Included as part of the PRECAUTIONS section.

Hepatotoxicity

A case of possible SELZENTRY-induced hepatotoxicity with allergic features has been reported in a study of healthy volunteers. In addition, an increase in hepatic adverse events with SELZENTRY was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade 3/4 liver function test abnormalities [see ADVERSE REACTIONS]. 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 (total exposure 267 patient-years), while no subjects who received placebo had such events (total exposure 99 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.

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.

Immune Reconstitution Syndrome

Immune reconstitution 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 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. 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. While there was a higher rate of certain upper respiratory tract infections reported in the SELZENTRY arm compared to placebo (20.0% versus 11.5%), there was a lower rate of pneumonia (2.1 % vs 4.8%) reported in patients receiving SELZENTRY. A higher incidence of Herpes virus infections (11.4 per 100 patient-years) was also reported in the SELZENTRY arm when adjusted for exposure compared to placebo (8.2 per 100 patient-years). 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.

Information for Patients

See Medication Guide.

Patients should be informed that if they develop signs or symptoms of hepatitis or allergic reaction following use of SELZENTRY (rash, skin or eyes look yellow, dark urine, vomiting, abdominal pain), they should stop SELZENTRY and seek medical evaluation immediately [see Warnings and PRECAUTIONS].

Patients should be informed that SELZENTRY is not a cure for HIV infection and patients may still develop illnesses associated with HIV infection, including opportunistic infections. The use of SELZENTRY has not been shown to reduce the risk of transmission of HIV to others through sexual contact, sharing needles or blood contamination.

Patients should be advised that it is important to:

• remain under the care of a physician when using SELZENTRY;
• take SELZENTRY every day as prescribed and in combination with other antiretroviral drugs;
• report to their physician the use of any other prescription or nonprescription medication or herbal products;
• inform their physician if they are pregnant, plan to become pregnant or become pregnant while taking SELZENTRY;
• not change the dose or dosing schedule of SELZENTRY or any antiretroviral medication without consulting their physician.

Patients should be advised that if they forget to take a dose, they should take the next dose of SELZENTRY as soon as possible and then take their next scheduled dose at its regular time. If it is less than 6 hours before their next scheduled dose, they should not take the missed dose and should instead wait and take the next dose at the regular time.

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

Noncliniocal Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term oral carcinogenicity studies of maraviroc were carried out in rasH2 transgenic mice (6 months) and in rats for up to 96 weeks (females) and 104 weeks (males). No drug-related increases in tumor incidence were found in mice at 1500 mg/kg/day and in male and female rats at 900 mg/kg/day. The highest exposures in rats were approximately 11 times those observed in humans at the therapeutic dose of 300 mg twice daily for the treatment of HIV-1 infection.

Mutagenesis

Maraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes and rat bone marrow micronucleus test.

Impairment of Fertility

Maraviroc did not impair mating or fertility of male or female rats and did not affect sperm of treated male rats at approximately 20-fold higher exposures (AUC) than in humans given the recommended 300 mg twice daily dose.

Use In Specific Populations

Pregnancy

Pregnancy Category B

The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with maraviroc in rats at exposures (AUC) approximately 20-fold higher and in rabbits at approximately 5-fold higher than human exposures at the recommended daily dose (up to 1000 mg/kg/day in rats and 75 mg/kg/day in rabbits). During the pre-and post-natal development studies in the offspring, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc.

However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, SELZENTRY should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to SELZENTRY and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV infection. Studies in lactating rats indicate that maraviroc is extensively secreted into rat milk. It is not known whether maraviroc is secreted into human milk. Because of the potential for both HIV transmission and serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving SELZENTRY.

Pediatric Use

The pharmacokinetics, safety and efficacy of maraviroc in patients < 16 years of age have not been established. Therefore, maraviroc should not be used in this patient population.

Geriatric Use

There were insufficient numbers of subjects aged 65 and over in the clinical studies to determine whether they respond differently from younger subjects. In general, caution should be exercised when administering SELZENTRY in elderly patients, also reflecting the greater frequency of decreased hepatic and renal function, of concomitant disease and other drug therapy.

Renal Impairment

The safety and efficacy of maraviroc have not been specifically studied in patients with renal impairment, therefore maraviroc should be used with caution in this population. In the absence of metabolic inhibitors, renal clearance accounts for approximately 25% of total clearance of maraviroc. Maraviroc concentrations may be increased in patients with renal impairment, especially when CYP3A inhibitors are coadministered. 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.

Hepatic Impairment

The pharmacokinetics of maraviroc have not been sufficiently studied in patients with hepatic impairment. Because maraviroc is metabolized by the liver, concentrations are likely to be increased in these patients [see Warnings and PRECAUTIONS].

Gender

Population pharmacokinetic analysis of pooled Phase 1/2a data indicated gender (female: n=96, 23.2% of the total population) does not affect maraviroc concentrations. Dosage adjustment based on gender is not necessary.

Race

Population pharmacokinetic analysis of pooled Phase 1/2a data indicated exposure was 26.5% higher in Asians (N=95) as compared to non-Asians (n=318). However, a study designed to evaluate pharmacokinetic differences between Caucasians (n=12) and Singaporeans (n=12) showed no difference between these two populations. Only 14 Black subjects were included in the population pharmacokinetic analysis. No dosage adjustment based on race is needed.

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