ISENTRESS® (raltegravir) film-coated tablets, for oral use; chewable tablets, for oral use; oral suspension and ISENTRESS® HD (raltegravir) film-coated tablets, for oral use

 

Efficacy for ISENTRESS

In a clinical study of treatment-experienced adults with HIV-1, ISENTRESS (raltegravir) + OBT showed:

Sustained virologic suppression at 96 weeks

  • At 48 weeks, 62% of patients taking ISENTRESS + OBT attained HIV-1 RNA <50 copies/mL vs 33% of patients taking placebo + OBT1
  • At 96 weeks, 55% of patients taking ISENTRESS + OBT attained HIV-1 RNA <50 copies/mL vs 27% of patients taking placebo + OBT

BENCHMRK 1 AND 2 STUDY DESIGN1,2

  • To evaluate the safety and efficacy of ISENTRESS 400-mg film-coated tablets compared with placebo, both in combination with OBT
  • Two randomized, double-blind, placebo-controlled studies in HIV-infected patients ≥16 years of age with triple-class–resistant virusa who received either ISENTRESS 400 mg BID + OBT (n=462) or placebo + OBT (n=237)
  • Key inclusion criteria: HIV-1 RNA >1000 copies/mL
  • Primary end point: HIV-1 RNA levels <400 copies/mL at Week 16

(a)

HIV-1 infected patients 16 years of age or older had failed therapy as documented by HIV-1 RNA >1000 copies/mL while on stable therapy and had documented resistance to at least 1 drug in each of 3 classes of licensed oral ARTs (NRTI, NNRTI, and PI), and had to meet a number of laboratory criteria.

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Definitions

  • ART = antiretroviral therapy
  • BID = twice daily
  • HIV-1 = human immunodeficiency virus type 1
  • NNRTI = non-nucleoside reverse transcriptase inhibitor
  • NRTI = nucleoside reverse transcriptase inhibitor
  • OBT = optimized background therapy
  • PI = protease inhibitor
  • RNA = ribonucleic acid

References

1. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359(4):339-354. doi:10.1056/ NEJMoa0708975.

2. Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials. Clin Infect Dis. 2010;50(4):605-612. doi:10.1086/650002.

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Indication

ISENTRESS and ISENTRESS HD are indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients.

Selected Safety Information

Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS or ISENTRESS HD and other suspect agents if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

ISENTRESS chewable tablets contain phenylalanine, a component of aspartame, which may be harmful to patients with phenylketonuria.

Coadministration of ISENTRESS or ISENTRESS HD with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may result in reduced plasma concentrations of raltegravir. Coadministration of ISENTRESS or ISENTRESS HD with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir.

Coadministration of ISENTRESS or ISENTRESS HD and other drugs may alter the plasma concentration of raltegravir. The potential for drug-drug interactions must be considered prior to and during therapy. Coadministration or staggered administration of aluminum and/or magnesium-containing antacids and ISENTRESS or ISENTRESS HD is not recommended. Coadministration of ISENTRESS HD with calcium carbonate antacids, tipranavir/ritonavir, or etravirine is also not recommended.

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS and ISENTRESS HD. Therefore, the dose of ISENTRESS for adults should be increased to 800 mg twice daily during coadministration with rifampin. There are no data to guide coadministration of ISENTRESS with rifampin in patients below 18 years of age. Coadministration with rifampin is not recommended with ISENTRESS HD.

The impact of other strong inducers of drug metabolizing enzymes on raltegravir is unknown (e.g., Carbamazepine, Phenobarbital, and Phenytoin). Coadministration of ISENTRESS or ISENTRESS HD with other strong inducers is not recommended.

The most commonly reported (≥2%) drug-related clinical adverse reactions of moderate to severe intensity in treatment-naïve adult patients receiving ISENTRESS compared with efavirenz were headache (4% vs 5%), insomnia (4% vs 4%), nausea (3% vs 4%), dizziness (2% vs 6%), and fatigue (2% vs 3%), respectively. The most commonly reported (≥2%) clinical adverse reactions of all intensities (Mild, Moderate, and Severe) in treatment-naïve adult patients receiving ISENTRESS HD or ISENTRESS were abdominal pain, diarrhea, vomiting, and decreased appetite. Intensities were defined as follows: Mild (awareness of sign or symptom, but easily tolerated); Moderate (discomfort enough to cause interference with usual activity); or Severe (incapacitating with inability to work or do usual activity).

Grade 2–4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS and ISENTRESS HD. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ISENTRESS or ISENTRESS HD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Women infected with HIV-1 should be instructed not to breastfeed if they are receiving ISENTRESS or ISENTRESS HD due to the potential for HIV transmission.

No dosage adjustment of ISENTRESS is necessary for patients with mild to moderate hepatic impairment. No hepatic impairment study has been conducted with ISENTRESS HD and therefore administration in patients with hepatic impairment is not recommended. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Before prescribing ISENTRESS or ISENTRESS HD, please read the accompanying Prescribing Information. The Patient Information and Instructions for Use also are available.

US-MFA-0024007/19