Acamprosate: safety and tolerability in the treatment of alcohol dependence.

Acamprosate, in conjunction with psychosocial treatment, has demonstrated efficacy in maintaining abstinence in alcohol-dependent patients in multiple clinical trials. Data from 13 short-term (≤26 weeks) and long-term (≥48 weeks) clinical trials were analyzed to assess the safety and tolerability of acamprosate: 4234 patients were randomized to placebo (N = 1962), acamprosate 1332 mg/d (N = 440), 1998 mg/d (N = 1749), or 3000 mg/d (N = 83). Overall incidence of treatment-emergent adverse events (AEs) was 61% for acamprosate and 56% for placebo (P < 0.01). The majority of AEs in all groups were reported as transient and considered "mild" or "moderate" in severity, and discontinuation rates due to AEs were comparable. Most common AEs were diarrhea (16% acamprosate versus 10% placebo, P < 0.01) and flatulence (3% acamprosate versus 2% placebo, P < 0.01). Patients taking concomitant medications commonly used to treat alcohol dependence reported comparable AEs between placebo- and acamprosate-treated groups.Acamprosate was shown to be safe in patients with hepatic impairment. A dose reduction is recommended in patients with renal impairment. No clinically meaningful between-group differences were reported for clinical chemistry tests or vital sign parameters. This ad hoc analysis demonstrates that acamprosate can be used safely in alcohol-dependent patients, including those taking concomitant medications, or having renal or hepatic impairment.

Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation.

This is the first US study to evaluate the clinical efficacy of acamprosate (Campral), a newly FDA-approved medication for maintaining abstinence in patients with alcohol dependence following alcohol withdrawal. We compared effects of the standard 2 g dose (n=258) and an exploratory 3 g dose of acamprosate (n=83) versus placebo (n=260), and evaluated drug safety in a double-blind, placebo-controlled 6-month trial conducted in 21 outpatient clinics across the US. Participants were 601 volunteers with current alcohol dependence recruited primarily by advertisement. All patients concomitantly received eight sessions of brief manual-guided counseling (www.alcoholfree.info). The main outcome measure was the percentage of alcohol-free days over the 6-month study. Self-report was validated by breath alcohol concentration, gamma-glutamyltransferase (GGT) and collateral informant interviews. The percentage of abstinent days did not differ significantly across groups in a priori analysis (54.3% for placebo, 56.1% for 2 g, 60.7% for 3 g). Post-hoc analysis controlling for baseline variables and treatment exposure found acamprosate was associated with a significantly higher percentage of abstinent days than placebo (52.3% for placebo, 58.2% for 2 g, 62.7% for 3 g; P=0.01), with an even greater effect in the subgroup of 241 patients having a baseline goal of abstinence (58.1% for placebo, 70.0% for 2 g, 72.5% for 3 g; P=0.02). There were no deaths or serious drug-related adverse events. The US study findings suggest that acamprosate is safe and well tolerated in a broadly inclusive sample of alcoholics and appears effective in populations of patients motivated to have a treatment goal of abstinence.

A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone.

Acamprosate and naltrexone have each demonstrated safety and efficacy for alcohol dependence in placebo-controlled clinical trials. There is scientific and clinical interest in evaluating these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes. Thus, this is the first human pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Twenty-four normal, healthy adult volunteers participated in a double-blind, multiple dose, within subjects, randomized, 3-way crossover drug interaction study of the standard therapeutic dose of acamprosate (2 g/d) and the standard therapeutic dose of naltrexone (50 mg/d), given alone and in combination, with seven days per treatment condition and seven days washout between treatments. Blood samples were collected on a standardized schedule for pharmacokinetic analysis of naltrexone, 6-beta-naltrexol, and acamprosate. A computerized assessment system evaluated potential drug effects on cognitive functioning. Coadministration of acamprosate with naltrexone significantly increased the rate and extent of absorption of acamprosate, as indicated by an average 33% increase in acamprosate maximum plasma concentration, 33% reduction in time to maximum plasma concentration, and 25% increase in area under the plasma concentration-time curve. Acamprosate did not affect the pharmacokinetic parameters of naltrexone or 6-beta-naltrexol. A complete absence of negative interactions on measures of safety and cognitive function supports the absence of a contraindication to co-administration of acamprosate and naltrexone in clinical practice.