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SELZENTRY^® (maraviroc) Tablets:

Indications and Usage

• SELZENTRY, in combination with other antiretroviral agents, is indicated for adult patients infected with only CCR5-tropic HIV-1.

• This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of SELZENTRY in treatment-experienced subjects and one study in treatment-naive subjects. Both studies in treatment-experienced subjects advanced 3-were conducted in clinically advanced, 3 class antiretroviral-experienced (NRTI, NNRTI, PI, or enfuvirtide) adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
• The following points should be considered when initiating therapy with SELZENTRY:
• Tropism testing must be conducted with a highly sensitive tropism assay that has demonstrated the ability to identify patients appropriate for use of SELZENTRY. Outgrowth of pre-existing low-level CXCR4- or dual/mixed-tropic HIV-1 not detected by tropism testing at screening has been associated with virologic failure on SELZENTRY.
• Use of SELZENTRY is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1 as efficacy was not demonstrated in a phase 2 study of this patient group.
• The safety and efficacy of SELZENTRY have not been established in pediatric patients.
• In treatment-naive subjects, more subjects treated with SELZENTRY experienced virologic failure and developed lamivudine resistance compared to efavirenz.

Important Safety Information

• Hepatotoxicity has been reported with the use of SELZENTRY. Evidence of a systemic allergic reaction (eg, pruritic rash, eosinophilia or elevated IgE) prior to the development of hepatotoxicity may occur.
• Patients with signs or symptoms of hepatitis or allergic reaction following use of SELZENTRY should be evaluated immediately.
• 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.
• No conclusions can be drawn regarding whether hepatitis C co-infected patients are at an increased risk for hepatic adverse events with administration of SELZENTRY, due to the small number of co-infected patients studied.
• Caution should be used when administering SELZENTRY to patients with preexisting liver dysfunction or who are co-infected with viral hepatitis B or C.

Cardiovascular

• SELZENTRY should be used with caution in patients at increased risk for cardiovascular events.
• In treatment-experienced subjects, 11 (1.3%) who received SELZENTRY and no subjects who received placebo had cardiovascular events, including myocardial ischemia and/or infarction.
• Total exposure was 609 patient-years for SELZENTRY and 111 patient-years for placebo.
• In a phase 2b/3 study of treatment-naive subjects, 3 (0.8%) who received SELZENTRY and 5 (1.4%) who received efavirenz had events related to ischemic heart disease.
• Total exposure was 506 patient-years for SELZENTRY and 508 patient-years for efavirenz.
• 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.

Immune reconstitution syndrome

• Immune reconstitution has been syndrome reported in patients treated with combination antiretroviral therapy, including SELZENTRY.
• During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii, Mycobacterium tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.

Potential risk of infection

• SELZENTRY antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections.
• In treatment-experienced subjects, the overall incidence and severity of infections, as well as AIDS-defining category C infections, was comparable between the SELZENTRY and placebo groups.
• There was a higher rate of certain upper respiratory tract infections reported in the SELZENTRY arm compared with the placebo arm (23% vs 13%).
• There was a lower rate of pneumonia reported in the SELZENTRY arm compared with the placebo arm (2% vs 5%).
• The incidence of Herpes virus infections, when adjusted for exposure, was 11 for SELZENTRY vs 8 for placebo per 100 patient-years of exposure.
• In a phase 2b/3 study of treatment-naive AIDS-In treatment subjects, the incidence of AIDS defining category C events, when adjusted for exposure, was 1.8 for SELZENTRY vs 2.4 for efavirenz per 100 patient-years of exposure.
• Patients should be monitored closely for evidence of infections while receiving SELZENTRY.

Potential risk of malignancy

• While no increase in malignancy has been observed with SELZENTRY, due to this drug’s 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.

Most common adverse reactions

• The most common adverse events reported with SELZENTRY twice-daily therapy in treatment-experienced patients 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%).

Pediatric

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

Renal impairment

• The safety and efficacy 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.

Dosing considerations

• SELZENTRY is a substrate of CYP3A and Pgp.
• Co-administration with CYP3A/Pgp inhibitors, including protease inhibitors (except tipranavir/ritonavir) or delavirdine, will increase the concentration of SELZENTRY.
• Co-administration 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 co-administered with CYP3A/Pgp inhibitors and/or CYP3A inducers since concentrations, therapeutic effects, and the safety of SELZENTRY may be affected.
• Maraviroc is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because maraviroc concentrations may be increased. Maraviroc has not been studied in subjects with severe hepatic impairment.
• Maraviroc should be used with caution in patients with renal impairment. Patients with a creatinine clearance of less than 50 mL/min who receive maraviroc and a CYP3A inhibitor may be at an increased risk of adverse effects related to increased maraviroc concentrations, such as dizziness and postural hypotension. Thus, patients with a creatinine clearance of less than 50 mL/min should receive maraviroc and a CYP3A inhibitor only if the potential benefit is felt to outweigh the risk, and they should be monitored for adverse effects.

St John’s wort

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

Reference: 1. IAS-USA Drug Resistance Mutations Figures
http://www.iasusa.org/pub/topics/2006/issue3/125.pdf