FDA: Isentress (raltegravir) indication extended for the treatment of HIV-1 infection in treatment-naive patients (AEGiS.org) - Isentress (raltegravir) indication extended for the treatment of HIV-1 infection in treatment-naive patients
Food and Drug Administration - July 9, 2009 Richard Klein & Kimberly Struble
http://www.aegis.org/news/fda/2009/FD090701.html

On July 8, 2009, FDA granted approval to Isentress (raltegravir), for the treatment of HIV-1 infection in treatment-na?ve patients. The recommended dose for treatment-na?ve adult patients is Isentress 400 mg twice daily, with or without food.
The use of Isentress in treatment-na?ve patients is based on a 48-week randomized, double-blind, active control trial to evaluate the safety and efficacy of Isentress 400 mg twice daily + emtricitabine + tenofovir versus Sustiva (efavirenz) 600 mg + emtricitabine + tenofovir. The proportion of patients with HIV RNA < 50 copies/mL was 87% for the Isentress group compared to 82% for the Sustiva group. The difference between Isentress and Sustiva with respect to HIV RNA < 50 copies/mL and the 95% confidence intervals is 4.7% (-1.3%, 10.6%).
Several other changes were made to the package insert and include the following major revisions -
Highlights Section:

• DRUG INTERACTIONS heading was included along with a warning about use with UGT (UDP-glucuronosyltransferases) inducers other than rifampin, specifically, "Coadministration of ISENTRESS with drugs that are strong inducers of UGT1A1 may result in reduced plasma concentrations of raltegravir"

Full Prescribing Information Section:

• Section 1: INDICATIONS AND USAGE was changed to incorporate use in treatment-na?ve patients: "ISENTRESS is indicated in combination with other anti-retroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients. This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults and one was conducted in treatment-na?ve adults. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response."


• Section 5.2: WARNINGS AND PRECAUTIONS, Drug Interactions: this section removed because the information is sufficiently included in Section 7: DRUG INTERACTIONS


• Section 6.1: Clinical Trials Experience, Treatment-Na?ve Studies: This section now includes 48 week safety and laboratory data from Protocol 021.


• Section 6.2: Postmarketing Experience: addition of paranoia and anxiety.


• Section 7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents adds information for CYP1A2, CYP2B6 and methadone.


• Section 12.4 Microbiology was updated to include the following headings and information: Antiviral Activity in Cell Culture

• In addition, 5 clinical isolates of HIV-1 subtype B had EC95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. 

Resistance
Treatment-Na?ve Subjects: By Week 48 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 3 (1 with Y143R and 2 with Q148H/R) of the 6 virologic failure subjects with evaluable paired genotypic data.
Section 14 CLINICAL STUDIES includes 48 week efficacy data from Protocol 02.
Minor editorial changes were made to the patient package insert for consistency with other antiretrovirals.
The revised label will be available soon on the FDA web site at Drugs@FDA or through the National Library of Medicine's DailyMed site.
Issentress (raltegravir) is an integrase inhibitor made by Merck & Co.
Richard Klein Office of Special Health Issues Food and Drug Administration
Kimberly Struble Division of Antiviral Drug Products Food and Drug Administration
090709 FD090701

SOURCE: Food and Drug Administration (FDA).
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