Acamprosate Calcium: Package Insert and Label Information (Page 2 of 3)

Concomitant Therapies

In clinical trials, the safety profile in subjects treated with acamprosate calcium concomitantly with anxiolytics, hypnotics and sedatives (including benzodiazepines), or non-opioid analgesics was similar to that of subjects taking placebo with these concomitant medications. Patients taking acamprosate calcium concomitantly with antidepressants more commonly reported both weight gain and weight loss, compared with patients taking either medication alone.

Other Events Observed During the Premarketing Evaluation of Acamprosate Calcium

Following is a list of terms that reflect treatment-emergent adverse events reported by patients treated with acamprosate calcium in 20 clinical trials (4,461 patients treated with acamprosate calcium, 3,526 of whom received the maximum recommended dose of 1998 mg/day for up to one year in duration). This listing does not include those events already listed above; events for which a drug cause was considered remote; event terms which were so general as to be uninformative; and events reported only once which were not likely to be acutely life threatening.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the summary of adverse events in controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients.

Body as a WholeFrequent: headache, abdominal pain, back pain, infection, flu syndrome, chest pain, chills, suicide attempt; Infrequent: fever, intentional overdose, malaise, allergic reaction, abscess, neck pain, hernia, intentional injury; Rare: ascites, face edema, photosensitivity reaction, abdomen enlarged, sudden death.

Cardiovascular SystemFrequent: palpitation, syncope; Infrequent: hypotension, tachycardia, hemorrhage, angina pectoris, migraine, varicose vein, myocardial infarct, phlebitis, postural hypotension; Rare: heart failure, mesenteric arterial occlusion, cardiomyopathy, deep thrombophlebitis, shock.

Digestive SystemFrequent: vomiting, dyspepsia, constipation, increased appetite; Infrequent: liver function tests abnormal, gastroenteritis, gastritis, dysphagia, eructation, gastrointestinal hemorrhage, pancreatitis, rectal hemorrhage, liver cirrhosis, esophagitis, hematemesis, nausea and vomiting, hepatitis; Rare: melena, stomach ulcer, cholecystitis, colitis, duodenal ulcer, mouth ulceration, carcinoma of liver.

Endocrine SystemRare: goiter, hypothyroidism.

Hemic and Lymphatic SystemInfrequent: anemia, ecchymosis, eosinophilia, lymphocytosis, thrombocytopenia; Rare: leukopenia, lymphadenopathy, monocytosis.

Metabolic and Nutritional DisordersFrequent: peripheral edema, weight gain; Infrequent: weight loss, hyperglycemia, SGOT increased, SGPT increased, gout, thirst, hyperuricemia, diabetes mellitus, avitaminosis, bilirubinemia; Rare: alkaline phosphatase increased, creatinine increased, hyponatremia, lactic dehydrogenase increased.

Musculoskeletal SystemFrequent: myalgia, arthralgia; Infrequent: leg cramps; Rare: rheumatoid arthritis, myopathy.

Nervous SystemFrequent: somnolence, libido decreased, amnesia, thinking abnormal, tremor, vasodilatation, hypertension; Infrequent: convulsion, confusion, libido increased, vertigo, withdrawal syndrome, apathy, suicidal ideation, neuralgia, hostility, agitation, neurosis, abnormal dreams, hallucinations, hypesthesia; Rare: alcohol craving, psychosis, hyperkinesia, twitching, depersonalization, increased salivation, paranoid reaction, torticollis, encephalopathy, manic reaction.

Respiratory SystemFrequent: rhinitis, cough increased, dyspnea, pharyngitis, bronchitis; Infrequent: asthma, epistaxis, pneumonia; Rare: laryngismus, pulmonary embolus.

Skin and AppendagesFrequent: rash; Infrequent: acne, eczema, alopecia, maculopapular rash, dry skin, urticaria, exfoliative dermatitis, vesiculobullous rash; Rare: psoriasis.

Special SensesFrequent: abnormal vision, taste perversion; Infrequent: tinnitus, amblyopia, deafness; Rare: ophthalmitis, diplopia, photophobia.

Urogenital SystemFrequent: impotence; Infrequent: metrorrhagia, urinary frequency, urinary tract infection, sexual function abnormal, urinary incontinence, vaginitis; Rare: kidney calculus, abnormal ejaculation, hematuria, menorrhagia, nocturia, polyuria, urinary urgency.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of acamprosate calcium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serious Adverse Events Observed During the Non-U.S. Post-marketing Evaluation of Acamprosate Calcium

The serious adverse event of acute kidney failure has been reported to be temporally associated with acamprosate calcium treatment in at least three patients and is not described elsewhere in the labeling.

7 DRUG INTERACTIONS

Acamprosate does not affect the pharmacokinetics of alcohol. The pharmacokinetics of acamprosate are not affected by alcohol, diazepam or disulfiram, and clinically important interactions between naltrexone and acamprosate were not observed [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Teratogenic Effects

Acamprosate calcium has been shown to be teratogenic in rats when given in doses that are approximately equal to the human dose (on a mg/m 2 basis) and in rabbits when given in doses that are approximately 3 times the human dose (on a mg/m 2 basis). Acamprosate calcium produced a dose related increase in the number of fetuses with malformations in rats at oral doses of 300 mg/kg/day or greater (approximately equal to the maximum recommended human daily (MRHD) oral dose on a mg/m 2 basis). The malformations included hydronephrosis, malformed iris, retinal dysplasia and retroesophageal subclavian artery. No findings were observed at an oral dose of 50 mg/kg/day (approximately one-fifth the MRHD oral dose on a mg/m 2 basis). An increased incidence of hydronephrosis was also noted in Burgundy Tawny rabbits at oral doses of 400 mg/kg/day or greater (approximately 3 times the MRHD oral dose on a mg/m 2 basis). No developmental effects were observed in New Zealand white rabbits at oral doses up to 1000 mg/kg/day (approximately 8 times the MRHD oral dose on a mg/m 2 basis). The findings in animals should be considered in relation to known adverse developmental effects of ethyl alcohol, which include the characteristics of fetal alcohol syndrome (craniofacial dysmorphism, intrauterine and postnatal growth retardation, retarded psychomotor and intellectual development) and milder forms of neurological and behavioral disorders in humans. There are no adequate and well controlled studies in pregnant women. Acamprosate calcium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

A study conducted in pregnant mice that were administered acamprosate calcium by the oral route starting on Day 15 of gestation through the end of lactation on postnatal day 28 demonstrated an increased incidence of still-born fetuses at doses of 960 mg/kg/day or greater (approximately 2 times the MRHD oral dose on a mg/m 2 basis). No effects were observed at a dose of 320 mg/kg/day (approximately one-half the MRHD dose on a mg/m 2 basis).

8.2 Labor and Delivery

The potential for acamprosate calcium to affect the duration of labor and delivery is unknown.

8.3 Nursing Mothers

In animal studies, acamprosate was excreted in the milk of lactating rats dosed orally with acamprosate calcium. The concentration of acamprosate in milk compared to blood was 1.3:1. It is not known whether acamprosate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when acamprosate calcium is administered to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of acamprosate calcium have not been established in the pediatric population.

8.5 Geriatric Use

Forty-one of the 4,234 patients in double-blind, placebo-controlled, clinical trials of acamprosate calcium were 65 years of age or older, while none were 75 years of age or over. There were too few patients in the ≥ 65 age group to evaluate any differences in safety or effectiveness for geriatric patients compared to younger 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 Clinical Pharmacology (12.3), Adverse Reactions (6.1) and Dosage and Administration (2.1)].

8.6 Renal Impairment

Acamprosate calcium is contraindicated in patients with severe renal impairment (creatinine clearance of ≤ 30 mL/min ) [see Dosage and Administration (2.1), Contraindications (4.2), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

In all reported cases of acute overdosage with acamprosate calcium (total reported doses of up to 56 grams of acamprosate calcium), the only symptom that could be reasonably associated with acamprosate calcium was diarrhea. Hypercalcemia has not been reported in cases of acute overdose. A risk of hypercalcemia should be considered in chronic overdosage only. Treatment of overdose should be symptomatic and supportive.

11 DESCRIPTION

Acamprosate calcium is supplied in an enteric-coated tablet for oral administration. Acamprosate calcium is a synthetic compound with a chemical structure similar to that of the endogenous amino acid homotaurine, which is a structural analogue of the amino acid neurotransmitter γ-aminobutyric acid and the amino acid neuromodulator taurine. Its chemical name is 3-(acetylamino)-1-propanesulfonic acid calcium salt (2:1). Its chemical formula is C 10 H 20 N 2 O 8 S 2 Ca and molecular weight is 400.48. Its structural formula is:

Acamprosate Calcium Structural Formula
(click image for full-size original)

Acamprosate calcium is a white odorless crystalline powder. It is freely soluble in water, and practically insoluble in absolute ethanol, dichloromethane and xylene.

Each acamprosate calcium delayed-release tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients in acamprosate calcium delayed-release tablets include: ammonium hydroxide, black iron oxide, colloidal silicon dioxide, glyceryl behenate, hypromellose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, propylene glycol, shellac and talc. Sulfites were used in the synthesis of the drug substance and traces of residual sulfites may be present in the drug product.

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