Raltegravir

Adult Patients: Raltegravir tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients. Pediatric Patients: Raltegravir tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg. Adult Patients: Raltegravir tablets 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: Raltegravir tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg ( 1 ).

Raltegravir Tablets USP, 400 mg: White to off-white oval shaped film coated tablets debossed with “H I” on one side and “4” on other side of the tablet.

• Film-Coated Tablets: 400 mg ( 3 ).

None None ( 4 ).

• 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 raltegravir 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 ).

5.1 Severe 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 raltegravir 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 raltegravir treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

5.2 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including raltegravir. 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.

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 raltegravir. 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 Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Treatment-Naïve Adults The safety of raltegravir was evaluated in HIV-infected treatment-naïve subjects in 2 Phase III studies: STARTMRK evaluated raltegravir 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate (TDF), and ONCEMRK evaluated ISENTRESS HD 1200 mg (2 x 600 mg) once daily versus raltegravir 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 (Raltegravir 400 mg twice daily) In STARTMRK, subjects received raltegravir 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 raltegravir 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 raltegravir + emtricitabine (+) tenofovir disoproxil fumarate and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate. ONCEMRK (ISENTRESS HD 1200 mg [2 x 600 mg] once daily) In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (n=531) or raltegravir 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 raltegravir 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 x 600 mg) once daily and 2% in subjects receiving raltegravir 400 mg twice daily. Clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with raltegravir 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or raltegravir 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 raltegravir 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 raltegravir 400 mg twice daily through Week 96 also include abdominal pain, diarrhea, vomiting, and decreased appetite. Table 6: Adverse Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving Raltegravir System Organ Class, Preferred Term STARTMRK Week 240 ONCEMRK Week 96 Raltegravir 400 mg Twice Daily (N= 281) Efavirenz 600 mg At Bedtime (N= 282) ISENTRESS HD 1200 mg Once Daily (N=531) Raltegravir 400 mg Twice Daily (N=266) 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% Note: Raltegravir BID, ISENTRESS HD and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate *Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely related to the drug. †Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). N= total number of subjects per treatment group 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 raltegravir 400 mg twice daily or efavirenz in STARTMRK or ISENTRESS HD 1200 mg once daily or raltegravir 400 mg twice daily in ONCEMRK are presented in Table 7. Table 7: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naïve Subjects STARTMRK Week 240 ONCEMRK Week 96 Laboratory Parameter Preferred Term (Unit) Limit Raltegravir 400 mg Twice Daily (N = 281) Efavirenz 600 mg At Bedtime (N = 282) ISENTRESS HD 1200 mg Once Daily (N=531) Raltegravir 400 mg Twice Daily (N=266) Hematology Absolute neutrophil count (10 3 /μL) Grade 2 Grade 3 Grade 4 0.75 to 0.999 0.50 to 0.749 <0.50 3% 3% 1% 5% 1% 1% 2% 1% <1% 1% 1% 0% Hemoglobin (gm/dL) Grade 2 Grade 3 Grade 4 7.5 to 8.4 6.5 to 7.4 <6.5 1% 1% <1% 1% 1% 0% 0% 0% 0% 0% 0% 0% Platelet count (10 3 /μL) Grade 2 Grade 3 Grade 4 50 to 99.999 25 to 49.999 <25 1% <1% 0% 0% <1% 0% 1% 0% 0% <1% 0% <1% Blood chemistry Fasting (non-random) serum glucose test (mg/dL) † Grade 2 Grade 3 Grade 4 126 to 250 251 to 500 >500 7% 2% 0% 6% 1% 0% – – – – – – Total serum bilirubin Grade 2 Grade 3 Grade 4 1.6 to 2.5 x ULN 2.6 to 5.0 x ULN >5.0 x ULN 5% 1% <1% <1% 0% 0% 3% 1% <1% 2% <1% 0% Creatinine Grade 2 Grade 3 Grade 4 1.4 to 1.8 x ULN 1.9 to 3.4 x ULN ≥3.5 x ULN 1% 0% 0% 1% <1% 0% 0% 0% 0% <1% 0% 0% Serum aspartate aminotransferase Grade 2 Grade 3 Grade 4 2.6 to 5.0 x ULN 5.1 to 10.0 x ULN >10.0 x ULN 8% 5% 1% 10% 3% <1% 5% 2% 1% 3% <1% <1% Serum alanine aminotransferase Grade 2 Grade 3 Grade 4 2.6 to 5.0 x ULN 5.1 to 10.0 x ULN >10.0 x ULN 11% 2% 2% 12% 2% 1% 4% 1% 1% 2% <1% <1% Serum alkaline phosphatase Grade 2 Grade 3 Grade 4 2.6 to 5.0 x ULN 5.1 to 10.0 x ULN >10.0 x ULN 1% 0% <1% 3% 1% <1% 1% <1% 0% 0% 0% 0% Lipase* Grade 2 Grade 3 Grade 4 1.6 to 3.0 x ULN 3.1 to 5.0 x ULN >5.0 x ULN – – – – – – 7% 2% 2% 5% 1% 1% Creatine kinase* Grade 2 Grade 3 Grade 4 6.0 to 9.9 x ULN 10.0 to 19.9 x ULN ≥20.0 x ULN – – – – – – 4% 3% 3% 5% 3% 2% ULN = Upper limit of normal range Notes: Raltegravir BID, ISENTRESS HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate * Test not done in STARTMRK † Test not done in ONCEMRK Lipids, Change from Baseline Changes from baseline in fasting lipids are shown in Table 8. Table 8: Lipid Values, Mean Change from Baseline, STARTMRK Study Laboratory Parameter Preferred Term Raltegravir 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 (mg/dL) Week 240 Mean (mg/dL) Mean Change (mg/dL) Baseline Mean (mg/dL) Week 240 Mean (mg/dL) Mean Change (mg/dL) LDL-Cholesterol* 96 106 10 93 118 25 HDL-Cholesterol* 38 44 6 38 51 13 Total Cholesterol* 159 175 16 157 201 44 Triglyceride* 128 130 2 141 178 37 *Fasting (non-random) laboratory tests at Week 240. […]

• Coadministration of raltegravir 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 raltegravir with drugs that are strong inducers of UGT1A1, such as rifampin, may result in reduced plasma concentrations of raltegravir ( 2.1 , 7.1 ).

7.1 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. Coadministration of raltegravir with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir and coadministration of raltegravir 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 raltegravir. Table 11: Selected Drug Interactions in Adults Concomitant Drug Class: Drug Name Effect on Concentration of Raltegravir Clinical Comment for Raltegravir Metal-Containing Antacids Aluminum and/or magnesium-containing antacids ↓ Coadministration or staggered administration is not recommended. Calcium carbonate antacid ↓ No dose adjustment Other Agents Rifampin ↓ The recommended dosage is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of raltegravir with rifampin in patients below 18 years of age [see Dosage and Administration (2.1) ]. Tipranavir/ritonavir No dose adjustment Etravirine ↓ No dose adjustment 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.

7.2 Drugs without Clinically Significant Interactions with Raltegravir In drug interaction studies performed using raltegravir 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 raltegravir 400 mg twice daily is coadministered with these drugs. There is no predicted pharmacokinetic drug interaction between raltegravir and tenofovir alafenamide.

Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission ( 8.2 ).

8.1 Pregnancy 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 raltegravir 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.

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. There are no data on the presence of raltegravir in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, raltegravir was present in milk [see Data]. Because of the potential for: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV-positive infants), and 3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving raltegravir. Data Raltegravir was excreted into the milk of lactating rats following oral administration (600 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 3 times that of maternal plasma concentrations observed 2 hours postdose on lactation day 14.

8.4 Pediatric Use HIV-1 Infected Children The safety, tolerability, pharmacokinetic profile, and efficacy of twice daily raltegravir were evaluated in HIV-1 infected infants, children and adolescents 4 weeks to 18 years of age in an open-label, multicenter clinical trial, IMPAACT P1066 [see Dosage and Administration (2.3) , Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. The safety profile was comparable to that observed in adults [see Adverse Reactions (6.1) ] . HIV-1 Exposed Neonates The safety and pharmacokinetics of ISENTRESS for oral suspension were evaluated in 42 full-term HIV-1 exposed neonates at high risk of acquiring HIV-1 infection in a Phase 1, open-label, multicenter clinical study, IMPAACT P1110. Cohort 1 neonates received 2 single doses of ISENTRESS for oral suspension: the first within 48 hours of birth and the second at 7 to 10 days of age. Cohort 2 neonates received daily dosing of ISENTRESS for oral suspension for 6 weeks: 1.5 mg/kg once daily starting within 48 hours of birth through Day 7 (week 1); 3 mg/kg twice daily on Days 8 to 28 of age (weeks 2 to 4); and 6 mg/kg twice daily on Days 29 to 42 of age (weeks 5 and 6). Sixteen neonates were enrolled in Cohort 1 (10 were exposed and 6 were unexposed to raltegravir in utero) and 26 in Cohort 2 (all unexposed to raltegravir in utero); all infants received a standard of care antiretroviral drug regimen for prevention of mother to child transmission. All enrolled neonates were followed for safety for a duration of 24 weeks. The 42 infants were 52% male, 69% Black and 12% Caucasian. HIV-1 status was assessed by nucleic acid test at birth, week 6 and week 24; all patients were HIV-1 negative at completion of the study. The safety profile was comparable to that observed in adults [see Adverse Reactions (6.1) ] . Raltegravir is not recommended in pre-term neonates or in pediatric patients weighing less than 2 kg.

8.5 Geriatric Use Clinical studies of raltegravir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Use in Patients with Hepatic Impairment No dosage adjustment of raltegravir is necessary for patients with mild to moderate (Child-Pugh A and B) hepatic impairment. No hepatic impairment study has been conducted with ISENTRESS HD and therefore administration in subjects with hepatic impairment is not recommended. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied [see Clinical Pharmacology (12.3) ] .

8.7 Use in Patients with Renal Impairment No dosage adjustment of raltegravir is necessary in patients with any degree of renal impairment [see Clinical Pharmacology (12.3) ] . The extent to which raltegravir may be dialyzable is unknown; therefore, dosing before a dialysis session should be avoided.

Raltegravir is an HIV-1 antiviral drug [see Microbiology ( 12.4 )] .