SELZENTRY™ (maraviroc) tablets Clinical Studies

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Prescribing Information

SELZENTRY^™ (maraviroc) tablets
Clinical Studies


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The clinical efficacy and safety of SELZENTRY is derived from analyses of 24-week data from two ongoing studies, A4001027(MOTIVATE-1) and A4001028(MOTIVATE-2), in antiretroviral treatment-experienced adult subjects infected with CCR5-tropic HIV-1. These studies are supported by a 24-week study in antiretroviral treatment-experienced adult subjects infected with dual/mixedtropic HIV-1, A4001029.

Studies in CCR5-tropic, Treatment-Experienced Subjects
Studies A4001027 and A4001028 are ongoing, double-blind, randomized, placebo-controlled, multicenter studies in subjects infected with CCR5-tropic HIV-1. Subjects were required to have an HIV-1 RNA of greater than 5,000 copies/mL despite at least 6 months of prior therapy with at least one agent from three of the four antiretroviral drug classes [≥1 nucleoside reverse transcriptase inhibitors (NRTI), ≥1 non-nucleoside reverse transcriptase inhibitors (NNRTI), ≥2 protease inhibitors (PI), and/or enfuvirtide] or documented resistance or intolerance to at least one member of each class. All subjects received an optimized background regimen consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the optimized background regimen, subjects were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo. Doses were adjusted based on background therapy as described in Dosing and Administration, Table 1.

In the pooled analysis for A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 7). Of the 1043 subjects with a CCR5 tropism result at screening, 7.6% had a dual/mixed tropism result at the baseline visit 4 to 6 weeks later. This illustrates the background change from CCR5 to dual/mixed tropism result over time in this treatment-experienced population, prior to a change in antiretroviral regimen or administration of a CCR5 co-receptor antagonist.

Table 7: Demographic and Baseline Characteristics of Subjects in Studies A4001027 and A4001028

The week 24 results for the pooled Studies A4001027 and A4001028 are shown in Table 8.

Table 8: Outcomes of Randomized Treatment at Week 24
Studies A4001027 and A4001028

After 24 weeks of therapy, the proportion of subjects with HIV-1 RNA <400 copies/mL receiving maraviroc compared to placebo was 61% and 28%, respectively. The mean changes in plasma HIV-1 RNA from baseline to week 24 was –1.96 log₁₀ copies/mL for subjects receiving maraviroc + OBT compared to –0.99 log₁₀ copies/mL for subjects receiving OBT only. The mean increase in CD4+ counts was higher on maraviroc twice daily + OBT (106.3 cells/mm³) than on placebo + OBT (57.4 cells/mm³ ).

Study in Dual/Mixed-tropic, Treatment-Experienced Subjects
Study A4001029 was an exploratory, randomized, double blind, multicenter trial to determine the safety and efficacy of maraviroc in subjects infected with dual/mixed co-receptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Studies A4001027 and A4001028 above and the subjects were randomized in a 1:1:1 ratio to SELZENTRY once daily, SELZENTRY twice daily, or placebo. No increased risk of infection or HIV disease progression was observed in the subjects who received SELZENTRY. SELZENTRY use was not associated with a significant decrease in HIV-1 RNA compared to placebo in these subjects and no adverse effect on CD4 count was noted.

PRINTER-FRIENDLY

SELZENTRY Safety Information

Important Safety Information

WARNING: See full prescribing information for complete boxed warning. Hepatotoxicity has been reported which may be preceded by evidence of a systemic allergic reaction (eg, pruritic rash, eosinophilia or elevated IgE). Immediately evaluate patients with signs or symptoms of hepatitis or allergic reaction.

SELZENTRY should be taken as part of an antiretroviral combination regimen. As with other antiretrovirals, SELZENTRY should be optimally combined with other antiretrovirals to which the patient's virus is sensitive.

There is limited experience in patients with reduced hepatic function; therefore, SELZENTRY should be used with caution in this population.

Discontinuation of SELZENTRY should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.

The safety and efficacy of SELZENTRY have not been specifically studied in patients with significant underlying liver disorders such as patients co-infected with viral hepatitis B or C. Caution should be used when administering SELZENTRY to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C.

Use with caution in patients at increased risk of cardiovascular events. More cardiovascular events, including myocardial ischemia and/or infarction, were observed in patients who received SELZENTRY.

Caution should be used when administering SELZENTRY in patients with a history of postural hypotension or who receive concomitant medication known to lower blood pressure. Patients should be advised that if they experience dizziness while receiving SELZENTRY, they should avoid driving or operating machinery.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SELZENTRY.

SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining Category C infections, was comparable in the treatment groups during the Phase 3 studies of SELZENTRY. Compared with patients receiving placebo, patients in the SELZENTRY arm had higher incidences of upper respiratory tract infections (23% vs 13%) and Herpes virus infections (8% vs 4%). However, patients taking SELZENTRY had a lower incidence of pneumonia (2% vs 5%). Patients should be monitored closely for evidence of infection while receiving SELZENTRY.

While no increase in malignancy has been observed with SELZENTRY, due to this drugs mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy. Long-term follow-up is needed to more fully assess this risk.

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 (23% vs 13%), cough (14% vs 5%), pyrexia (13% vs 9%), rash (11% vs 5%), and dizziness (9% vs 8%).

There are no data available in pediatric patients; therefore, SELZENTRY should not be used in patients <16 years old.

The safety and efficacy of SELZENTRY have not been specifically studied in patients with renal impairment; therefore, SELZENTRY should be used with caution in this population. Patients with a creatinine clearance of less than 50 mL/min should receive SELZENTRY and a CYP3A inhibitor only if the potential benefit is felt to outweigh the risk, and should be monitored because of potential increased risk of adverse effects (including dizziness and postural hypotension) due to increased concentrations of SELZENTRY.

SELZENTRY is a substrate of CYP3A and Pgp. Coadministration with CYP3A/Pgp inhibitors, including protease inhibitors (except tipranavir/ritonavir) or delavirdine, will increase the concentration of SELZENTRY. Coadministration with CYP3A inducers, including efavirenz, may decrease the concentration of SELZENTRY. Physicians should ensure that an appropriate dose adjustment of SELZENTRY is made when SELZENTRY is coadministered with CYP3A/Pgp inhibitors and/or CYP3A inducers since concentrations, therapeutic effects, and the safety of SELZENTRY may be affected.

Concomitant use of SELZENTRY and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended.

Please see full Prescribing Information, including boxed warnings