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| |  FDA Grants Traditional Approval To Crixivan For HIV WEST POINT, PA -- March 5, 1998 -- The United States Food and Drug Administration has granted traditional approval to Merck & Co., Inc.'s HIV protease inhibitor Crixivan(R) (indinavir sulfate), based on the results from two endpoint studies that confirm the clinical benefits of combination therapy with Crixivan. Data from ACTG 320 and Merck's Protocol 028 demonstrated that treatment with Crixivan in combination therapy both prolonged HIV RNA suppression (less than 500 copies/mL) and significantly reduced the risk of AIDS-defining illnesses or death. These studies lasted approximately one year and compared Crixivan-containing treatment regimens to regimens containing nucleoside analogues only (AZT and/or 3TC). Crixivan was initially cleared for marketing in March 1996 under the FDA's accelerated review procedures. This indication was based on an analysis of surrogate endpoints (CD4 cell counts increases and viral load decreases) in studies of up to 24 weeks in duration. With traditional approval, Crixivan in combination with antiretroviral agents is indicated for the treatment of HIV infection. "The data from these studies show the clinical benefit that indinavir in combination with nucleoside analogues can provide for patients," said Roy Gulick, M.D., assistant professor of medicine, Cornell University Medical College, and an investigator in several key Crixivan studies. "These studies support the goal of successful HIV therapy-suppressing viral levels to as low as possible for as long as possible. Now we need to encourage people at risk for HIV to get tested and talk to their doctors about their treatment options." Results from ACTG 320 and Protocol 028 which were recently presented at the 5th Annual Conference on Retroviruses and Opportunistic Infections in Chicago, showed fewer new infections and deaths occurred in patients whose viral levels were reduced to less than 500 copies/mL by Crixivan in combination therapy. In ACTG 320, a 1,156-patient study that compared triple therapy with Crixivan, AZT and 3TC to AZT and 3TC alone, the group treated with Crixivan had a 44 percent reduction in the number of patients who developed an AIDS-defining illness or died compared to the two-drug group (35 versus 63 events). Patients had been previously treated with AZT, but had not been on therapy with a protease inhibitor or with 3TC. The study included a diverse group of patients -- 17 percent women, 28 percent African-American and 18 percent Hispanic. ACTG 320, which was published in the New England Journal of Medicine, is the first clinical endpoint trial to compare triple therapy with a protease inhibitor to the two-drug combination of AZT and 3TC. A second clinical endpoint trial (Protocol 028) studied Crixivan plus AZT, Crixivan alone, and AZT alone (3TC was added to the AZT arms over the course of the study). The study showed that patients on the Crixivan combination had a 69 percent reduction in deaths or progression to an AIDS-defining illness compared to patients on nucleoside analog therapy (21 events versus 62 events respectively). The study evaluated 996 treatment-naive patients with CD4 cell counts between 50 and 250 cells/mm3. Twenty-eight percent of study participants were women. The prescribing information for Crixivan also includes results from Merck's Protocol 035, the first study to show that HIV could be reduced below the level of detection (less than 500 copies/mL, by an experimental use of the Amplicor Hiv Monitor assay) in the blood of the majority of patients. This ongoing landmark study helped to establish the goal of HIV treatment. In this trial, published in the New England Journal of Medicine, of the patients who had previously received AZT, 90 percent of patients taking triple therapy with Crixivan, AZT and 3TC had virus levels below the level of detection at 24 weeks (28 out of 31 patients). This result was sustained for up to one year in the limited number of patients who remained on blinded treatment in the study. Crixivan therapy is generally well-tolerated. Crixivan should not be administered concurrently with terfenadine, cisapride, astemizole, triazolam, midazolam or ergot derivatives. Inhibition of CYP3A4 by Crixivan could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. Nephrolithiasis has been reported in approximately 9.3 percent of patients taking Crixivan in clinical trials, compared to 2.1 percent in the control arms. In some cases, nephrolithiasis has been associated with renal insufficiency or acute renal failure. If signs and symptoms of nephrolithiasis occur (including flank pain, with or without hematuria or microscopic hematuria), temporary interruption (one to three days) or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with Crixivan. Acute hemolytic anemia, including cases resulting in death, has been reported with Crixivan. Hepatitis, including hepatic failure and death, has been reported in patients treated with Crixivan. The following adverse events have been noted for all protease inhibitors -- new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia. There have been reports of spontaneous bleeding in patients with hemophilia A and B. More information on: Crixivan, Merck & Co., Inc.
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