Raltegravir

1 INDICATIONS AND USAGE 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 ).

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

2 DOSAGE AND ADMINISTRATION Raltegravir tablets can be administered with or without food ( 2.1 ). Do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the raltegravir tablets 400 mg Adults • Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of raltegravir tablets 400 mg twice daily: • 400 mg film-coated tablet orally, twice daily ( 2.2 ). • Treatment experienced patients: • 400 mg film-coated tablet orally, twice daily ( 2.2 ). • During coadministration with rifampin in adults, 800 mg (2 x 400 mg) twice daily ( 2.2 ). Pediatrics • If weighing at least 40 kg, and either • treatment-naïve patients or • patients who are virologically suppressed on an initial regimen of raltegravir tablets 400 mg twice daily: • 400 mg film-coated tablet orally, twice daily • If weighing at least 25 kg: One 400 mg film-coated tablet orally, twice daily. 2.1 General Dosing Recommendations o Because the formulations have different pharmacokinetic profiles, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the raltegravir 400 mg film-coated tablets. o Because the extent to which raltegravir tablets may be dialyzable is unknown, dosing before a dialysis session should be avoided [see Clinical Pharmacology (12.3) ] . o Raltegravir film-coated tablets must be swallowed whole. 2.2 Adults The recommended adult dosage of raltegravir film-coated tablets is displayed in Table 1. Raltegravir tablets should be taken by mouth and may be taken with or without food [see Clinical Pharmacology (12.3) ] . Table 1: Dosing Recommendations for Raltegravir Tablets in Adult Patients Population Recommended Dose Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of raltegravir tablets 400 mg twice daily 400 mg twice daily Treatment-experienced 400 mg twice daily Treatment-naïve or treatment-experienced when coadministered with rifampin [see Drug Interactions (7.1) ] 800 mg (2 x 400 mg) twice daily 2.3 Pediatrics The recommended pediatric dosage of raltegravir tablets is displayed in Table 2. Raltegravir film-coated tablets should be taken by mouth and may be taken with or without food [ see C linical Pharmacology (12.3) ] . Table 2: Dosing Recommendations for Raltegravir Tablets in Pediatric Patients Recommended Pediatric Dosage and Formulation Population/Weight Film-Coated Tablets 400 mg If at least 40 kg and either: treatment-naïve or virologically suppressed on an initial regimen of raltegravir tablets 400 mg twice daily 400 mg twice daily If at least 25 kg 400 mg twice daily* If at least 4 weeks of age and weighing 3 kg to less than 25 kg NA From birth to 4 weeks (28 days) weighing at least 2 kg NA *If able to swallow a tablet

6 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 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 Se

5 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 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.

4 CONTRAINDICATIONS None None ( 4 ).

10 OVERDOSAGE In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. The extent to which raltegravir may be dialyzable is unknown.