3 ) ] • The most common adverse events in treatment-experienced adult subjects (greater than 8% incidence) which occurred at a higher frequency compared with placebo are upper respiratory tract infections, cough, pyrexia, rash, and dizziness.
1 ) • The most common adverse events in treatment-naive adult subjects (greater than 8% incidence) which occurred at a higher frequency than the comparator arm are upper respiratory tract infections, bronchitis, flatulence, bloating and distention, upper respiratory tract signs and symptoms, and gastrointestinal atonic and hypomotility disorders.
1 ) • The most common adverse reactions in treatment-experienced pediatric subjects (greater than or equal to 3% incidence) are vomiting, abdominal pain, diarrhea, nausea, and dizziness. gov/medwatch. 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.
Clinical Trials Experience in Adult Subjects Treatment-Experienced Subjects:
The safety profile of maraviroc is primarily based on 840 HIV-1-infected subjects who received at least 1 dose of maraviroc 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 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with maraviroc for subjects in these trials was 48 weeks, with the total exposure on maraviroc twice daily at 309 patient-years versus 111 patient-years on placebo each administered with 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 maraviroc with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness.
In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received maraviroc 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 maraviroc. The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving maraviroc twice daily and the placebo group, respectively.
Correcting for the longer duration of exposure on maraviroc compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both maraviroc twice daily and placebo. 5%) permanently discontinuing therapy due to dizziness.
Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 5. Selected events occurring at greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on placebo are not displayed.
Table 5. 5 1 Erythema 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 6 shows the treatment-emergent Grade 3 to 4 laboratory abnormalities that occurred in greater than 2% of subjects receiving maraviroc. Table 6. 4 ULN = Upper limit of normal. a Percentages based on total subjects evaluated for each laboratory parameter.
Treatment-Naive Subjects:
Treatment-Emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a double-blind, comparative, controlled trial in which 721 treatment-naive subjects received maraviroc 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR) for 96 weeks, are summarized in Table 7.
Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on efavirenz are not displayed. Table 7.
Selected Treatment-Emergent Adverse Events (All Causality) ≥2% on maraviroc (and at a Higher Rate Compared with Efavirenz) in Trial A4001026 (96 Weeks) Body System/ Adverse Event Maraviroc tablets 300 mg Twice Daily + Lamivudine/Zidovudine (n = 360) (%) Efavirenz 600 mg Once Daily + Lamivudine/Zidovudine (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 Infections and Infestations Upper respiratory tract infection 32 30 Bronchitis 13 9 Herpes infection 7 6 Bacterial infections NEC 6 3 Herpes zoster /varicella 5 4 Tinea infections 4 3 Lower respiratory tract and lung infections 3 2 Neisseria infections 3 0 Viral infections NEC 3 2 Musculoskeletal and Connective Tissue Disorders Joint-related signs and symptoms 6 5 Nervous System Disorders Parasthesias and dyesthesias 4 3 Memory loss (excluding dementia) 3 1 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 Nail and nail bed conditions (excluding infections and infestations) 6 2 Lipodystrophies 4 3 Acnes 3 2 Alopecias 2 1 Laboratory Abnormalities: Table 8.
3 ULN = Upper limit of normal. 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 greater than 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 less than 2% of subjects treated with maraviroc or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on maraviroc or are potential risks due to the mechanism of action.
Events attributed to the subject’s underlying HIV-1 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, 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. Clinical Trials Experience in Pediatric Subjects HIV-1–Infected Pediatric Subjects: Trial A4001031 is an open-label trial in which 103 treatment-experienced, CCR5-tropic, HIV-1–infected pediatric subjects aged 2 to less than 18 years weighing at least 10 kg received maraviroc twice daily in combination with OBT.
The dose of maraviroc was based on body surface area (BSA) and on whether the subject was receiving potent CYP3A inhibitors and/or inducers. The median duration of therapy with maraviroc was 131 weeks with 72% of subjects receiving study treatment for greater than 48 weeks and 62% of subjects receiving study treatment for 96 weeks.
In these 103 children and adolescents, the safety profile through 96 weeks was similar to that for adults. Most of the adverse reactions reported were mild to moderate; severe (Grade 3 and 4) adverse reactions occurred in 2% of subjects.
The most common adverse reactions (all grades) reported with twice-daily therapy with maraviroc were vomiting (12%), abdominal pain (4%), diarrhea (4%), nausea (4%), and dizziness (3%). Three subjects (3%) discontinued due to adverse events.
Maraviroc-related gastrointestinal adverse events through 48 weeks (nausea, vomiting, diarrhea, constipation, and abdominal pain/cramps) were observed more commonly in subjects who received the maraviroc oral solution (21%) compared with those who received maraviroc tablets (16%).
Subjects were permitted to change formulations after Week 48. 2 Postmarketing Experience The following adverse events have been identified during post-approval use of maraviroc. 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.
Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).