Adult Patients: ISENTRESS and ISENTRESS HD are human immunodeficiency virus integrase strand transfer inhibitors (HIV-1 INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients ( 1 ). Pediatric Patients: ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg ( 1 ).
ISENTRESS HD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg ( 1 ). Adult Patients: ISENTRESS ® and ISENTRESS ® HD are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients. Pediatric Patients: ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg.
ISENTRESS HD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg.
Contraindications
None None ( 4) .
Warnings and precautions
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 ( 5.1 ).
Monitor for Immune Reconstitution Syndrome ( 5.2 ). Inform patients with phenylketonuria that the 100 mg and 25 mg chewable tablets contain phenylalanine ( 5.3 ).
5.1Severe Skin and Hypersensitivity Reactions
Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS or ISENTRESS HD and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema).
Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS or ISENTRESS HD treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.
5.2Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.3Phenylketonurics
ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.
Interactions
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 ( 7 ). Coadministration of ISENTRESS or ISENTRESS HD with drugs that are strong inducers of UGT1A1, such as rifampin, may result in reduced plasma concentrations of raltegravir ( 2.1 , 7.1 ).
7.1Effect 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. Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir and coadministration of ISENTRESS with drugs that induce UGT1A1, such as rifampin, may reduce plasma levels of raltegravir (see Table 11 ).
Selected drug interactions are presented in Table 11 [see Clinical Pharmacology (12.3) ] . In some cases, recommendations differ for ISENTRESS versus ISENTRESS HD. Table 11: Selected Drug Interactions in Adults Concomitant Drug Class: Drug Name Effect on Concentration of Raltegravir Clinical Comment for ISENTRESS Clinical Comment for ISENTRESS HD Metal-Containing Antacids Aluminum and/or magnesium-containing antacids ↓ Coadministration or staggered administration is not recommended.
Calcium carbonate antacid ↓ No dose adjustment Co-administration is not recommended Other Agents Rifampin ↓ The recommended dosage is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration (2.1) ]. Coadministration is not recommended. Tipranavir/ritonavir No dose adjustment Coadministration is not recommended Etravirine ↓ No dose adjustment Coadministration is not recommended.
Strong inducers of drug metabolizing enzymes not mentioned above e.g., Carbamazepine Phenobarbital Phenytoin ↓↔ The impact of other strong inducers of drug metabolizing enzymes on raltegravir is unknown. Coadministration is not recommended.
7.2Drugs without Clinically Significant Interactions with
ISENTRESS or ISENTRESS HD ISENTRESS In drug interaction studies performed using ISENTRESS film-coated tablets 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: ethinyl estradiol/norgestimate, methadone, midazolam, lamivudine, tenofovir disoproxil fumarate, etravirine, darunavir/ritonavir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of 400 mg twice daily raltegravir.
No dose adjustment is required when ISENTRESS 400 mg twice daily is coadministered with these drugs. There is no predicted pharmacokinetic drug interaction between ISENTRESS and tenofovir alafenamide. ISENTRESS HD In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics of ISENTRESS HD 1200 mg (2 × 600 mg) once daily. No dose adjustment is recommended when ISENTRESS HD 1200 mg once daily is coadministered with atazanavir, atazanavir/ritonavir, hormonal contraceptives, methadone, lamivudine, tenofovir disoproxil fumarate, darunavir/ritonavir, boceprevir, efavirenz and omeprazole.
There is no predicted pharmacokinetic drug interaction between ISENTRESS HD and tenofovir alafenamide.
Pregnancy and breastfeeding
8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the rate of overall birth defects for raltegravir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ) .
The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation (see Data ) .
In animal reproduction studies in rats and rabbits, no evidence of adverse developmental outcomes was observed with oral administration of raltegravir during organogenesis at doses that produced exposures up to approximately 4 times the maximum recommended human dose (MRHD) of 1200 mg (see Data ) . Data Human Data Based on prospective reports from the APR of over 850 exposures to raltegravir during pregnancy resulting in live births (including over 450 exposures in the first trimester), there was no difference between the overall risk of birth defects for raltegravir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.
The prevalence of defects in live births was 3.1% (95% CI: 1.7% to 5.1%) following first trimester exposure to raltegravir-containing regimens and 3.7% (95% CI: 2.1% to 6.0%) following second and third trimester exposure to raltegravir-containing regimens. There are limited data on the use of ISENTRESS 1200 mg (2 x 600 mg) once daily in pregnant women. Animal Data In a combined embryo/fetal and pre/postnatal development study, raltegravir was administered orally to rats at doses of 100, 300, 600 mg/kg/day on gestation day 6 to 20 or from gestation day 6 to lactation day 20.
No effects on pre/postnatal development were observed up to the highest dose tested. Embryo-fetal findings were limited to an increase in the incidence of supernumerary ribs in the 600 mg/kg/day group. Systemic exposure (AUC) at 600 mg/kg/day was approximately 3 times higher than exposure at the MRHD of 1200 mg. In pregnant rabbits, raltegravir was administered orally at doses of 100, 500, or 1000 mg/kg/day during the gestation days 7 to 20.
No embryo/fetal effects were noted up to the highest dose of 1000 mg/kg/day. Systemic exposure (AUC) at 1000 mg/kg/day was approximately 4 times higher than exposures at the MRHD of 1200 mg. In both species, raltegravir has been shown to cross the placenta, with fetal plasma concentrations observed in rats approximately 1.5 to 2.5 times greater than in maternal plasma and fetal plasma concentrations in rabbits approximately 2% that of maternal concentrations on gestation day 20.
Adverse reactions
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. The most common adverse reactions of moderate to severe intensity (≥2%) are insomnia, headache, dizziness, nausea and fatigue ( 6.1 ). Creatine kinase elevations were observed in subjects who received ISENTRESS or 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 ( 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The safety of ISENTRESS was evaluated in HIV-infected treatment-naïve subjects in 2 Phase III studies: STARTMRK evaluated ISENTRESS 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate (TDF), and ONCEMRK evaluated ISENTRESS HD 1200 mg (2 × 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate.
Safety data from these two studies are presented side-by-side in Tables 6 and 7 to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up and study design. STARTMRK (ISENTRESS 400 mg twice daily) In STARTMRK, subjects received ISENTRESS 400 mg twice daily (N=281) or efavirenz (EFV) 600 mg at bedtime (N=282) both in combination with emtricitabine (+) tenofovir disoproxil fumarate, (N=282).
During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate. In STARTMRK, the rate of discontinuation of therapy due to adverse events through Week 240 was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate.
ONCEMRK (ISENTRESS HD 1200 mg [2 × 600 mg] once daily) In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (n=531) or ISENTRESS 400 mg twice daily (n=266) both in combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up for subjects with ISENTRESS HD 1200 mg once daily was 913 patient-years and for ISENTRESS 400 mg twice daily was 450 patient-years.
In ONCEMRK, the rate of discontinuation of therapy due to adverse events through Week 96 was 1% in subjects receiving ISENTRESS HD 1200 mg (2 × 600 mg) once daily and 2% in subjects receiving ISENTRESS 400 mg twice daily. Clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK through Week 96 are presented in Table 6.
In STARTMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS 400 mg twice daily through Week 240 also include diarrhea, flatulence, asthenia, decreased appetite, abnormal dreams, depression and nightmare. In ONCEMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS HD or ISENTRESS 400 mg twice daily through Week 96 also include abdominal pain, diarrhea, vomiting, and decreased appetite.
Table 6: Adverse Reactions Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely related to the drug. of Moderate to Severe Intensity Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving ISENTRESS and ISENTRESS HD System Organ Class, Preferred Term STARTMRK Week 240 ONCEMRK Week 96 ISENTRESS 400 mg Twice Daily (N= 281) Efavirenz 600 mg At Bedtime (N= 282) ISENTRESS HD 1200 mg Once Daily (N=531) ISENTRESS 400 mg Twice Daily (N=266) Note: ISENTRESS BID, ISENTRESS HD and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate N= total number of subjects per treatment group Headache 4% 5% 1% <1% Insomnia 4% 4% <1% <1% Nausea 3% 4% 1% 0% Dizziness 2% 6% <1% 0% Fatigue 2% 3% 0% 0% Laboratory Abnormalities The percentages of adult subjects with selected Grade 2 to 4 laboratory abnormalities (that represent a worsening Grade from baseline) who were treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK are presented in Table 7.
Table 8: Lipid Values, Mean Change from Baseline, STARTMRK Study Laboratory Parameter Preferred Term ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir Disoproxil Fumarate N = 207 Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir Disoproxil Fumarate N = 187 Change from Baseline at Week 240 Change from Baseline at Week 240 Baseline Mean Week 240 Mean Mean Change Baseline Mean Week 240 Mean Mean Change (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) Notes: N = total number of subjects per treatment group with at least one lipid test result available.
The analysis is based on all available data. If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis.
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Composition
Active ingredients
RALTEGRAVIR POTASSIUM EQ 100MG BASE/PACKET
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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