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

 

Clinical Data for ISENTRESS

Selected lipid values

View study design

In the STARTMRK trial, treatment-naïve adults with HIV-1 on ISENTRESS + Truvada experienced less effect on lipids at 240 weeks

Study Results Showing Less Effect on Lipids at 240 Weeks During the STARTMRK Trial for Treatment-Naïve Adults With HIV-1

(a) Fasting (nonrandom) laboratory tests at Week 240.

Percent of patients taking serum lipid-reducing agents by regimen2

Baseline Week 240
ISENTRESS + Truvada 5% 9%
Efavirenz + Truvada 3% 15%

Study design

Objective1

  • To evaluate the safety and efficacy of ISENTRESS®(raltegravir) 400-mg Film-Coated Tablets twice daily + Truvada (n=281) vs efavirenz 600 mg at bedtime + Truvada (n=282)

End points1,3

  • The primary end point was noninferiority with respect to the percentage of patients with HIV-1 RNA<50 copies/mL at Week 48, with a secondary time point at 96 weeks
  • Secondary end points (at Week 48 and Week 96):
    • Noninferiority with respect to the percentage of patients with HIV-1 RNA <400 copies/mL
    • Change from baseline in CD4 cell count
  • Prespecified exploratory analyses were conducted at Weeks 156 and 240
  • For calculation of virologic response rates, the primary approach to handling missing data was to include all NC=F. The snapshot analysis included a window of ±6 weeks around the week 240 visit.

Study design1

  • Multicenter, double-blind, randomized (1:1), active-controlled noninferiority study in treatment-naïve adult patients with HIV-1
  • Randomization was stratified by screening HIV-1 RNA levels (≤50,000 or >50,000 copies/mL) and by hepatitis status
  • Key inclusion criteria:
    • Susceptible to efavirenz, emtricitabine, tenofovir at entry
    • No prior ART
    • HIV-1 RNA >5,000 copies/mL
    • Aged ≥18 years
  • N=563
  • Patients received either ISENTRESS 400 mg + Truvada or efavirenz 600 mg at bedtime + Truvada

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Definitions

ART = antiretroviral therapy 

HDL-C = high-density lipoprotein cholesterol 

HIV-1 = human immunodeficiency virus type 1 

LDL-C = low-density lipoprotein cholesterol 

RNA = ribonucleic acid 

T CHOL = total cholesterol 

TG = triglycerides

References

1. Rockstroh JK, DeJesus E, Lennox JL, et al; for STARTMRK Investigators. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1 infected patients; final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77-85. 

2. Rockstroh JK, DeJesus E, Lennox JL, et al; for STARTMRK Investigators. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naïve HIV-1–infected patients: Final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77–85. 

3. Lennox JL, DeJesus E, Lazzarin A, et al; for STARTMRK Investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naïve patients with HIV-1 infection: a multicentre, double-blind randomized controlled trial. Lancet. 2009;374(9692):796–806.

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.