Voxelotor

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 )

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 )

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 )

• Hypersensitivity Reactions: Observe for signs and symptoms and manage promptly. ( 5.1 )
• Laboratory Test Interference: Perform quantification of hemoglobin species when patient is not receiving OXBRYTA. ( 5.2 )

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions after administration of OXBRYTA have occurred in <1% of patients treated. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Adverse Reactions (6.1) ] . Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in postmarketing experience with OXBRYTA [see Adverse Reactions (6.2) ] . Patients who develop a combination of skin rash, fever, peripheral eosinophilia, and internal systemic organ involvement (e.g., hepatic, renal, pulmonary) while receiving OXBRYTA should undergo medical evaluation. Advise patients of the signs and symptoms of severe hypersensitivity reactions, including DRESS. If hypersensitivity reactions occur, discontinue OXBRYTA and administer appropriate medical therapy. Do not reinitiate OXBRYTA in patients who experience these symptoms with previous use.

5.2 Laboratory Test Interference OXBRYTA administration may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography (HPLC) [see Drug Interactions (7.3) ]. 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.

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 <12 years are pyrexia, vomiting, rash, abdominal pain, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults and Pediatric Patients 12 Years and Older The safety of OXBRYTA was evaluated in the HOPE trial based on data from 88 patients with SCD who received OXBRYTA 1,500 mg and 91 patients who received placebo orally once daily [see Clinical Studies (14.1) ] . Seventy-four patients received OXBRYTA 1,500 mg once daily for ≥24 weeks, 65 patients for ≥48 weeks, and 63 patients completed the 72-week treatment period. In patients who received OXBRYTA 1,500 mg once daily the median age was 24 years (range:12 to 59 years); 65% female; 66% Black or African American and 23% Arab/Middle Eastern; and 65% receiving hydroxyurea at baseline. Serious adverse reactions occurred in 3% (3/88) of patients receiving OXBRYTA 1,500 mg, which included headache, drug hypersensitivity, and pulmonary embolism occurring in 1 patient each. Permanent discontinuation due to an adverse reaction (Grades 1-4) occurred in 5% (4/88) of patients who received OXBRYTA 1,500 mg. Dosage modifications (dose reduction or dosing interruption) due to adverse reactions occurred in 14% (12/88) of patients who received OXBRYTA 1,500 mg. The adverse reactions requiring dosage modification included rash (4.5%), diarrhea (3.4%), headache (2.3%), nausea (2.3%), abdominal pain (1.1%), and drug hypersensitivity (1.1%). The safety profile observed in pediatric patients 12 to <17 years treated with OXBRYTA in the HOPE trial was similar to that seen in adult patients. The most common adverse reactions occurring in ≥10% of patients treated with OXBRYTA 1,500 mg with a difference of >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% of patients included:

• Drug hypersensitivity Pediatric Patients 4 to <12 Years The safety of OXBRYTA in pediatric patients 4 to <12 years with SCD was evaluated in an open-label, Phase 2 study [see Clinical Studies (14.2) ] . In this study, 45 patients 4 to <12 years of age received doses of OXBRYTA tablets for oral suspension based on weight at baseline. Thirty-five patients received OXBRYTA for 24 weeks and 26 patients for 48 weeks. The most common adverse reactions (>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).

• 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.

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 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) ].

8.5 Geriatric Use Clinical studies of OXBRYTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment Severe hepatic impairment increases voxelotor exposures [see Clinical Pharmacology (12.3) ] . Reduce OXBRYTA dose [see Dosage and Administration (2.3 , 2.4) ].

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.