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
Patients Co-infected with Hepatitis B and/or Hepatitis C Virus
In the clinical studies, P018 and P019, subjects with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection (N = 114/699 or 16%) were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). The rates of AST and ALT abnormalities were higher in the subgroup of subjects with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to subjects without hepatitis B and/or hepatitis C virus co-infection. Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 25%, 31% and 12%, respectively, of co-infected subjects treated with ISENTRESS as compared to 8%, 7% and 8% of all other subjects treated with ISENTRESS.

Postmarketing Experience
The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Tissue Disorders: rash, Stevens-Johnson syndrome
Psychiatric Disorders: depression (particularly in patients with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors

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
ISENTRESS may be administered with or without food. Raltegravir was administered without regard to food in the pivotal safety and efficacy studies in HIV-infected patients. The effect of consumption of low-, moderate- and high-fat meals on steady-state raltegravir pharmacokinetics was assessed in healthy volunteers. Administration of multiple doses of raltegravir following a moderate-fat meal (600 Kcal, 21 g fat) did not affect raltegravir AUC to a clinically meaningful degree with an increase of 13% relative to fasting. Raltegravir C12 hr was 66% higher and Cmax was 5% higher following a moderate-fat meal compared to fasting. Administration of raltegravir following a high-fat meal (825 Kcal, 52 g fat) increased AUC and Cmax by approximately 2-fold and increased C12 hr by 4.1-fold. Administration of raltegravir following a low-fat meal (300 Kcal, 2.5 g fat) decreased AUC and Cmax by 46% and 52%, respectively; C12 hr was essentially unchanged. Food appears to increase pharmacokinetic variability relative to fasting.

The Special Populations subsection was revised to state:

UGT1A1 Polymorphism
There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09).

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.

The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R and D232N). Amino acid substitution at Y143C/H/R is another pathway to raltegravir resistance. By Week 48 in the BENCHMRK trials, at least one of the 3 primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 63 (64.3%) of the 98 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. Some (n=18) of those HIV isolates harboring one or more of the 3 primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 47.3-fold (mean 73.1 ? 60.8-fold decrease, ranging from 0.9- to 200-fold) compared to baseline isolates.

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

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