OXBRYTA

Dosage and Administration ( 2 ) 10/2022 Warnings and Precautions, Hypersensitivity Reactions ( 5.1 ) 08/2023

1 INDICATIONS AND USAGE OXBRYTA is indicated for the treatment of sickle cell disease (SCD) in adults and pediatric patients 4 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin (Hb) [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). OXBRYTA is a hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease in adults and pediatric patients 4 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin (Hb). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1 )

2 DOSAGE AND ADMINISTRATION OXBRYTA can be taken with or without food. ( 2.7 ) Recommended dosage: • Adults and pediatric patients 12 years and older: 1,500 mg orally once daily. ( 2.1 ) • Pediatric patients 4 to less than 12 years: Dosing with OXBRYTA is based on body weight. See Table 1 for complete dosing recommendations. ( 2.2 ) Recommended dosage for severe hepatic impairment (Child Pugh C) : • Adults and pediatric patients 12 years and older: 1,000 mg orally once daily. ( 2.3 ) • Pediatric patients 4 to less than 12 years: Reduce the dose of OXBRYTA based on body weight. See Table 2 for complete dosing recommendations. ( 2.4 ) 2.1 Recommended Dosage for Adults and Pediatric Patients 12 Years and Older The recommended dosage of OXBRYTA is 1,500 mg orally once daily. 2.2 Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years For pediatric patients 4 years to less than 12 years, select the appropriate product (OXBRYTA tablets or OXBRYTA tablets for oral suspension) based on patient's ability to swallow tablets and patient's weight. The recommended dosage of OXBRYTA for pediatric patients 4 years to less than 12 years is shown in Table 1. Table 1: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years Body Weight Recommended Dose (once daily) 40 kg or greater 1,500 mg 20 kg to less than 40 kg 900 mg 10 kg to less than 20 kg 600 mg 2.3 Recommended Dosage for Adults and Pediatric Patients 12 Years and Older with Hepatic Impairment The recommended dosage of OXBRYTA in adults and pediatric patients 12 years and older with severe hepatic impairment (Child Pugh C) is 1,000 mg orally once daily. No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment [ see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 2.4 Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years with Hepatic Impairment The recommended dosage of OXBRYTA in pediatric patients 4 years to less than 12 years with severe hepatic impairment (Child Pugh C) is described in Table 2. No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . Table 2: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years with Severe Hepatic Impairment (Child Pugh C) Body Weight Recommended Dose (once daily) 40 kg or greater 1,000 mg (two 500 mg tablets) or 900 mg (three 300 mg tablets for oral suspension or three 300 mg tablets) 20 kg to less than 40 kg 600 mg 10 kg to less than 20 kg 300 mg 2.5 Recommended Dosage of OXBRYTA for Adults and Pediatric Patients 12 Years and Older When Used with Concomitant Strong or Moderate CYP3A4 Inducers CYP3A4 Inducers Avoid concomitant use of strong or moderate CYP3A4 inducers with OXBRYTA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . If concomitant use of strong CYP3A4 inducers is unavoidable, the recommended dosage of OXBRYTA is 2,500 mg orally once daily. If concomitant use of moderate CYP3A4 inducers is unavoidable, the recommended dosage of OXBRYTA is 2,000 mg orally once daily. 2.6 Recommended Dosage of OXBRYTA for Pediatric Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers CYP3A4 Inducers Avoid concomitant use of strong or moderate CYP3A4 inducers with OXBRYTA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . If concomitant use of strong or moderate CYP3A4 inducers is unavoidable, see Table 3 for dosage. Table 3: OXBRYTA Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers Body Weight Recommended Dose (once daily) Concomitant Use of Strong CYP3A4 Inducers Concomitant Use of Moderate CYP3A4 Inducers 40 kg or greater 2,500 mg (five 500 mg tablets) or 2,400 mg (eight 300 mg tablets for oral suspension or eight 300 mg tablets) 2,000 m …

3 DOSAGE FORMS AND STRENGTHS Tablets: 300 mg light purple to purple, oval shaped, biconvex, debossed with "G 300" on one side. Tablets: 500 mg light yellow to yellow, oval shaped, biconvex, debossed with "GBT 500" on one side. Tablets for oral suspension: 300 mg light yellow to yellow, round shaped, debossed with "300 D" on one side. • Tablets: 300 mg and 500 mg ( 3 ) • Tablets for oral suspension: 300 mg ( 3 )

4 CONTRAINDICATIONS OXBRYTA is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. Prior drug hypersensitivity to voxelotor or excipients. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reaction is discussed in other sections of the labeling: • Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.1) ]. Most common adverse reactions (incidence ≥10% with a difference of >3% compared to placebo) are headache, diarrhea, abdominal pain, nausea, rash, and pyrexia. ( 6.1 ) Most common adverse reactions (incidence >10%) reported in pediatric patients 4 to 3% compared to placebo are summarized in Table 4. Table 4: Adverse Reactions (≥10%) in Patients Receiving OXBRYTA with a Difference Between Arms of >3% Compared to Placebo in HOPE Adverse Reaction Adverse reactions were Grades 1 or 2 except for Grade 3 headache (2), diarrhea (1), nausea (1), rash (1), and rash generalized (3) OXBRYTA 1,500 mg (N=88) Placebo (N=91) Headache 32% 25% Diarrhea 23% 11% Abdominal Pain Abdominal pain (grouped PTs) includes the following PTs: abdominal pain, lower abdominal pain, and upper abdominal pain 23% 16% Nausea 19% 10% Rash Rash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, macular rash, maculo-papular rash, pruritic rash, and papular rash 15% 11% Pyrexia 15% 8% Clinically relevant adverse reactions occurring in 10%) reported in pediatric patients 4 to <12 years were pyrexia (36%), vomiting (33%), rash (20%), abdominal pain (18%), diarrhea (18%), and headache (18%). The overall safety profile of OXBRYTA in pediatric patients 4 to <12 years was similar to that seen in adults and pediatric patients 12 years and older. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of OXBRYTA. 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: • Drug reaction with eosinophilia and systemic symptoms (DRESS), Pruritis, Angioedema (including swelling of eyelid, face edema, lip swelling, and periorbital swelling).

7 DRUG INTERACTIONS • Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. ( 7.2 ) • Strong or moderate CYP3A4 Inducers: Avoid coadministration with strong or moderate CYP3A4 inducers. If unavoidable, increase the dose of OXBRYTA. ( 2.5 , 2.6 , 7.1 ) 7.1 Effect of Other Drugs on Voxelotor Strong or Moderate CYP3A4 Inducers Coadministration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma and whole blood concentrations and may lead to reduced efficacy. Avoid coadministration of OXBRYTA with strong or moderate CYP3A4 inducers. Increase the OXBRYTA dosage when coadministration with a strong or moderate CYP3A4 inducer is unavoidable [see Dosage and Administration (2.5 , 2.6) and Clinical Pharmacology (12.3) ]. 7.2 Effect of Voxelotor on Other Drugs Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate) [see Clinical Pharmacology (12.3) ]. Avoid coadministration of OXBRYTA with sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A4 substrate(s). 7.3 Laboratory Test Interference OXBRYTA administration may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by HPLC [see Warnings and Precautions (5.2) ]. If precise quantitation of Hb species is required, chromatography should be performed when the patient has not received OXBRYTA therapy in the immediately preceding 10 days.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy 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. Clinical Considerations 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. Data 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. 8.2 Lactation 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. 8.4 Pediatric Use 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 Pharma …

12.1 Mechanism of Action Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs). By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Nonclinical studies suggest that voxelotor may inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity.

11 DESCRIPTION OXBRYTA contains voxelotor, a hemoglobin S polymerization inhibitor. The chemical name of voxelotor is 2-hydroxy-6-((2-(1-isopropyl-1 H -pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde with a molecular formula of C 19 H 19 N 3 O 3 and a molecular weight of 337.4. The chemical structure of voxelotor is: Voxelotor is a white-to-yellow-to-beige compound in crystalline Form II of its free base. It is non-hygroscopic and highly soluble in common organic solvents such as acetone and toluene and insoluble in water. OXBRYTA film-coated tablets for oral use contain either 300 mg or 500 mg of voxelotor. Both strengths of OXBRYTA film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. In addition, the 500 mg tablet film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide. The 300 mg tablet film coating contains: black and red iron oxide, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. Each OXBRYTA tablet for oral suspension contains 300 mg of voxelotor with the following inactive ingredients: artificial grape flavor, colloidal silicon dioxide, croscarmellose sodium, iron oxide pigment, magnesium stearate, microcrystalline cellulose, and sucralose. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING The 300 mg tablet is film-coated, light purple to purple, oval shaped, biconvex, debossed with "G 300" on one side, available in: • Bottles of 60 tablets with one desiccant canister, a polyester coil and child-resistant closure: NDC 72786-102-02 • Bottles of 90 tablets with one desiccant canister, a polyester coil and child-resistant closure: NDC 72786-102-03 The 500 mg tablet is film-coated, light yellow to yellow, oval shaped, biconvex, debossed with "GBT 500" on one side, and available in: • Bottles of 90 tablets with one desiccant canister, a polyester coil and child-resistant closure: NDC 72786-101-01 The 300 mg tablet for oral suspension is light yellow to yellow, round shaped, debossed with "300 D" on one side, and available in: • Bottles of 60 tablets for oral suspension with a polyester coil and child-resistant closure: NDC 72786-111-02 • Bottles of 90 tablets for oral suspension with a polyester coil and child-resistant closure: NDC 72786-111-03 Do not eat the desiccant canister or the polyester coil. Store OXBRYTA at 20°C to 30°C (68°F to 86°F).