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adverse reactions
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 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