Long-term safety from the raltegravir clinical development program.

BACKGROUND: Raltegravir has demonstrated potent and durable efficacy and a favorable safety profile in 3 phase III studies in treatment-naïve and treatment-experienced patients with HIV-1 infection. This manuscript provides a review of the raltegravir safety profile using data from these and other studies in the clinical development program. METHODS: Comprehensive 96-week safety data from STARTMRK (raltegravir versus efavirenz, each with tenofovir/emtricitabine) and BENCHMRK (raltegravir versus placebo, each with optimized background therapy) are summarized. A cumulative meta-analysis of raltegravir 400 mg bid was conducted across the entire development program. RESULTS: In STARTMRK, drug-related adverse events (AEs) occurred less frequently with raltegravir than efavirenz. In BENCHMRK, the most common drug-related AEs occurred at generally similar frequencies in both groups. Drug-related serious AEs were uncommon. Rash was observed in raltegravir-treated patients at a higher frequency than placebo but a lower frequency than efavirenz. Depression and immune reconstitution inflammatory syndrome occurred at similar rates for raltegravir and comparators. Isolated elevations of creatine kinase were more common with raltegravir than placebo but occurred without clinical manifestations. The frequency of aminotransferase elevations was greater in patients with viral hepatitis co-infection, but similar in the raltegravir and comparator groups. The relative risk (95% CI) of cancer was 0.75 (0.30, 1.91) indicating no difference between raltegravir and comparator. Overall trends in the cumulative meta-analysis were similar to those observed in the phase III studies. CONCLUSIONS: Long-term data from the phase III clinical trials demonstrate that raltegravir was generally well-tolerated in both treatment-naïve and treatment-experienced patients with HIV infection.

A five-year evaluation of reports of overdose with indinavir sulfate.

PURPOSE: To describe the adverse event profile for indinavir sulfate overdose. METHODS: Analysis of indinavir overdose reports in Merck & Co., Inc.'s safety database through the first 5 years following US licensure of indinavir. Reports were classified as acute (single high dose in excess of 2400 mg), chronic (multiple extra doses, not exceeding 2400 mg per dose), single extra dose (not exceeding 2400 mg) and dose not reported. RESULTS: Seventy-nine reports of indinavir overdose were reviewed (15 acute, 43 chronic, 13 single extra dose and 8 dose not reported). A total of 52/79 (66%) reports were associated with adverse events. For acute overdose reports with adverse events, indinavir doses ranged from 2.8 g to 48 g (median 6 g; mean 13 g); for acute overdose reports without adverse events, indinavir doses ranged from 4 g to 80 g (median 56 g; mean 45 g). Adverse events following acute and chronic exposures were similar; the most commonly reported adverse events included nausea, vomiting, abdominal pain and nephrolithiasis. Of the 52 patients with adverse events, 39 recovered, 6 had not recovered at the time of reporting and no information regarding outcome was provided in 7 reports. CONCLUSIONS: Overdose with indinavir was associated with adverse events in the majority of reports. These were most commonly gastrointestinal and renal events, and were generally consistent with the known safety profile of indinavir. The majority of patients recovered.