Campral Clears FDA For Alcohol Dependence: Renal Study Part Of Phase IV

Merck KGaA subsidiary Lipha will determine appropriate Campral dosing in patients with severe renal impairment as a postmarketing commitment following FDA approval of the alcoholism therapy.

FDA cleared Campral (acamprosate) July 29 for the "maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation" (¹ 'The Pink Sheet' Aug. 2, 2004, In Brief).

Campral is to be used as "part of a comprehensive management program that includes psychosocial support," ² labeling says.

Until appropriate dosing for patients with severe renal impairment can be determined, Campral is contraindicated in patients with creatinine clearance less than or equal to 30 mL/min, labeling says.

Patients with moderate renal impairment (creatinine clearance 30-50 mL/min) require a dose reduction to one 333 mg tablet taken three times daily, versus the recommended two 333 mg tablets three times daily for healthy patients.

The Phase IV pharmacokinetic dosing study will include at least six subjects with severe renal impairment and at least six healthy subjects. The study must be completed by August 2007, FDA said.

The study will attempt to determine "an appropriate dosing regimen for patients with severe renal impairment...by using modeling and simulation analyses," the Campral ³ approval letter states.

The dosing regimen will then be evaluated to "see if the exposure is comparable to that seen in normal patients receiving a recommended dose."

Lipha has also committed to conduct postmarketing studies that address Campral use in pediatric patients (ages 12-16), potential carcinogenicity effects in mice, and the effect of concomitant use of acamprosate and alcohol during pregnancy on the fetus.

Other than the contraindication for severe renal patients, labeling for Campral is relatively clean and does not include a warnings section.

The precautions section of labeling discusses an increased potential for "adverse events of a suicidal nature" with acamprosate patients during clinical trials (1.4% vs. 0.5% in studies of six months or less; 2.4% vs. 0.8% in year-long studies).

"Although many of these events occurred in the context of alcohol relapse, no consistent pattern of relationship between the clinical course of recovery from alcoholism and the emergence of suicidality was identified," labeling says.

The precautions section also notes that Campral has only been shown to be effective when used in conjunction with a counseling program, and that patients should continue use of the drug in the event of a relapse.

In ex-U.S. postmarketing experience with Campral, "the serious adverse event of acute kidney failure has been reported to be temporally associated with Campral in at least 3 patients and is not described elsewhere in the labeling," the adverse events section says.

Campral's approval was based on the results of three efficacy studies (ranging from 90 to 360 days) in a total of 998 abstinent patients who had undergone detoxification. Campral plus psychosocial therapy was found to be statistically superior to placebo.

A fourth study in patients that had not gone through detox and were not abstinent at the time of treatment failed to show superiority to placebo, labeling says.

Forest, which will market Campral for Lipha in the U.S., will launch the drug by year-end using a subset of its antidepressant sales force. Reps already detailing alcohol treatment facilities will promote Campral, targeting psychiatrists involved in alcohol counseling.

The company said it will work with alcoholic treatment groups and psychiatrists to develop the "comprehensive management program." Of the 17 mil. alcoholics in the U.S., Forest estimates that 10% seek treatment and would be candidates for Campral.

Lipha submitted the NDA in December 2001 and received priority review. An FDA advisory committee recommended approval in May 2002, but the NDA was deemed "not approvable" by FDA in July 2002, pending an additional safety and efficacy trial, further pharmacokinetic analyses and preclinical studies (⁴ 'The Pink Sheet' July 8, 2002, In Brief).