------
Continuous release, circular, flat, tan colored patch (1.5 mg
scopolamine) (3)
-------------------------------CONTRAINDICATIONS-----------------------
Patients with angle closure glaucoma (4, 6.2)
Persons who are hypersensitive to scopolamine or to other belladonna
alkaloids (4, 7)
-------------------------WARNINGS AND PRECAUTIONS---------------
Use with caution in patients with open angle glaucoma (51)
Stop use if patient experiences symptoms of angle closure glaucoma
(5.1, 6.2)
Can cause temporary dilation and blurred vision if scopolamine
contacts the eyes (5.2, 6, 16)
Use caution in patients with a history of seizures or psychosis (5.4)
Use with caution in patients with pyloric obstruction, urinary bladder
neck obstruction, or patients suspected of having intestinal
obstruction (5.3)
Stop use if patient has difficulty urinating (5.3, 6)
Idiosyncratic reactions, such as confusion, agitation, speech disorder,
hallucinations, paranoia and delusions, may occur with therapeutic
doses of scopolamine (5.5, 6.2)
A safe and effective dose has not been established in the pediatric
population (5.6, 8.4)
Use with caution in the elderly because of the increased likelihood of
CNS effects, such as hallucinations, confusion and dizziness (5.6, 8.5)
Should be used with caution in patients with impaired renal or hepatic
function because of the increased likelihood of CNS effects (5.6, 8.5,
8.6)
May cause drowsiness or disorienting effects, therefore patients
should be cautioned against engaging in activities that require mental
alertness, such as driving a motor vehicle or operating dangerous
machinery (5.7)
Skin burns have been reported in patients undergoing MRI testing
(5.8)
-----------------------------ADVERSE REACTIONS-------------------------
Most common adverse reactions during motion sickness clinical trials
are dry mouth, drowsiness and blurred vision. (6.1)
Most common adverse reactions during PONV trials (≥ than 3%) are dry
mouth, dizziness, somnolence, urinary retention, agitation, visual
impairment, confusion, mydriasis and pharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
Novartis Consumer Health, Inc. at 1-800-452-0051 or FDA at 1
800-FDA-1088 or www.fda.gov/medwatch.
---------------------------------DRUG INTERACTIONS----------------------
Absorption of oral medications may be decreased (7)
Use with care while taking sedatives, tranquilizers or alcohol (7)
Potential interactions with drugs having anticholinergic properties
(7)
Scopolamine interferes with the gastric secretion test (7.1)
------------------------USE IN SPECIFIC POPULATIONS----------------
Pregnancy: Based on animal data, may cause fetal harm (8.1)
Nursing mothers: Caution should be exercised when administered to a
nursing woman (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised: April 2013
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
_____________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
8
USE IN SPECIFIC POPULATIONS
1
INDICATIONS AND USAGE
8.1
Pregnancy
1.1 Motion Sickness
8.2
Labor and Delivery
1.2 Post Operative Nausea and Vomiting (PONV)
8.3
Nursing Mothers
2
DOSAGE AND ADMINISTRATION
8.4
Pediatric Use
2.1 Initiation of Therapy
8.5 Geriatric Use
2.2
Continuation of Therapy
8.6 Renal or Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
9
DRUG ABUSE AND DEPENDENCE
4
CONTRAINDICATIONS
9.1 Controlled Substance
5
WARNINGS AND PRECAUTIONS
9.2
Abuse
5.1
Open Angle Glaucoma
9.3
Dependence
5.2
Temporary Dilation of the Pupil
10
OVERDOSAGE
5.3
Preexisting Gastrointestinal or Urinary Bladder
11
DESCRIPTION
Obstructions
12
CLINICAL PHARMACOLOGY
5.4
History of Seizures or Psychosis
12.1 Mechanism of Action
5.5
Idiosyncratic Reactions
12.3 Pharmacokinetics
5.6
Specific Populations
13
NONCLINICAL TOXICOLOGY
5.7
Safety Hazards
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
5.8
MRI Skin Burns
14
CLINICAL STUDIES
6
ADVERSE REACTIONS
14.1 Motion Sickness
6.1
Clinical Trials Experience
14.2
Post Operative Nausea and Vomiting
6.2 Postmarketing Experience
16
HOW SUPPLIED/STORAGE AND HANDLING
6.3 Drug Withdrawal/Post-Removal Symptoms
17
PATIENT COUNSELING INFORMATION
7
DRUG INTERACTIONS
7.1 Laboratory Test Interactions
*Sections or subsections omitted from the full prescribing information are
not listed.
Reference ID: 3301616
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
Motion Sickness
Transderm Scōp® is indicated in adults for prevention of nausea and vomiting associated with motion sickness. [see
Clinical Studies (14.1)]
1.2
Post Operative Nausea and Vomiting (PONV)
Transderm Scōp is indicated in adults for prevention of nausea and vomiting associated with recovery from
anesthesia and/or opiate analgesia and surgery. [see Clinical Studies (14.2)]
2
DOSAGE AND ADMINISTRATION
Each Transderm Scōp patch is formulated to deliver in-vivo approximately 1 mg of scopolamine over 3 days. Only
one patch should be worn at any time. Do not cut the patch.
The patch should be applied only to the skin in the postauricular (hairless area behind one ear) area.
Handling
After the patch is applied on the dry skin behind the ear, the hands should be washed thoroughly with soap and
water and dried. Upon removal, the patch should be discarded. To prevent any traces of scopolamine from coming
into direct contact with the eyes, after administration of the patch, the hands and the application site should be
washed thoroughly with soap and water and dried. [see How Supplied/Storage and Handling (16) and Patient
Counseling Information (17)]
2.1
Initiation of Therapy
Motion Sickness
To prevent the nausea and vomiting associated with motion sickness, one Transderm Scōp patch (formulated to
deliver approximately 1 mg of scopolamine over 3 days) should be applied to the hairless area behind one ear at
least 4 hours before the antiemetic effect is required.
Post Operative Nausea and Vomiting
To prevent post operative nausea and vomiting, one Transderm Scōp patch should be applied the evening before
scheduled surgery, except for caesarian section.
For caesarian section surgery, to minimize exposure of the newborn baby to the drug, apply the patch one hour
prior to caesarian section.
2.2
Continuation of Therapy
Should the patch become displaced, it should be discarded, and a fresh one placed on the hairless area behind the
other ear.
Motion Sickness
If therapy is required for longer than 3 days, the first patch should be removed and a fresh one placed on the hairless
area behind the other ear.
Post Operative Nausea and Vomiting
For perioperative use, the patch should be kept in place for 24 hours following surgery at which time it should be
removed and discarded.
3
DOSAGE FORMS AND STRENGTHS
The Transderm Scōp system is a tan-colored circular flat patch which contains 1.5 mg of scopolamine base and is
formulated to deliver in-vivo approximately 1 mg of scopolamine over 3 days.
4
CONTRAINDICATIONS
Transderm Scōp is contraindicated in the following populations:
Patients with angle closure glaucoma. [see Adverse Reactions (6)]
Persons who are hypersensitive to the drug scopolamine or other belladonna alkaloids or to any ingredient or
component in the formulation or delivery system. [see Drug Interactions (7) and Description (11)]
5
WARNINGS AND PRECAUTIONS
5.1
Open Angle Glaucoma
Patients currently being treated for Open Angle Glaucoma
Glaucoma therapy in patients with open angle glaucoma should be monitored and may need to be adjusted during
Transderm Scōp use, as the mydriatic effect of scopolamine may cause an increase in intraocular pressure.
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be advised to remove the patch immediately and promptly contact a physician in the event that they
experience symptoms of acute angle closure glaucoma (pain and reddening of the eyes, accompanied by dilated
pupils).
5.2
Temporary Dilation of the Pupil
Scopolamine can cause temporary dilation of the pupils and blurred vision if it comes in contact with the eyes.
Patients should be strongly advised to wash their hands thoroughly with soap and water immediately after handling
the patch. [see Adverse Reactions (6)] In addition, it is important that used patches be disposed of properly to avoid
contact with children or pets. [see How Supplied/Storage and Handling (16)]
5.3
Preexisting Gastrointestinal or Urinary Bladder Obstructions
Transderm Scōp should be used with caution in patients with pyloric obstruction or urinary bladder neck
obstruction. Caution should be exercised when administering an antiemetic or anticholinergic drug, including
Transderm Scōp, to patients suspected of having intestinal obstruction.
Patients should be instructed to remove the patch if they develop any difficulties in urinating. [see Adverse
Reactions (6)]
5.4
History of Seizures or Psychosis
Transderm Scōp should be used with caution in patients with a history of seizures or psychosis since scopolamine
can potentially aggravate both disorders.
5.5
Idiosyncratic Reactions
Idiosyncratic reactions may occur with ordinary therapeutic doses of scopolamine. The most serious of these that
have been reported are: acute psychosis, including confusion, agitation, speech disorder, hallucinations, paranoia,
and delusions. [see Adverse Reactions (6)]
5.6
Specific Populations
Pediatric
A safe and effective dose has not been established in the pediatric population [see Use in Specific Populations
(8.4)]. Children are particularly susceptible to the side effects of belladonna alkaloids; including mydriasis,
hallucinations, amyblyopia, and drug withdrawal syndrome. Neurologic and psychiatric adverse reactions, such as
hallucinations, amblyopia and mydriasis have also been reported when one half or one quarter of a patch has been
applied.
Elderly
Transderm Scōp should be used with caution in the elderly because of the increased likelihood of CNS effects, such
as hallucinations, confusion, dizziness and drug withdrawal syndrome. Clinical trials of Transderm Scop did not
include sufficient number of subjects aged 65 years and older to determine if they respond differently from younger
subjects. [see Use in Specific Populations (8.5)]
Renal and Hepatic Impaired
Transderm Scōp should be used with caution in individuals with impaired renal or hepatic functions because of the
increased likelihood of CNS effects. Transderm Scop has not been studied in these populations. [see Use in Specific
Populations (8.6)]
5.7
Safety Hazards
Drowsiness
Since drowsiness, disorientation, and confusion may occur with the use of scopolamine, patients should be warned
of the possibility and cautioned against engaging in activities that require mental alertness, such as driving a motor
vehicle or operating dangerous machinery.
Disorienting Effects
Patients who expect to participate in underwater sports should be cautioned regarding the potentially disorienting
effects of scopolamine. [see Patient Counseling Information (17)]
5.8
MRI Skin Burns
Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during
a Magnetic Resonance Imaging scan (MRI). Because Transderm Scōp contains aluminum, it is recommended to
remove the system before undergoing an MRI.
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.
Page 4 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Motion Sickness
In motion sickness clinical studies of Transderm Scōp, the most frequent adverse reaction was dry mouth. This
occurred in about two thirds of patients on drug. A less frequent adverse drug reaction was drowsiness, which
occurred in less than one sixth of patients on drug. Transient impairment of eye accommodation, including blurred
vision and dilation of the pupils, was also observed.
Post-Operative Nausea and Vomiting
In a total of five clinical studies in which Transderm Scōp was administered perioperatively to a total of 461 patients
where safety was assessed, dry mouth was the most frequently reported adverse drug reaction, which occurred in
approximately 29% of patients on drug. Dizziness was reported by approximately 12% of patients on drug. Other
adverse drug reactions reported from these studies, with a frequency of ≥3% of patients treated with Transderm
Scop and with a frequency higher than placebo were, in descending order: somnolence, urinary retention,
agitation/restlessness, visual impairment, confusion, mydriasis and pharyngitis (see Table 6.1).
Table 6-1
PONV: Adverse Drug Reactions in ≥3% of Patients
Transderm
Scōp
Placebo
(N=461)
(N=457)
n
%
n
%
Adverse Drug Reactions
303
65.7
259
56.7
Dry Mouth
133
28.9
72
15.8
Dizziness
57
12.4
33
7.2
Somnolence
36
7.8
16
3.5
Urinary Retention
33
7.2
30
6.6
Agitation
28
6.1
20
4.4
Visual Impairment
23
5.0
12
2.6
Confusion
18
3.9
14
3.1
Mydriasis
16
3.5
2
0.4
Pharyngitis
15
3.3
10
2.2
6.2
Postmarketing Experience
The following adverse drug reactions, further to those reported from clinical trials, have been identified during
postapproval use of Transderm Scop. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or to confirm a definite causal
relationship.
In worldwide marketing with Transderm Scōp, the following adverse drug reactions were reported by body system.
Psychiatric disorders: acute psychosis including: hallucinations disorientation, and paranoia.
Nervous system disorders: headache, amnesia, coordination abnormalities, speech disorder, disturbance in attention,
restlessness.
General disorders and administration site conditions: application site burning.
Eye disorders: dry eyes, eye pruritis, angle closure glaucoma, amblyopia, eyelid irritation.
Skin and subcutaneous tissue disorders: rash generalized, skin irritation, erythema.
Renal and urinary disorders: dysuria.
Ear and Labyrinth Disorders: vertigo.
6.3
Drug Withdrawal/Post-Removal Symptoms
Symptoms such as dizziness, nausea, vomiting, abdominal cramps, sweating, headache mental confusion, muscle
weakness, bradycardia and hypotension may occur following abrupt discontinuation of anticholinergic drugs such as
Transderm Scōp. Similar symptoms, including disturbances of equilibrium, have been reported in some patients
following discontinuation of use of the Transderm Scōp system. These symptoms usually do not appear until 24
hours or more after the patch has been removed. These symptoms can be severe and may require medical
intervention. Some symptoms may be related to adaptation from a motion environment to a motion-free
environment.
.
Page 5 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These symptoms can be severe and may require medical intervention.
7
DRUG INTERACTIONS
The absorption of oral medications may be decreased during the concurrent use of scopolamine because of
decreased gastric motility and delayed gastric emptying. [see Warnings and Precautions (5.3)]
Scopolamine should be used with caution in patients taking other drugs that are capable of causing CNS effects such
as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having
anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic
antidepressants, and muscle relaxants.
In vitro studies indicated that the potential for scopolamine to alter the pharmacokinetics of other concomitant
medications through inhibition of CYP 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4 or induction of CYP 1A2 and 3A4 is
low; however, in vivo studies have not been conducted. [see Clinical Pharmacology (12.3)]
7.1
Laboratory Test Interactions
Scopolamine will interfere with the gastric secretion test.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Based on data from one prospective study of Transderm Scōp in cesarean delivery, the rate of newborn adverse
events in both the Transderm Scōp and placebo groups were the same. The rates were 10.5% (12 events in 114
newborns) in both treatment groups. None of these events were considered life threatening or drug related.
Jaundice was the only adverse event occurring more frequently with Transderm Scōp than placebo: 9 events (7.9%)
versus 2 events (1.8%) (p=0.031). Jaundice, a common occurrence in newborns, resolved with ultraviolet light and
did not prolong the hospital stay.
There are no adequate and well-controlled studies of Transderm Scōp use during pregnancy. In animal reproduction
studies, when pregnant rats and rabbits received scopolamine hydrobromide by daily intravenous injection, no
adverse effects were observed in rats. An embryotoxic effect was observed in rabbits at doses producing plasma
levels approximately 100 times the levels achieved in humans using a transdermal system. Transderm Scōp should
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus and the mother.
8.2
Labor and Delivery
During a clinical study among women undergoing cesarean section treated with Transderm Scōp in conjunction with
epidural anesthesia and opiate analgesia, no evidence of CNS depression was found in newborns. [see Clinical
Studies (14.2)] Scopolamine administered parenterally to rats and rabbits at doses higher than the dose delivered by
Transderm Scōp did not affect uterine contractions or increase the duration of labor. Scopolamine does cross the
placenta.
8.3
Nursing Mothers
Scopolamine is excreted in human milk. Caution should be exercised when Transderm Scōp is administered to a
nursing woman.
8.4
Pediatric Use
A safe and effective dose has not been established in the pediatric population. [see Warnings and Precautions (5.6)]
8.5
Geriatric Use
Transderm Scōp should be used with caution in the elderly because of the increased likelihood of CNS effects, such
as hallucinations, confusion and dizziness. Clinical trials of Transderm Scop did not include sufficient number of
subjects aged 65 years and older to determine if they respond differently from younger subjects. [see Warnings and
Precautions (5.6)]
8.6
Renal or Hepatic Impairment
Transderm Scōp should be used with caution in individuals with impaired renal or hepatic functions because of the
increased likelihood of CNS effects. [see Warnings and Precautions (5.6)]
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance Class
Scopolamine is not a controlled substance.
Page 6 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9.2
Abuse
Scopolamine is an antagonist at muscarinic receptors in the cholinergic system. Drugs in this class are not known to
have significant abuse potential in humans.
9.3
Dependence
Abrupt termination of Transderm Scōp may result in withdrawal symptoms such as dizziness, nausea, vomiting,
abdominal cramps, sweating, headache, mental confusion, muscle weakness, bradycardia and hypotension. [see
Adverse Reactions (6.3) and Overdosage (10)] These withdrawal symptoms indicate that anticholinergic drugs, like
scopolamine may produce physical dependence. These symptoms can be severe and may require medical
intervention.
10
OVERDOSAGE
Because strategies for the management of drug overdose continually evolve, it is strongly recommended that a
poison control center be contacted to obtain up-to-date information regarding the management of Transderm Scōp®
patch overdose. The prescriber should be mindful that antidotes used routinely in the past may no longer be
considered optimal treatment. For example, physostigmine, used more or less routinely in the past, is seldom
recommended for the routine management of anticholinergic syndromes.
Until up-to-date authoritative advice is obtained, routine supportive measures should be directed to maintaining
adequate respiratory and cardiac function.
The signs and symptoms of anticholinergic toxicity include: lethargy, somnolence, coma, confusion, agitation,
hallucinations, convulsion, visual disturbance, dry flushed skin, dry mouth, decreased bowel sounds, urinary
retention, tachycardia, hypertension, and supraventricular arrhythmias. These symptoms can be severe and may
require medical intervention.
In cases of toxicity remove the patch. Serious symptomatic cases of overdosage involving multiple patch
applications and/or ingestion may be managed by initially ensuring the patient has an adequate airway, and
supporting respiration and circulation. This should be rapidly followed by removal of all patches from the skin and
the mouth. If there is evidence of patch ingestion, gastric lavage, endoscopic removal of swallowed patches, or
administration of activated charcoal should be considered, as indicated by the clinical situation. In any case where
there is serious overdosage or signs of evolving acute toxicity, continuous monitoring of vital signs and ECG,
establishment of intravenous access, and administration of oxygen are all recommended.
The symptoms of overdose/toxicity due to scopolamine should be carefully distinguished from the occasionally
observed syndrome of withdrawal. [see Adverse Reactions (6.3)] Although mental confusion and dizziness may be
observed with both acute toxicity and withdrawal, other characteristic findings differ: tachyarrhythmias, dry skin,
and decreased bowel sounds suggest anticholinergic toxicity, while bradycardia, headache, nausea and abdominal
cramps, and sweating suggest post-removal withdrawal. Obtaining a careful history is crucial to making the correct
diagnosis.
11
DESCRIPTION
The Transderm Scōp® (scopolamine) transdermal system is a circular flat patch designed for continuous release of
scopolamine following application to an area of intact skin on the head, behind the ear. Each system contains 1.5 mg
of scopolamine base. Scopolamine is α -(hydroxymethyl) benzeneacetic acid 9-methyl-3-oxa-9-azatricyclo
[3.3.1.02,4] non-7-yl ester. The empirical formula is C17H21NO4 and its structural formula is: structural formula
Scopolamine is a viscous liquid that has a molecular weight of 303.35 and a pKa of 7.55-7.81. The Transderm Scōp
system is a film 0.2 mm thick and 2.5 cm2, with four layers. Proceeding from the visible surface towards the surface
attached to the skin, these layers are: (1) a backing layer of tan-colored, aluminized, polyester film; (2) a drug
reservoir of scopolamine, light mineral oil, and polyisobutylene; (3) a microporous polypropylene membrane that
controls the rate of delivery of scopolamine from the system to the skin surface; and (4) an adhesive formulation of
mineral oil, polyisobutylene, and scopolamine. A protective peel strip of siliconized polyester, which covers the
adhesive layer, is removed before the system is used. The inactive components, light mineral oil (12.4 mg) and
polyisobutylene (11.4 mg), are not released from the system.
Page 7 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cross section of the system: usage illustration
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Scopolamine, a belladonna alkaloid, is an anticholinergic agent. Scopolamine acts: i) as a competitive inhibitor at
postganglionic muscarinic receptor sites of the parasympathetic nervous system, and ii) on smooth muscles that
respond to acetylcholine but lack cholinergic innervation. It has been suggested that scopolamine acts in the central
nervous system (CNS) by blocking cholinergic transmission from the vestibular nuclei to higher centers in the CNS
and from the reticular formation to the vomiting center. Scopolamine can inhibit the secretion of saliva and sweat,
decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress
motor function.
12.3
Pharmacokinetics
The pharmacokinetics of scopolamine delivered via the system are due to the characteristics of both the drug and
dosage form. The system is formulated to deliver in-vivo approximately 1 mg of scopolamine at an approximately
constant rate to the systemic circulation over 3 days. Upon application to the postauricular skin, an initial priming
dose of scopolamine is released from the adhesive layer to saturate skin-binding sites. The subsequent delivery of
scopolamine to the blood is determined by the rate controlling membrane and is designed to produce stable plasma
levels in a therapeutic range. Following removal of the used system, there is some degree of continued systemic
absorption of scopolamine bound in the skin layers.
Absorption
Scopolamine is well absorbed percutaneously. Following application to the skin behind the ear, circulating plasma
levels are detected within 4 hours with peak levels being obtained, on average, within 24 hours. The average plasma
concentration produced is 87 pg/mL (0.28 nM) for free scopolamine and 354 pg/mL for total scopolamine (free +
conjugates).
Distribution
The distribution of scopolamine is not well characterized. It crosses the placenta and the blood brain barrier and may
be reversibly bound to plasma proteins.
Metabolism and Excretion
The exact elimination pattern of scopolamine has not been determined. Following patch removal, plasma levels of
scopolamine decline in a log linear fashion with an observed half-life of 9.5 hours. Less than 10% of the total dose is
excreted in the urine as the parent drug and metabolites over 108 hours. Scopolamine is extensively metabolized and
conjugated with less than 5% of the total dose appearing unchanged in the urine. The enzymes responsible for
metabolizing scopolamine are unknown.
Drug Interaction
An in vitro study using human hepatocytes examined the induction of CYP1A2 and CYP3A4 by scopolamine.
Scopolamine did not induce CYP1A2 and CYP3A4 isoenzymes at the concentrations up to 10 nM.
In an in vitro study using human liver microsomes which evaluated the inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6
and 3A4, scopolamine did not inhibit these cytochrome P450 isoenzymes at the concentrations up to 1 mcM.
13
NONCLINICAL PHARMACOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been conducted to evaluate the carcinogenic potential of scopolamine. The
mutagenic potential of scopolamine has not been evaluated.
Fertility studies were performed in female rats and revealed no evidence of impaired fertility or harm to the fetus
due to scopolamine hydrobromide administered by daily subcutaneous injection. Maternal body weights were
reduced in the highest-dose group (plasma level approximately 500 times the level achieved in humans using a
transdermal system). However, fertility studies in male animals were not performed.
Page 8 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
CLINICAL STUDIES
14.1
Motion Sickness
In 195 adult subjects of different racial origins who participated in clinical efficacy studies at sea or in a controlled
motion environment, there was a 75% reduction in the incidence of motion-induced nausea and vomiting.
14.2
Post-Operative Nausea and Vomiting
In two pivotal clinical efficacy studies in 391 adult female patients undergoing cesarean section or gynecological
surgery with anesthesia and opiate analgesia, 66% of those treated with Transderm Scōp® (compared to only 46% of
those receiving placebo) reported no retching/vomiting within the 24-hour period following administration of
anesthesia/opiate analgesia. When the need for additional antiemetic medication was assessed during the same
period, there was no need for medication in 76% of patients treated with Transderm Scōp as compared to 59% of
placebo-treated patients.
16
HOW SUPPLIED/STORAGE AND HANDLING
The Transderm Scōp® system is a tan-colored circular patch, 2.5 cm2, on a clear, oversized, hexagonal peel strip,
which is removed prior to use.
Each Transderm Scōp system contains 1.5 mg of scopolamine and is formulated to deliver in-vivo approximately
1 mg of scopolamine over 3 days. Transderm Scōp is available in packages of four patches. Each patch is foil
wrapped. Patient instructions are included. [see Patient Counseling Information (17)]
1 Package (4 patches) NDC 0067-4345-04
Storage
The system should be stored at controlled room temperature between 20°C-25°C (68°F-77°F).
Handling
Since scopolamine can cause temporary dilation of the pupils and blurred vision if it comes in contact with the eyes,
patients should be strongly advised to wash their hands thoroughly with soap and water immediately after handling
the patch. In addition, it is important that used patches be disposed of properly to avoid contact with children or pets.
[see Dosage and Administration (2), Warnings and Precautions (5.2), and Patient Counseling Information (17))]
17
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information)
Please read this instruction sheet carefully before opening the system package.
Transderm Scōp® Transdermal System
Generic Name: scopolamine, pronounced skoe-POL-a-meen
Elderly patients should be informed that Transderm Scōp may cause a greater likelihood of CNS effects, such as
hallucinations, confusion, dizziness and drug withdrawal syndrome and to seek immediate medical care if they
become confused, disoriented or dizzy while wearing the patch or after removing.
Patients should be informed that since Transderm Scōp may cause drowsiness, disorientation and confusion
they should avoid engaging in activities that require mental alertness such as driving a motor vehicle or
operating dangerous machinery.
Patients who expect to participate in underwater sports should be cautioned regarding the potentially
disorienting effects of Transderm Scop.
Because of the possibility of drowsiness, disorientation and confusion, patients should be informed that they
should avoid drinking alcohol. In addition, patients should be informed that the following medications should
be used with caution when taking Transderm Scop:
sedatives or tranquilizers
drugs with anticholinergic properties (e.g., other belladonna alkaloids),
antihistamines (including meclizine)
tricyclic antidepressants
muscle relaxants
Patients with the following conditions should be informed about the chance of developing serious reactions with
Transderm Scōp:
patients with open angle glaucoma (may cause an increase in intraocular pressure)
patients with impaired kidney or liver function (increased likelihood of CNS effects)
patients with a history of seizures or psychosis (can potentially worsen both disorders)
Page 9 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients with obstruction at the level of the pylorus, which is the outlet of the stomach, or urinary
bladder neck obstruction (may cause difficulties in urinating)
patients suspected of having intestinal obstruction
pregnant or nursing mothers
Patients should be informed that if they remove the Transderm Scōp patch suddenly before treatment is
complete, the following withdrawal symptoms may occur: dizziness, nausea, vomiting, abdominal cramps,
sweating, headache, mental confusion, muscle weakness, slow heart rate and low blood pressure. Patients
should be instructed to seek immediate medical care if they develop any of these symptoms after removing
Transderm Scōp.
Patients should be informed that Transderm Scop can cause temporary dilation of the pupils and blurred vision
if it comes in contact with the eyes. Patients should be informed to wash their hands thoroughly with soap and
water immediately after handling the patch. In addition, patients should be informed that used patches must be
disposed of properly to avoid contact with children or pets.
Patients should be informed that skin burns have been reported at the patch site in several patients wearing an
aluminized transdermal system during a Magnetic Resonance Imaging scan (MRI). Because Transderm Scōp
contains aluminum, patients should be advised to remove the system before undergoing an MRI.
Patients should be advised to use only one patch at a time.
Patients should be advised not to cut the patch.
Page 10 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FDA-Approved Patient Labeling
PATIENT INFORMATION
Transderm Scōp®, pronounced tran(t)s-derm skōp
(scopolamine)
transdermal system patch
Read this Patient Information before you start using Transderm Scōp® and each
time you get a refill. There may be new information. This information does not take
the place of talking to your doctor about your medical condition or your treatment.
What is Transderm Scōp®?
The Transderm Scōp® patch is a prescription medicine used for adults to:
help prevent nausea and vomiting from motion sickness
help prevent nausea and vomiting from anesthesia or taking opioid pain
medicines after surgery
It is not known if Transderm Scōp® is safe or effective in children.
Who should not use Transderm Scōp®?
Do not use Transderm Scōp® if you:
have an eye problem called angle closure glaucoma
if you are allergic to any of the ingredients in Transderm Scōp® or other
medicines called belladonna alkaloids. See the end of this leaflet for a list of
the ingredients in Transderm Scōp® . Ask your doctor if you are not sure.
What should I tell my doctor before using Transderm Scōp®?
Before you use Transderm Scōp®, tell your doctor if you:
are scheduled to have a gastric secretion test
have glaucoma (increased pressure in the eye)
have liver or kidney problems
have problems with your stomach or intestines
have trouble urinating
have a history of seizures or psychosis
have any other medical conditions
are pregnant or plan to become pregnant. It is not known if Transderm
Scōp® can harm your unborn baby.
are breast-feeding or plan to breast-feed. Transderm Scōp® can pass into
your breast milk and may harm your baby. Talk to your doctor about the
best way to feed your baby if you use Transderm Scōp® .
Tell your doctor about all the medicines you take, including prescription and
non-prescription medicines, vitamins and herbal supplements. Transderm Scōp®
may affect the way other medicines work, and other medicines may affect how
Page 11 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Transderm Scōp® works. Medicines that you take by mouth may not be absorbed
well while you use Transderm Scōp® .
Especially tell your doctor if you take:
a sedative or tranquilizer (medicines that make you sleepy)
an antidepressant medicine
an anticholinergic medicine, such as an allergy or cold medicine, a medicine to
treat bladder or bowel spasms, certain asthma medicines, or other medicines
for motion sickness.
Ask your doctor if you are not sure if your medicine is one that is listed above.
Know the medicines you take. Keep a list of them and show it to your doctor or
pharmacist when you get a new medicine.
How should I use Transderm Scōp®?
Use Transderm Scōp® exactly as your doctor tells you to use it.
Transderm Scōp® is a tan-colored circle shaped patch.
Wear only one patch at any time.
Do not cut the patch.
To help prevent nausea and vomiting from motion sickness:
Apply one Transderm Scōp® patch to your skin on a hairless area behind one
ear at least 4 hours before the activity to prevent nausea and vomiting.
If the treatment is needed for longer than 3 days, remove the patch from the
hairless area behind your ear. Get a new Transderm Scōp® patch and place it
on the hairless area behind your other ear.
To help prevent nausea and vomiting after surgery:
Follow your doctor’s instructions about when to apply Transderm Scōp® before
your scheduled surgery.
The Transderm Scōp® patch should be left in place for 24 hours after surgery.
After 24 hours the patch should be removed and thrown away.
Apply Transderm Scōp® as follows:
Inside the Transderm Scōp® package, you will find one Transderm Scōp® patch. A
tan colored patch with a metallic (silver) sticky surface is adhered to a clear
disposable backing (See Figure 1).
Page 12 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
1. Select a hairless area of skin behind one of your ears. Avoid areas on your skin
that may have cuts, pain or tenderness. Wipe the area of your skin with a clean,
dry tissue.
2. Cut along dotted line on the Transderm Scōp® package to open (See Figure 2). usage illustration
3. Remove the clear plastic backing from the tan-colored round patch (See Figure
3). usage illustration
4. Avoid touching the metallic adhesive (sticky) surface on the patch with your
hands (See Figure 4).
Page 13 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
5. Apply the metallic adhesive surface of the patch firmly to the dry area of skin
behind you ear. The tan-colored side of the patch should be facing up and
showing (See Figure 5). Wash your hands with soap and water right away after
applying the patch, so that any medicine from the patch that gets on your hands
will not get into your eyes. usage illustration
After removing the patch, be sure to wash your hands and the area behind your ear
thoroughly with soap and water. Note that the used patch will still contain some of
the active ingredient after use. To avoid accidental contact or ingestion by children
or pets, fold the used patch in half with the sticky side together. Dispose in the
trash out of the reach of children and pets.
If you use too much Transderm Scōp®, call your doctor or local poison control
center, or go to the nearest hospital emergency room right away.
What should I avoid while using Transderm Scōp®?
You should not drink alcohol while using Transderm Scōp®. It can increase
your chances of having serious side effects.
You should not drive, operate heavy machinery, or do other dangerous
activities until you know how Transderm Scōp® affects you.
You should not use Transderm Scōp® during a Magnetic Resonance Imaging
scan (MRI). Remove Transderm Scōp® patch before undergoing an MRI; it
can cause your skin to burn.
You should be careful if you use Transderm Scōp® while you participate in
watersports because you may feel lost or confused (disoriented).
Page 14 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Limit contact with water while swimming and bathing because the Transderm
Scōp® patch may fall off. If the patch falls off, throw it away and apply a new
one on the hairless area behind your other ear.
What are the possible side effects of Transderm Scōp®?
Transderm Scōp® may cause serious side effects, including:
angle closure glaucoma. If you have open angle glaucoma and use
Transderm Scōp®, remove the patch and call a doctor right away if you get
pain and reddening of your eyes with an increase in the size of your pupil
(the small dark circle in the eye).
temporary increase in the size of your pupil and blurry vision,
especially if Transderm Scōp® comes in contact with your eyes
difficulties in urinating
difficulties in food passing from the stomach to the small intestines,
which may cause abdominal pain, nausea or vomiting.
worsening of seizures. Tell your doctor about any worsening of seizures
while using Transderm Scōp® .
an unusual reaction called acute psychosis: Tell your doctor if you have
any of these symptoms:
•
confusion
•
agitation
•
rambling speech
•
hallucinations (seeing or hearing things that are not there)
•
paranoid behaviors and delusions (false belief in something)
skin burns at the site of the patch. This can happen during a medical test
called a Magnetic Resonance Imaging scan (MRI). Transderm Scōp® contains
aluminum and should be removed from your skin before you have an MRI.
The most common side effects of using Transderm Scōp® include:
dry mouth
drowsiness
disorientation (confusion)
blurred vision
pharyngitis
memory trouble
dizziness
restlessness
agitation
problems urinating
skin rashes or redness, application site burning
dry itchy, or reddened whites of the eyes, and eye pain
Symptoms when removing Transderm Scōp®. Some people may have certain
symptoms 24 hours or more after removing Transderm Scōp®. These symptoms
may include:
dizziness
nausea
Page 15 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
vomiting
headache
problems with balance and walking
decrease in blood pressure
muscle weakness
decrease in heart rate
Tell your doctor if you have any side effect that bothers you or that does not go
away. These are not all the possible side effects of Transderm Scōp®. For more
information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may reports side effects
to FDA at 1-800-FDA-1088.
How should I store Transderm Scōp®?
Store Transderm Scōp® at room temperature between 68°F and 77°F (20°C
and 25°C) until you are ready to use it.
Keep Transderm Scōp® and all medicines out of reach of children.
General Information about Transderm Scōp®
Medicines are sometimes prescribed for purposes other than those listed in a
patient information leaflet. Do not use Transderm Scōp® for a condition for which it
was not prescribed. Do not give Transderm Scōp® to other people, even if they
have the same symptoms you have. It may harm them.
This patient information leaflet summarizes the most important information about
Transderm Scōp®. If you would like more information, talk with your doctor. You
can ask your pharmacist or doctor for information about Transderm Scōp® that is
written for the health professionals.
For more information, go to www. transdermscop.com or call 1-800-452-0051.
What are the ingredients in the Transderm Scōp® patch?
Active ingredient: Scopolamine
Inactive ingredients: light mineral oil and polyisobutylene and aluminized
polyester film
Manufactured by: ALZA Corporation
Vacaville, CA 95688
Distributed by:
Novartis Consumer Health, Inc.
Parsippany, NJ 07054-0622
©2013
Page 16 of 17
Reference ID: 3301616
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
XXXXXX
Printed in U.S.A.
(Rev. 4/13)
Page 17 of 17
Reference ID: 3301616
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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2025-02-12T13:44:23.669138
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017874s038lbl.pdf', 'application_number': 17874, 'submission_type': 'SUPPL ', 'submission_number': 38}
|
11,083
|
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
|
custom-source
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2025-02-12T13:44:23.703337
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/017874s18s27lbl.pdf', 'application_number': 17874, 'submission_type': 'SUPPL ', 'submission_number': 18}
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