ACAMPROSATE calcium delayed-release tablets
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 calcium acetylaminopropane sulfonate. Its chemical formula is C10H20N2O8S2Ca and molecular weight is 400.5.
Acamprosate calcium is a white or almost white powder. It is freely soluble in water, practically insoluble in alcohol and in methylene chloride.
Each acamprosate calcium delayed-release tablet intended for oral administration contains 333 mg of acamprosate calcium equivalent to 300 mg of acamprosate. In addition, each tablet contains the following inactive ingredients: colloidal anhydrous silica, methacrylic acid copolymer type c, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium bicarbonate, sodium lauryl sulfate, sodium starch glycolate and talc. Sulfites were used in the synthesis of the drug substance and traces of residual sulfites may be present in the drug product.
Indications and usage
Acamprosate calcium delayed-release tablets are indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. Treatment with acamprosate calcium delayed-release tablets should be part of a comprehensive management program that includes psychosocial support.
Mechanism of Action
The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. In vitro and in vivo studies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance.
Pharmacodynamic studies have shown that acamprosate calcium reduces alcohol intake in alcoholdependent animals in a dose-dependent manner and that this effect appears to be specific to alcohol and the mechanisms of alcohol dependence.
Acamprosate calcium has negligible observable central nervous system (CNS) activity in animals outside of its effects on alcohol dependence, exhibiting no anticonvulsant, antidepressant, or anxiolytic activity.
The administration of acamprosate calcium is not associated with the development of tolerance or dependence in animal studies. Acamprosate calcium did not produce any evidence of withdrawal symptoms in patients in clinical trials at therapeutic doses. Post marketing data, collected retrospectively outside the U.S. have provided no evidence of acamprosate calcium abuse or dependence.
Acamprosate calcium is not known to cause alcohol aversion and does not cause a disulfiram-like reaction as a result of ethanol ingestion.
Dosage and administration
The recommended dose of acamprosate calcium delayed-release tablets is two 333 mg tablets (each dose should total 666 mg) taken three times daily. A lower dose may be effective in some patients.
Although dosing may be done without regard to meals, dosing with meals was employed during clinical trials and is suggested in those patients who regularly eat three meals daily.
Treatment with acamprosate calcium delayed-release tablets should be initiated as soon as possible after the period of alcohol withdrawal, when the patient has achieved abstinence, and should be maintained if the patient relapses. Acamprosate calcium delayed-release tablets should be used as part of a comprehensive psychosocial treatment program.
Dosage in Renal Impairment For patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min), a starting dose of one 333 mg tablet taken three times daily is recommended. Acamprosate calcium delayed-release tablets are contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min).
Hypers ensitivity to Acamprosate Calcium: Acamprosate calcium is contraindicated in patients who previously have exhibited hypersensitivity to acamprosate calcium or any of its components.
Severe Renal Impairment: Acamprosate calcium is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min).
Warnings and precautions
Renal Impairment: Treatment with acamprosate calcium in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min) requires a dose reduction. Acamprosate calcium is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min).
Suicidality and Depression: In controlled clinical trials of acamprosate calcium, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were infrequent overall, but were more common in acamprosate calcium-treated patients than in patients treated with placebo (1.4% vs. 0.5% in studies of 6 months or less; 2.4% vs. 0.8% in year-long studies). Completed suicides occurred in 3 of 2272 (0.13%) patients in the pooled acamprosate group from all controlled studies and 2 of 1962 patients (0.10%) in the placebo group. Adverse events coded as “depression” were reported at similar rates in acamprosate calcium-treated and placebo-treated patients.
Alcohol Withdrawal: Use of acamprosate calcium does not eliminate or diminish withdrawal symptoms.
Common adverse events that occurred in any acamprosate calcium treatment group at a rate of 3% or greater and greater than the placebo group in controlled clinical trials with spontaneously reported adverse events are: accidental injury, asthenia, pain, anorexia, diarrhea, flatulence, nausea, anxiety, depression, dizziness, dry mouth, insomnia, paresthesia, pruritus and sweating.
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
Use in specific populations
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 basis) and in rabbits when given in doses that are approximately 3 times the human dose (on a mg/m basis).
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.
Pediatric Use: The safety and efficacy of acamprosate calcium have not been established in the pediatric population.
Geriatric use: 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.
Renal Impairment: Acamprosate calcium is contraindicated in patients with severe renal impairment (creatinine clearance of ≤30 mL/min).
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.