Raltegravir
Therapeutic agent (verify pharmacological class)
What it is used for
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 ).
Warnings
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.
Possible side effects
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 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
Storage
16 HOW SUPPLIED/STORAGE AND HANDLING Raltegravir tablets USP, 400 mg are white to off-white oval shaped film coated tablets debossed with “H I” on one side and “4” on other side of the tablet. They are supplied as follows: Bottles of 60 tablets (NDC 31722-584-60) Storage and Handling Store at 20° to 25°C (68° to 77°F) with excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] .
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