Changes to SELZENTRY (maravrioc) labeling to include safety and PK data in pediatric patients weighing at least 2kg

U.S. Food and Drug Administration sent this bulletin at 11/02/2020 06:18 PM EST

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Changes to SELZENTRY (maraviroc) labeling to include safety and PK data in pediatric patients weighing at least 2 kg.

FDA approved changes to the SELZENTRY (maraviroc) 20 mg/mL oral solution label to include safety and pharmacokinetic data for pediatric patients weighing at least 2 kg. In addition a 3 mL dosing syringe is included in the convenience kit for the oral solution formulation. A summary of major changes is provided below.

Section 1 INDICATIONS AND USAGE was revised to include adult and pediatric patients weighing at least 2 kg.

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 adult and pediatric patients weighing at least 2 kg

Section 1 DOSAGE AND ADMINISTRATION was revised as follows

2.4 Recommended Dosage in Pediatric Patients with Normal Renal Function

The recommended oral dosage of SELZENTRY tablets in pediatric patients aged 2 years and older weighing at least 10 kg is shown in the table below

Concomitant Medications	Dosage of SELZENTRY Based on Weight
Concomitant Medications	10 kg to <14 kg	14 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)^a	50 mg twice daily	50 mg twice daily	75 mg twice daily	100 mg twice daily	150 mg twice daily
Noninteracting concomitant medications^b	150 mg twice daily	200 mg twice daily	200 mg twice daily	300 mg twice daily	300 mg twice daily
Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor)^c	Not recommended^d

^aPotent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin.

^bNoninteracting concomitant medications including all medications that are not potent CYP3A inhibitors or inducers such as: dolutegravir, enfuvirtide, nevirapine, all NRTIs, raltegravir, and tipranavir/ritonavir.

^cPotent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin.

^dInsufficient data are available to recommend use.

The recommended oral dosage of SELZENTRY oral solution in pediatric patients weighing at least 2 kg is presented in the table below

Concomitant Medications	Dosage (Volume of Solution) of SELZENTRY Based on Weight
Concomitant Medications	2 kg to <4 kg	4 kg to <6 kg	6 kg to <10 kg	10 kg to <14 kg	14 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)^a	Not recommended^b			50 mg (2.5 mL) twice daily	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^c	30 mg (1.5 mL) twice daily	40 mg (2 mL) twice daily	100 mg (5 mL) twice daily	150 mg (7.5 mL) twice daily	200 mg (10 mL) twice daily	200 mg (10 mL) twice daily	300 mg (15 mL) twice daily	300 mg (15 mL) twice daily
Potent and moderate CYP3A inducers (without a potent CYP3A inhibitor)^d	Not recommended^b

^a Potent CYP3A inhibitors (with or without a CYP3A inducer) including: clarithromycin, cobicistat, elvitegravir/ritonavir, itraconazole, ketoconazole, nefazodone, protease inhibitors (except tipranavir/ritonavir), telithromycin.

^bInsufficient data are available to recommend use.

^cNoninteracting concomitant medications including all medications that are not potent CYP3A inhibitors or inducers such as: dolutegravir, enfuvirtide, nevirapine, all NRTIs, raltegravir, and tipranavir/ritonavir.

^dPotent and moderate CYP3A inducers (without a potent CYP3A inhibitor) including: carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, and rifampin.

Administer the oral solution using the included press-in bottle adapter and the appropriate oral dosing syringe: for doses of 2.5 mL or less, use the 3-mL syringe; for doses greater than 2.5 mL, use the 10-mL syringe.

Care should be taken when measuring neonate doses due to the small volumes of oral solution required.

Section 6 ADVERSE REACTIONS includes the following information from HIV-1 exposed neonates

HIV-1–Exposed Neonates: The IMPAACT P2007 trial was an open-label trial in which 47 full-term HIV-1–exposed neonates (born to HIV-1–infected mothers) received at least one dose of SELZENTRY in combination with other antiretrovirals, mostly zidovudine and/or nevirapine Cohort 1 received 2 single doses of SELZENTRY: the first within 3 days of birth and the second at 7 to 14 days of age. Cohort 2 received SELZENTRY twice daily for 6 weeks beginning within 3 days of birth and continued through Week 6. Both cohorts received SELZENTRY with or without exposure to maternal efavirenz (in utero only in Cohort 1, and both in utero and after birth while breastfeeding in Cohort 2). The population was 51% male and 81% black. All infants were followed for safety through 16 weeks, with a total of 37 infants evaluable for safety.

There were no additional adverse reactions observed in neonates compared with those seen in adults. All adverse reactions reported were mild to moderate. The most common adverse reaction (all grades) reported with SELZENTRY was hemoglobin decreased (14%). One subject (3%) discontinued due to an adverse event (Grade 3 staphylococcal sepsis).

Section 8 USE IN SPECIAL POPULATIONS was updated as follows.

8.4 Pediatric Use

HIV-1–Infected Pediatric Patients Aged Older Than 6 Weeks to Less Than 2 Years: No clinical trials have been conducted in children aged older than 6 weeks to less than 2 years. Dosing recommendations for SELZENTRY in this population when concomitantly receiving noninteracting medications are based on population pharmacokinetic modeling and simulation only.

HIV-1–Infected Neonates Aged from Birth to 6 Weeks: The recommendation of SELZENTRY for the treatment of HIV-1 infection in this pediatric population is based on safety and pharmacokinetic data obtained from clinical trial IMPAACT P2007. In IMPAACT P2007, the safety and pharmacokinetic profiles of SELZENTRY were evaluated in full-term HIV-1–exposed neonates (born to HIV-1–infected mothers) aged from birth through 6 weeks. Pharmacokinetics were evaluated in 38 of 47 enrolled neonates who received SELZENTRY as a single dose (n = 13) or multiple doses (n = 25) up to 6 weeks of age concomitantly with other antiretrovirals (mostly zidovudine and/or nevirapine) with or without maternal exposure to efavirenz. HIV-1 status was assessed by nucleic acid test at birth, Week 6, and Week 16; all 47 enrolled neonates were HIV-1 negative at completion of the study.

There are insufficient data to make dosing recommendations for use of SELZENTRY 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.

SELZENTRY is not recommended in pre-term neonates or in pediatric patients weighing less than 2 kg.

The following information is included in section 12 CLINICAL PHARMACOLOGY.

Aged from Birth to Less Than 6 Weeks: The pharmacokinetics of maraviroc were evaluated in 38 of 47 enrolled HIV-1–exposed neonates (born to HIV-1–infected mothers) aged from birth up to 6 weeks. In the IMPAACT P2007 trial, 13 neonates received weight-based maraviroc dosing as single doses at birth and approximately 7 days, and 25 neonates received maraviroc twice daily up to 6 weeks of age without exposure to potent CYP3A inhibitors and/or inducers. Maraviroc pharmacokinetic parameters in neonates weighing at least 2 kg at birth (Table 13) were similar to those observed in adults. Exposure to maternal efavirenz both in utero (for a minimum of 2 weeks immediately prior to delivery) and after birth while breastfeeding did not have a meaningful impact on maraviroc pharmacokinetic parameters. Please refer to product labeling for maraviroc pharmacokinetic parameters in full term neonates (birth up to 6 weeks of age) receiving SELZENTRY with noninteracting concomitant medications.

Clinical pharmacokinetic data with maraviroc in pediatric patients aged older than 6 weeks to less than 2 years are not available and clinical pharmacokinetic data in pediatric patients aged 2 to less than 18 years receiving noninteracting concomitant medications are limited. Based on population pharmacokinetic modeling and simulation, the recommended dosing regimen of SELZENTRY for this population is predicted to result in similar maraviroc exposures when compared with exposures achieved in adults receiving SELZENTRY 300 mg twice daily (with noninteracting concomitant medications)