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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)] Cardiovascular events [see Warnings and Precautions (5.2)] The most common adverse events in treatment-experienced subjects (>8% incidence) which occurred at a higher frequency compared with placebo are upper respiratory tract infections, cough, pyrexia, rash, and dizziness. (6) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Studies in Treatment-Experienced Subjects: The safety profile of SELZENTRY is primarily based on 840 HIV-infected subjects who received at least 1 dose of SELZENTRY during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen. Assessment of treatment-emergent adverse events is based on the pooled data from 2 studies in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of maraviroc therapy for subjects in these studies was 48 weeks, with the total exposure on SELZENTRY twice daily at 309 patient-years versus 111 patient-years on placebo + optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily. The most common adverse events reported with twice-daily therapy with SELZENTRY with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. Additional adverse events that occurred with once-daily dosing at a higher rate than both placebo and twice-daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities. In these 2 studies, the rate of discontinuation due to adverse events was 5% for subjects who received SELZENTRY twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of SELZENTRY. The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving SELZENTRY twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on SELZENTRY compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both SELZENTRY twice daily and placebo. Dizziness or postural dizziness occurred in 8% of subjects on either SELZENTRY or placebo, with 2 subjects (0.5%) on SELZENTRY permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness. Treatment-emergent adverse events, regardless of causality, from A4001027 and A4001028 are summarized in Table 3. Selected events occurring at ≥2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at the same or higher rate on placebo are not displayed. Table 3. Percentage of Subjects With Selected Treatment-Emergent Adverse Events (All Causality)(≥2% on SELZENTRY and at a higher rate compared with placebo) Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks) SELZENTRY Twice Daily a Placebo N = 426 (%) Exposure-adjusted rate (per 100 pt-yrs) PYE = 309 b N = 426 (%) Exposure-adjusted rate (per 100 pt-yrs) PYE = 111 b Eye Disorders Conjunctivitis 2 3 1 3 Ocular infections, inflammations, and associated manifestations 2 3 1 2 Gastrointestinal Disorders Constipation 6 9 3 6 General Disorders and Administration Site Conditions Pyrexia 13 20 9 17 Pain and discomfort 4 5 3 5 Infections and Infestations Upper respiratory tract infection 23 37 13 27 Herpes infection 8 11 4 8 Sinusitis 7 10 3 6 Bronchitis 7 9 5 9 Folliculitis 4 5 2 4 Pneumonia 2 3 5 10 Anogenital warts 2 3 1 3 Influenza 2 3 0.5 1 Otitis media 2 3 0.5 1 Metabolism and Nutrition Disorders Appetite disorders 8 11 7 13 Musculoskeletal and Connective Tissue Disorders Joint-related signs and symptoms 7 10 3 5 Muscle pains 3 4 0.5 1 Neoplasms Benign, Malignant, and Unspecified Skin neoplasms benign 3 4 1 3 Nervous System Disorders Dizziness/postural dizziness 9 13 8 17 Paresthesias and dysesthesias 5 7 3 6 Sensory abnormalities 4 6 1 3 Disturbances in consciousness 4 5 3 6 Peripheral neuropathies 4 5 3 6 Psychiatric Disorders Disturbances in initiating and maintaining sleep 8 11 5 10 Depressive disorders 4 6 3 5 Anxiety symptoms 4 5 3 7 Renal and Urinary Disorders Bladder and urethral symptoms 5 7 1 3 Urinary tract signs and symptoms 3 4 1 3 Respiratory, Thoracic, and Mediastinal Disorders Coughing and associated symptoms 14 21 5 10 Upper respiratory tract signs and symptoms 6 9 3 6 Nasal congestion and inflammations 4 6 3 5 Breathing abnormalities 4 5 2 5 Paranasal sinus disorders 3 4 0.5 1 Skin and Subcutaneous Tissue Disorders Rash 11 16 5 11 Apocrine and eccrine gland disorders 5 7 4 7.5 Pruritus 4 5 2 4 Lipodystrophies 3 5 0.5 1 Erythemas 2 3 1 2 Vascular Disorders Vascular hypertensive disorders 3 4 2 4 a 300-mg dose equivalent. b PYE = Patient-years of exposure. Laboratory Abnormalities: Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in >2% of subjects receiving SELZENTRY. Table 4. Maximum Shift in Laboratory Test Values (Without Regard to Baseline) Incidence ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks) Laboratory Parameter Preferred Term Limit SELZENTRY Twice Daily + OBT (N = 421) a % Placebo + OBT (N = 207) a % Aspartate aminotransferase >5.0x ULN 4.8 2.9 Alanine aminotransferase >5.0x ULN 2.6 3.4 Total bilirubin >5.0x ULN 5.5 5.3 Amylase >2.0x ULN 5.7 5.8 Lipase >2.0x ULN 4.9 6.3 Absolute neutrophil count <750/mm 3 4.3 2.4 a Percentages based on total subjects evaluated for each laboratory parameter. Study in Treatment-Naive Subjects: Treatment-Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Study A4001026, a double-blind, comparative, controlled study in which 721 treatment-naive subjects received SELZENTRY 300 mg twice daily (N = 360) or efavirenz (N = 361) in combination with zidovudine/lamivudine for 96 weeks, are summarized in Table 5. Selected events occurring at ≥2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at the same or higher rate on efavirenz are not displayed. Table 5. Percentage of Subjects With Selected Treatment-Emergent Adverse Events (All Causality) (≥2% on SELZENTRY and at a higher rate compared with efavirenz) Study A4001026 (96 Weeks) SELZENTRY + Zidovudine/Lamivudine 300 mg Twice Daily (N = 360) % Efavirenz + Zidovudine/Lamivudine 600 mg Once Daily (N = 361) % Blood and Lymphatic System Disorders Anemias NEC 8 5 Neutropenias 4 3 Ear and Labyrinth Disorders Ear disorders NEC 3 2 Gastrointestinal Disorders Flatulence, bloating, and distention 10 7 Gastrointestinal atonic and hypomotility disorders NEC 9 5 Gastrointestinal signs and symptoms NEC 3 2 General Disorders and Administrtion Site Conditions Body temperature perception 3 1 Infections and Infestations Bronchitis 13 9 Herpes infection 7 6 Upper respiratory tract infection 32 30 Bacterial infections NEC 6 3 Herpes zoster/varicella 5 4 Lower respiratory tract and lung infections 3 2 Neisseria infections 3 0 Tinea infections 4 3 Viral infections NEC 3 2 Musculoskeletal and Connective Tissue Disorders Joint-related signs and symptoms 6 5 Nervous System Disorders Memory loss (excluding dementia) 3 1 Paresthesias and dyesthesias 4 3 Renal and Urinary Disorders Bladder and urethral symptoms 4 3 Reproductive System and Breast Disorders Erection and ejaculation conditions and disorders 3 2 Respiratory, Thoracic, and Mediastinal Disorders Upper respiratory tract signs and symptoms 9 5 Skin and Subcutaneous Disorders Acnes 3 2 Alopecias 2 1 Lipodystrophies 4 3 Nail and nail bed conditions (excluding infections and infestations) 6 2 Laboratory Abnormalities: Table 6. Maximum Shift in Laboratory Test Values (Without Regard to Baseline) Incidence ≥2% of Grade 3-4 Abnormalities (ACTG Criteria) Study A4001026 (96 Weeks) Laboratory Parameter Preferred Term Limit SELZENTRY 300 mg Twice Daily + Zidovudine/Lamivudine (N = 353) a % Efavirenz 600 mg Once Daily+ Zidovudine/Lamivudine (N = 350) a % Aspartate aminotransferase >5.0 x ULN 4.0 4.0 Alanine aminotransferase >5.0 x ULN 3.9 4.0 Creatine kinase 3.9 4.8 Amylase >2.0 x ULN 4.3 6.0 Absolute neutrophil count <750/mm 3 5.7 4.9 Hemoglobin <7.0 g/dL 2.9 2.3 a N = Total number of subjects evaluable for laboratory abnormalities. Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had >1 occurrence of the same abnormality, only the most severe is counted. Less Common Adverse Events in Clinical Trials: The following adverse events occurred in <2% of subjects treated with SELZENTRY. These events have been included because of their seriousness and either increased frequency on SELZENTRY or are potential risks due to the mechanism of action. Events attributed to the patient’s underlying HIV infection are not listed. Blood and Lymphatic System: Marrow depression and hypoplastic anemia. Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia. Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, hypertransaminasemia, jaundice. Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis. Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased. Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen’s disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified. Nervous System Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect. 6.2 Postmarketing Experience The following events have been identified during post-approval use of SELZENTRY. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to estimate their frequency or establish a causal relationship to exposure to SELZENTRY. Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome.