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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 to placebo are upper respiratory tract infections, cough, pyrexia, rash, and dizziness ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 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 to 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 one 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 two 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 + OBT. The population was 89% male and 84% white, with mean age of 46 years (range 17–75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily. The most common adverse events reported with SELZENTRY twice daily therapy 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 two studies, the rate of discontinuation due to adverse events was 5% for subjects who received SELZENTRY twice daily + optimized background therapy (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 SELZENTRY twice daily dosing. The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the SELZENTRY twice daily and placebo groups, respectively. Correcting for the longer duration of exposure on SELZENTRY compared to 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 to placebo) Studies A4001027 and A4001028 (Pooled Analysis, 48 Weeks) SELZENTRY Twice Daily 300 mg dose equivalent Exposure-adjusted rate (per 100 pt-yrs) PYE=309 PYE = patient years of exposure Placebo Exposure-adjusted rate (per 100 pt-yrs) PYE=111 N=426 (%) N=209 (%) 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 I NFECTIONS 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 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 Placebo + OBT N =421 Percentages based on total subjects evaluated for each laboratory parameter % N =207 % Aspartate aminotransferase >5.0× ULN 4.8 2.9 Alanine aminotransferase >5.0× ULN 2.6 3.4 Total bilirubin >5.0× ULN 5.5 5.3 Amylase >2.0× ULN 5.7 5.8 Lipase >2.0× ULN 4.9 6.3 Absolute neutrophil count <750/mm 3 4.3 2.4 Study in Treatment-Naïve 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-naïve subjects received SELZENTRY 300 mg BID (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 to efavirenz) Study A4001026 (96 Weeks) SELZENTRY + zidovudine/lamivudine 300 mg BID N = 360 (%) EFAVIRENZ + zidovudine/lamivudine 600 mg QD 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 ADMINISTRATION SITE CONDITIONS Body Temperature perception 3 1 I NFECTIONS 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 Parasthesias 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 TISSUE 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 Twice daily + zidovudine/lamivudine N =353 N = total number of subjects evaluable for laboratory abnormalities. % Efavirenz 600 mg QD + zidovudine/lamivudine N =350 % 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. Aspartate aminotransferase >5.0× ULN 4.0 4.0 Alanine aminotransferase >5.0× ULN 3.9 4.0 Creatine kinase 3.9 4.8 Amylase >2.0× ULN 4.3 6.0 Absolute neutrophil count <750/mm 3 5.7 4.9 Hemoglobin <7.0 g/dL 2.9 2.3 Less Common Adverse Events in Clinical Trials The following adverse events occurred in <2% of SELZENTRY-treated subjects. 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 SELZENTRY exposure. Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome.