Risk Summary
There are no available data on OXBRYTA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of voxelotor to pregnant rats and rabbits during organogenesis at exposures up to 2.8-times (rats) and 0.3-times (rabbits) the exposure at the maximum recommended human dose resulted in no adverse developmental effects (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
There are adverse effects on maternal and fetal outcomes associated with SCD in pregnancy (see Clinical Considerations). OXBRYTA should only be used during pregnancy if the benefit of the drug outweighs the potential risk.
Disease-Associated Maternal and/or Embryo/Fetal Risk
Women with SCD have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for vasoocclusive crises, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality.
Animal Data
In embryo-fetal development studies, voxelotor was administered orally to pregnant rats at 15, 50, and 250 mg/kg/day (gestation days 7 through 17) and rabbits at 25, 75, and 150 mg/kg/day (gestation days 7 through 19) through organogenesis. Maternal toxicity was observed at the highest dose levels in these studies equivalent to 2.8-times (rats) and 0.3-times (rabbits) the exposures in patients receiving OXBRYTA at the recommended daily dose. There was no evidence of adverse developmental outcomes in rats or rabbits.
In a pre- and postnatal development study, voxelotor was administered orally to pregnant rats at 15, 50 and 250 mg/kg/day (gestation day 6 through lactation day 20). Maternal gestational body weights were decreased at 250 mg/kg/day, which continued to the end of lactation. The findings in offspring included reduced survival and reduced body weights throughout lactation, weaning and maturation. The effects in offspring were observed at the maternal dose of 250 mg/kg/day with an exposure approximately 2.8-times the exposure in patients at the recommended dose.
Risk Summary
There are no data on the presence of voxelotor in human milk, the effects on the breastfed child, or the effects on milk production. Voxelotor was detected in milk in lactating rats. Plasma concentrations of voxelotor in pregnant rats were higher than the concentration in milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The concentration of voxelotor in animal milk does not necessarily predict the concentration of drug in human milk. Because of the potential for serious adverse reactions in the breastfed child, including changes in the hematopoietic system, advise patients that breastfeeding is not recommended during treatment with OXBRYTA, and for at least 2 weeks after the last dose.
The safety and effectiveness of OXBRYTA for SCD have been established in pediatric patients aged 4 years and older. The safety and efficacy of OXBRYTA in pediatric patients with SCD below the age of 4 years have not been established.
Use of OXBRYTA in pediatric patients 12 to <17 years for SCD is supported by evidence from an adequate and well-controlled study in adults and pediatric patients (HOPE trial). The HOPE trial enrolled 26 pediatric patients aged 12 to <17 years, in which 12 pediatric patients received OXBRYTA 1,500 mg once daily and 14 pediatric patients received OXBRYTA 900 mg once daily [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].
Use of OXBRYTA in pediatric patients 4 to <12 years for SCD is supported by evidence from an open-label, Phase 2 study. The study enrolled 45 pediatric patients aged 4 to <12 years and 11 patients aged 12 to <17 years with SCD. Patients 12 to <17 years received OXBRYTA 1,500 mg once daily. Patients 4 to <12 years were administered OXBRYTA based on body weight. OXBRYTA doses of 600 mg, 900 mg, or 1,500 mg once daily were administered to patients weighing 10 kg to <20 kg, 20 kg to <40 kg, or ≥40 kg, respectively [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
Pharmacokinetics, safety and efficacy were similar across the pediatric age groups and across pediatric and adult patients [see Dosage and Administration (2), Clinical Pharmacology (12.3) and Clinical Studies (14)].
The adverse reactions observed were similar across the pediatric age groups and across pediatric and adult patients [see Adverse Reactions (6.1)].
Clinical studies of OXBRYTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Severe hepatic impairment increases voxelotor exposures [see Clinical Pharmacology (12.3)]. Reduce OXBRYTA dose [see Dosage and Administration (2.3, 2.4)].
Risk Summary
There are no available data on OXBRYTA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of voxelotor to pregnant rats and rabbits during organogenesis at exposures up to 2.8-times (rats) and 0.3-times (rabbits) the exposure at the maximum recommended human dose resulted in no adverse developmental effects (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
There are adverse effects on maternal and fetal outcomes associated with SCD in pregnancy (see Clinical Considerations). OXBRYTA should only be used during pregnancy if the benefit of the drug outweighs the potential risk.
Disease-Associated Maternal and/or Embryo/Fetal Risk
Women with SCD have an increased risk of adverse pregnancy outcomes for the mother and the fetus. Pregnant women are at greater risk for vasoocclusive crises, pre-eclampsia, eclampsia, and maternal mortality. For the fetus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and perinatal mortality.
Animal Data
In embryo-fetal development studies, voxelotor was administered orally to pregnant rats at 15, 50, and 250 mg/kg/day (gestation days 7 through 17) and rabbits at 25, 75, and 150 mg/kg/day (gestation days 7 through 19) through organogenesis. Maternal toxicity was observed at the highest dose levels in these studies equivalent to 2.8-times (rats) and 0.3-times (rabbits) the exposures in patients receiving OXBRYTA at the recommended daily dose. There was no evidence of adverse developmental outcomes in rats or rabbits.
In a pre- and postnatal development study, voxelotor was administered orally to pregnant rats at 15, 50 and 250 mg/kg/day (gestation day 6 through lactation day 20). Maternal gestational body weights were decreased at 250 mg/kg/day, which continued to the end of lactation. The findings in offspring included reduced survival and reduced body weights throughout lactation, weaning and maturation. The effects in offspring were observed at the maternal dose of 250 mg/kg/day with an exposure approximately 2.8-times the exposure in patients at the recommended dose.
Risk Summary
There are no data on the presence of voxelotor in human milk, the effects on the breastfed child, or the effects on milk production. Voxelotor was detected in milk in lactating rats. Plasma concentrations of voxelotor in pregnant rats were higher than the concentration in milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The concentration of voxelotor in animal milk does not necessarily predict the concentration of drug in human milk. Because of the potential for serious adverse reactions in the breastfed child, including changes in the hematopoietic system, advise patients that breastfeeding is not recommended during treatment with OXBRYTA, and for at least 2 weeks after the last dose.
The safety and effectiveness of OXBRYTA for SCD have been established in pediatric patients aged 4 years and older. The safety and efficacy of OXBRYTA in pediatric patients with SCD below the age of 4 years have not been established.
Use of OXBRYTA in pediatric patients 12 to <17 years for SCD is supported by evidence from an adequate and well-controlled study in adults and pediatric patients (HOPE trial). The HOPE trial enrolled 26 pediatric patients aged 12 to <17 years, in which 12 pediatric patients received OXBRYTA 1,500 mg once daily and 14 pediatric patients received OXBRYTA 900 mg once daily [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].
Use of OXBRYTA in pediatric patients 4 to <12 years for SCD is supported by evidence from an open-label, Phase 2 study. The study enrolled 45 pediatric patients aged 4 to <12 years and 11 patients aged 12 to <17 years with SCD. Patients 12 to <17 years received OXBRYTA 1,500 mg once daily. Patients 4 to <12 years were administered OXBRYTA based on body weight. OXBRYTA doses of 600 mg, 900 mg, or 1,500 mg once daily were administered to patients weighing 10 kg to <20 kg, 20 kg to <40 kg, or ≥40 kg, respectively [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
Pharmacokinetics, safety and efficacy were similar across the pediatric age groups and across pediatric and adult patients [see Dosage and Administration (2), Clinical Pharmacology (12.3) and Clinical Studies (14)].
The adverse reactions observed were similar across the pediatric age groups and across pediatric and adult patients [see Adverse Reactions (6.1)].
Clinical studies of OXBRYTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Severe hepatic impairment increases voxelotor exposures [see Clinical Pharmacology (12.3)]. Reduce OXBRYTA dose [see Dosage and Administration (2.3, 2.4)].
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