home > drugs a-z list > selzentry (maraviroc) drug center > selzentry (maraviroc) drug - warnings and precautions

Included as part of the PRECAUTIONS section.

Hepatotoxicity

Hepatotoxicity with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity. These events occurred approximately 1 month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.

Appropriate laboratory testing including ALS, AST, and bilirubin should be conducted prior to initiating therapy with SELZENTRY and at other time points during treatment as clinically indicated. Hepatic laboratory parameters should be obtained in any patient who develops rash, or signs or symptoms of hepatitis, or allergic reaction. 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.

Caution should be used when administering SELZENTRY to patients with pre-existing liver dysfunction or who are coinfected with viral hepatitis B or C. 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 administration of SELZENTRY.

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 (total exposure 609 patient-years [300 on SELZENTRY once daily + 309 on SELZENTRY twice daily]), 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 use of SELZENTRY, 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 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 [see DOSAGE AND ADMINISTRATION].

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 treatment-experienced studies of SELZENTRY. While there was a higher rate of certain upper respiratory tract infections reported in the arm receiving SELZENTRY compared with 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 arm receiving SELZENTRY when adjusted for exposure compared with 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 with 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 with 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.

Patient Counseling Information

See Medication Guide.

Patients should be informed that liver problems including life-threatening cases have been reported with SELZENTRY. 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. Patients should understand that laboratory tests for liver enzymes and bilirubin will be ordered prior to starting SELZENTRY, at other times during treatment, and if they develop severe rash or signs and symptoms of hepatitis or an allergic reaction on treatment [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 it is important to take all their anti-HIV medicines as prescribed and at the same time(s) each day.

Patients should be advised that when their supply of SELZENTRY starts to run low, they should ask their doctor or pharmacist for a refill.

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.

Nonclinical 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 1,500 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 1,000 mg/kg/day in rats and 75 mg/kg/day in rabbits). During the pre- and postnatal 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 breastfeed 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 breastfeed if they are receiving SELZENTRY.

Pediatric Use

The pharmacokinetics, safety and efficacy of maraviroc in patients aged < 16 years 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

Recommended doses of SELZENTRY for patients with impaired renal function (CrCl ≤ 80 mL/min) are based on the results of a pharmacokinetic study conducted in healthy subjects with various degrees of renal impairment. The pharmacokinetics of maraviroc in subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function [see CLINICAL PHARMACOLOGY]. A limited number of subjects with mild and moderate renal impairment in the Phase 3 clinical trials (n = 131 and n = 12, respectively) received the same dose of SELZENTRY as that administered to subjects with normal renal function. In these subjects there was no apparent difference in the adverse event profile for maraviroc compared with subjects with normal renal function.

If patients with severe renal impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking SELZENTRY 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No studies have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of SELZENTRY can be recommended, and SELZENTRY is contraindicated for these patients [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Hepatic Impairment

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 concentrations are higher when SELZENTRY 150 mg is administered with a potent CYP3A inhibitor compared with following administration of 300 mg without a CYP3A inhibitor, so patients with moderate hepatic impairment who receive SELZENTRY 150 mg with a potent CYP3A inhibitor should be monitored closely for maraviroc-associated adverse events. Maraviroc has not been studied in subjects with severe hepatic impairment [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Gender

Population pharmacokinetic analysis of pooled Phase ½a 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 ½a data indicated exposure was 26.5% higher in Asians (N = 95) as compared with 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 2 populations. No dose adjustment based on race is needed.

Last reviewed on RxList: 11/7/2011
This monograph has been modified to include the generic and brand name in many instances.