Maraviroc (Page 4 of 10)

6.2 Postmarketing Experience

The following adverse events have been identified during post-approval use of maraviroc. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).

7 DRUG INTERACTIONS

7.1 Effect of Concomitant Drugs on the Pharmacokinetics of Maraviroc

Maraviroc is metabolized by CYP3A and is also a substrate for P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP)1B1, and multidrug resistance-associated protein (MRP)2. The pharmacokinetics of maraviroc are likely to be modulated by inhibitors and inducers of CYP3A and P-gp and may be modulated by inhibitors of OATP1B1 and MRP2.

Therefore, a dosage adjustment may be required when maraviroc is coadministered with those drugs [ see Dosage and Administration ( 2.3, 2.4) ].

Concomitant use of maraviroc and St. John’s wort ( Hypericum perforatum) or products containing St. John’s wort is not recommended. Coadministration of maraviroc with St. John’s wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc.

Additional drug interaction information is available [ see Clinical Pharmacology ( 12.3) ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to maraviroc during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Limited data on the use of maraviroc during pregnancy from the APR and case reports are not sufficient to inform a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with maraviroc. During organogenesis in the rat and rabbit, systemic exposures (AUC) to maraviroc were approximately 20 times (rats) and 5 times (rabbits) the exposure in humans at the recommended 300-mg twice-daily dose. In the rat pre- and post-natal development study, maternal systemic exposure (AUC) to maraviroc was approximately 14 times the exposure in humans at the recommended 300-mg twice-daily dose ( see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data:

Maraviroc was administered orally to pregnant rats (up to 1,000 mg per kg per day) and rabbits (up to 75 mg per kg per day) on gestation Days 6 to 17 and 7 to 19, respectively. No adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC) approximately 20 times (rats) and 5 times (rabbits) higher than human exposures at the recommended daily dose. In the rat pre- and post-natal development study, maraviroc was administered orally at up to 1,000 mg per kg per day on gestation Day 6 to lactation/post-partum Day 20, with development of the offspring (including fertility and reproductive performance) unaffected by maternal administration of maraviroc at an exposure (AUC) approximately 14 times higher than human exposure at the recommended daily dose.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

There are no data on the presence of maraviroc in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, maraviroc was present in milk ( see Data). Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving maraviroc.

Data

Maraviroc (and related metabolites) was excreted into the milk of lactating rats following a single oral dose of maraviroc (100 mg per kg) on lactation Day 12, with a maximal milk concentration achieved one hour post-administration at a milk concentration approximately 2.5 times that of maternal plasma concentrations.

8.4 Pediatric Use

The safety and efficacy of maraviroc have been established in pediatric patients aged from aged 2 to less than 18 years. The use of maraviroc in pediatric patients was supported by pharmacokinetic and safety data described below and by previous demonstration of efficacy in adult patients [ see Indications and Usage (1)], Dosage and Administration ( 2.4) ].

HIV-1–Infected Pediatric Patients Aged 2 to Less Than 18 Years: The safety, pharmacokinetic profile, and antiviral activity of maraviroc were evaluated in treatment-experienced, CCR5- tropic, HIV-1–infected pediatric subjects aged 2 to less than 18 years weighing at least 10 kg in an open-label, multicenter clinical trial, A4001031 [ see Adverse Reactions ( 6.1), Clinical Studies ( 14.2) ]. Pharmacokinetics were evaluated in a total of 98 pediatric subjects: 85 subjects received maraviroc and concomitant medications that included potent CYP3A inhibitors with or without potent CYP3A inducers, 10 subjects received maraviroc and noninteracting medications (not containing potent CYP3A inhibitors or potent CYP3A inducers), and three subjects received maraviroc and medications that included potent CYP3A inducers without potent CYP3A inhibitors [ see Clinical Pharmacology ( 12.3) ].

There are insufficient data to make dosing recommendations for use of maraviroc in pediatric patients concomitantly receiving potent CYP3A inhibitors and weighing less than 10 kg, or in any pediatric patients concomitantly receiving potent CYP3A inducers without a potent CYP3A inhibitor [ see Dosage and Administration ( 2.4, 2.5) ].

Maraviroc is not recommended in pediatric patients weighing less than 10 kg.

8.5 Geriatric Use

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

8.6 Renal Impairment

Recommended doses of maraviroc for adult patients with impaired renal function (CrCl less than or equal to 80 mL per minute) are based on the results of a pharmacokinetic trial conducted in healthy adult subjects with various degrees of renal impairment. Maraviroc has not been studied in pediatric patients with renal impairment. There are no data to recommend specific doses of maraviroc in pediatric patients with mild to moderate renal impairment [ see Use in Specific Populations ( 8.4) ]. Maraviroc is contraindicated in pediatric patients with severe renal impairment or ESRD on regular hemodialysis who are receiving potent CYP3A inhibitors [ see Contraindications ( 4) ].

The pharmacokinetics of maraviroc in adult subjects with mild and moderate renal impairment was similar to that in subjects with normal renal function [ see Clinical Pharmacology ( 12.3) ]. A limited number of adult subjects with mild and moderate renal impairment in the Phase 3 clinical trials (n = 131 and n = 12, respectively) received the same dose of maraviroc 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 adult patients with severe renal impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No trials have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of maraviroc can be recommended, and maraviroc is contraindicated for these patients [ see Dosage and Administration ( 2.3), Contraindications ( 4), Warnings and Precautions ( 5.3), Clinical Pharmacology ( 12.3) ].

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