FDA Approvals: Aptivus, MetroGel, Topamax

Yael Waknine

July 21, 2005

July 21, 2005 — The U.S. Food and Drug Administration (FDA) has approved tipranavir capsules for coadministration with low-dose ritonavir as part of antiretroviral therapy for adults with HIV-1 who are highly treatment experienced or have viral strains resistant to multiple protease inhibitors; metronidazole 1% topical gel for the treatment of inflammatory lesions due to rosacea; and topiramate as initial monotherapy for partial onset or primary generalized tonic-clonic seizures in patients aged 10 years and older.

Tipranavir (Aptivus) for HIV in Multidrug Resistant Patients

On June 22, the FDA granted accelerated approval of the protease inhibitor (PI) tipranavir (Aptivus 250-mg capsules, made by Boehringer Ingelheim Pharmaceuticals, Inc.) for coadministration with low-dose ritonavir as part of combination antiretroviral therapy for HIV-1 in adults with evidence of viral replication who are highly treatment experienced or have HIV-1 strains resistant to multiple PIs.

The approval was based on 24-week data from ongoing phase 3 clinical trials (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir [RESIST-1 and RESIST-2]) in more than 1,000 patients with advanced HIV disease and documented PI resistance who had previously received an average of 12 antiretroviral drugs and were experiencing virologic failure.

Patients were randomized to receive either tipranivir or a comparator PI (CPI) plus low-dose ritonavir in addition to a background regimen designed on the basis of genotypic resistance testing.

Results showed that tipranivir/ritonavir was associated with a significantly increased response rate compared with CPI/ritonavir treatment (40% vs 18%; P < .0001), as defined by a decrease in viral load from baseline of at least 1 log 10.

Also, a significantly greater proportion of patients in the tipranivir/ritonavir group achieved a reduction of viral load to undetectable levels (400 copies/mL or less) at 24 weeks relative to the CPI/ritonavir group (34% vs 16%; P < .0001), and 23% vs 9% achieved levels of less than 50 copies per mL ( P < .0001). Increases in CD4+ cell counts from baseline were also greater in those receiving tipranivir/ritonavir (mean, +34 vs +4 cells/mm 3; P < .0001) compared with CPI/ritonavir therapy.

Within the tipranivir/ritonavir group, patients receiving concurrent treatment with enfurvitide achieved a significantly better virologic outcome.

Tipranavir/ritonavir was associated with an increased incidence of liver enzyme (grade 2 - 4; 17.5% vs 9.9%) and lipid elevations (cholesterol, 14.6% vs 8.6%; triglycerides, 45.1% vs 23.7%) compared with CPI/ritonavir therapy. In clinical trials extending up to 48 weeks, the rate of grade 2 to 4 liver enzyme elevations was 24.4% in the tipranavir/ritonavir group and 12.8% in those administered CPI/ritonavir.

Because tipranivir/ritonavir therapy has been associated with reports of clinical hepatitis and hepatic decompensation (including some fatalities), liver enzyme levels should be evaluated prior to and during therapy. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C coinfection because of the increased risk of hepatotoxicity.

Consideration should also be given to the extensive drug-drug interaction potential of tipranivir/ritonavir when coadministered with multiple classes of drugs prior to and during therapy.

As a condition of approval, the company will be continuing to evaluate the safety and efficacy of tipranavir in certain subpopulations, including pediatric patients, treatment-naive adults, HIV-positive women, and hepatitis coinfected patients. Long-term data will be required prior to FDA granting traditional approval of the drug.

Metronidazole 1% Topical Gel (MetroGel) for Rosacea

On June 30, the FDA approved metronidazole 1% topical gel (MetroGel, made by Dow Pharmaceutical Sciences) for the treatment of inflammatory lesions due to rosacea.

The approval was based on results of a 10-week, randomized study in 746 patients, showing that a once-daily application of the active gel decreased the number of inflammatory lesions relative to baseline by 50.7% (9.4 lesions) vs 32.6% (5.6 lesions) for the vehicle alone ( P < .001).

Also, 38.42% of patients applying 1% metronidazole gel achieved an investigator global assessment score of "clear or almost clear" at 10 weeks compared with 27.51% using the vehicle alone ( P = .0060). No significant toxicities were reported in the study.

Topiramate (Topamax) First-Line Monotherapy for Seizures in Patients Aged 10 Years and Older

On June 29, the FDA approved a new indication for topiramate (Topamax tablets, capsules, and sprinkle capsules, made by Ortho-McNeil Pharmaceutical, Inc.), allowing its use as initial monotherapy for partial onset or primary generalized tonic-clonic seizures in patients aged 10 years and older.

The approval was based on results of a double-blind clinical efficacy trial in 470 patients randomized to titrate up to 50 or 400 mg per day of topiramate. Approximately 58% of patients achieved the maximal dose (mean dose, 275 mg/day). All patients had experienced one or two documented seizures for a three-month pretrial period.

Comparison of Kaplan-Meier survival curves of time to first seizure favored the 400-mg per day group vs the 50-mg per day group ( P = .0002).

Adverse events more commonly reported in adults administered 400 vs 50 mg per day of tipranavir included paresthesias, weight loss, somnolence, anorexia, dizziness, and difficulty with memory. Weight loss, upper respiratory tract infection, paresthesias, anorexia, diarrhea, and mood problems were more commonly reported in children aged 10 to 16 years.

Topiramate was previously approved as adjunctive therapy for this indication in patients aged two years and older, for the treatment of seizures associated with Lennox-Gastaut syndrome in patients aged two years and older, and for migraine prophylaxis in adults.

Reviewed by Gary D. Vogin, MD

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