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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.
Adverse Reactions in Adult Subjects: Treatment-Experienced Subjects: The safety profile of CELSENTRI is primarily based on 840 HIV-1-infected subjects who received at least 1 dose of CELSENTRI 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 CELSENTRI for subjects in these trials was 48 weeks, with the total exposure on CELSENTRI 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 CELSENTRI 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 CELSENTRI 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 as follows occurred with twice-daily dosing of CELSENTRI.
The total numbers of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving CELSENTRI twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on CELSENTRI compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both CELSENTRI twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of subjects on either CELSENTRI or placebo, with 2 subjects (0.5%) on CELSENTRI 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 Trials A4001027 and A4001028 are summarized in Table 12. Selected events occurring at greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with CELSENTRI are included; events that occurred at the same or higher rate on placebo are not displayed. (See Table 12.)
Click on icon to see table/diagram/imageLaboratory Abnormalities: Table 13 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving CELSENTRI. (See Table 13.)
Click on icon to see table/diagram/imageTreatment-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 CELSENTRI 300 mg twice daily (n = 360) or efavirenz 600mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR) for 96 weeks, are summarized in Table 14. Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with CELSENTRI are included; events that occurred at the same or higher rate on efavirenz are not displayed. (See Table 14.)
Click on icon to see table/diagram/imageLaboratory Abnormalities: See Table 15.
Click on icon to see table/diagram/imageLess Common Adverse Events in Clinical Trials: The following adverse events occurred in less than 2% of subjects treated with CELSENTRI or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on CELSENTRI or are potential risks due to the mechanism of action. Events attributed to the subjects' 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.
Postmarketing Experience: The following adverse events have been identified during post-approval use of CELSENTRI. 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).
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