Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Treatment-Experienced Studies

The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019), and the randomized, double-blind, placebo-controlled, dose-ranging trial (Protocol 005) in antiretroviral treatment-experienced HIV-1 infected adult subjects reported using the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) in 507 subjects, in comparison to 282 subjects taking placebo in combination with OBT. During double-blind treatment, the total follow-up was 332.2 patient-years in the ISENTRESS 400 mg twice daily group and 150.2 patient-years in the placebo group.

The most commonly ( > 10%) reported adverse reactions, of all intensities, regardless of causality in subjects treated with ISENTRESS and OBT versus placebo and OBT are presented in Table 1.

Table 1: Percentage of Subjects with the Most Commonly Reported ( > 10%) Adverse Reactions of All Intensities* and Regardless of Causality Occurring in Treatment-Experienced Adult Subjects

The clinical adverse reactions listed below were considered by investigators to be of moderate to severe intensity and causally related to any drug in the combination regimen (ISENTRESS/placebo alone or in combination with OBT, or OBT alone):

Common Adverse Reactions

Drug-related clinical adverse reactions of moderate to severe intensity occurring in ≥ 2% of subjects treated with ISENTRESS + OBT are presented in Table 2.

Table 2: Percentage of Subjects with Drug-Related* Adverse Reactions of Moderate to Severe Intensity^† Occurring in ≥ 2% of Treatment-Experienced Adult Subjects

Less Common Adverse Reactions

Drug-related adverse reactions occurring in at least 1% but less than 2% of treatment-experienced subjects (n=507) receiving ISENTRESS + OBT and of moderate (discomfort enough to cause interference with usual activity) to severe (incapacitating with inability to work or do usual activity) intensity are listed below by system organ class:

Gastrointestinal Disorders: abdominal pain, vomiting

General Disorders and Administration Site Conditions: asthenia, fatigue

Nervous System Disorders: dizziness

Skin and Subcutaneous Tissue Disorders: lipodystrophy acquired

Discontinuations

In the pooled analyses for studies P005, P018 and P019, the rates of discontinuation of therapy due to adverse reactions were 2.0% in subjects receiving ISENTRESS + OBT and 1.4% in subjects receiving placebo + OBT.

Serious Events

Drug Related

The following serious drug-related reactions were reported in the clinical studies, P005, P018 and P019: hypersensitivity (hypersensitivity was seen in 2 subjects with ISENTRESS; therapy was interrupted and upon rechallenge the subjects were able to resume drug), anemia, neutropenia, myocardial infarction, gastritis, hepatitis, herpes simplex, toxic nephropathy, renal failure, chronic renal failure and renal tubular necrosis.

Regardless of Drug Relationship

Cancers were reported in treatment-experienced subjects who initiated ISENTRESS with OBT; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ cell counts below 50 cells/mm³ and most had prior AIDS diagnoses). The cancers included Kaposi's sarcoma, lymphoma, squamous cell carcinoma, hepatocellular carcinoma and anal cancer. Most subjects had other risk factors for cancer including tobacco use, papillomavirus and active hepatitis B virus infection. It is unknown if these cancer diagnoses were related to ISENTRESS use.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 3). Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

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 = 113/699 or 16.2%) 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 somewhat 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 from baseline of AST, ALT or total bilirubin occurred in 26%, 27% and 12%, respectively, of raltegravir-treated coinfected subjects as compared to 9%, 8% and 7% of all other raltegravir-treated subjects.

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily in P005, P018 and P019 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening from baseline are presented in Table 3.

Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects

Effect of Raltegravir on the Pharmacokinetics of Other Agents

Raltegravir does not inhibit (IC₅₀ > 100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC₅₀ > 50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, methadone, opioid analgesics, statins, azole antifungals, proton pump inhibitors, oral contraceptives, and anti-erectile dysfunction agents).

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: lamivudine, tenofovir.

Effect of Other Agents on the Pharmacokinetics of Raltegravir

Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, caution should be used when coadministering ISENTRESS with rifampin or other strong inducers of UGT1A1 [see Warnings and PRECAUTIONS]. The impact of other inducers of drug metabolizing enzymes, such as phenytoin and phenobarbital, on UGT1A1 is unknown. Other less strong inducers (e.g., efavirenz, nevirapine, rifabutin, St. John's wort) may be used with the recommended dose of ISENTRESS.

Similar to rifampin, tipranavir/ritonavir reduces plasma concentrations of ISENTRESS. However, approximately 100 subjects received raltegravir in combination with tipranavir/ritonavir in Protocols 018 and 019. Comparable efficacy was observed in this subgroup relative to subjects not receiving tipranavir/ritonavir. Based on these data, tipranavir/ritonavir may be coadministered with ISENTRESS without dose adjustment of ISENTRESS.

Atazanavir, a strong inhibitor of UGT1A1, and atazanavir/ritonavir increase plasma concentrations of raltegravir. However, concomitant use of ISENTRESS and atazanavir/ritonavir did not result in a unique safety signal in Protocol 005 and Protocols 018 and 019. Based on these data, atazanavir/ritonavir may be coadministered with ISENTRESS without dose adjustment of ISENTRESS.

Coadministration of ISENTRESS with other drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.

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