Maraviroc warnings and precautions

# Warnings and Precautions

## Hepatotoxicity
A case of possible SELZENTRY-induced hepatotoxicity with allergic features has been reported in a study of healthy volunteers. 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. In studies of treatment-experienced HIV-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were co-infected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with SELZENTRY administration. However, 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.

## Cardiovascular Events
Use with caution in patients at increased risk for cardiovascular events. Eleven subjects (1.3%) who received SELZENTRY had cardiovascular events including myocardial ischemia and/or infarction during the Phase 3 studies in treatment-experienced studies , while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to SELZENTRY use, and the relative contribution of SELZENTRY to these events is not known.
In the Phase 2b/3 study in treatment-naive subjects, 3 subjects (0.8%) who received SELZENTRY had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for SELZENTRY and efavirenz, respectively).
When SELZENTRY was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when SELZENTRY was given at the recommended dose in HIV subjects in Phase 3 studies, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering SELZENTRY in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure.

## Postural Hypotension in Patients with Renal Impairment
Patients with impaired renal function may have cardiovascular co-morbidities and could be at increased risk of cardiovascular adverse events triggered by postural hypotension. An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with end-stage renal disease (ESRD) due to increased maraviroc exposure in some patients. SELZENTRY should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer. However, the use of SELZENTRY in these patients should only be considered when no alternative treatment options are available. If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily the dose should be reduced to 150 mg twice daily .

## Immune Reconstitution Syndrome
Immune reconstitution inflammatory syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. 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 withMycobacterium 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. 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 treatment-experienced studies of SELZENTRY. While there was a higher rate of certain upper respiratory tract infections reported in the SELZENTRY arm compared to placebo (23% versus 13%), there was a lower rate of pneumonia (2% vs 5%) reported in subjects receiving SELZENTRY. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the SELZENTRY arm when adjusted for exposure compared to placebo (8 per 100 patient-years).
In the Phase 2b/3 study in treatment-naive subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for SELZENTRY compared to 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.
The exposure-adjusted rate for malignancies per 100 patient-years of exposure in treatment-experienced studies was 4.6 for SELZENTRY compared to 9.3 on placebo. In treatment-naive subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for SELZENTRY and efavirenz, respectively.
Long-term follow-up is needed to more fully assess this risk.