Clinical Trials Experience

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 34 weeks, with the total exposure on SELZENTRY twice daily at 267 patient-years versus 99 patient-years on placebo. 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.

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 events reported with SELZENTRY twice daily therapy with frequency rates higher than placebo, regardless of causality, were cough, pyrexia, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain 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 rates of discontinuation due to adverse events were 3.8% in subjects receiving SELZENTRY twice daily + optimized background therapy (OBT) compared to 3.8% in those receiving 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 214 (50.2%) and 80 (38.3%) 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 similar: 126 and 118 for SELZENTRY and placebo, respectively.

Dizziness or postural dizziness occurred in 8.2% and 7.7% on SELZENTRY and placebo, respectively, with 2 subjects (0.5%) on SELZENTRY discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) discontinuing therapy due to dizziness.

Treatment-emergent adverse events, regardless of causality, from A4001027 and A4001028 are summarized in Table 2. Selected events occurring at ≥ 2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at a higher rate on placebo are not displayed.

Table 2 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, Up to 48 Weeks)

Less Common Adverse Events

The following adverse events [defined as always serious by MedDRA-Preferred -(Critical)- Terms] occurred in < 2% of SELZENTRY-treated patients. 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.

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

Infections and Infestations: Clostridium difficile colitis, viral meningitis, pneumonia, septic shock

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, lymphoma, metastases to liver, esophageal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified)

Nervous System Disorders: cerebrovascular accident

Laboratory Abnormalities

Table 3 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in > 2% of patients receiving SELZENTRY.

Table 3 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, Up to 48 Weeks)

Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Maraviroc is a substrate of CYP3A and Pgp and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters. Therefore, a dose adjustment may be required when maraviroc is coadministered with those drugs [see DOSAGE AND ADMINISTRATION].

Concomitant use of maraviroc and St. John's wort (hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc.

For additional drug interaction information see CLINICAL PHARMACOLOGY.

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