Selzentry approved for pediatric use

On Friday November 4, 2016, FDA approved Selzentry (maraviroc) 20 mg/mL oral solution, Selzentry (maraviroc) 25 mg and 75 mg tablets and updated the label to include use in pediatric patients 2 years of age and older weighing at least 10 kg. The major changes to the label are summarized below. 

 

INDICATIONS AND USAGE

 

SELZENTRY is indicated in combination with other antiretroviral agents for the treatment of only CCR5 tropic human immunodeficiency virus type 1 (HIV 1) infection in patients 2 years of age and older weighing at least 10 kg.

 

Limitations of Use:

• SELZENTRY is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1

DOSAGE AND ADMINISTRATION

Testing prior to Initiation of SELZENTRY

Prior to initiation of SELZENTRY, test all patients for CCR5 tropism using a highly sensitive tropism assay. SELZENTRY is recommended for patients with only CCR5-tropic HIV-1 infection. 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.

Monitor patients for ALT, AST, and bilirubin prior to initiation of SELZENTRY and at other time points during treatment as clinically indicated.

 

Recommended Dosage in Pediatric Patients

The recommended dosage of SELZENTRY should be based on body weight (kg) and should not exceed the recommended adult dose. The recommended dosage also differs based on concomitant medications due to drug interactions (Table 2 and Table 3)

Before prescribing SELZENTRY tablets, assess children for the ability to swallow tablets. If a child is unable to reliably swallow SELZENTRY tablets, the oral solution formulation should be prescribed. Administer the oral solution using the included press-in bottle adapter and oral dosing syringe.

Table 2. Recommended Dosage in Pediatric Patients Aged 2 Years and Older Weighing at Least 10 kg (Tablets) 

Concomitant Medications	Dosage of Selzentry Based on Weight
	10 kg to < 20 kg	20 kg to < 30 kg	30 kg to < 40 kg to < 20g	≥40 kg
Potent CYP3A inhibitors (with or without a CYP3A inducer) protease inhibitors (except tipranavir/ritonavir) delavirdine elvitegravir/ritonavir ketoconazole, itraconazole, clarithromycin other potent CYP3A inhibitors (e.g., nefazodone, telithromycin)	50 mg twice daily	75 mg twice daily	100 mg twice daily	150 mg twice daily
Noninteracting concomitant medications, including tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide a	Not recommended	Not recommended	300 mg twice daily	300 mg twice daily
Potent CYP3A inducers (without a potent CYP3A inhibitor) including: efavirenz, rifampin, etravirine,  carbamazepine, phenobarbital, and phenytoin	Not recommended

^a Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers.

Table 3. Recommended Dosage in Pediatric Patients Aged 2 Years and Older Weighing at Least 10 kg (Oral Solution)

Concomitant Medications
	Dosage of Selzentry is based on weight
	10 kg to < 20 kg	20 kg to < 30 kg	30 kg to < 40 kg	≥40 kg
Potent CYP3A inhibitors (with or without a CYP3A inducer) including: protease inhibitors (except tipranavir/ritonavir)  delavirdine elvitegravir/ritonavir ketoconazole, itraconazole, clarithromycin other potent CYP3A inhibitors (e.g., nefazodone, telithromycin) boceprevir	50 mg (2.5 mL) twice daily	80 mg (4 mL) twice daily	100 mg (5 mL) twice daily	150 mg (7.5 mL) twice daily
Noninteracting concomitant medications,  including tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide a	Not recommended	Not recommended	300 mg (15 mL) twice daily	300 mg (15 mL) twice daily
Potent CYP3A inducers (without a potent CYP3A inhibitor) efavirenz, rifampin, etravirine,carbamazepine, phenobarbital, and phenytoin	Not recommended

^a    Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers.

Hepatic Impairment

Pediatric Patients

There are no data to recommend specific doses of SELZENTRY in pediatric patients with mild or moderate renal impairment [see Use in Specific Populations (8.6)]. Additionally, SELZENTRY is contraindicated for pediatric patients with severe renal impairment or end-stage renal disease (ESRD) on regular hemodialysis who are receiving potent CYP3A inhibitors

 

ADVERSE REACTIONS

 

Clinical Trials Experience in Pediatric Subjects

Trial A4001031 is an open-label trial in which 103 treatment-experienced, CCR5-tropic, HIV-1–infected pediatric subjects aged 2 to less than 18 years weighing at least 10 kg received SELZENTRY twice daily in combination with OBT. The dose of SELZENTRY was based on body surface area (BSA) and on whether the subject was receiving potent CYP3A inhibitors and/or inducers. The median duration of therapy with SELZENTRY was 131 weeks with 72% of subjects receiving study treatment for greater than 48 weeks and 62% of subjects receiving study treatment for 96 weeks.

 

In these 103 children and adolescents, the safety profile through 96 weeks was similar to that for adults. Most of the adverse reactions reported were mild to moderate; severe (Grade 3 and 4) adverse reactions occurred in 2% of subjects. The most common adverse reactions (all grades) reported with twice-daily therapy with SELZENTRY, were vomiting (12%), abdominal pain (4%), diarrhea (4%), nausea (4%), and dizziness (3%). Three subjects (3%) discontinued due to adverse events.

Maraviroc-related gastrointestinal adverse events through 48 weeks (nausea, vomiting, diarrhea, constipation, and abdominal pain/cramps) were observed more commonly in subjects who received the SELZENTRY oral solution (21%) compared with those who received SELZENTRY tablets (16%). Subjects were permitted to change formulations after Week 48.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SELZENTRY 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 SELZENTRY 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.

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 breastfeedif they are receiving SELZENTRY.

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.

Pediatric Use

The safety, pharmacokinetic (PK) profile, and antiviral activity of SELZENTRY 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. Pharmacokinetics were evaluated in a total of 98 pediatric subjects: 85 subjects received SELZENTRY and concomitant medications that included potent CYP3A inhibitors with or without potent CYP3A inducers, 10 subjects received SELZENTRY and noninteracting medications (not containing potent CYP3A inhibitors or potent CYP3A inducers), and three subjects received SELZENTRY and medications that included potent CYP3A inducers without potent CYP3A inhibitors [see Clinical Pharmacology (12.3)].
See Dosage and Administration (2.4, 2.5) for dosing recommendations for pediatric patients aged 2 years and older and weighing at least 10 kg. The pharmacokinetics, safety, and efficacy of maraviroc in patients younger than 2 years have not been established. Therefore, SELZENTRY is not recommended in this patient population. Additionally, there are insufficient data to make dosing recommendations for use of SELZENTRY in pediatric patients concomitantly receiving noninteracting medications and weighing less than 30 kg or in pediatric patients concomitantly receiving potent CYP3A inducers without a potent CYP3A inhibitor.

Clinical Pharmacology

Pediatric Patients: The pharmacokinetics of maraviroc were evaluated in CCR5-tropic, HIV-1–infected, treatment-experienced pediatric subjects aged 2 to less than 18 years. In the dose-finding stage of Trial A4001031, doses were administered with food on intensive PK evaluation days and optimized to achieve an average concentration over the dosing interval (Cavg) of greater than 100 ng per mL. Throughout the trial, on non-intensive PK evaluation days maraviroc was taken with or without food.

The initial dose of maraviroc was based on BSA and concomitant medication category (i.e., presence of CYP3A inhibitors and/or inducers). The conversion of dosing to a weight (kg)-band basis in children provides comparable exposures with those observed in the trial at the corresponding BSA.

Maraviroc pharmacokinetic parameters in pediatric subjects receiving potent CYP3A inhibitors with or without a potent CYP3A inducer (Table 12) and in subjects weighing greater than or equal to 30 kg and receiving noninteracting concomitant medications (Table 13) were similar to those observed in adults. Insufficient pharmacokinetic data are available to make a comparison between adults and pediatric subjects weighing less than 30 kg and receiving noninteracting concomitant medications or between adult and pediatric subjects receiving concomitant medications consisting of a potent CYP3A inducer without CYP3A inhibitor.

Table 12. Maraviroc Pharmacokinetic Parameters in Treatment-Experienced Pediatric Patients Receiving SELZENTRY with Potent CYP3A Inhibitors (with or without a Potent CYP3A Inducer)

Weight	Dose of SELZENTRY	Maraviroc Pharmacokinetic Parameter a Geometric Mean
		AUC12 (ng.h/mL)	Cavg (ng/mL)	Cmax (ng/mL)	Cmin (ng/mL)
10 kg to < 20 kg	50 mg twice daily	2,349	196	324	78
20 kg to < 30 kg	75 mg twice daily	3,020	252	394	118
30 kg to < 40 kg	100 mg twice daily	3,229	269	430	126
≥40 kg	150 mg twice daily	4,044	337	563	152

^a The covariate distribution of the study population of 85 subjects on CYP3A-inhibitor-containing regimens was randomly sampled with replacement to obtain 1,000 subjects. Shown in the table are model-predicted steady-state PK parameters for the 1,000 subjects in the simulation dataset.

Table 13. Maraviroc Pharmacokinetic Parameters in Treatment-Experienced Pediatric Patients Receiving SELZENTRY with Noninteracting Concomitant Medications ^a

Weight (n)	Dose of SELZENTRY	Maraviroc Pharmacokinetic Parameter Geometric Mean
		AUC12 (ng.h/mL)	Cavg (ng/mL)	Cmax (ng/mL)	Cmin (ng/mL)
< 30 kg	Insufficient data
≥30 kg (n = 5) b	300 mg twice daily	1,998	167	413	50.6

^a Noninteracting concomitant medications include all medications that are not potent CYP3A inhibitors or inducers.

^b Nine observations from 5 subjects

Antiretroviral Treatment Experienced Pediatric Subjects (Trial A4001031): In the Week 48 analysis of Trial A4001031 (n = 103), the mechanisms of resistance to maraviroc observed in the treatment-experienced pediatric population were similar to those observed in adult populations: reasons for virologic failure included failing with CXCR4- or dual/mixed-tropic virus, evidence of reduced maraviroc susceptibility as measured by a decrease in maximal percentage inhibition (MPI), and emergence of resistance to background drug in the regimen.

CLINICAL STUDIES

Clinical Studies in Pediatric Subjects

Trial in CCR5 Tropic, Treatment Experienced Subjects

Trial A4001031 is an open-label, multicenter trial in pediatric subjects aged 2 to less than 18 years infected with only CCR5 tropic HIV 1. Subjects were required to have HIV 1 RNA greater than 1,000 copies per mL at screening. All subjects (n = 103) received SELZENTRY twice daily and OBT. Dosing of SELZENTRY was based on BSA and doses were adjusted based on whether the subject was receiving potent CYP3A inhibitors and/or inducers.

At 48 weeks, 48% of subjects treated with SELZENTRY and OBT achieved plasma HIV-1 RNA less than 48 copies per mL and 65% of subjects achieved plasma HIV-1 RNA less than 400 copies per mL. The mean CD4+ cell count (percent) increase from baseline to Week 48 was 247 cells per mm3 (5%).

 

How Supplied

 

SELZENTRY oral solution is a clear, colorless, strawberry-flavored liquid. Each mL of the solution contains 20 mg of maraviroc. It is packaged in plastic bottles as follows:

 

Bottle of 230 mL (NDC 49702-237-55). Each bottle is packaged with one press-in bottle adapter and one 10–mL oral dosing syringe with 0.5–mL gradations. The press-in bottle adapter and oral dosing syringe are not made with natural rubber latex. This product does not require reconstitution.

 

SELZENTRY oral solution should be stored at 20oC to 25oC (68oF to 77oF); excursions permitted between 15oC and 30oC (59oF and 86oF) [see USP Controlled Room Temperature].

The updated label will soon be available drugs@fda or DailyMed

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

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