Raltegravir

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. 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. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving raltegravir and 3% in the efavirenz group. Through Week 240, serum lipid-reducing agents were used in 9% of subjects in the group receiving raltegravir and 15% in the efavirenz group. Treatment-Experienced Adults The safety assessment of raltegravir in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 in antiretroviral treatment-experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of raltegravir 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 96 weeks for subjects receiving raltegravir and 38 weeks for subjects receiving placebo. The total exposure to raltegravir was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving raltegravir and 5% in subjects receiving placebo. Clinical ADRs were considered by investigators to be causally related to raltegravir + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with raltegravir and occurring at a higher rate compared to placebo are presented in Table 9. Table 9: Adverse Drug Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Experienced Adult Subjects Receiving Raltegravir and at a Higher Rate Compared to Placebo (96 Week Analysis) System Organ Class, Adverse Reactions Randomized Studies BENCHMRK 1 and BENCHMRK 2 Raltegravir 400 mg Twice Daily + OBT (n = 462) Placebo + OBT (n = 237) Nervous System Disorders Headache 2% <1% *Includes adverse reactions 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 treated with raltegravir 400 mg twice daily or placebo in Studies BENCHMRK 1 and BENCHMRK 2 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 10. Table 10: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis) Laboratory Parameter Preferred Term (Unit) Limit Randomized Studies BENCHMRK 1 and BENCHMRK 2 Raltegravir 400 mg Twice Daily + OBT (N = 462) Placebo + OBT (N = 237) 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 4% 3% 1% 5% 3% <1% Hemoglobin (gm/dL) Grade 2 Grade 3 Grade 4 7.5 to 8.4 6.5 to 7.4 <6.5 1% 1% <1% 3% 1% 0% Platelet count (10 3 /µL) Grade 2 Grade 3 Grade 4 50 to 99.999 25 to 49.999 <25 3% 1% 1% 5% <1% <1% Blood chemistry Fasting (non-random) serum glucose test (mg/dL) Grade 2 Grade 3 Grade 4 126 to 250 251 to 500 >500 10% 3% 0% 7% 1% 0% Total serum bilirubin Grade 2 Grade 3 Grade 4 1.6 to 2.5 × ULN 2.6 to 5.0 × ULN >5.0 × ULN 6% 3% 1% 3% 3% 0% Serum aspartate aminotransferase Grade 2 Grade 3 Grade 4 2.6 to 5.0 × ULN 5.1 to 10.0 × ULN >10.0 × ULN 9% 4% 1% 7% 3% 1% Serum alanine aminotransferase Grade 2 Grade 3 Grade 4 2.6 to 5.0 × ULN 5.1 to 10.0 × ULN >10.0 × ULN 9% 4% 1% 9% 2% 2% Serum alkaline phosphatase Grade 2 Grade 3 Grade 4 2.6 to 5.0 × ULN 5.1 to 10.0 × ULN >10.0 × ULN 2% <1% 1% <1% 1% <1% Serum pancreatic amylase test Grade 2 Grade 3 Grade 4 1.6 to 2.0 × ULN 2.1 to 5.0 × ULN >5.0 × ULN 2% 4% <1% 1% 3% <1% Serum lipase test Grade 2 Grade 3 Grade 4 1.6 to 3.0 × ULN 3.1 to 5.0 × ULN >5.0 × ULN 5% 2% 0% 4% 1% 0% Serum creatine kinase Grade 2 Grade 3 Grade 4 6.0 to 9.9 × ULN 10.0 to 19.9 × ULN ≥20.0 × ULN 2% 4% 3% 2% 3% 1% ULN = Upper limit of normal range Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving raltegravir or ISENTRESS HD in a combination regimen. These events have been included because of their seriousness, increased frequency compared with efavirenz or placebo, or investigator’s assessment of potential causal relationship. Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting General Disorders and Administration Site Conditions: asthenia Hepatobiliary Disorders: hepatitis Immune System Disorders: hypersensitivity Infections and Infestations: genital herpes, herpes zoster Psychiatric Disorders: depression (particularly in subjects with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors Renal and Urinary Disorders: nephrolithiasis, renal failure Selected Adverse Events – Adults In studies of raltegravir 400 mg twice daily, cancers were reported in treatment-experienced subjects who initiated raltegravir or placebo, both with OBT, and in treatment-naïve subjects who initiated raltegravir or efavirenz, both with emtricitabine (+) tenofovir disoproxil fumarate; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving raltegravir and the group receiving the comparator. Grade 2 to 4 creatine kinase laboratory abnormalities were observed in subjects treated with raltegravir and ISENTRESS HD (see Tables 6 and 8). Myopathy and rhabdomyolysis have been reported with raltegravir. 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. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing raltegravir + darunavir/ritonavir compared to subjects receiving raltegravir without darunavir/ritonavir or darunavir/ritonavir without raltegravir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash. Patients with Co-existing Conditions – Adults Patients Co-infected with Hepatitis B and/or Hepatitis C Virus In Phase III studies of raltegravir, patients with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In the treatment-experienced studies, BENCHMRK 1 and BENCHMRK 2, 16% of all patients (114/699) were co-infected; in the treatment-naïve studies, STARTMRK and ONCEMRK, 6% (34/563) and 3% (23/797), respectively, were co-infected. In general the safety profile of raltegravir in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. At 96 weeks, in treatment-experienced subjects receiving raltegravir 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with raltegravir as compared to 11%, 10% and 9% of all other subjects treated with raltegravir. At 240 weeks, in treatment-naïve subjects receiving raltegravir 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with raltegravir as compared to 13%, 13% and 5% of all other subjects treated with raltegravir. At 96 weeks, in treatment-naïve subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 27%, 40% and 13%, respectively, of co-infected subjects treated with ISENTRESS HD 1200 mg once daily as compared to 7%, 5% and 3% of all other subjects treated with ISENTRESS HD 1200 mg once daily. Pediatrics 2 to 18 Years of Age Raltegravir has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations (8.4) and Clinical Studies (14.4) ] . Of the 126 patients, 96 received the recommended dose of raltegravir. In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 24 were comparable to those observed in adults. One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash. One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious. 4 Weeks to Less than 2 Years of Age Raltegravir has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see Use in Specific Populations (8.4) and Clinical Studies (14.4) ] . In these 26 infants and toddlers, the frequency, type and severity of drug-related adverse reactions through Week 48 were comparable to those observed in adults. One patient experienced a Grade 3 serious drug-related allergic rash that resulted in treatment discontinuation. HIV-1 Exposed Neonates Forty-two neonates were treated with raltegravir for up to 6 weeks from birth, and followed for a total of 24 weeks in IMPAACT P1110 [see Use in Specific Populations (8.4) ] . There were no drug-related clinical adverse reactions and three drug-related laboratory adverse reactions (one case of transient Grade 4 neutropenia in a subject receiving zidovudine-containing regimen for prevention of mother to child transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considered non-serious and not requiring specific therapy). The safety profile in neonates was generally similar to that observed in older patients treated with raltegravir. No clinically meaningful differences in the adverse event profile of neonates were observed when compared to adults.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of raltegravir. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: thrombocytopenia Gastrointestinal Disorders: diarrhea Hepatobiliary Disorders: hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Nervous System Disorders: cerebellar ataxia Psychiatric Disorders: anxiety, paranoia

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.

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

12.2 Pharmacodynamics In a monotherapy study raltegravir (400 mg twice daily) demonstrated rapid antiviral activity with mean viral load reduction of 1.66 log 10 copies/mL by Day 10. Cardiac Electrophysiology At a dose 1.33 times the maximum approved recommended dose (and peak concentrations 1.25-fold higher than the maximum approved dose), raltegravir does not prolong the QT interval or PR interval to any clinically relevant extent.

12.3 Pharmacokinetics Adults Absorption Raltegravir, given 400 mg twice daily, is absorbed with a T max of approximately 3 hours postdose in the fasted state in healthy subjects. Raltegravir 1200 mg once daily is rapidly absorbed with median T max of ~1.5 to 2 hours in the fasted state. Raltegravir increases dose proportionally (AUC and C max ) or slightly less than dose proportionally (C 12hr ) over the dose range 100 mg to 1600 mg. The absolute bioavailability of raltegravir has not been established. The chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet. Relative to the raltegravir 400 mg formulation, the raltegravir 600 mg formulation has higher relative bioavailability. Steady-state is generally reached in 2 days, with little to no accumulation with multiple dose administration for the 400 mg twice daily and 1200 once daily formulation. Effect of Food on Oral Absorption The food effect of various formulations are presented in Table 12. Table 12: Effect of Food on the Pharmacokinetics of Raltegravir Formulations PK parameter ratio (fed/fasted) Formulation Meal Type AUC Ratio (90% CI) C max Ratio (90% CI) C min Ratio (90% CI) 400 mg twice daily Low Fat 0.54 (0.41 to 0.71) 0.48 (0.35 to 0.67) 0.86 (0.54 to 1.36) Moderate Fat 1.13 (0.85 to 1.49) 1.05 (0.75 to 1.46) 1.66 (1.04 to 2.64) High Fat 2.11 (1.60 to 2.80) 1.96 (1.41 to 2.73) 4.13 (2.60 to 6.57) 1200 mg once daily Low Fat 0.58 (0.46 to 0.74) 0.48 (0.37 to 0.62) 0.84 (0.63 to 1.10) High Fat 1.02 (0.86 to 1.21) 0.72 (0.58 to 0.90) 0.88 (0.66 to 1.18) Chewable tablet High Fat 0.94 (0.78 to 1.14) 0.38 (0.28 to 0.52) 2.88 (2.21 to 3.75) Oral suspension The effect of food on oral suspension was not studied. Low-fat meal: 300 Kcal, 2.5 g fat Moderate-fat meal: 600 Kcal, 21 g fat High-fat meal: 825 Kcal, 52 g fat Distribution Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM. In one study of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was measured in the cerebrospinal fluid. In the study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. This median proportion was approximately 3-fold lower than the free fraction of raltegravir in plasma. The clinical relevance of this finding is unknown. Metabolism and Excretion The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. The major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation. Table 13: Multiple-Dose Pharmacokinetic Parameters of Raltegravir Following the Administration of 400 mg Twice Daily and 1200 mg Once Daily in HIV-infected Subjects Parameter 400 mg BID Geometric Mean (%CV) N=6 1200 mg QD Geometric Mean (%CV) N=524 AUC (µM ∙ hr) AUC 0-12 = 14.3 (88.6) AUC 0-24 = 55.3 (41.5) C max (µM) 4.5 (128) 15.7 (45.8) C min (nM) C 12 = 142 (63.8) C 24 = 107 (97.5) Special Populations Pediatric Raltegravir Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet. The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet. In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet. These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension. As displayed in Table 14, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age [see Dosage and Administration (2.3) ] resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily. Overall, dosing in pediatric patients achieved exposures (C trough ) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed. Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM) [see Clinical Studies (14.4) ] . As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet [see Dosage and Administration (2.3) ] . In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups. Table 14: Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Twice-Daily Doses Body Weight Formulation Dose N * Geometric Mean (%CV † ) AUC 0-12hr (µM∙hr) Geometric Mean (%CV † ) C 12hr (nM) ≥25 kg Film-coated tablet 400 mg twice daily 18 14.1 (121%) 233 (157%) ≥25 kg Chewable tablet Weight-based dosing, see Table 3 9 22.1 (36%) 113 (80%) 11 to less than 25 kg Chewable tablet Weight-based dosing, see Table 4 13 18.6 (68%) 82 (123%) 3 to less than 20 kg Oral suspension Weight-based dosing, see Table 4 19 24.5 (43%) 113 (69%) * Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. † Geometric coefficient of variation. Elimination of raltegravir in vivo in human is primarily through the UGT1A1-mediated glucuronidation pathway. UGT1A1 catalytic activity is negligible at birth and matures after birth. The dose recommended for neonates less than 4 weeks of age takes into consideration the rapidly increasing UGT1A1 activity and drug clearance from birth to 4 weeks of age. Table 15 displays pharmacokinetic parameters for neonates receiving the granules for oral suspension at the recommended dose [see Dosage and Administration (2.3) ] . Age/Race/Gender There is no clinically meaningful effect of age (18 years and older), race, or gender on the pharmacokinetics of raltegravir. Hepatic Impairment Raltegravir is eliminated primarily by glucuronidation in the liver. The pharmacokinetics of a single 400 mg dose of raltegravir were not altered in patients with moderate (Child-Pugh Score 7 to 9) hepatic impairment. Renal Impairment Renal clearance of unchanged drug is a minor pathway of elimination. The pharmacokinetics of a single 400 mg dose of raltegravir were not altered in patients with severe (24-hour creatinine clearance of <30 mL/min/1.73 m 2 ) renal impairment. The extent to which raltegravir may be dialyzable is unknown. Drug Interactions In vitro , raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. In vivo , raltegravir does not inhibit CYP3A4. Moreover, in vitro , raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of UGT1A1 or UGT2B7, and raltegravir does not inhibit P-glycoprotein-mediated transport. Raltegravir drug interaction study results are shown in Tables 16 and 17. For information regarding clinical recommendations [see Drug Interactions (7) ] . Table 16: Effect of Other Agents on the Pharmacokinetics of Raltegravir in Adults Coadministered Drug Coadministered Drug Dose/Schedule Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Raltegravir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 n C max AUC C min aluminum and magnesium hydroxide antacid* 20 mL single dose given with raltegravir 400 mg twice daily 25 0.56 (0.42, 0.73) 0.51 (0.40, 0.65) 0.37 (0.29, 0.48) 20 mL single dose given 2 hours before raltegravir 23 0.49 (0.33, 0.71) 0.49 (0.35, 0.67) 0.44 (0.34, 0.55) 20 mL single dose given 2 hours after raltegravir 23 0.78 (0.53, 1.13) 0.70 (0.50, 0.96) 0.43 (0.34, 0.55) 20 mL single dose given 4 hours before raltegravir 17 0.78 (0.55, 1.10) 0.81 (0.63, 1.05) 0.40 (0.31, 0.52) 20 mL single dose given 4 hours after raltegravir 18 0.70 (0.48, 1.04) 0.68 (0.50, 0.92) 0.38 (0.30, 0.49) 20 mL single dose given 6 hours before raltegravir 16 0.90 (0.58, 1.40) 0.87 (0.64, 1.18) 0.50 (0.39, 0.65) 20 mL single dose given 6 hours after raltegravir 16 0.90 (0.58, 1.41) 0.89 (0.64, 1.22) 0.51 (0.40, 0.64) aluminum and magnesium hydroxide antacid* 20 mL single dose given 12 hours after raltegravir 1200 mg single dose 19 0.86 (0.65, 1.15) 0.86 (0.73, 1.03) 0.42 (0.34, 0.52) atazanavir 400 mg daily 100 mg single dose 10 1.53 (1.11, 2.12) 1.72 (1.47, 2.02) 1.95 (1.30, 2.92) atazanavir 400 mg daily 1200 mg single dose 14 1.16 (1.01, 1.33) 1.67 (1.34, 2.10) 1.26 (1.08, 1.46) atazanavir/ritonavir 300 mg/100 mg daily 400 mg twice daily 10 1.24 (0.87, 1.77) 1.41 (1.12, 1.78) 1.77 (1.39, 2.25) boceprevir 800 mg three times daily 400 mg single dose 22 1.11 (0.91, 1.36) 1.04 (0.88, 1.22) 0.75 (0.45, 1.23) calcium carbonate antacid* 3000 mg single dose given with raltegravir 400 mg twice daily 24 0.48 (0.36, 0.63) 0.45 (0.35, 0.57) 0.68 (0.53, 0.87) calcium carbonate antacid* 3000 mg single dose given with raltegravir 1200 mg single dose 19 0.26 (0.21, 0.32) 0.28 (0.24, 0.32) 0.52 (0.45, 0.61) 3000 mg single dose given 12 hours after raltegravir 0.98 (0.81, 1.17) 0.90 (0.80, 1.03) 0.43 (0.36, 0.51) efavirenz 600 mg daily 400 mg single dose 9 0.64 (0.41, 0.98) 0.64 (0.52, 0.80) 0.79 (0.49, 1.28) efavirenz 600 mg daily 1200 mg single dose 21 0.91 (0.70, 1.17) 0.86 (0.73, 1.01) 0.94 (0.76, 1.17) etravirine 200 mg twice daily 400 mg twice daily 19 0.89 (0.68, 1.15) 0.90 (0.68, 1.18) 0.66 (0.34, 1.26) omeprazole* 20 mg daily 400 mg twice daily 18 1.51 (0.98, 2.35) 1.37 (0.99, 1.89) 1.24 (0.95, 1.62) rifampin 600 mg daily 400 mg single dose 9 0.62 (0.37, 1.04) 0.60 (0.39, 0.91) 0.39 (0.30, 0.51) rifampin 600 mg daily 400 mg twice daily when administered alone; 800 mg twice daily when administered with rifampin 14 1.62 (1.12, 2.33) 1.27 (0.94, 1.71) 0.47 (0.36, 0.61) ritonavir 100 mg twice daily 400 mg single dose 10 0.76 (0.55, 1.04) 0.84 (0.70, 1.01) 0.99 (0.70, 1.40) tenofovir disoproxil fumarate 300 mg daily 400 mg twice daily 9 1.64 (1.16, 2.32) 1.49 (1.15, 1.94) 1.03 (0.73, 1.45) tipranavir/ritonavir 500 mg/200 mg twice daily 400 mg twice daily 15 (14 for C min ) 0.82 (0.46, 1.46) 0.76 (0.49, 1.19) 0.45 (0.31, 0.66) *Study conducted in HIV-infected subjects. Table 17: Effect of Raltegravir on the Pharmacokinetics of Other Agents in Adults Substrate Drug Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Substrate Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 n C max AUC C min Tenofovir disoproxil fumarate 300 mg 400 mg 9 0.77 (0.69, 0.85) 0.90 (0.82, 0.99) C 24hr 0.87 (0.74, 1.02) Etravirine 200 mg 400 mg 19 1.04 (0.97, 1.12) 1.10 (1.03, 1.16) 1.17 (1.10, 1.26) In drug interaction studies, there was no effect of raltegravir on the PK of ethinyl estradiol, methadone, midazolam or boceprevir.

12.4 Microbiology Mechanism of Action Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration, of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases α, β, and γ. Antiviral Activity in Cell Culture Raltegravir at concentrations of 31 ± 20 nM resulted in 95% inhibition (EC 95 ) of viral spread (relative to an untreated virus-infected culture) in human T-lymphoid cell cultures infected with the cell-line adapted HIV-1 variant H9IIIB. In addition, 5 clinical isolates of HIV-1 subtype B had EC 95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV-1 isolates representing 5 non-B subtypes (A, C, D, F, and G) and 5 circulating recombinant forms (AE, AG, BF, BG, and cpx) with EC 50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC95 value = 6 nM). No antagonism was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, or zidovudine); protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir); or the entry inhibitor enfuvirtide. Resistance The mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance (evolved either in cell culture or in subjects treated with raltegravir) generally included an amino acid substitution at either Y143 (changed to C, H, or R) or Q148 (changed to H, K, or R) or N155 (changed to H) plus one or more additional substitutions (i.e., L74M, E92Q, Q95K/R, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230R, and D232N). E92Q, T97A, and F121C are occasionally seen in the absence of substitutions at Y143, Q148, or N155 in raltegravir-treatment failure subjects. Treatment-Naïve Adult Subjects: By Week 240 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 4 (2 with Y143H/R and 2 with Q148H/R) of the 12 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. By Week 96 in the ONCEMRK trial, primary raltegravir resistance substitutions were observed in on treatment isolates obtained from 4 (3 with N155H and 1 with E92Q) of 14 virologic failure subjects with evaluable genotypic data in the 1,200 mg QD arm and 2 (1 with N155H and 1 with T97A) of 6 virologic failure subjects in the 400 mg BID arm. Additional integrase substitutions observed included L74M, Q95K, V151I, E170A, I203M and D232N. These resistant isolates exhibited 6.2- to 19-fold reductions in susceptibility to raltegravir. Overall, at Week 96, detection of raltegravir resistance was not different between the QD and BID arms in subjects who were failing treatment and had resistance data evaluable (28.6% versus 33.3%, respectively). Treatment-Experienced Adult Subjects: By Week 96 in the BENCHMRK trials, at least one of the primary raltegravir resistance-associated substitutions, Y143C/H/R, Q148H/K/R, and N155H, was observed in 76 of the 112 virologic failure subjects with evaluable genotypic data from paired baseline and raltegravir treatment-failure isolates. The emergence of the primary raltegravir resistance-associated substitutions was observed cumulatively in 70 subjects by Week 48 and 78 subjects by Week 96, 15.2% and 17% of the raltegravir recipients, respectively. Some (n=58) of those HIV-1 isolates harboring one or more of the primary raltegravir resistance-associated substitutions were evaluated for raltegravir susceptibility yielding a median decrease of 26.3-fold (mean 48.9 ± 44.8-fold decrease, ranging from 0.8- to 159-fold) compared to the wild-type reference. Cross Resistance Cross resistance has been observed among HIV-1 integrase strand transfer inhibitors (INSTIs). Amino acid substitutions in HIV-1 integrase conferring resistance to raltegravir generally also confer resistance to elvitegravir. Substitutions at amino acid Y143 confer greater reductions in susceptibility to raltegravir than to elvitegravir, and the E92Q substitution confers greater reductions in susceptibility to elvitegravir than to raltegravir. Viruses harboring a substitution at amino acid Q148, along with one or more other raltegravir resistance substitutions, may also have clinically significant resistance to dolutegravir.

12.5 Pharmacogenomics UGT1A1 Polymorphism There is no evidence that common UGT1A1 polymorphisms alter raltegravir pharmacokinetics to a clinically meaningful extent. In a comparison of 30 adult subjects with *28/*28 genotype (associated with reduced activity of UGT1A1) to 27 adult subjects with wild-type genotype, the geometric mean ratio (90% CI) of AUC was 1.41 (0.96, 2.09). In the neonatal study IMPAACT P1110, there was no association between apparent clearance (CL/F) of raltegravir and UGT1A1 genotype polymorphisms.

Adults Absorption Raltegravir, given 400 mg twice daily, is absorbed with a T max of approximately 3 hours postdose in the fasted state in healthy subjects. Raltegravir 1200 mg once daily is rapidly absorbed with median T max of ~1.5 to 2 hours in the fasted state. Raltegravir increases dose proportionally (AUC and C max ) or slightly less than dose proportionally (C 12hr ) over the dose range 100 mg to 1600 mg. The absolute bioavailability of raltegravir has not been established. The chewable tablet and oral suspension have higher oral bioavailability compared to the 400 mg film-coated tablet. Relative to the raltegravir 400 mg formulation, the raltegravir 600 mg formulation has higher relative bioavailability. Steady-state is generally reached in 2 days, with little to no accumulation with multiple dose administration for the 400 mg twice daily and 1200 once daily formulation. Effect of Food on Oral Absorption The food effect of various formulations are presented in Table 12. Table 12: Effect of Food on the Pharmacokinetics of Raltegravir Formulations PK parameter ratio (fed/fasted) Formulation Meal Type AUC Ratio (90% CI) C max Ratio (90% CI) C min Ratio (90% CI) 400 mg twice daily Low Fat 0.54 (0.41 to 0.71) 0.48 (0.35 to 0.67) 0.86 (0.54 to 1.36) Moderate Fat 1.13 (0.85 to 1.49) 1.05 (0.75 to 1.46) 1.66 (1.04 to 2.64) High Fat 2.11 (1.60 to 2.80) 1.96 (1.41 to 2.73) 4.13 (2.60 to 6.57) 1200 mg once daily Low Fat 0.58 (0.46 to 0.74) 0.48 (0.37 to 0.62) 0.84 (0.63 to 1.10) High Fat 1.02 (0.86 to 1.21) 0.72 (0.58 to 0.90) 0.88 (0.66 to 1.18) Chewable tablet High Fat 0.94 (0.78 to 1.14) 0.38 (0.28 to 0.52) 2.88 (2.21 to 3.75) Oral suspension The effect of food on oral suspension was not studied. Low-fat meal: 300 Kcal, 2.5 g fat Moderate-fat meal: 600 Kcal, 21 g fat High-fat meal: 825 Kcal, 52 g fat Distribution Raltegravir is approximately 83% bound to human plasma protein over the concentration range of 2 to 10 µM. In one study of HIV-1 infected subjects who received raltegravir 400 mg twice daily, raltegravir was measured in the cerebrospinal fluid. In the study (n=18), the median cerebrospinal fluid concentration was 5.8% (range 1 to 53.5%) of the corresponding plasma concentration. This median proportion was approximately 3-fold lower than the free fraction of raltegravir in plasma. The clinical relevance of this finding is unknown. Metabolism and Excretion The apparent terminal half-life of raltegravir is approximately 9 hours, with a shorter α-phase half-life (~1 hour) accounting for much of the AUC. Following administration of an oral dose of radiolabeled raltegravir, approximately 51 and 32% of the dose was excreted in feces and urine, respectively. In feces, only raltegravir was present, most of which is likely derived from hydrolysis of raltegravir-glucuronide secreted in bile as observed in preclinical species. Two components, namely raltegravir and raltegravir-glucuronide, were detected in urine and accounted for approximately 9 and 23% of the dose, respectively. The major circulating entity was raltegravir and represented approximately 70% of the total radioactivity; the remaining radioactivity in plasma was accounted for by raltegravir-glucuronide. The major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation. Table 13: Multiple-Dose Pharmacokinetic Parameters of Raltegravir Following the Administration of 400 mg Twice Daily and 1200 mg Once Daily in HIV-infected Subjects Parameter 400 mg BID Geometric Mean (%CV) N=6 1200 mg QD Geometric Mean (%CV) N=524 AUC (µM ∙ hr) AUC 0-12 = 14.3 (88.6) AUC 0-24 = 55.3 (41.5) C max (µM) 4.5 (128) 15.7 (45.8) C min (nM) C 12 = 142 (63.8) C 24 = 107 (97.5) Special Populations Pediatric Raltegravir Two pediatric formulations were evaluated in healthy adult volunteers, where the chewable tablet and oral suspension were compared to the 400 mg tablet. The chewable tablet and oral suspension demonstrated higher oral bioavailability, thus higher AUC, compared to the 400 mg tablet. In the same study, the oral suspension resulted in higher oral bioavailability compared to the chewable tablet. These observations resulted in proposed pediatric doses targeting 6 mg/kg/dose for the chewable tablets and oral suspension. As displayed in Table 14, the doses recommended for HIV-infected infants, children and adolescents 4 weeks to 18 years of age [see Dosage and Administration (2.3) ] resulted in a pharmacokinetic profile of raltegravir similar to that observed in adults receiving 400 mg twice daily. Overall, dosing in pediatric patients achieved exposures (C trough ) above 45 nM in the majority of subjects, but some differences in exposures between formulations were observed. Pediatric patients above 25 kg administered the chewable tablets had lower trough concentrations (113 nM) compared to pediatric patients above 25 kg administered the 400 mg tablet formulation (233 nM) [see Clinical Studies (14.4) ] . As a result, the 400 mg film-coated tablet is the recommended dose in patients weighing at least 25 kg; however, the chewable tablet offers an alternative regimen in patients weighing at least 25 kg who are unable to swallow the film-coated tablet [see Dosage and Administration (2.3) ] . In addition, pediatric patients weighing 11 to 25 kg who were administered the chewable tablets had the lowest trough concentrations (82 nM) compared to all other pediatric subgroups. Table 14: Raltegravir Steady State Pharmacokinetic Parameters in Pediatric Patients Following Administration of Recommended Twice-Daily Doses Body Weight Formulation Dose N * Geometric Mean (%CV † ) AUC 0-12hr (µM∙hr) Geometric Mean (%CV † ) C 12hr (nM) ≥25 kg Film-coated tablet 400 mg twice daily 18 14.1 (121%) 233 (157%) ≥25 kg Chewable tablet Weight-based dosing, see Table 3 9 22.1 (36%) 113 (80%) 11 to less than 25 kg Chewable tablet Weight-based dosing, see Table 4 13 18.6 (68%) 82 (123%) 3 to less than 20 kg Oral suspension Weight-based dosing, see Table 4 19 24.5 (43%) 113 (69%) * Number of patients with intensive pharmacokinetic (PK) results at the final recommended dose. † Geometric coefficient of variation. Elimination of raltegravir in vivo in human is primarily through the UGT1A1-mediated glucuronidation pathway. UGT1A1 catalytic activity is negligible at birth and matures after birth. The dose recommended for neonates less than 4 weeks of age takes into consideration the rapidly increasing UGT1A1 activity and drug clearance from birth to 4 weeks of age. Table 15 displays pharmacokinetic parameters for neonates receiving the granules for oral suspension at the recommended dose [see Dosage and Administration (2.3) ] . Age/Race/Gender There is no clinically meaningful effect of age (18 years and older), race, or gender on the pharmacokinetics of raltegravir. Hepatic Impairment Raltegravir is eliminated primarily by glucuronidation in the liver. The pharmacokinetics of a single 400 mg dose of raltegravir were not altered in patients with moderate (Child-Pugh Score 7 to 9) hepatic impairment. Renal Impairment Renal clearance of unchanged drug is a minor pathway of elimination. The pharmacokinetics of a single 400 mg dose of raltegravir were not altered in patients with severe (24-hour creatinine clearance of <30 mL/min/1.73 m 2 ) renal impairment. The extent to which raltegravir may be dialyzable is unknown. Drug Interactions In vitro , raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A. In vivo , raltegravir does not inhibit CYP3A4. Moreover, in vitro , raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Similarly, raltegravir is not an inhibitor (IC50>50 µM) of UGT1A1 or UGT2B7, and raltegravir does not inhibit P-glycoprotein-mediated transport. Raltegravir drug interaction study results are shown in Tables 16 and 17. For information regarding clinical recommendations [see Drug Interactions (7) ] . Table 16: Effect of Other Agents on the Pharmacokinetics of Raltegravir in Adults Coadministered Drug Coadministered Drug Dose/Schedule Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Raltegravir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 n C max AUC C min aluminum and magnesium hydroxide antacid* 20 mL single dose given with raltegravir 400 mg twice daily 25 0.56 (0.42, 0.73) 0.51 (0.40, 0.65) 0.37 (0.29, 0.48) 20 mL single dose given 2 hours before raltegravir 23 0.49 (0.33, 0.71) 0.49 (0.35, 0.67) 0.44 (0.34, 0.55) 20 mL single dose given 2 hours after raltegravir 23 0.78 (0.53, 1.13) 0.70 (0.50, 0.96) 0.43 (0.34, 0.55) 20 mL single dose given 4 hours before raltegravir 17 0.78 (0.55, 1.10) 0.81 (0.63, 1.05) 0.40 (0.31, 0.52) 20 mL single dose given 4 hours after raltegravir 18 0.70 (0.48, 1.04) 0.68 (0.50, 0.92) 0.38 (0.30, 0.49) 20 mL single dose given 6 hours before raltegravir 16 0.90 (0.58, 1.40) 0.87 (0.64, 1.18) 0.50 (0.39, 0.65) 20 mL single dose given 6 hours after raltegravir 16 0.90 (0.58, 1.41) 0.89 (0.64, 1.22) 0.51 (0.40, 0.64) aluminum and magnesium hydroxide antacid* 20 mL single dose given 12 hours after raltegravir 1200 mg single dose 19 0.86 (0.65, 1.15) 0.86 (0.73, 1.03) 0.42 (0.34, 0.52) atazanavir 400 mg daily 100 mg single dose 10 1.53 (1.11, 2.12) 1.72 (1.47, 2.02) 1.95 (1.30, 2.92) atazanavir 400 mg daily 1200 mg single dose 14 1.16 (1.01, 1.33) 1.67 (1.34, 2.10) 1.26 (1.08, 1.46) atazanavir/ritonavir 300 mg/100 mg daily 400 mg twice daily 10 1.24 (0.87, 1.77) 1.41 (1.12, 1.78) 1.77 (1.39, 2.25) boceprevir 800 mg three times daily 400 mg single dose 22 1.11 (0.91, 1.36) 1.04 (0.88, 1.22) 0.75 (0.45, 1.23) calcium carbonate antacid* 3000 mg single dose given with raltegravir 400 mg twice daily 24 0.48 (0.36, 0.63) 0.45 (0.35, 0.57) 0.68 (0.53, 0.87) calcium carbonate antacid* 3000 mg single dose given with raltegravir 1200 mg single dose 19 0.26 (0.21, 0.32) 0.28 (0.24, 0.32) 0.52 (0.45, 0.61) 3000 mg single dose given 12 hours after raltegravir 0.98 (0.81, 1.17) 0.90 (0.80, 1.03) 0.43 (0.36, 0.51) efavirenz 600 mg daily 400 mg single dose 9 0.64 (0.41, 0.98) 0.64 (0.52, 0.80) 0.79 (0.49, 1.28) efavirenz 600 mg daily 1200 mg single dose 21 0.91 (0.70, 1.17) 0.86 (0.73, 1.01) 0.94 (0.76, 1.17) etravirine 200 mg twice daily 400 mg twice daily 19 0.89 (0.68, 1.15) 0.90 (0.68, 1.18) 0.66 (0.34, 1.26) omeprazole* 20 mg daily 400 mg twice daily 18 1.51 (0.98, 2.35) 1.37 (0.99, 1.89) 1.24 (0.95, 1.62) rifampin 600 mg daily 400 mg single dose 9 0.62 (0.37, 1.04) 0.60 (0.39, 0.91) 0.39 (0.30, 0.51) rifampin 600 mg daily 400 mg twice daily when administered alone; 800 mg twice daily when administered with rifampin 14 1.62 (1.12, 2.33) 1.27 (0.94, 1.71) 0.47 (0.36, 0.61) ritonavir 100 mg twice daily 400 mg single dose 10 0.76 (0.55, 1.04) 0.84 (0.70, 1.01) 0.99 (0.70, 1.40) tenofovir disoproxil fumarate 300 mg daily 400 mg twice daily 9 1.64 (1.16, 2.32) 1.49 (1.15, 1.94) 1.03 (0.73, 1.45) tipranavir/ritonavir 500 mg/200 mg twice daily 400 mg twice daily 15 (14 for C min ) 0.82 (0.46, 1.46) 0.76 (0.49, 1.19) 0.45 (0.31, 0.66) *Study conducted in HIV-infected subjects. Table 17: Effect of Raltegravir on the Pharmacokinetics of Other Agents in Adults Substrate Drug Raltegravir Dose/Schedule Ratio (90% Confidence Interval) of Substrate Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1.00 n C max AUC C min Tenofovir disoproxil fumarate 300 mg 400 mg 9 0.77 (0.69, 0.85) 0.90 (0.82, 0.99) C 24hr 0.87 (0.74, 1.02) Etravirine 200 mg 400 mg 19 1.04 (0.97, 1.12) 1.10 (1.03, 1.16) 1.17 (1.10, 1.26) In drug interaction studies, there was no effect of raltegravir on the PK of ethinyl estradiol, methadone, midazolam or boceprevir.