HIV/AIDS Update: Traditional Approval of Isentress (raltegravir)
February 5, 2009
On January 29, 2009, the Food and Drug Administration (FDA) granted traditional approval for Isentress (raltegravir) 400 mg tablets in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients. The product label and patient package insert have been updated to include 48 week data from Studies 018 and 019.
Major changes include the following:
Section 2: DOSAGE AND ADMINISTRATION, Section 5.2: Drug Interactions and Section 7.2, Effect of Other Agents on the Pharmacokinetics of Raltegravir was updated to include the recommendation to increase raltegravir dose to 800 mg twice daily during coadministration with rifampin. Additionally, caution is recommended when coadministering raltegravir with other strong UGT1A1 inducers due to reduced raltegravir plasma concentrations
Section 6 ADVERSE REACTIONS was updated to include the 48 week safety and laboratory data from Protocols 018 and 019
Patients with Co-existing Conditions
Section 7.1 Effect of Raltegravir on the Pharmacokinetic of Other Agents was revised to include information on hormonal contraceptives and etravirine as follows:
In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives,lamivudine, tenofovir, etravirine.
Section 7.2, Effect of Other Agents on the Pharmacokinetics of Raltegravir now includes a table of selected drug interactions with corresponding clinical comment for each interaction. In addition, information on etravirine, efavirenz, rifampin and omeprazole was added.
Section 12.3 Pharmacokinetics was updated to include results from food effect study as follows:
Effect of Food on Oral Absorption
The Special Populations subsection was revised to state:
Table 4 ? Drug Interactions was updated to include results from the etravirine, rifampin and omeprazole studies.
Section 12.4 Microbiology, Resistance was updated to include the Week 48 data from studies 018 and 019 as follows.
Section 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility was updated to include the two year carcinogenicity study results.
Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 µM•hr) at the 400-mg twice daily human dose. Treatment related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 µM•hr) at the 400-mg twice daily human dose.
Section 14 CLINICAL STUDIES was updated with the 48 week study results from Protocols 018 and 019.
The complete revised label can be found on the FDA web site at http://www.fda.gov/cder/foi/label/2009/022145s001lbl.pdf
HIV/AIDS Update: Isentress (Raltegravir) Indication Extended for the Treatment of HIV-1 Infection in Treatment-Naive Patients
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