Viramune Labeling Revised To Require Liver Monitoring In First 12 Weeks

Revised black box labeling for Boehringer Ingelheim/Roxane antiretroviral Viramune (nevirapine) states that patients must receive liver monitoring during the first 12 weeks of therapy.

The first 12 weeks are "a critical period during which it is essential that patients be monitored intensively to detect potentially life-threatening hepatotoxicity or skin reactions," the revised black box states.

The amended black box also warns that "in some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure," and stresses that "Viramune should not be restarted following severe hepatic, skin or hypersensitivity reactions."

The previous labeling stated that Viramune be permanently discontinued only "if liver function abnormalities recur upon readministration."

Boehringer will send out a "Dear Doctor" letter regarding the safety of the non-nucleoside reverse transcriptase inhibitor at the end of November. The letter will go to more than 8,000 HIV treatment specialists, including physicians and advocacy groups.

The labeling changes for the drug were made "in response to continued reports of severe, life-threatening and in some cases, fatal hepatotoxicity" observed in clinical trials and postmarketing, the letter states. Boehringer said that one of the reports involved a hepatotoxicity-induced liver transplant.

Although patient symptoms varied in the reports, labeling notes that "frequently occurring features included...signs and symptoms of fatigue, malaise, anorexia and nausea, with or without abnormal serum transaminase levels." Symptoms "progressed to jaundice, hepatomegaly, elevation of transaminase levels and hepatic failure over a period of several days."

Data from a 2,250-patient clinical trial suggested the Viramune-attributable risk of hepatitis is 1.4%, Boehringer said.

The Warnings section of the revised labeling notes that "the optimal frequency of monitoring during the first 12 weeks of therapy with Viramune has not been established," but adds that some experts recommend monitoring liver function "at baseline, prior to dose escalation and at two weeks post dose escalation."

European labeling for the drug, revised in April due to the same postmarketing AE reports, is more specific. Liver function monitoring is urged every two weeks for the first two months of therapy, at the end of the third month, and every three to six months thereafter (¹ (Also see "Viramune European Labeling Warnings Strengthened For Hepatic Reactions" - Pink Sheet, 24 Apr, 2000.)).

Boehringer said that it proactively submitted the reports to both European regulatory authorities and FDA last spring.

To aid in risk management, Boehringer has developed a new Viramune patient package insert "intended...to be dispensed with each new prescription and refill," the "Dear Doctor" letter informs providers.

The company also will be sending out a set of detailed guidelines for the management of hepatic reactions pending final negotiations with FDA regarding content. The guidelines will receive wider distribution than the "Dear Doctor" letter, and will be mailed to HIV practices and clinics nationwide.

The Warnings section of the revised labeling notes that while serious hepatic events occur most frequently during the first 12 weeks on Viramune, such events "have been reported to occur as early as within the first few weeks of therapy."

"However," revised labeling continues, "approximately one-third of cases...occur after the critical 12-week period," when "frequent clinical and laboratory monitoring should continue."

The European Medicines Evaluation Agency's review of the reports concluded that most hepatitis cases occur within the first eight weeks of treatment.

Previous Viramune labeling stated that liver function monitoring is "strongly recommended," especially during the first six months therapy, and added that tests "should be performed prior to initiating...therapy and at appropriate intervals during therapy."

The revised labeling elevates the previous 14-day 200-mg daily lead-in dosing period to the black box, stating that it "must be strictly followed."